melphalan and Breast-Neoplasms

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median follow-up of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Epirubicin; Female; Humans; Incidence; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphatic Metastasis; Melphalan; Middle Aged; Mitoxantrone; Neoplasms, Second Primary; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Radiotherapy, Adjuvant; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

An uncommon case of breast metastasis from multiple myeloma that regressed significantly after treatment by radiation is described.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Fatal Outcome; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Palliative Care; Prednisone; Radiotherapy, Adjuvant; Radiotherapy, High-Energy; Tomography, X-Ray Computed; Treatment Outcome

The role of amenorrhea induced by chemotherapy in premenopausal women with early breast cancer is very controversial. Analyses by various authors of the effect of drug-induced amenorrhea (DIA) on treatment outcome have yielded conflicting results. In order to gain insight into the role of DIA, we reviewed all published data addressing the issue of DIA as a prognostic factor.. Computerised and manual searches were conducted of relevant studies published from 1966 to 1995.. Thirteen studies involving 3929 patients were selected. In two papers, the prognostic role of DIA was analysed in three and two different groups of patients, respectively. Overall, 16 groups of patients were evaluated. With 12 groups, a higher disease free survival was observed in patients developing DIA compared to those who did not. This difference was statistically significant in eight groups. Data on overall survival, reported in only five studies, indicated that it was always improved in patients who became amenorrheic.. Available data on the role of DIA support its importance as a favorable prognostic factor for early breast cancer patients. However, due to the possible biases of this type of evaluation, this result should be interpreted with caution.

Topics: Amenorrhea; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Fluoxymesterone; Humans; Melphalan; Methotrexate; Premenopause; Prognosis; Thiotepa; Vinblastine

To review the clinical pharmacology and clinical trials that have used intravenous (IV) high-dose melphalan (HDM).. We reviewed the mechanism of action, clinical pharmacology, and clinical studies of HDM with and without autologous bone marrow support (ABMT) or peripheral-blood progenitor cells (PBPCs) in the following disease areas: myeloma, ovarian cancer, malignant lymphoma, breast cancer, neuroblastoma, Ewing's sarcoma, and acute leukemia.. HDM has a distribution half-life (t1/2 alpha) of 5 to 15 minutes and an elimination half-life (t1/2 beta) of 17 to 75 minutes at doses of 140 to 180 mg/m2, with significant intrapatient variability. At these doses, a wide range of areas under the concentration/time curve (AUC) have been reported, ie, 146 to 1,515 mg/min/mL. HDM has significant clinical activity in patients with multiple myeloma in relapse or when used as consolidative therapy in relapsed ovarian cancer, relapsed Hodgkin's disease, breast cancer, and relapsed neuroblastoma. Additional studies are required to determine the activity of HDM in Ewing's sarcoma or acute leukemia. Toxicities of HDM include myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease.. HDM has become an established and effective salvage regimen for children with relapsed neuroblastoma, as well as an effective consolidative treatment for children with high-risk disease (stage IV). HDM is emerging as an active and effective mode of treatment in patients with stage II and III myeloma. The favorable toxicity profile of HDM and the availability of PBPCs allows for repetitive therapy.

Topics: Acute Disease; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Forecasting; Half-Life; Humans; Infusions, Intravenous; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Neuroblastoma; Ovarian Neoplasms; Sarcoma, Ewing

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Drug Therapy, Combination; Female; Fluocortolone; Humans; Mammography; Melphalan; Plasmacytoma; Remission Induction

Investigators have compiled extensive experience with mitomycin in the treatment of patients with breast cancer. Given as a single agent in intermittent schedules, mitomycin has induced responses of 26-38% in previously untreated patients and of 15-25% in those exposed to multiple prior chemotherapy regimens. Duration of response has been short. Toxicity, primarily myelosuppression, is largely dose-dependent. The dose-dependent efficacy of mitomycin has not yet been addressed. Preclinical studies suggest that optimal single-agent results are obtained when mitomycin is given in intermittent, high-dose schedules. Combination chemotherapy with mitomycin has proven more effective than single-agent therapy. Mitomycin given in combination with doxorubicin produces higher response rates than have been obtained with mitomycin alone. The 3M combination (mitomycin/mitoxantrone/methotrexate) appears effective and well tolerated at the doses described. Future research should focus on the development of polychemotherapeutic regimens that can be delivered in sequential or alternating schedules. Such regimens may yield quicker responses, and thus improve survival, in patients with breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Melphalan; Methotrexate; Mitomycin; Mitomycins

Although the optimal efficacy of cytotoxic therapy plateaued in the 1970s, no consensus yet exists regarding which cytotoxic combination to offer as first-line therapy for metastatic breast cancer. Comparison of a combination of CAF/CEF with other cytotoxic combinations reveals that an anthracycline-containing regimen not only increases response rate, but also improves time to progression and survival. Regarding appropriate duration of cytotoxic therapy, randomized trials indicate that therapy in excess of 6 months is beneficial. Although the main objective of cytotoxic therapy in patients with metastatic disease is to palliate symptoms at the least toxic cost, the finding that adjuvant cytotoxic therapy improves survival provides a clinical and ethical rational for continued research into new drugs and combinations in the hope that new strategies can be employed not only against metastatic breast cancer but may be applied with benefit also in the adjuvant situation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Dactinomycin; Doxorubicin; Epirubicin; Etoposide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Mitomycin; Mitoxantrone; Neoplasm Metastasis; Vincristine

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

The incidence of second malignancies was assessed by retrospectively analyzing data from previous studies in well-defined and closely followed patient cohorts. After a median follow-up of more than 6 years following MOPP (mechlorethamine/vincristine/procarbazine/prednisone) chemotherapy with or without radiotherapy, 5% of patients with Hodgkin's disease developed second primaries, 60% of which were leukemias. Melphalan caused a 3% leukemia rate among 1129 patients with ovarian cancer who were followed for a median period of 4 years. No leukemia was observed among 1132 breast cancer patients treated with adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) after a median follow-up of 7.5 years. Long-term, comprehensive studies are needed to improve the current knowledge and the prognosis of patients with second primary neoplasms.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Mechlorethamine; Melphalan; Neoplasms, Multiple Primary; Ovarian Neoplasms; Prednisone; Procarbazine; Randomized Controlled Trials as Topic; Retrospective Studies; Vincristine

Topics: Adjuvants, Pharmaceutic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Prednisone; Tamoxifen; Vincristine

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Division; Estrogen Antagonists; Estrogens; Fluorouracil; Humans; In Vitro Techniques; Melphalan; Mice; Tamoxifen

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Breast Neoplasms; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Therapy, Combination; Dyspnea; Fluorouracil; Hodgkin Disease; Humans; Hypercalcemia; Leukemia; Leukemia, Lymphoid; Lymphoma; Mechlorethamine; Melphalan; Methotrexate; Multiple Myeloma; Palliative Care; Prednisone; Procarbazine; Receptors, Glucocorticoid; Vinblastine; Vincristine; Vomiting

The available evidence suggests that if benefit is to be obtained from high dose chemotherapy regimens, it will be in patients whose tumours are either untreated or still responding to conventional therapy. In each of the diseases discussed in this chapter the optimum timing of the treatment regimen has still to be determined. Effective regimens have been found but it is probable that further improvements can be made. In small cell lung cancer initial high dose therapy followed by non-cross-resistant regimens may prove effective. In glioma studies with high dose therapy before irradiation are awaited and may offer the best means of exploiting this approach to treatment. In breast cancer some impressive responses have occurred but the category of patient likely to benefit has not yet been defined. In melanoma high dose treatment is likely to benefit only those patients with probable minimal disease after surgery.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Carcinoma, Small Cell; Carmustine; Cell Separation; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Etoposide; Glioma; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Neoplasms; Testicular Neoplasms; Whole-Body Irradiation

This review summarizes the available data of phase II and phase III single-agent trials with predminustine and one phase II trial of prednimustine in combination with methotrexate, 5-fluorouracil, and tamoxifen in the treatment of advanced breast cancer. The data available so far indicate that the drug is more active than in combined treatment with the two components, chlorambucil and prednisolone. Future trials should be designed to analyze whether this could be ascribed to a sustained release of the components from the parent drug. The data also indicate that prednimustine is as active but less toxic than cyclophosphamide, but this needs to be confirmed in ongoing randomized comparisons. A number of phase II and phase III trials with prednimustine as a part of combinations are in progress. Mature results from these studies are needed to define the future role of prednimustine in the systemic therapy of breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Female; Fluorouracil; Humans; Leukocyte Count; Melphalan; Methotrexate; Prednimustine; Time Factors

This article considers the role of adjuvant therapy in primary breast cancer, utilizing data from randomized prospective clinical trials as illustrative examples. The ongoing efforts targeted toward addressing some of the unresolved issues are underscored.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Hospitalization; Humans; Lymph Nodes; Melphalan; Methotrexate; Middle Aged; Prednisone; Prospective Studies; Random Allocation; Tamoxifen; Time Factors; United States; Vincristine

Topics: Adult; Alkylating Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Methotrexate; Middle Aged; Prednisone; Surgery, Plastic; Tamoxifen; Thiotepa; Vincristine

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Castration; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Random Allocation; Receptors, Estrogen; Tamoxifen; Time Factors

The paper critically reviews major accomplishments achieved with the use of chemotherapy in the treatment of various stages of breast cancer. In spite of innumerable clinical trials, there is no evidence that in advanced breast cancer the addition of more drugs, either in concomitant, sequential or alternating fashion, to known effective combinations, was able to significantly improve the incidence and the magnitude of objective response or its median duration or survival. The addition of endocrine therapy to chemotherapy has failed so far to improve the most important end-point, i.e. total survival. Second-line chemotherapy is only moderately effective for a fairly short period of time. Thus, in women with advanced breast cancer excessive tumor cell burden and permanent drug resistance remain the major obstacles to obtaining complete remission and long-term disease free survival. In the adjuvant setting, the initial trials with combination chemotherapy have achieved consistent results, particularly in women with minimal axillary node involvement. Unless a woman has undergone a surgical breast-saving procedure, postoperative radiotherapy does not appear to play an important therapeutic role, either with or without concomitant or sequential chemotherapy. Present results would suggest that in advanced breast cancer little progress can be expected in the near future. Therefore, medical oncologists should focus on the correct application of established drug regimens, using a sequential flow of hormonal manipulations and cytotoxic chemotherapy. In high-risk groups, full dose adjuvant polydrug therapy given for a relatively short period of time appears to be at present the only means able to significantly decrease the failure rate following local regional treatment. Present consistent achievements, which appear devoid of important delay morbidity (e.g. cancerogenesis, chronic organ damage) will require further clinical research to identify more effective and less toxic treatments.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Receptors, Estrogen; Research Design

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Time Factors

Topics: Adult; Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Middle Aged; Prednisone; Vincristine

Topics: Adult; Aged; Arsenic; Benzene; Bone Marrow; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Ovarian Neoplasms; Paraproteinemias; Waldenstrom Macroglobulinemia

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Osteosarcoma

Topics: Breast Neoplasms; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Menopause; Methotrexate; Postoperative Care

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

Chemotherapy is of significant benefit to patients with advanced breast cancer, as measured by tumor regression and increased survival. Yet these tumor regressions are short-lived, and the patient survival benefit is measured in terms of months. This relative refractoriness is due either to drug resistance or to what is called "kinetic" resistance. Kinetic resistance implies large numbers of cells and long doubling times. Experimentally, surgery combined with chemotherapy offers the best chance of cure of several solid tumors in animals. Several clinical trials in combined surgery and chemotherapy indicating a markedly favorable effect of this approach are in progress. This suggests that, as in the animal systems, kinetic resistance can be overcome by the combined-modality approach. The response to endocrine manipulation can be predicted by estrogen receptors. Clinical trials to combine chemotherapy, surgery and hormonal treatment are under way.

Topics: Breast Neoplasms; Castration; Cyclophosphamide; Drug Resistance; Estrogens; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Prednisone; Thiotepa

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Castration; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Nitrogen Mustard Compounds; Prednisone; Thiotepa; Vinblastine; Vincristine

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Cyclophosphamide; Drug Synergism; Female; Fluorouracil; Humans; Hydroxyurea; Melphalan; Menopause; Methotrexate; Mice; Vinblastine; Vincristine

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Inflammatory Breast Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Survival Analysis; Thiotepa; Treatment Outcome

Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model.. MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine.. We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells.. ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.

Topics: Amifostine; Antimutagenic Agents; Antineoplastic Agents, Alkylating; Breast Neoplasms; Cell Line, Tumor; DNA Mismatch Repair; Female; Humans; Leukemia; Leukocytes, Mononuclear; Melphalan; Microsatellite Instability; Microsatellite Repeats; Middle Aged; MutS Homolog 2 Protein; Reference Values

Inflammatory breast cancer (IBC) is a rare clinicopathologic entity with a poor prognosis, lagging far behind any other form of nonmetastatic breast cancer. Since the advent of systemic chemotherapy over 35 years ago, only minimal progress has been made in long-term outcome. Although multiple randomized trials of high-dose chemotherapy and autologous progenitor cell transplantation (ASCT) for the treatment of breast cancer have yielded disappointing results, these data are not necessarily relevant to IBC, a distinct clinical and pathologic entity. Therefore, the optimal multimodality therapy for IBC is not well established, and remains unsatisfactory. We treated 21 women with nonmetastatic IBC with a multimodality strategy including high-dose melphalan (Mel)/etoposide and ASCT. The treatment was overall tolerated with acceptable morbidity, and no post-ASCT 100-day mortality. With a median potential follow-up of approximately 8 years, the estimated progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) at 6 years from on-study date are: 67%, 55%, and 69%, respectively. These results from a small phase II study are among the most promising of mature outcome data for IBC. They strongly suggest, along with results of several already published phase II trials, that ASCT could play a significant role in the first line treatment of IBC.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Combined Modality Therapy; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Inflammation; Melphalan; Middle Aged; Remission Induction; Survival Analysis; Treatment Outcome

The aim of our study was to evaluate the impact on time to progression (TTP) and overall survival (OS) of high-dose chemotherapy (HD-CT) over conventional CT in metastatic breast cancer patients. Between 09/92 and 12/96, 61 patients with chemosensitive metastatic breast cancer were randomised between HD-CT using the CMA regimen (Mitoxantrone, Cyclophosphamide, Melphalan) applied as consolidation (32 patients) or maintenance CT (29 patients). At randomisation, 13 patients were in complete response, 47 in partial response and one had stable disease. The median TTPs from randomisation were 6 and 12 months in the standard and intensive groups, respectively (P < 0.0056), with a relapse rate of 86.2% vs. 62.5% at 2 years, and 100% vs. 81.3% at 5 years. The median OS times were 19.3 and 44.1 months, with an OS rate of 13.8% vs. 36.8% at 5 years (P < 0.0294). The CMA regimen could prolong the TTP of patients with chemosensitive metastatic breast cancer. Further studies are needed to determine if this translates into an effect on OS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Risk Factors; Survival Analysis; Treatment Outcome

The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel.. In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment.. Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups.. In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.

Topics: Action Potentials; Administration, Oral; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Electrophysiology; Glutamine; Granulocyte Colony-Stimulating Factor; Humans; Melphalan; Neural Conduction; Neuroprotective Agents; Paclitaxel; Peripheral Nervous System Diseases; Stem Cell Transplantation; Thiotepa

Cyclophosphamide is an alkylating agent given frequently as a component of many conditioning regimens. In high doses, its nonhematological dose-limiting toxicity is cardiomyopathy.. We combined paclitaxel, melphalan and high-dose cyclophosphamide, thiotepa, and carboplatin in a triple sequential high-dose regimen for patients with metastatic breast cancer. Analysis was performed on 61 women with chemotherapy-responsive metastatic breast cancer receiving 96-h infusional cyclophosphamide as part of a triple sequential high-dose regimen to assess association between presence of peritransplant congestive heart failure (CHF) and the following pretreatment characteristics: presence of electrocardiogram (EKG) abnormalities, age, hypertension, prior cardiac history, smoking, diabetes mellitus, prior use of anthracyclines, and left-sided chest irradiation.. Six of 61 women (10%) developed clinically reversible grade 3 CHF following infusional cyclophosphamide with a median percent decline in ejection fraction of 31%. Incidence of transient cyclophosphamide-related cardiac toxicity (10%) is comparable to previous recorded literature. Older age was significantly correlated with the CHF development; with median ages for the entire group and for patients developing CHF of 45 and 59, respectively. No association was found with other pretreatment characteristics.. As a result of these findings, oncologists should carefully monitor fluid balance in older patients. Routine EKG monitoring during infusional cyclophosphamide did not predict CHF development.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Drug Administration Schedule; Female; Heart Failure; Humans; Melphalan; Middle Aged; Paclitaxel; Thiotepa

To assess patterns of locoregional failure (LRF) in lymph node-positive (LN+) breast cancer patients treated with mastectomy and adjuvant chemotherapy (+/- tamoxifen) and without postmastectomy radiotherapy (PMRT) in five National Surgical Adjuvant Breast and Bowel Project trials.. We examined 5,758 patients enrolled onto the B-15, B-16, B-18, B-22, and B-25 trials. Median follow-up time was 11.1 years. Distribution of pathologic tumor size was < or = 2 cm, 2.1 to 5 cm, and more than 5 cm in 30%, 52%, and 11% of patients, respectively. Distribution of the number of LN+ was one to three, four to nine, and > or = 10 in 51%, 32%, and 16% of patients, respectively. Ninety percent of patients received doxorubicin-based chemotherapy.. The overall 10-year cumulative incidences of isolated LRF, LRF with or without distant failure (DF), and DF alone as first event were 12.2%, 19.8%, and 43.3%, respectively. Cumulative incidences for LRF as first event with or without DF for patients with one to three, four to nine, and > or = 10 LN+ were 13.0%, 24.4%, and 31.9%, respectively (P < .0001). For patients with a tumor size of < or = 2 cm, 2.1 to 5.0 cm, and more than 5.0 cm, these incidences were 14.9%, 21.3%, and 24.6%, respectively (P < .0001). Multivariate analysis showed age, tumor size, premenopausal status, number of LN+, and number of dissected LN as significant predictors for LRF as first event.. In patients with large tumors and four or more LN+, LRF as first event remains a significant problem. Although PMRT is currently recommended for patients with four or more LN+, it may also have value in selected patients with one to three LN+. However, in the absence of a randomized trial examining the worth of radiotherapy in this group of patients, the value of PMRT remains unknown.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Statistics, Nonparametric; Survival Analysis; Tamoxifen; Treatment Outcome

Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil plus vincristine and prednisone (CMFVP) was compared with single-agent L-phenylalanine mustard (L-PAM) for the treatment of patients with axillary lymph node positive primary breast carcinoma over 20-years of follow-up.. Four hundred forty-one women with axillary lymph node positive breast carcinoma were randomized to receive either combination chemotherapy with cyclophosphamide (60 mg/m(2) orally every day for 1 year), fluorouracil (300 mg/m(2) intravenously [IV] weekly for 1 year), methotrexate (15 mg/m(2) IV weekly for 1 year), vincristine (0.625 mg/m(2) IV for 10 weeks), prednisone (30 mg/m(2) orally on Days 1-14, 20 mg/m(2) on Days 15-28, and 10 mg/m(2) on Days 29-42), or single-agent chemotherapy with L-PAM (5 mg/m(2) orally every day for 5 days every 6 weeks for 2 years) after undergoing surgery. Patients were stratified according to menopausal status and number of positive lymph nodes (1-3 positive lymph nodes or > 3 positive lymph nodes). Seventy-seven patients were ineligible.. The maximum follow-up is 24 years, with a median follow-up of 21.5 years. Disease free survival and overall survival were superior with CMFVP (two-sided log-rank test; P = 0.0008 and P = 0.007, respectively). For all patients, the estimated 20-year survival rate of patients who received CMFVP was 40% compared with 27% for patients who received L-PAM. There was a substantial survival benefit for CMFVP compared with L-PAM in the subsets of premenopausal patients and patients with four or more positive lymph nodes. The estimated 20-year survival rate for premenopausal women who received CMFVP was 49% compared with 33% for premenopausal women who received L-PAM. Among women with > or = 4 positive lymph nodes, the estimated survival rate for patients who received CMFVP was 31% compared with 15% for patients who received L-PAM. Both regimens were tolerated well. Toxicity was more severe and frequent among patients who received CMFVP.. The authors conclude that, after 20 years of follow-up, adjuvant chemotherapy with CMFVP remains superior to L-PAM for the treatment of patients with lymph node positive breast carcinoma.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Cyclophosphamide; Disease-Free Survival; Female; Fluorouracil; Humans; Lymph Nodes; Lymphatic Metastasis; Mastectomy, Modified Radical; Mastectomy, Radical; Melphalan; Menopause; Methotrexate; Middle Aged; Prednisone; Survival Rate; Vincristine

We evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Renal Cell; Female; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Peripheral Blood Stem Cell Transplantation; Remission Induction; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Humans; Melphalan; Middle Aged; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Polyneuropathies; Remission Induction; Survival Analysis; Survival Rate; Thiotepa

Although high-dose chemotherapy (HDC) with stem cell rescue for the treatment of women with metastatic breast cancer (MBC) is currently a controversial strategy, we report the long-term outcomes of women undergoing high-dose therapy for MBC over the past 12 years while participating in a sequence of research studies transitioning between a single to a double intensification approach. Univariate and multivariate analyses provide a framework to understand the prognostic factors important for event-free and overall survival. Between May 1988 and April 1998, we enrolled 188 women with MBC into 3 trials of previously reported sequential transplantation strategies. Trial I (long induction/single transplantation) accepted 62 women in partial or complete response to an unspecified induction therapy and treated them with high-dose CTCb (cyclophosphamide, thiotepa, and carboplatin) supported by marrow or peripheral blood progenitor cells (PBPC). Trial II (long induction/double transplantation) accepted 68 women in partial or complete response to an unspecified induction therapy, and mobilized stem cells with 2 cycles of AF (doxorubicin and 5-fluorouracil) with granulocyte colony-stimulating factor (G-CSF). These women then received 1 cycle of high-dose single-agent melphalan followed 3 to 5 weeks later by CTCb, each with marrow or PBPC support. Trial III (short induction/double transplantation) enrolled 58 women prior to chemotherapy treatment for metastatic disease. Induction/mobilization consisted of 2 cycles given 14 days apart of doxorubicin and G-CSF. In contrast to trials I and II, patients with stable disease or better response to induction were eligible to proceed ahead with 2 cycles of HDC, 1 being CTCb and the other being dose escalated paclitaxel together with high-dose melphalan (TxM). These 2 HDC regimens were administered 5 weeks apart. TxM was given first in 32 patients and CTCb was given first in 26 patients. The median follow-up periods for trials I, II, and III were 98, 62, and 39 months from the initiation of induction chemotherapy and 92, 55, and 36 months from last high-dose therapy, respectively. The patient characteristics upon entry into these trials were similar. Important differences were that only those patients achieving a partial response or better to induction therapy were enrolled and analyzed for trials I and II, but all patients were analyzed on an intent-to-treat basis for trial III, including those who did not receive intensificat

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Estrogens; Female; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Life Tables; Melphalan; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Progesterone; Prognosis; Proportional Hazards Models; Remission Induction; Survival Analysis; Thiotepa; Time Factors; Treatment Outcome

We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825 mg/m2 continuous infusion over 24 h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer.. Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclophosphamide/thiotepa/carboplatin.. The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05 microM (t > 0.05 microM) for paclitaxel were (means SD): 9.11 +/- 7.45 microM, 145 +/- 88 microM x h, 8.06 +/- 2.90 l/h per m2 and 82.4 +/- 31.2 h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1 h (r2 = 0.87), 12 h (r2 = 0.85) and 23 h (r2 =0.92) and the AUC (P < 0.0001). Duration of neutropenia was brief (median 3 days, range 0-5 days) and neutrophil recovery occurred earlier (median 6 days, range 0-7 days) than could be attributed to infused PBPC. Median nadir count for platelets was 66 x 10(9)/l (range 13-160 x 10(9)/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t > 0.05 microM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2 = 0.46, P = 0.03).. HDP (825 mg/m2 continuous infusion over 24 h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.

Topics: Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Carboplatin; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neutropenia; Paclitaxel; Peripheral Nervous System Diseases; Regression Analysis; Thiotepa; Time Factors

Preliminary data from phase III randomized studies have failed to show benefit of HDC given as consolidation after anthracycline and alkylating-based chemotherapy in metastatic breast cancer (MBC). Moderate activity of induction regimens and selection of chemoresistant clones are among the possible reasons for these disappointing results. We therefore have designed a phase II study where high-dose alkylating agents are given as consolidation after an induction treatment including the most active agents (epirubicin and paclitaxel) without alkylating agents.. Patients with MBC not previously treated with chemotherapy for metastatic disease were eligible. After six courses of epirubicin-paclitaxel +/- gemcitabine patients received a course of thiotepa 600 mg/m2 + melphalan 160 mg/m2 with hemopoietic support. Pharmacokinetic parameters of thiotepa and melphalan were measured and related to treatment outcomes. The L-VEF of the patients was monitored before and after treatment.. Forty-eight patients have been treated. Before HDC 14 patients were in CR, and 34 in PR. A median of 6.92 x 10(6) (range 1.53-16.6) CD34+ cells/kg were reinfused after HDC. Median days (range) to neutrophils > 0.5 x 10(9)/l and platelets > 20,000 x 10(9)/l were 9.5 (9-33) and 10 days (9-32), respectively. Symptomatic CHF was observed in two patients (4.1%). Cmax and AUC of thiotepa showed a linear relationship with time to progression (TTP) and overall survival (OS): r2 = 0.6. After HDC the conversion rate from PR to CR was 44.1%. At five years progression-free and overall survival rates are 37.5% and 65%, respectively. A treatment-related death was observed.. High-dose thiotepa and melphalan after an epirubicin-paclitaxel-containing treatment is feasible, devoid of significant cardiotoxicity and very active. Pharmacokinetic parameters of high-dose thiotepa might be linked to treatment outcome.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Deoxycytidine; Disease Progression; Epirubicin; Female; Gemcitabine; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Paclitaxel; Survival Analysis; Thiotepa; Treatment Outcome

A single cycle of high-dose chemotherapy with stem cell support (HDC) in women with responsive metastatic breast cancer (BC) consistently achieves over 50% complete and near complete response (CR/nCR). This significant cytoreduction results in a median event-free survival (EFS) of 8 months, and approximately 20% 3-year and 16% 5-year EFS in selected patients. To improve long-term outcomes, new strategies to treat minimal residual tumor burden are needed. Increased total dose delivered can be achieved with two cycles of HDC. Critical design issues include shortening induction chemotherapy to avoid development of drug resistance and the use of different agents for each HDC cycle. We have determined the maximum tolerated dose (MTD) for paclitaxel combined with high-dose melphalan in the context of a double transplant and explored the impact of a short induction phase. Between June 1994 and August 1996, we enrolled 32 women with metastatic BC on to this phase I double transplant trial. Induction consisted of doxorubicin 30 mg/m2/day days 1-3 given for 2 cycles every 14 days with G-CSF 5 microg/kg s.c. days 4-12. Stem cell collection was performed by leukapheresis in each cycle when the WBC recovered to above 1000/microl. Patients with stable disease or better response to induction were eligible to proceed with HDC. HDC regimen I (TxM) included paclitaxel with dose escalation from 0 to 300 mg/m2 given on day 1 and melphalan 180 mg/m2 in two divided doses given on day 3. HDC regimen II was CTCb (cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 total doses) delivered by 96-h continuous infusion. At the first dose level of 150 mg/m2 paclitaxel by 3 h infusion, four of five patients developed dose-limiting toxicity consisting of diffuse skin erythema and capillary leak syndrome. Only two of these five completed the second transplant. Subsequently, paclitaxel was delivered by 24-h continuous infusion together with 96 h of dexamethasone and histamine receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression. All others completed both cycles of transplant. Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Melphalan; Middle Aged; Paclitaxel; Remission Induction; Survival Rate

We evaluated the feasibility of tandem-cycle high-dose chemotherapy (HDCT) with cisplatin, melphalan, and peripheral blood progenitor cells (PBPCs). Fifty patients with high-risk primary (n = 17) or stage IV breast cancer (n = 29) or other malignancies (n = 4) received 2 cycles of intravenous melphalan, 20 to 151.8 mg/m2, and cisplatin, 200 mg/m2, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF. Starting at 40 mg/m2 of melphalan, patients also received PBPCs. Delayed platelet recovery defined the maximum tolerated dose (MTD) for melphalan at 101.2 mg/m2 per cycle. There were no treatment-related deaths. Cycle 2 was delivered at a median of 1.7 months after cycle 1; 72% of patients treated at the MTD received both cycles. Cycle 2 was omitted when patients refused it or had disease progression or toxicities, primarily prolonged thrombocytopenia. Complete response rates in stage IV breast cancer patients increased from 28% pre-HDCT to 55% after cycle 2. At a median follow-up of 4.6 years (range, 1.5-8.1 years), 11 of 29 patients with stage IV breast carcinoma were alive with 5-year projected progression-free and overall survival rates of 19% (95% confidence interval [CI], 7%-41%) and 39% (95% CI, 20%-62%), respectively. Five-year projected progression-free and overall survival rates for patients with stage IV breast cancer in complete response following HDCT versus all others were 35% (95% CI, 15%-70%) versus 0% (P = .01) and 61% (95% CI, 35%-91%) versus 10% (95% CI, 2%-60%) (P = .003; log-rank test), respectively. Estrogen-receptor positivity was predictive of reduced risk of progression (relative risk [RR], 0.25; 95% CI, 0.10-0.65; P = .003) and death (RR, 0.27; 95% CI, 0.10-0.72; P = .009) after adjusting for response status. Five-year projected relapse-free and overall survival rates were 71% (95% CI, 43%-96%) and 82% (95% CI, 56%-100%), respectively, for the 17 patients with high-risk primary breast cancer. Tandem-cycle high-dose melphalan and cisplatin with PBPCs is feasible. Preliminary data suggest significant activity in selected patients with stage IV responding breast carcinoma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Disease-Free Survival; Feasibility Studies; Female; Follow-Up Studies; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Maximum Tolerated Dose; Melphalan; Middle Aged; Neoplasm Staging; Survival Analysis; Treatment Outcome

Two cycles of high-dose chemotherapy with stem cell support (HDC) may increase the total dose delivered and dose intensity. A brief induction phase and different non-cross-resistant agents for each HDC cycle were used to avoid drug resistance. Twenty-six women with metastatic BC had induction and stem cell mobilization with two cycles of doxorubicin/G-CSF given every 14 days. Patients with stable disease or better after induction received HD CTCb followed by HD melphalan and dose-escalated paclitaxel. At 475 mg/m(2) of paclitaxel by 24-h infusion, dose-limiting transient peripheral sensory neuropathy was encountered. No toxic deaths occurred. Complete and near complete response after completion of therapy was achieved in 22 (85%) of 26 patients. The median EFS was 38 months. The median OS has not yet been reached. At a median follow-up of 33 (25-43) months, actuarial EFS and OS were 54% (95% confidence interval (CI), 39-69%) and 69% (95% CI, 56-79%), respectively. This double transplant approach lasts only 14 weeks and is feasible, safe, and tolerable. Whilst selection biases may in part contribute to favorable EFS and OS, a randomized comparison of standard therapy vs double transplant in both metastatic and locally advanced breast cancer is warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Remission Induction; Survival Rate; Treatment Failure; Treatment Outcome

The purpose of this study was to evaluate the toxicity and efficacy of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) in patients with high-risk non-inflammatory breast cancer defined as stage II disease > or =10 lymph nodes (n = 52) or stage III (n = 69), and prognostic factors for treatment outcome. One hundred and twenty-one patients (median age, 46 years) were treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) (HDC) followed by autologous stem cell infusion (ASCI). One hundred patients were initially treated with surgery followed by standard adjuvant chemotherapy prior to HDC/ASCI. Twenty-one patients with stage III disease had inoperable tumors at diagnosis and were treated with neoadjuvant chemotherapy and surgery before HDC/ASCI. Transplant-related mortality was 6%. The probabilities of event-free survival (EFS) at 3 and 5 years (median follow-up of 36 months) from transplant were, for all patients: 0.62-0.60; stage II: 0.71-0.67: stage III: 0.55-0.55 (for stage III adjuvant and neoadjuvant groups: 0.60-0.60 and 0.42-0.42, respectively). Multivariate analysis did not identify variables associated with poor outcome. The efficacy of Bu/Mel/TT is similar to other HDC regimens reported for patients with high-risk non-inflammatory breast cancer. Bu/Mel/TT has high activity in stage II disease and a moderate benefit in stage III operable tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Inflammation; Melphalan; Middle Aged; Multivariate Analysis; Neoplasm Staging; Survival Rate; Thiotepa; Time Factors

We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients.. A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF.. The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm.. The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Topics: Adenine; Adult; Aged; Aminoglycosides; Analysis of Variance; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Imides; Isoquinolines; Melphalan; Middle Aged; Naphthalimides; Neoplasm Staging; Organophosphonates; Prospective Studies; Survival Analysis; Trimetrexate

We report hereby the results of the french multicentric randomized PEGASE 04 protocol established to evaluate the impact on survival of high-dose chemotherapy over conventional chemotherapy for MBC patients.. Inclusion criteria were: age < or = 60 year, PS < 2, adenocarcinoma initially metastatic or in first relapse, chemosensitive disease. Randomization was done after 4-6 courses of conventionnal chemotherapy between high-dose (Mitoxantrone, 45 mg/m2, Cyclophosphamide: 120 mg/kg, Melphalan: 140 mg/m2), and the pursuit of the same conventionnal chemotherapy. Between 09/92 and 12/96, 61 chemosensitive patients were enrolled: 29 were referred to standard chemotherapy, 32 to intensive therapy. At randomization, 13 pts (21.3%) were in complete response and 48 in partial response.. The median progression-free survivals were 20 and 35.3 months in the standard and intensive groups (p=0.06). The relapse rates were respectively 79.3% vs 50.8% at 3 years and 90.8% vs 90.7% at 5 years. The median overall survivals were 20 and 43.4 months, with an overall survival rate of 18.5% vs 29.8% at 5 years (p=0.12).. The CMA regimen could prolong the progression-free survival of MBC patients, however without any significant impact on overall survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Remission Induction; Survival Analysis; Transplantation, Autologous

We analyzed the relationship between the reinfusion of large or very large amounts of peripheral blood progenitor cells (PBPC) and hematologic toxicity in twenty-one advanced breast cancer patients subjected to a myeloablative dose of melphalan at the end of a high-dose sequential chemotherapy (HDSC) program. We also evaluated the influence of the white blood cell (WBC) count to predict an optimal PBPC harvest after high-dose chemotherapy and growth factor priming. Twenty-one patients with high-risk or metastatic breast cancer sequentially received: high-dose cyclophosphamide (HD-Cy) and G-CSF followed by PBPC harvest, HD-methotrexate plus vincristine, HD-doxorubicin, cisplatin and finally HD-melphalan 200 mg/m2 (HD-L-PAM) followed by PBPC reinfusion. No growth factor was administered after HD-L-PAM. CD34+ cytofluorimetric analysis, WBC count and clonogenic assays were employed to monitor circulating cells and to analyze the PBPC harvest. Correlation between different PBPC doses and hematologic toxicity as well as leukocyte and platelet recovery time was attempted. Patients received a median number of 16 (4-25.1) x 10(6)/kg CD34+ cells, 81.3 (30.8-228) x 10(4)/kg CFU-GM and 4.2 (1.3-7.3) x 10(8)/kg nucleated cells (NC) after HD-L-PAM. The number of days with fewer than 1 x 10(9)/l leukocytes and 20 x 10(9)/l platelets were 6 (range 4-9) and 0 (range 0-3), respectively. The CD34+ cell dose significantly correlated with both platelet count nadir (r = 0.73) and time to 50 x 10(9)/l platelets (r = 0.7), but did not correlate with time to reach more than 1 x 10(9)/l WBC count (r = 0.2). In particular, we found that in 12 patients given very large amounts of CD34+ cells, ranging between 15.8 and 25. 1 x 10(6)/kg (V-LA-CD34+), the platelet nadir count never fell below 20 x 10(9)/l and platelet transfusions were not required. Conversely, nine patients who received only large amounts of CD34+ cells, ranging between 4 and 12 x 10(6)/kg (LA-CD34+), experienced a platelet nadir lower than 20 x 10(9)/l and required 2 days (range 1-4) to achieve independence from platelet transfusions (P = 0.001 and P = 0. 0005). The requirement for packed red blood cells (RBC) was 1.5 vs 3 units in the V-LA-CD34+ and LA-CD34+ groups respectively (P = 0.063). The analysis of 44 PBPC collections demonstrated that 29 aphereses performed with a WBC count <20 x 10(9)/l yielded a mean of 312 +/- 43 x 10(6) CD34+ cells and 1831 +/- 201 x 10(4) CFU-GM, whereas 15 collections performed with WB

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukocyte Count; Melphalan; Middle Aged; Platelet Count; Thrombocytopenia; Transplantation, Autologous

Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two pa

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Recurrence; Thiotepa; Transplantation, Autologous; Treatment Outcome

Breast cancer patients who, following treatment with primary chemotherapy (FAC 50) present an axillary node involvement of more than 4 nodes together with clinically palpable residual disease (minor response to chemotherapy) and the presence of tumour cell emboli in lymphatics have a very poor outcome. DFS rates of 50 patients treated between 1990 and 1994 were 31% at 5 years. Our aim was therefore to evaluate an entirely different therapeutic regime in these very high risk patients. 32 patients selected for these criteria entered a pilot study consisting in treatment with 3 four weekly cycles of vinorelbine, ifosfamide, cisplatinum followed by a high dose chemotherapy (HDCT) course and rescue by peripheral hematopoietic stem cells which had been collected by cytapheresis after the second course of chemotherapy. HDCT consisted of thiotepa, L-Pam, CBDCA (800 mg/m(2) d1), ifosfamide and mesna. Following primary chemotherapy, 14 patients had breast conservation and 18 had a modified mastectomy. Median number of involved lymph nodes was 11 (range 4-26). 29 patients received the complete HDCT course. Median age was 40 (range 24-59). Engraftment was prompt with a median of 10 days to leucocyte recovery to 1,000/microl and 9 days to platelet recovery. One patient developed reversible renal failure, and subsequently died of Gram-septicemia. To date, with a median follow up of 20 months (range 14-36), 6 patients have relapsed and 2 patients have died. It is too early to make any firm conclusions, but we feel that this alternative regime is feasible and may prove superior to the classical optimal dose anthracycline-containing regimes in patients who have a tendency to rapidly develop resistance to anthracyclines.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Lymphatic Metastasis; Melphalan; Mesna; Middle Aged; Pilot Projects; Salvage Therapy; Tegafur; Thiotepa; Vinblastine; Vinorelbine

Sequential high-dose chemotherapy may increase the threshold dose of CD34+ cells necessary for rapid and successful hematologic recovery. There are limited data regarding the pharmacodynamics and threshold CD34+ cell dose required for engraftment following high-dose paclitaxel. To determine the dose of CD34+ PBPC sufficient for rapid engraftment, 65 women with metastatic breast cancer undergoing a sequential high-dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin (CTCb) chemotherapy regimen were evaluated. The intertreatment interval was a median of 27 days. Paclitaxel was escalated from 400 to 825 mg/m2, infused continuously (CI) over 24 h on day -4 with PBPC reinfusion on day 0. Following marrow recovery, 90 mg/m2/day of melphalan was given over 30 min on days -2 and -1, with PBPC reinfusion on day 0. On recovery, patients received CTCb on days -7 to -3, with PBPC reinfusion on day 0. G-CSF was administered after each cycle until WBCC recovery. For paclitaxel, an ANC >0.5 x 10(9)/L occurred at a median of 6 days (range 0-7 days) after PBPC reinfusion. The median nadir platelet count was 63 x 10(9)/L (range 6 x 10(9)/L-176 x 10(9)/L). Eight patients (12%) had platelet nadir <20 x 10(9)/L, and all recovered their counts to >20 x 10(9)/L on day 7. There was no clinical difference in days to engraftment between women receiving <2 or > or =2 x 10(6) CD34+ PBPC/kg following paclitaxel. All patients recovered neutrophil and platelet counts within 7 days after reinfusion of > or =1 x 10(6) CD34+ cells/kg and G-CSF. The data suggest that a paclitaxel dose of 825 mg/m2 is not myeloablative. For melphalan, median days to ANC >0.5 x 10(9)/L was 10 days (range 9-15), and platelet recovery to >20 x 10(9)/L was 13 days (range 0-28) after PBPC reinfusion. Median time to engraftment was more rapid in patients receiving > or =2 x 10(6) CD34+/kg versus <2 x 10(6)CD34+/kg, for both neutrophils (11 days versus 10 days, p = 0.05) and platelets (14 days versus 12 days, p < 0.01). Ninety-eight percent of patients infused with > or =2 x 10(6) CD34+/kg engrafted within 21 days. Following CTCb in this sequential regimen, a dose of > or =2 x 10(6) CD34+ cells/kg provided for significantly more rapid neutrophil engraftment than <2 x 10(6) CD34+ cells/kg (9 days versus 10 days,p = 0.01), but a dose > or =3 X 10(6) CD34+ cells/kg is necessary for reliable, rapid, and sustained neutrophil and platelet engraftment by day 21.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Thiotepa; Transplantation, Autologous

A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Female; Hematopoietic Stem Cell Mobilization; Humans; Melphalan; Middle Aged; Neoplasm Staging; Nervous System Diseases; Neutropenia; Paclitaxel; Thiotepa; Treatment Outcome

The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Humans; Length of Stay; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Recombinant Proteins; Survival Rate

In this phase II trial, we used a double dose-intensive chemotherapy and stem cell rescue protocol to treat breast cancer (BCA) patients or non-Hodgkin's lymphoma patients (NHL). The first cycle consisted of high-dose melphalan followed by ABMT. The second cycle used a novel chemotherapy combination; thiotepa, etoposide, carboplatin and cyclophosphamide (TECC) followed by ABMT. We treated 12 patients in total, nine with BCA, three with NHL. All nine BCA patients were treated with the two cycle protocol. The three NHL patients were treated with the second cycle only. Bone marrow (BM, 1 patient), peripheral blood stem cells (PBSC, 10 patients) or both (1 patient) were reinfused 60-72 h after completion of each cycle of chemotherapy. Recovery was rapid; the ANC rose to greater than 500/microl on day +11 (+8 to + 20) and the platelet count to greater than 20000/microl on day +12 (+6 to +20). The toxicities included the expected neutropenic fevers, severe mucositis, diarrhea, and a low incidence of mild renal insufficiency. No patients developed veno-occlusive disease, hemorrhagic cystitis or overt bleeding. With a mean follow-up of 37 months, 83.3% of the patients are alive. Six patients are in complete remission; one patient with BCA relapsed and expired; one patient with NHL is in CR now over 18 months after relapse and subsequent treatment with interferon; one patient is too early to evaluate. Progression-free survival overall is 75%, which is at least equivalent to many other recent studies using similar regimens. In addition, we have also found that delayed addition of G-CSF during the mobilization of PBSC was feasible and resulted in excellent CD34+ cell counts and engraftments, and reduced treatment costs. These results indicate that this chemotherapy is effective with good remission rates and high progression-free survival rates. It is also well tolerated with acceptable toxicities that are manageable. Long-term follow-up of a larger cohort of patients will be needed to ascertain the overall efficacy of this type of therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Cyclophosphamide; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Recurrence; Thiotepa; Transplantation, Autologous

To assess the efficacy, toxicity, and applicability of high-dose therapy administered as adjuvant initial treatment to women with breast cancer with extensive nodal involvement.. Sixty-seven patients with stage II to III breast cancer involving > or = 10 axillary nodes received a novel high-dose sequential (HDS) regimen, including the high-dose administration of three non-cross-resistant drugs (cyclophosphamide, methotrexate, and melphalan) given within the shortest interval of time as possible with hematologic and nonhematologic toxicity.. Sixty-three patients completed the program as planned, one patient died of acute toxicity, and three patients were switched to standard-dose adjuvant therapy. After a median follow-up duration of 48.5 months and a lead follow-up of 78 months, actuarial relapse-free survival for all 67 registered patients is 57% and overall survival is 70%, respectively. Comparison with a historical control group of 58 consecutive patients showed a significantly superior rate of freedom from relapse for the HDS-treated group (57% v 41%, respectively), in particular when two subgroups of patients, more homogeneous for their number of involved nodes, were compared (65% v 42%). Overall, treatment was of short duration (median, 70 days), required a median of 32 days of hospital stay, and was associated with only a few severe side effects (the most distressing being oral mucositis after melphalan therapy).. HDS therapy emerges as an effective and applicable regimen, whose major toxicity was occasional. Final assessment of its value in a randomized, multicenter trial is presently underway.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Lymph Nodes; Mastectomy; Melphalan; Methotrexate; Middle Aged

The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Survival; Dose-Response Relationship, Drug; Female; Hematopoiesis; Hematopoietic Stem Cells; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Mitoxantrone

The purpose of this study was to develop a high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) regimen for treatment of patients with ovarian carcinoma that could be administered in an outpatient setting. Fourteen patients with advanced ovarian (n = 9) or breast (n = 5) carcinoma, who had failed conventional chemotherapy, were entered into a dose-escalation trial to determine the maximum tolerated dose (MTD) of carboplatin that could be administered with fixed doses of melphalan (160 mg/m2) and mitoxantrone (50 mg/m2). Twenty-five additional patients were included in a phase II trial at the MTD. Two of two patients had grade 4 severe regimen-related toxicities (RRT), one fatal, at a dose level of 1600 mg/m2. Two of 29 patients (6.9%) treated at the MTD (carboplatin, 1400 mg/m2) died of RRT. All three patients who died of toxicity had a calculated AUC for carboplatin >30 mg/ml/min. Thirty-one patients with ovarian cancer who had failed chemotherapy were treated, 24 at the MTD. Fourteen of 20 patients (70%) with ovarian carcinoma with evaluable disease achieved a CR and seven (35%) are alive disease-free a median of 20 months (range, 7-26). Five of seven patients with ovarian cancer who had failed chemotherapy but were rendered clinically disease-free following surgery survive without progression a median of 13 months (range, 9-19). Eight of 16 (50%) platinum-resistant and 4/12 (33%) platinum-sensitive patients with ovarian cancer survive disease-free.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carboplatin; Carcinoma; Cerebral Hemorrhage; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Lung Diseases, Interstitial; Melphalan; Middle Aged; Mitoxantrone; Ovarian Neoplasms; Renal Insufficiency; Salvage Therapy; Treatment Outcome

Cytopenia after high-dose chemotherapy and autologous stem cell reinfusion is a major cause of morbidity. Ex vivo cultured expansion and differentiation of CD34+ peripheral blood progenitor cells (PBPC) to neutrophil precursors may shorten the neutropenic period further. We explored the use of these ex vivo cultured PBPCs in nine patients with metastatic breast cancer. All underwent PBPC mobilization with cyclophosphamide, VP-16, and G-CSF. Subsequently, they underwent four to five apheresis procedures. One apheresis product from each patient was prepared using the Isolex 300 Magnetic Cell Separation System (Baxter Immunotherapy, Irvine, CA) to obtain CD34+ cells. These cells were then cultured in gas permeable bags containing serum-free X-VIVO 10 (BioWhittaker, Walkersville, MD) medium supplemented with 1% human serum albumin and 100 ng/mL PIXY321. At day 12 of culture the mean fold expansion was 26x with a range of 6 to 64x. One patient's cells did not expand because of a technical difficulty. The final cell product contained an average of 29.3% CD15+ neutrophil precursors with a range of 18.5% to 48.1%. The patients underwent high-dose chemotherapy with cyclophosphamide, carboplatin, and thiotepa. On day 0, the cryopreserved PBPCs were reinfused and on day +1 the 12-day cultured cells were washed, resuspended, and reinfused into eight of nine patients. One patient was not infused with cultured cells. The mean number of cultured cells reinfused was 44.6 x 10(6) cells/kg with a range of 0.8 to 156.6 x 10(6) cells/kg. No toxicity was observed after reinfusion. The eight patients have recovered absolute neutrophil counts > 500/microL on a median of 8 days (range 8 to 10 days); the median platelet transfusion independence occurred on day 10 (range 8 to 12 days) and platelet counts > 50,000/microL were achieved by day 12 (range 9 to 14) for the seven patients whose platelet counts could be determined. Expanded CD34+ selected PBPC can be obtained and safely reinfused into patients.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cell Culture Techniques; Cells, Cultured; Combined Modality Therapy; Culture Media; Cyclophosphamide; Doxorubicin; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunomagnetic Separation; Leukapheresis; Lewis X Antigen; Melphalan; Middle Aged; Neutropenia; Tamoxifen; Thiotepa; Thrombocytopenia

The aim of this phase II study was to determine the feasibility of using two (tandem) courses of high-dose alkylating agents with bone marrow or peripheral blood progenitor cell support in women with stage IV breast cancer. Women with stage IV breast cancer who had achieved a CR or PR during conventional chemotherapy were enrolled in a phase II trial of high-dose cyclophosphamide 7500 mg/m2 and thiotepa 675 mg/m2 (C+T) followed within 180 days by high-dose melphalan (M) 140 mg/m2. Bone marrow and/or GM-CSF mobilized peripheral blood hematopoietic progenitor cells were used to support high-dose C+T and high-dose M. Twenty-seven women were enrolled in this trial. The median age was 45 years (range 32-56). The median PS was 0 and all patients had achieved either a CR (4/27, 15%) or PR (23/27, 85%) to conventional chemotherapy. All 27 women underwent high dose C+T. The predominant toxicities were mucositis (81%), and diarrhea (81%); two patients (7%) died from infectious complications. Following C+T, the median time to hematologic recovery for neutrophils (ANC > 500 cells/mu 1) was 12 days and for platelets (>20 000 cell/mu 1), 23 days. Following C+T, 18 of 22 patients received high dose M; the predominant toxicities were nausea, vomiting (70%), and mucositis (91%). The median time to hematologic recovery for the ANC was 13 days and for platelets, 18 days. The overall response after high dose C+T and high dose M was 67% (CR, 15/27 patients (56%) and PR* (complete resolution of all measurable disease but persistent lytic disease or positive bone scan) 3/27 patients (11%). With median follow-up of 24 months, the actuarial freedom from relapse or treatment failure is 56% at 24 months. At 30 months 56% of patients are alive. For patients who achieve a CR or PR* the actuarial freedom from relapse or treatment failure at 24 months is 88%. In women with stage IV breast cancer who attain a CR or PR to conventional chemotherapy, tandem high-dose chemotherapy with ABMT can lead to prolonged relapse-free survival.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Disease-Free Survival; Feasibility Studies; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Leukocyte Count; Life Tables; Melphalan; Middle Aged; Palliative Care; Remission Induction; Survival Analysis; Thiotepa; Treatment Outcome

The purpose of this study was to determine the toxicities and potential effectiveness of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) followed by autologous peripheral blood stem cell (PBSC) infusion in patients with a variety of diseases. A phase II clinical trial of Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC infusion in 104 patients with breast cancer (n = 48), malignant lymphoma (n = 25), ovarian cancer (n = 13), multiple myeloma (n = 7) and other malignancies (n = 11) was performed. Sixty-two patients were treated in an academic medical center and 42 in a community cancer center. Grade 3-4 regimen-related toxicities occurred in 14% of patients, causing regimen-related mortality in six (6%) patients with an overall transplant-related mortality of 9%. Transplant-related deaths occurred in 6/62 patients (10%) treated in an academic medical center and in 3/42 (7%) treated in a community cancer center. Complete remissions (CR) were achieved in 1/17 (6%) patients with refractory stage IV breast cancer, 4/4 patients with responsive stage IV breast cancer, 6/13 (46%) with more-advanced lymphoma and 4/4 with less-advanced lymphoma. These patients are alive and disease-free a median of 712, 279, 461 and 404 days after transplant, respectively. Nineteen of 22 patients with stage II-III breast cancer remain alive and disease-free a median of 365 days after transplant. Complete remissions were also seen in 4/9 patients with ovarian cancer and 3/7 with multiple myeloma. The Bu/Mel/TT regimen followed by autologous PBSC infusion is associated with acceptable morbidity and mortality, appears to have significant activity in patients with breast cancer and is well tolerated in the adjuvant setting of stage II-III breast cancer. Bu/Mel/TT also appears to have significant activity in patients with lymphoma, multiple myeloma and possibly ovarian cancer. Further phase II-III studies are warranted in patients with these and other malignancies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neoplasms; Ovarian Neoplasms; Thiotepa; Transplantation, Autologous

Dose-intensive treatment followed by ABMT is currently used in different approaches to treat breast cancer patients. An active non cross-resistant regimen combining cyclophosphamide (C), mitoxantrone (M) and melphalan (A) (CMA), was developed as the conditioning regimen before ABMT. The purpose of this phase II study was to evaluate this protocol and the duration of its effect in metastatic patients, who responded to chemotherapy. Criteria for inclusion included histologically documented breast cancer, age < 55 years and the first detection of measurable metastatic lesions. Following first-line chemotherapy in responding patients, histologically negative bone marrow was collected and cryopreserved. Then, intensification with cyclophosphamide (120 mg/kg), mitoxantrone (60 mg/m2), and melphalan (140 mg/m2) was followed by ABMT. Sixty-one metastatic breast cancer patients with a mean age of 40 years were included. Sites of measurable metastases included: liver 24, lung 14, central nervous system four, pleura three, skin six, and chest wall six, nodes eight and bone marrow one. Nineteen patients had lesions in two or more sites, and 22 had bone involvement. The response of 60 patients could be evaluated: before ABMT 31 were in clinical complete response (CR), 22 in partial response > 50% (PR), and seven had new progression. After ABMT, 36 patients were in CR, 16 in PR, one progressed and one was stable. Seven (11.5%) toxic deaths occurred. Mean time for hematological recovery was 32.5 days, without hematopoietic growth factors. Median survival was 33 +/- 9.4 months from the start of therapy, and 25.7 +/- 4.6 months from the date of ABMT. Median event-free survival was 20 months from the start of therapy, and 13 +/- 2 months from ABMT. With a median follow-up of 51 months, probability of actuarial survival, measured from the beginning of initial chemotherapy, was 36%, and event-free survival was 18%. In metastatic breast cancer responding to chemotherapy, high-dose consolidation with CMA and ABMT resulted in a median survival of 33 months. These results lay the ground work for evaluation in a randomized trial in metastatic breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Metastasis

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Central Nervous System Neoplasms; Chi-Square Distribution; Confidence Intervals; Diarrhea; Disease-Free Survival; Etoposide; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Humans; Liver Neoplasms; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Staging; Survival Rate; Thiotepa; Treatment Outcome

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.

Topics: Antigens, CD; Antigens, CD34; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Female; Filgrastim; Fluorouracil; Follow-Up Studies; Genes, Reporter; Genetic Markers; Genetic Therapy; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kanamycin Kinase; Male; Melphalan; Middle Aged; Multiple Myeloma; Phosphotransferases (Alcohol Group Acceptor); Recombinant Proteins; Treatment Outcome; Whole-Body Irradiation

This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms.. Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center.. Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported.. This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Injections, Intravenous; Melphalan; Middle Aged; Proportional Hazards Models; Prospective Studies; Quality of Life; Survival Rate; Vinblastine; Vinorelbine

High-dose chemotherapy produces high complete remission (CR) rates and some survival advantage in patients with metastatic breast cancer (BC). A current issue is the possibility that these patients may have an even better prognosis with multiple high-dose treatments. In this study, we evaluated the feasibility of a four-step, high-dose sequential chemotherapy (HDSC) with double autologous hematopoietic progenitor-cell rescue. We also tested the hypothesis that peripheral-blood progenitor cells (PBPCs) harvested following a single recruitment with cyclophosphamide (CY) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allow the safe administration of the whole HDSC with closely timed repeated courses of several non-cross-resistant agents.. The treatment plan included CY 7 g/m2, followed by GM-CSF 5 to 7 micrograms/kg/d administered by continuous intravenous (i.v.) infusion on days 2 to 14; PBPCs with or without bone marrow (BM) harvest; mitoxantrone (NOV) 60, 75, or 90 mg/m2 plus melphalan (L-PAM) 140 to 180 mg/m2 with hematopoietic rescue; methotrexate (MTX) 8 g/m2 plus vincristine (VCR) 1.4 mg/m2; and etoposide (VP-16) 1.5 g/m2 plus carboplatin (PP) 1.5 g/m2 with hematopoietic rescue.. All 15 patients enrolled completed the entire treatment and there were no toxic deaths. Hematologic reconstitution was good at each step. The median number of days with an absolute neutrophil count (ANC) less than 100/microL and platelet count less than 20,000/microL were 8 and 3, respectively, after NOV plus L-PAM, and 7 and 4, respectively, after VP-16 plus PP. The main non-hematologic toxicity was mucositis, while organ toxicity was mild and reversible.. This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Feasibility Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Remission Induction; Thrombocytopenia; Vincristine

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Carmustine; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Analysis; Thiotepa; Treatment Outcome

The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Combined Modality Therapy; Drug Tolerance; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Neoplasms; Thiotepa; Transplantation, Autologous

Breast cancer is the commonest form of cancer in Australian women. Although approximately 50% of women with breast cancer achieve long term survival by current management methods, recurrent or metastatic disease is generally incurable. In addition, women with Stage II disease with > 10 positive axillary lymph nodes and also women with locally advanced disease (Stage III) have a poor survival even with adjuvant therapy.. To assess the toxicity and efficacy of high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation in women with both metastatic and poor prognosis primary breast cancer.. Twenty-eight women with either metastatic (15) or poor prognosis (13) primary breast cancer were enrolled in the study between November 1988 to January 1993. PBSC were harvested using high-dose cyclophosphamide (Cy) with or without granulocyte-colony stimulating factor (G-CSF) and a myeloablative regimen of Cy, melphalan and carboplatin (CMCp) was used in the transplantation phase.. Optimum numbers of stem cells were harvested in 85% of patients. The use of five G/m2 Cy plus G-CSF resulted in better PBSC yields and a significant reduction in haematologic morbidity when compared to mobilisation with Cy alone. Twenty-two women underwent 23 PBSC transplants (PBSCT). There have been two early deaths due to sepsis. The predominant morbidities observed following high dose chemotherapy and transplantation have been nausea, mucositis and diarrhoea. The median number of days to discharge following infusion of PBSC was 15 (range 11-21). At a median follow up time of 1.1 years (range 0 months-3.6 years), 8/22 (36%) evaluable patients remain alive and disease free while 14/22 (64%) have relapsed or progressed or died.. High-dose chemotherapy and autologous PBSCT is a potentially highly effective treatment of women with metastatic and poor prognosis primary breast cancer. Randomised studies are required to compare this form of therapy to more standard forms of treatment in breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Staging; Treatment Outcome

High dose chemotherapy with autologous bone marrow support (ABMT) can achieve prolonged relapse-free survival in relapsed lymphomas, leukemias, and certain solid tumors. The principal morbidity and mortality relate to the infectious complications that occur during the 3-4 week aplasia until the marrow autograft recovers. Progenitor cells can be mobilized into the peripheral blood compartment by hematopoietic growth factors, used alone or after chemotherapy. We describe four trials using cytokine-mobilized peripheral blood progenitor cells (PBPC). In the first trial, PBPC collected after GM-CSF administration were used to augment marrow. Reconstitution of trilineage marrow function occurred promptly, resulting in short hospital stays and fewer platelet transfusions. In a second study, GM-CSF/chemotherapy-mobilized PBPC were used as the sole hematopoietic support during high dose chemotherapy. Granulocyte and platelet reconstitution was rapid. Time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC compared with similar patients receiving marrow alone. While most patients experienced prompt hematopoietic recovery they showed sluggish platelet engraftment. The next two trials built on the observation that a few PBPC alone could support both granulocyte and platelet recovery and were designed to test the feasibility of sequential high-dose therapies. In one trial, PBPC given with and without marrow made it possible to deliver two sequential cycles of high-dose therapy. The second trial utilized PBPC plus cytokines to deliver four cycles of dose-intensive chemotherapy at doses that could not be given with cytokine support alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Graft Survival; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukapheresis; Male; Melphalan; Methotrexate; Middle Aged; Neoplasms; Neutropenia; Salvage Therapy; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovariectomy; Postmenopause; Premenopause; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Tamoxifen; Treatment Outcome

Investigators have compiled extensive experience with mitomycin in the treatment of patients with breast cancer. Given as a single agent in intermittent schedules, mitomycin has induced responses of 26-38% in previously untreated patients and of 15-25% in those exposed to multiple prior chemotherapy regimens. Duration of response has been short. Toxicity, primarily myelosuppression, is largely dose-dependent. The dose-dependent efficacy of mitomycin has not yet been addressed. Preclinical studies suggest that optimal single-agent results are obtained when mitomycin is given in intermittent, high-dose schedules. Combination chemotherapy with mitomycin has proven more effective than single-agent therapy. Mitomycin given in combination with doxorubicin produces higher response rates than have been obtained with mitomycin alone. The 3M combination (mitomycin/mitoxantrone/methotrexate) appears effective and well tolerated at the doses described. Future research should focus on the development of polychemotherapeutic regimens that can be delivered in sequential or alternating schedules. Such regimens may yield quicker responses, and thus improve survival, in patients with breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Melphalan; Methotrexate; Mitomycin; Mitomycins

MMM (mitomycin 7-8 mg/m2 i.v.) every 6 weeks; mitoxantrone 7-8 mg/m2 i.v. every 3 weeks; methotrexate 35 mg/m2 i.v. every 3 weeks) is a new combination chemotherapy regimen for advanced breast cancer. It has been compared in two complementary randomized trials with CMF (cyclophosphamide 100 mg orally, days 1-14; methotrexate 35 mg/m2 i.v. days 1 and 8; 5-fluorouracil 1 g i.v. days 1 and 8; courses repeated at 28-day intervals) and VAC (vincristine 1.4 mg/m2 every 3 weeks, anthracycline 30 mg/m2 every 3 weeks, cyclophosphamide 400 mg/m2 every 3 weeks) in patients with advanced metastatic breast cancer. In the first trial, which involved 227 patients, 53% of patients receiving MMM and 49% receiving VAC responded to treatment. There was no significant difference between treatment groups in median response duration or survival. Incidence of neuropathy, alopecia, and nausea and vomiting was significantly higher in patients receiving VAC. Hematologic toxicity was greater in the MMM group. In the second trial, which involved 120 patients, 51% of patients receiving MMM and 60% receiving CMF responded to treatment. Again, there was no significant difference between treatment groups in median response duration or survival. Both regimens were well tolerated with a low incidence of alopecia and serious nausea and vomiting, and there were no significant differences in toxicity. Significant reductions in serial left ventricular ejection fractions occurred in 4 patients given CMF and in 2 given MMM. MMM is an effective, well-tolerated regimen for advanced breast cancer, with toxicity similar to that of CMF and less than that of an anthracycline-containing regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Dactinomycin; Female; Fluorouracil; Humans; Melphalan; Menopause; Methotrexate; Middle Aged; Mitomycin; Neoplasm Metastasis; Neoplasm Staging; Vincristine

Two decades ago the National Surgical Adjuvant Breast Project (NSABP) began to test the hypothesis that adjuvant chemotherapy would influence favorably the postsurgical survival rates of women with breast cancer. Although the use of phenylalanine mustard (melphalan or (L-PAM) has been supplemented by other agents, the thrust to recommend adjuvant chemotherapy as standard treatment was created by an L-PAM series of five trials using L-PAM or L-PAM plus fluorouracil. Only the first trial, B-05, contained an untreated group. The main treated groups in these five trials are similar to each other in survival probabilities, and the main untreated group in B-05 is not different in survival than the combined results of these five trials. There were a total of nine comparison in each study-and in B-05 the subgroup of treated women 49 years or younger with one to three positive node was found to be different than the untreated group. Four subsequent subgroups of women who were 49 years or younger with one to three positive nodes are not similar in survival despite the fact that they were developed from similar main groups that had similar treatment. The initial treated subgroup in B-05 had a survival outcome that was never again achieved in the subsequent four studies. The untreated subgroup in B-05 was not different than three of the four subsequently treated subgroups. The NSABP now has evidence that denies the conclusion that adjuvant chemotherapy prolongs survival in premenopausal node-positive women. Recommendations that adjuvant chemotherapy become standard treatment for premenopausal node-positive women should be seriously reconsidered and probably withdrawn.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Middle Aged; Neoplasm Staging; Survival Rate

158 evaluable patients with stage II, lymph node positive, carcinoma of the breast were randomized to adjuvant therapy with either melphalan (L-PAM) or cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy. In addition, patients were randomized to be treated with or without post-operative irradiation therapy (RT) in addition to their chemotherapy. At a median follow-up time of 11 years, there is no difference in time to relapse (P = 0.69) or survival (P = 0.55) among the four treatment groups. Multivariate analysis including treatment arm, age, race, tumor size, histologic type, performance status, time to onset of treatment, menopausal status, and number of positive nodes, revealed that only the number of positive nodes (less than 4 vs greater than or equal to 4) was related to disease-free and overall survival. Ten year relapse-free survival for patients with less than 4 positive nodes compared to those with greater than or equal to 4 positive nodes was 63% versus 30%, and overall survival 63% versus 41%, respectively. Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone (P = 0.03) but without improvement in relapse-free or overall survival. In this trial, post-operative radiation therapy when added to chemotherapy decreased the risk of local recurrence without adverse effects on survival. Treatment outcome was not influenced by chemotherapy regimen, but differences may have been obscured by the small sample size.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Lymph Nodes; Lymphatic Metastasis; Melphalan; Methotrexate; Middle Aged; Survival Rate

Studies are described of high-dose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing's sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Humans; Melphalan; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Prednisone; Prognosis; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vincristine

Topics: Adjuvants, Pharmaceutic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Prednisone; Tamoxifen; Vincristine

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Estrogens; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Middle Aged; Multicenter Studies as Topic; Neoplasms, Hormone-Dependent; Randomized Controlled Trials as Topic; Tamoxifen

During the 1970s, information obtained from animal tumor models and from patients with a spectrum of solid tumors indicated the worth of a variety of immunostimulating agents. These findings provided a biological and clinical rationale for conducting randomized trials to evaluate the worth of those agents. Consequently, in May 1977 the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented a randomized trial to determine whether Corynebacterium parvum (C. parvum, CP) plus chemotherapy would be more effective than chemotherapy alone in prolonging the disease-free survival (DFS) and survival (S) of patients with primary operable breast cancer and positive axillary nodes. The results of that trial through 8 years of follow-up fail to indicate that treatment with CP used in conjunction with l-phenylalanine mustard (L-PAM) plus 5-fluorouracil (PF) results in a better DFS and S than that observed after chemotherapy alone. Use of the immunomodulator has instead resulted in a poorer, but not statistically significant, outcome. Despite adjustments made to account for any imbalance in distribution of prognostic factors between the two treatment groups and despite considering treatment compliance as a factor, the unfavorable outcome persisted. A high incidence of fever and chills was associated with the administration of CP. The administration of hydrocortisone before each CP treatment reduced the frequency of those and other systemic effects. The failure to demonstrate a benefit from CP is in keeping with the failure of other nonspecific stimulating agents to contribute to the creation of a new paradigm for the treatment of breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bacterial Vaccines; Breast Neoplasms; Combined Modality Therapy; Drug Evaluation; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Middle Aged; Patient Compliance; Prognosis; Propionibacterium acnes; Randomized Controlled Trials as Topic; Survival Analysis

Despite numerous reports of findings obtained following the use of doxorubicin (Adriamycin [A]; Adria Laboratories, Columbus, OH) for the postoperative treatment of patients with primary breast cancer and positive axillary nodes, no clear consensus exists regarding its worth when used in that setting. In June 1981, the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented two randomized clinical trials aimed at evaluating the worth of doxorubicin when administered in conjunction with melphalan (L-PAM) and fluorouracil (5-FU) (PF). A prior NSABP study identified cohorts of patients who did or did not benefit from tamoxifen (TAM, T) when used with chemotherapy. That information was employed in the design of the present studies. Women considered responsive to TAM (1,106) were randomized between PFT and PAFT, and those nonresponsive to TAM (707) were randomized between PF and PAF. Findings through 6 years of follow-up (mean duration of potential time on study, 64 months and 63 months, respectively) indicate that non-TAM-responsive patients who received PAF had a significantly better disease-free survival (DFS) (P = .003) and survival (P = .05) than did those receiving PF. By contrast, there was no significant difference in DFS (P = .6) or survival (P = .7) between PFT- and PAFT-treated patients. No disparity in the amount of drug received, whether related to the median amount or to dose-intensity, is present to account for the difference in findings between the studies. Aside from alopecia and emesis, the toxicity from the doxorubicin-containing regimens was similar to those in which doxorubicin was omitted. Cardiomyopathy was not a significant finding; there were no deaths from cardiac toxicity. The incidence of arterial and venous complications in patients receiving TAM was less than reported by others.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Protocols; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Random Allocation; Tamoxifen

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Lymphatic Metastasis; Mastectomy, Modified Radical; Mastectomy, Radical; Melphalan; Methotrexate; Prednisone; Vincristine

Prognostic factors and treatment were analyzed for 2,578 patients to assess the impact of various forms of adjuvant chemotherapy on the natural history of operable stage II (node-positive) breast cancer. The outcome after surgery alone (or with radiotherapy) was determined in 1,014 patients in the natural history data base (NHDB). Adjuvant chemotherapy consisted of L-phenylalanine mustard (L-PAM; 130 patients); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF; 645 patients); doxorubicin and cyclophosphamide (AC; 241 patients); CMF plus vincristine and prednisone (CMFVP; 263 patients); and 5-fluorouracil plus AC (FAC; 285 patients). L-PAM had minimal effect on relapse-free survival (RFS) compared to the NHDB, but all combination chemotherapy programs significantly improved RFS and survival compared to the NHDB. In women with 1-3 positive nodes, all combination chemotherapy programs produced similar results. In women with 4-9 positive nodes, the FAC regimen appeared to be associated with superior RFS compared to other programs, but all were superior to the NHDB. In women with 10 or more positive nodes, FAC was the only regimen associated with improved RFS. The use of a NHDB and known pretreatment characteristics, such as nodal status and tumor size, permits comparison of patients at similar risk of recurrence of breast cancer who have received adjuvant chemotherapy and provides leads for evaluation in future prospective clinical trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Information Systems; Lymphatic Metastasis; Medical Records; Melphalan; Methotrexate; Middle Aged; Postoperative Care; Prednisone; Random Allocation; Time Factors; Vincristine

To determine whether prolonging the duration of tamoxifen administration beyond the cessation of a combined chemotherapy regimen benefits patients with primary breast cancer with positive findings in axillary nodes who benefit initially from the combined regimen.. Nonrandomized, nonconcurrent cohort study.. National Surgical Adjuvant Breast and Bowel Project, conducted in 68 institutions in North America.. Women were included if they had breast cancer with positive nodes and were aged 49 years or less with both estrogen and progesterone receptor levels of 10 fmol or more, aged 50 to 59 years with progesterone receptor levels of 10 fmol or more, or aged 60 to 69 years. Two cohorts were compared: patients who were randomly assigned to the tamoxifen arm of the adjuvant chemotherapy trial (randomized patients) and women who were added to this arm after randomization had ceased (registered patients). Three hundred seventy-seven women in each group who were disease free at the end of the initial 2-year treatment period were followed for an additional 3 years.. All received melphalan, fluorouracil, and tamoxifen (10 mg twice daily by mouth) for 2 years. Registered patients (but not randomized patients) were offered tamoxifen for a third year after the initial 2-year treatment period, and 273 (72%) agreed.. Women receiving a third year of tamoxifen had a better disease-free survival rate (odds ratio, 1.54; 95% confidence interval, 1.14 to 2.07; p = 0.004) and survival rate (odds ratio, 1.56; 95% Cl, 1.02 to 2.37; p = 0.04) through their fifth postoperative year. Women aged 50 years or more benefited, but those aged 49 years or less did not.. The benefit of tamoxifen given to tamoxifen-responsive patients in conjunction with melphalan and fluorouracil appears to be enhanced when the tamoxifen treatment is continued beyond cessation of treatment with these agents.

Topics: Actuarial Analysis; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Random Allocation; Tamoxifen

In this National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial, 1,891 women with primary operable breast cancer and positive axillary nodes were randomized between Jan, 1977 and May 1980 to receive L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) either with or without tamoxifen (TAM)-PFT. This report presents life table probabilities, cumulative odds ratios, and P values for disease-free survival (DFS) and survival at yearly intervals through 5 years of observation (mean time on study, 72 months). When patients were examined overall without regard for any discriminant associated with outcome, ie, age, number of positive nodes, or tumor receptor status, there was a significant prolongation of DFS (P = .002), but not survival through the fifth postoperative year. The benefit was almost entirely restricted to those greater than or equal to 50 years with greater than or equal to 4 positive nodes. In that group there was a 66% greater chance of remaining disease free if PFT was received (P less than .001), and there was also a significant survival benefit (P = .02). The advantage from PFT was found to be associated with tumor estrogen receptor (ER) and progesterone receptor (PR) as well as patient age and nodal status. Overall there was a significant improvement in DFS from PFT in those having tumors with an ER or PR level greater than or equal to 10 femtomole (fmol) (P = .01 and .009, respectively). No significant benefit in DFS or survival has been observed in patients less than or equal to 49 years old related either to nodes or tumor receptor status. Survival continues to be adversely affected by TAM in those patients (less than or equal to 49 years old), particularly when their tumors have a PR of 0 to 9 fmol (P = .007). In patients greater than or equal to 50 years old with four or more positive nodes, a significant DFS benefit persisted through the fifth year of observation in those having tumor ER or PR levels greater than 10 fmol (P less than .001 and .002). The advantage was observed in patients 50 to 59 years old as well as those 60 to 70. Women in the older decade demonstrated some advantage from PFT when their tumor ER or PR was 0 to 9 fmol. The most likely explanation for this finding is analytical error in receptor analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Melphalan; Middle Aged; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

This review summarizes the available data of phase II and phase III single-agent trials with predminustine and one phase II trial of prednimustine in combination with methotrexate, 5-fluorouracil, and tamoxifen in the treatment of advanced breast cancer. The data available so far indicate that the drug is more active than in combined treatment with the two components, chlorambucil and prednisolone. Future trials should be designed to analyze whether this could be ascribed to a sustained release of the components from the parent drug. The data also indicate that prednimustine is as active but less toxic than cyclophosphamide, but this needs to be confirmed in ongoing randomized comparisons. A number of phase II and phase III trials with prednimustine as a part of combinations are in progress. Mature results from these studies are needed to define the future role of prednimustine in the systemic therapy of breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Female; Fluorouracil; Humans; Leukocyte Count; Melphalan; Methotrexate; Prednimustine; Time Factors

Between 1972 and 1974, patients were entered into a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate L-phenylalanine mustard (L-PAM) as an adjuvant to mastectomy in patients with primary breast cancer and pathologically positive axillary nodes. Overall, findings through 10 years of observation indicate an 8% difference in disease-free survival (DFS) (P = .06) and a 5% difference in survival (P = .4). Women less than or equal to 49 years of age who received L-PAM demonstrate a significant (P = .03) prolongation of DFS and a significant (P = .05) survival benefit compared with those who received a placebo. There is a 37% reduction in their mortality and a cumulative odds of survival of 1.67. In that age group, both those with one to three and greater than or equal to 4 positive nodes benefited, but the advantage was greater when there were fewer positive nodes. There was a significant (P = .009) reduction in mortality (64%) and a cumulative odds of survival of 3.25 in patients less than or equal to 49 years old with one to three positive nodes. No advantage from L-PAM was observed in patients greater than or equal to 50 years old. When L-PAM response is related to nuclear grade, a marker of tumor differentiation, there is a highly significant improvement in DFS (less than .001), distant DFS (.001), and survival (.004) through 10 years of observation for all patients with tumors classified as nuclear grade poor (poorly differentiated), regardless of age and nodal status. Mortality was reduced by 32% and the cumulative odds of survival was 2.10 at 10 years. Of singular importance is the observation of a benefit in those greater than or equal to 50 years of age as well as in those less than or equal to 49 years of age with poorly differentiated tumors. There is a significant (P = .003) survival benefit for those in the older age group with a 37% reduction in mortality, and a cumulative odds of survival of 2.75. Patients in both age groups with well-differentiated tumors demonstrated no benefit from L-PAM. Those who are older seem to do less well following chemotherapy. We conclude that tumor differentiation is a better discriminant of response to chemotherapy than is age, and that both younger and older women are responsive to adjuvant chemotherapy when they have poorly differentiated tumors.

Topics: Actuarial Analysis; Age Factors; Breast Neoplasms; Cell Nucleus; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Lymph Nodes; Mastectomy; Melphalan; Middle Aged; Neoplasm Recurrence, Local; North America; Placebos; Random Allocation

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Methotrexate; Middle Aged; Receptors, Estrogen; Tamoxifen

Topics: Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Humans; Mastectomy; Melphalan; Middle Aged

This report provides an overview of information presented by us at a recent National Institutes of Health Consensus Development Conference on Adjuvant Chemotherapy. The data, derived from 7 randomized clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) since 1958, permit us to conclude that the use of systemic adjuvant therapy is of benefit in both premenopausal and postmenopausal patients with primary breast cancer. Data from the first NSABP trial begun in 1958 with short-course perioperative thiotepa demonstrated a long-term survival benefit in premenopausal but not postmenopausal patients. Ten-year findings from a second trial evaluating response to melphalan (P) implemented in 1972 indicated that, when related to age and nodes, there was a benefit from this drug in both the 1-3 and greater than or equal to 4 positive node premenopausal groups but those with fewer nodes were most improved. In this group characterized by premenopausal women with 1-3 positive nodes, mortality was reduced 64% with a cumulative odds ratio of 3.25 (P = .009) at 10 years after surgery. When related to nuclear grade, there was a striking benefit in survival from P in patients less than or equal to 49 and greater than or equal to 50 years with undifferentiated tumors. The addition of 5-fluorouracil (F) to melphalan (PF) resulted in an increase in disease-free survival and survival over that observed with P in patients less than or equal to 49 and greater than or equal to 50 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Lymph Nodes; Mastectomy; Melphalan; Methotrexate; Middle Aged; Tamoxifen

The Southwest Oncology Group has conducted a series of randomized studies of adjuvant therapy in patients with primary breast cancer and positive axillary nodes. The first study, during which combined chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) administered for 1 year was compared with single agent therapy with melphalan (L-PAM) for 2 years, was activated in 1975 and closed in 1978. Of the 366 patients who were eligible, 191 received L-PAM and 175 were given CMFVP. The 2 groups were comparable with regard to known prognostic factors. At a median follow-up of 8 years, CMFVP continues to be superior to L-PAM in disease-free (P = .005) and overall survival (P = .01). Thirty-five percent of patients on CMFVP have died compared with 46% on L-PAM. The greatest survival benefit is apparent in premenopausal women and women with 4 or more positive axillary nodes. Acute toxicity was more frequent with CMFVP than with L-PAM, but it was acceptable and reversible with both regimens. Long-term toxicity was limited to myeloproliferative disease in 2 patients on L-PAM and 1 on CMFVP. The second-generation series of studies, activated in 1979, were designed according to nodal status, estrogen receptor (ER) status, and menopausal status. We randomized ER-negative, node-negative patients to 6 months of combination chemotherapy or to no treatment. Because of slow accrual, the study was closed and patients are now being entered onto a similar intergroup study with the Eastern Cooperative Oncology Group. We randomized ER-negative, node-positive patients to either 1 or 2 years of CMFVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Lymph Nodes; Melphalan; Methotrexate; Middle Aged; Prednisone; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Staging; Random Allocation

Topics: Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Lymph Nodes; Melphalan; Methotrexate; Prednisone; Vincristine

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Male; Melphalan; Menopause; Methotrexate; Neoplasm Metastasis; Prednisone; Random Allocation; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Prednisone; Prognosis; Tamoxifen; Vincristine

A randomized controlled trial of the value of oral adjuvant cytotoxic chemotherapy in the treatment of potentially curable breast cancer has been in progress in the Oxford Region since 1977. Eighty-seven patients were allocated to treatment with melphalan 0.2 mg/kg for 5 consecutive days every 6 weeks for 2 years; 98 patients were allocated to treatment with oral combination therapy consisting of melphalan 10 mg daily for 5 consecutive days, plus methotrexate 15 mg and 5-fluorouracil 250 mg on the first day, courses being repeated every 6 weeks for 2 years; and 88 patients were allocated to a control group which received no adjuvant chemotherapy. So far, 125 patients have suffered a recurrence of breast cancer and 85 have died. No statistically significant differences in outcome are apparent between the three treatment groups, although there is some indication of a beneficial effect of chemotherapy on disease-free interval in pre-menopausal women. Toxic effects of treatment, notably nausea, vomiting and bone marrow depression, have been moderately severe. In our view, the beneficial effects of current adjuvant cytotoxic chemotherapy, if any, are too modest to justify the suffering which such treatment can cause at a time when a woman with breast cancer might otherwise expect to feel physically well.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Female; Fluorouracil; Humans; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Patient Compliance; Random Allocation

Sixteen patients with clinical primary inflammatory carcinoma of the breast were treated with initial immunochemotherapy from September 1974 to May 1977. This chemotherapy was an association of adriamycin, vincristine, fluorouracil, methotrexate, and melphalan. Thermographic cooling was taken as the criterion of operability. Chemotherapy was resumed after surgery up to a total of ten periods, and followed by a minimum one year chemotherapy. I-BCG-F Pasteur was used as immunotherapy and associated with the chemotherapy regimen. Five patients have died, four are alive with disease, and seven are free of disease at time of reporting. Median survival exceeds 90 months. Our data supports the conclusion that mastectomy combined with preoperative and postoperative immunochemotherapy may permit a better prognosis for inflammatory carcinoma of the breast: this benefit seems to be the consequence of adapting the length of initial chemotherapy to the data given by plate-thermography.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Immunotherapy; Mastectomy; Melphalan; Middle Aged; Thermography; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Staging; Prospective Studies; Random Allocation; Tamoxifen

Topics: Adult; Alkylating Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Methotrexate; Middle Aged; Prednisone; Surgery, Plastic; Tamoxifen; Thiotepa; Vincristine

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Methotrexate; Prognosis; Tamoxifen

Between July 1975 and June 1979, 194 patients with State II or III breast carcinoma were randomized to receive either L-phenylalanine mustard (L-PAM), cyclophosphamide and 5-fluorouracil and prednisolone (CFP), or CFP and BCG. Sixty-one patients have recurred despite the adjuvant chemoimmunotherapy trial. Fifty-three are evaluable for survival and 36 for response to chemo-hormonal therapy. Those treated with a chemo-hormonal regimen for their first recurrence exhibited a 53% objective response rate to cytotoxic therapy or a 35% response to hormonal therapy. Prior exposure to L-PAM, cyclophosphamide, or 5-fluorouracil did not preclude response to "salvage" therapy regimens containing those agents. Neither menopausal status, estrogen receptor content, size of the primary tumor, adjuvant treatment, nor extent of the recurrence had any effect on subsequent survival. Overall, the entire group exhibited median survival of 37 months from initial diagnosis and 13 months from recurrence. Unlike recurrent Hodgkin's disease, there was no demonstrable relationship between the length of the disease-free interval and the likelihood of subsequent response to cytotoxic or hormonal treatment. Comparison is made to the results of "salvage" therapy administered after three other large adjuvant treatment series.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prednisolone; Prospective Studies; Random Allocation

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Castration; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Random Allocation; Receptors, Estrogen; Tamoxifen; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Neoplasm Staging; Prednisone; Prognosis; Vincristine

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Staging; Prednisone; Prognosis; Vincristine

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis

370 patients who had carcinoma of the breast with involved axillary lymph-nodes were randomised after total mastectomy and axillary clearance to receive either no additional treatment or melphalan 6 mg/m2 daily for 5 days every 6 weeks for sixteen cycles. There was a trend towards longer relapse-free survival (RFS) in patients treated with melphalan, but this was not significant either in the whole series or in sub-groups according to menopausal status or extent of nodal involvement. In patients receiving melphalan RFS was not significantly affected by either the occurrence of amenorrhoea or the dosage of melphalan received. Overall survival did not differ significantly between the two groups. The results of this trial suggest that there is no place for the use of melphalan as adjuvant therapy in the management of early breast cancer.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Mastectomy; Melphalan; Menopause; Middle Aged; Postoperative Care; Quality of Life; Random Allocation

Topics: Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Melphalan; Random Allocation

Between September 1976 and May 1980, 135 patients with operable breast cancer and positive axillary nodes received l-phenylalanine mustard, adjunct to surgery, 0.15 mg/kg for five days, six weekly, and were randomised prospectively to levamisole 150 mg for three days, two weekly, or a placebo. Treatment was continued for two years or until evidence of treatment failure, whichever was the sooner. At 4 1/2 years, for all patients, there was no significant difference between the two groups (P = 0.09), but in a subgroup of women less than or equal to 50 with 1-3 positive nodes, levamisole had a negative effect (P = 0.05). Although an analysis of the same age group, independent of the nodal status, did not reach significance, there was a trend in favor of placebo (P = 0.08) which was also apparent in premenopausal women (P = 0.15). In postmenopausal patients, however, and in those with more advanced disease with four or more positive nodes, although the results also failed to reach significance the trend in these subgroups favored levamisole. The results of this study suggest that levamisole has no place in the primary therapy of breast cancer in younger women and those with more favorable disease. The value of this agent in older patients and those with more advanced primary disease, remains unproven, but the favorable trends are in accord with a number of other studies with levamisole in metastatic breast and resectable lung cancer. Retrospective analysis confined to those women who received 75% or more of the total dose of l-phenylalanine mustard showed no evidence for a dose-responsive effect of adjuvant chemotherapy on the described pattern of results.

Topics: Age Factors; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leukopenia; Levamisole; Lymphatic Metastasis; Melphalan; Menopause; Middle Aged; Placebos; Retrospective Studies; Thrombocytopenia

The paper critically reviews major accomplishments achieved with the use of chemotherapy in the treatment of various stages of breast cancer. In spite of innumerable clinical trials, there is no evidence that in advanced breast cancer the addition of more drugs, either in concomitant, sequential or alternating fashion, to known effective combinations, was able to significantly improve the incidence and the magnitude of objective response or its median duration or survival. The addition of endocrine therapy to chemotherapy has failed so far to improve the most important end-point, i.e. total survival. Second-line chemotherapy is only moderately effective for a fairly short period of time. Thus, in women with advanced breast cancer excessive tumor cell burden and permanent drug resistance remain the major obstacles to obtaining complete remission and long-term disease free survival. In the adjuvant setting, the initial trials with combination chemotherapy have achieved consistent results, particularly in women with minimal axillary node involvement. Unless a woman has undergone a surgical breast-saving procedure, postoperative radiotherapy does not appear to play an important therapeutic role, either with or without concomitant or sequential chemotherapy. Present results would suggest that in advanced breast cancer little progress can be expected in the near future. Therefore, medical oncologists should focus on the correct application of established drug regimens, using a sequential flow of hormonal manipulations and cytotoxic chemotherapy. In high-risk groups, full dose adjuvant polydrug therapy given for a relatively short period of time appears to be at present the only means able to significantly decrease the failure rate following local regional treatment. Present consistent achievements, which appear devoid of important delay morbidity (e.g. cancerogenesis, chronic organ damage) will require further clinical research to identify more effective and less toxic treatments.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Receptors, Estrogen; Research Design

Loss of a breast to cancer can have a profound psychologic effect on a woman. Within the last few years, research in breast cancer has centered on trying to find procedures that are less mutilating than but just as effective as the conventional surgical procedures discussed in part 1 (page 126). In this second part by Dr Pilch, recent and ongoing studies of a newer promising method known as segmental mastectomy are reviewed. How simple excision with irradiation is being used in early disease is described in part 3 (page 151). Part 4 (page 161) considers adjuvant therapies in early and late disease.

Topics: Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Lymph Node Excision; Mastectomy; Melphalan; Postoperative Care; Prospective Studies; Radiotherapy Dosage; Random Allocation

In 1977 the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a prospectively randomized clinical trial to evaluate the relative merits of 1-phenylalanine mustard and 5-fluorouracil (PF) with and without tamoxifen (T) as adjuvant therapy for patients with primary breast cancer and positive axillary nodes. A previous presentation of findings noted that there was a strong relationship between the outcome of those receiving PFT and the estrogen receptor (ER) and progesterone receptor (PR) content of their tumors. This report relates the outcome of the PF-treated patients in that trial with these tumor receptors. It indicates that the results observed following nonhormonal therapy (PF) are also related to tumor receptors. Both the disease-free survival (DFS) and survival (S) of women following PF therapy were influenced by the ER and PR content of their tumors. Subsequent to adjustment for other prognostic variables, the predictive influence of tumor ER persisted. Both the DFS (p = 0.0003) and the S (p = 0.00003) were significantly higher in those with greater than or equal to 10 fmol tumor ER than in those with less than 10 fmol ER. The PR significantly added to the predictive value of ER. Thus, this analysis is the first to demonstrate that having information on both ER and PR is important for predicting outcome of patients receiving adjuvant chemotherapy. The study does not provide information which correlates receptor status with the response of patients to adjuvant chemotherapy since there is no similar nonchemotherapy-treated group of patients in the trial. The findings continue to emphasize that there is a heterogeneity in outcome of breast cancer patients to adjuvant chemotherapy which is related to an increasing number of host and tumor variables. For proper assessment of overall results, it is essential that analyses employ tests for interaction to indicate homogeneity or heterogeneity of patient subsets and that adjustments be made for imbalances in tumor ER and PR as well as in other prognostic factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Lymph Nodes; Melphalan; Neoplasm Recurrence, Local; Receptors, Estrogen; Receptors, Progesterone; Risk; Tamoxifen

In 1977 the National Surgical Adjuvant Breast and Bowel Project initiated a prospectively randomized clinical trial for women with primary operable breast cancer and positive axillary nodes. In this study 1891 patients were randomized to receive L-phenylalanine mustard and 5-fluorouracil (PF) either with or without tamoxifen (T). In this interim report findings are presented concerning disease-free survival (DFS) and survival as related to age and to estrogen receptor (ER) and/or progesterone receptor (PR) content of the tumor. The median follow-up time is 3 yr. Patients 50 yr of age or older with either 1-3 or more than 3 positive axillary nodes had a markedly longer disease-free survival on PFT than did those receiving PF adjuvant therapy (p less than 0.001). The effectiveness of PFT was related to the levels of tumor receptors. Patients 50 yr old or more with both tumor ER and PR levels of 10 fmole or more ("high") displayed the greatest benefit in disease-free survival from PFT (p = 0.004). Analyses by age indicated that it is more appropriate to divide patients of 50 yr or older into two age groups, 50-59 and 60-70 yr old. In the former the survival results were poorer on PFT when tumor PR was low, whereas, regardless of receptor levels, those 60-70 yr old experienced an advantage on PFT. In women under 50 yr of age, there was no difference in disease-free survival (p = 0.64), but survival results favored the PF over the PFT treated (p = 0.06). Patients under 50 yr with tumor ER and PR levels under 10 fmole ("low") had a poorer survival when given PFT (p = 0.003). Those whose tumors demonstrated a high ER and a low PR also had a shorter survival on PFT (p = 0.01). The observation of no benefit in younger patients when both receptor levels were high, but a benefit in older patients with receptor-poor tumors, indicates that, at least according to the conditions of this study, the difference between the two age groups cannot be explained by the association of age with receptor content. Multivariate analyses considered the effects of the number of positive nodes, age, ER, and PR. They support the conclusion that, while nodes and ER exert strong prognostic influences in both PF- and PFT-treated patients, the PR content of tumors is a stronger predictor of the effectiveness of PFT therapy than is ER content.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Lymph Nodes; Melphalan; Middle Aged; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Statistics as Topic; Tamoxifen

Data derived from 1848 patients entered into three adjuvant chemotherapy protocols are presented. The three studies were performed sequentially and were designed to identify patient subsets responding to one, two, or three chemotherapeutic agents. Comparison of disease-free survival in patients receiving L-PAM or placebo disclosed that L-PAM was beneficial in patients less than or equal to 49 years of age, but not in women greater than or equal to 50 years. Further analysis indicated that the subset of patients less than or equal to 49 years with 1-3 positive nodes sustained the greatest increment in disease-free survival with single-agent L-PAM. The addition of 5-FU to L-PAM was superior to L-PAM alone in patients greater than or equal to 50 years of age, particularly those with greater than or equal to 4 positive nodes. The three-drug combination of L-PAM, 5-FU, and methotrexate failed to provide a benefit over and above that achieved by the L-PAM-5-FU combination in all subsets examined. The results underscore the heterogeneous response to chemotherapy demonstrated by patient subsets characterized on the basis of age and nodal status. The implications of the findings relative to the current status of adjuvant therapy are discussed.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Middle Aged

Adjuvant therapy trials in breast cancer have grown steadily more complex since 1971, when the first long-term adjuvant trial in the United States was initiated. From L-PAM alone or in combination with a few other cytotoxic agents, ECOG protocols have expanded to consider different multidrug combinations with tamoxifen and other endocrine agents, administered for various lengths of time, sometimes alternating between two combinations. Nevertheless, we are still in the gestational stages of adjuvant studies, with many critical questions yet to be answered.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Prednisone; Tamoxifen

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) to two years of intermittent L-phenylalanine mustard (L-PAM) in women with operable breast cancer with histologically positive axillary lymph nodes. In fully and partially evaluable patients with a 68-month median follow-up, treatment failures have occurred in 27% of 172 receiving CMFVP and 47% of 186 women given L-PAM (p = 0.002). The advantage for women receiving CMFVP was seen for all subsets regardless of menopausal status except among women who were premenopausal and had 1-3 positive nodes. Based on this study, a second study was implemented using both the estrogen-receptor (ER) content of the primary tumor and axillary nodal status to select therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Prednisone; Vincristine

This trial studied the possibility that tamoxifen, added to L-phenylalanine mustard and 5-fluorouracil, enhances the established benefit of the latter two drugs in treatment of women with breast cancer and positive axillary nodes. The addition of tamoxifen resulted in a 25% decrease in treatment failure at 24 months and a 23% decrease at 36 months. In patients greater than or equal to 50 years old, there was a 48% reduction at 24 months and a 39% reduction at 36 months. This advantage was statistically significant at both two and three years' follow-up (p less than 0.001). Higher receptor levels were associated with a greater probability of disease-free survival. Patients less than or equal to 49 years old were less responsive. There was some evidence at 24 months that patients in this age group with four or more positive nodes who also had high ER levels might benefit from tamoxifen. At 36 months, however, this benefit was no longer evident. This form of adjuvant therapy is not recommended in patients less than or equal to 49 years of age whose tumor estrogen and progesterone levels are below 10 fmol; there is an appearance of benefit in patients greater than or equal to 50 with low estrogen and progesterone levels, and stronger evidence of benefit when these levels are high among the older group of patients.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Middle Aged; Receptors, Estrogen; Tamoxifen

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Time Factors

A total of 241 patients with early breast cancer had serial bone scans and chest radiographs during the first two years of follow-up after primary treatment. Each patient had had a modified radical mastectomy and been found to have involved axillary nodes. They were part of a prospective randomized trial testing the use of L-phenylalanine mustard L-PAM as adjuvant chemotherapy. During the two years, these patients had a total of 832 serial bone scans and 1091 serial chest radiographs. Twenty-five patients (10.4 per cent) had bone metastases detected on sequential scanning, only 13 of whom, however, were asymptomatic at the time of the positive scan. Twelve (5 per cent) patients were found to have pulmonary metastases on routine sequential chest radiography of whom only 8 were asymptomatic at the time of the positive chest radiograph. It is concluded from this study that, apart from their usefulness in the monitoring of clinical trials, serial bone scans and chest radiographs cannot be recommended routinely in the follow-up of asymptomatic patients because of the low yield and high cost involved.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Follow-Up Studies; Humans; Lung Neoplasms; Melphalan; Middle Aged; Prospective Studies; Radiography; Radionuclide Imaging; Time Factors

Patients with stage II or III carcinoma of the breast were assigned to one of three adjuvant chemotherapy and chemoimmunotherapy treatment groups following radical or modified radical mastectomy. This study compares the efficacy of single drug treatment (melphalan) versus multiple drug regimens (CFP and CFP + BCG). In the initial phase of the project participants in the melphalan group showed a higher recurrence rate than those in the CFP and CFP + BCG groups. The recurrence rate of the melphalan group was 4.4 times higher than the recurrence rate of the combined polychemotherapy arms. However, after the initial phase, the recurrence rates for the polychemotherapy arms steadily increased and approached the dropping rate of the melphalan group. Currently (247 weeks after the beginning of the study and nine months after the last patient accrual), 194 patients have been treated (median follow-up time of 101 weeks), and no significant differences can be detected between the three treatment arms using any of the following criteria: disease-free interval, proportion of recurrence and recurrence rate. The only factors which are significant with respect to recurrence are the two prognostic factors: tumor size and degree of nodal involvement. The two chemotherapy groups, CFP and CFP + BCG, show no significant difference with respect to recurrence rate along the entire span of the study.

Topics: Antineoplastic Agents; BCG Vaccine; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Melphalan; Neoplasm Recurrence, Local; Prednisone; Prognosis; Prospective Studies

Peptichemio is a polypeptide complex of L-phenylalanine mustard. Because of structural similarities between melphalan (L-PAM) and Peptichemio a prospective randomized study was done to compare the therapeutic efficacy of these two agents. After failing various combinations of doxorubicin, cyclophosphamide, fluorouracil, methotrexate, and vincristine patients with advanced breast cancer were randomized to receive either Peptichemio or L-PAM. Peptichemio was administered at 75-100 mg/m2 and L-PAM at 30-40 mg/m2 IV q 3-4 week interval. Of 56 evaluable patients, 28 received peptichemio and 28 received L-PAM. There were no objective responses in the L-PAM group, and disease stabilized in four patients (14%). The median duration of stable disease was three months (range, 3-4 months). In the peptichemio group seven patients (25%) achieved a partial remission, one patient (3%) achieved less than partial remission and three patients (11%) had stable disease. The median duration of response was six months (range, 5-7+ months) for responding patients and three months (range, 2-5 months) for stable disease. The major toxicity of both drugs was myelosuppression which was cumulative. In conclusion, peptichemio is an active agent in advanced breast cancer, but L-PAM is ineffective in previously treated patients with metastatic breast cancer.

Topics: Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Melphalan; Middle Aged; Peptichemio; Prognosis; Prospective Studies; Random Allocation

One hundred seventy-one patients received one year of melphalan or intermittent cyclophosphamide, methotrexate, and fluorouracil after mastectomy for breast cancer with involved axillary nodes. Analysis with a median follow-up of three years indicates a favorable outcome only for patients with 1-3 positive nodes who were treated with melphalan and who experienced a leukocyte count less than 3,000/mm3 (3.0 X 10(9)/l). Tumor size, average percentage of dose received, menopausal status, and type of chemotherapy were not significant factors in recurrence of disease, after adjustment for the number of positive nodes and leukocyte count nadir during treatment based on a multifactorial analysis. These data suggest that administration of a dose of melphalan which does not produce a leukocyte count of less than 3,000/mm3 is ineffective in preventing early recurrence of disease. Since oral melphalan is known to be erratically absorbed, lack of hematologic toxicity may well be due to variable absorption of the drug on a fixed-dose region. Failure to prevent recurrence of disease in this and other trials using oral melphalan may be due to chemotherapy-related as well as disease-related factors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L-PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42-month median and 30-month minimum follow-up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L-PAM (P = 0.002). Disease-free survival times were significantly longer with CMFVP than with L-PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1-3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre- and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L-PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L-PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L-PAM in decreasing recurrences and increasing survival in both pre- and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

Topics: Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Prednisone; Vincristine

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Mastectomy; Melphalan; Menopause; Placebos

Two hundred ninety-three patients were randomly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer: L-PAM, CFP, or CFP with radiation therapy. For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs, large number of lymph nodes involved, greater body weight, younger age, and L-PAM treatment. For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease: large tumor size, large number of lymph nodes involved, and inner/central location of the primary lesion. Specifically, the treatment employed has shown no effect. Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered. Furthermore, evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression, here is no benefit for severe myelosuppression over moderate, myelosuppression.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukocyte Count; Leukopenia; Mastectomy; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prognosis; Random Allocation; Thrombocytopenia

Topics: Age Factors; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Middle Aged; Prognosis; Thiotepa

Topics: Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Menopause; Methotrexate

We studied the possibility that the addition of tamoxifen to L-phenylalanine mustard combined with 5-fluorouracil enhances the benefit from the latter two drugs that has been observed in women with primary breast cancer and positive axillary nodes. Recurrence of disease was reduced at two years in patients given the three-drug regimen whose tumor estrogen-receptor levels were greater than or equal to 10 fmol. Among patients greater than or equal to 50 years old treatment failure was significantly reduced (P less than 0.001): by 51 per cent in those with one to three positive nodes and by 64 per cent in those with four or more. Higher receptor levels were associated with a greater probability of disease-free survival. Patients less than or equal to 49 years old were less responsive: those with one to three positive nodes received no benefit from tamoxifen at any receptor level, whereas those with four or more appeared to have reduced treatment failure associated with higher receptor levels. This adjuvant chemotherapy is not indicated in patients less than or equal to 49 years old whose tumor receptor levels are below 10 fmol; there is a suggestion of benefit in patients greater than or equal to 50 years old whose levels are low.

Topics: Age Factors; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Melphalan; Middle Aged; Random Allocation; Receptors, Estrogen; Tamoxifen

Topics: Adult; Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Middle Aged; Prednisone; Vincristine

One hundred fifty-eight evaluable patients with Stage II carcinoma of the breast with positive lymph nodes were treated either with adjuvant chemotherapy or irradiation therapy followed by chemotherapy. Patients were randomized to test the effectiveness of L-phenylalanine mustard (L-PAM) with and without postoperative irradiation therapy (R.T.) against cyclophosphamide, 5-fluorouracil, and methotrexate (CMF) with and without postoperative irradiation therapy in decreasing the frequency of recurrence. No significant difference was observed between L-PAM as compared with R.T. plus L-PAM (P = 0.85). The difference between CMF and R.T. plus CMF was significant in support of CMF alone (P = 0.04). The frequency of recurrence between R.T. plus L-PAM and R.T. plus CMF showed no difference. A comparison of the chemotherapy only regimens showed an advantage of CMF over L-PAM (P = 0.05). Both the delay in starting chemotherapy and the significant decrease in percent optimal drug dosage during the first six cycles of therapy are factors that may influence the high frequency of relapse observed in the R.T. plus chemotherapy groups. Of the four treatments, CMF has the lowest frequency of recurrence.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Postoperative Care; Prospective Studies; Radiotherapy Dosage; Random Allocation

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials evaluating three different regimens of adjuvant chemotherapy (L-PAM, L-PAM + 5-FU, L-PAM + 5-FU + MTX) in patients with primary breast cancer and positive axillary nodes indicate that each regimen has significantly contributed toward achieving the initial goal of such therapy, namely to diminish or prevent treatment failure in all or major subsets of patients during the first two years following operation when women are at greatest risk for a recurrence. Because of this hazard, chemotherapy was administered in all protocols for two years. Findings were examined at the end of the first year of therapy and at the termination of the second year for those who entered that year of therapy disease-free in order to determine whether the second year of treatment contributed a benefit beyond that achieved from the first year of therapy. A reduction in the incidence of treatment failure was evident in every subgroup of patients at completion of the first year of therapy. There was evidence of added improvement during the second year of treatment in patients aged 49 years or younger but not in those aged 50 years or older. Despite the finding, it is not possible from these studies to be absolutely certain that a second year of therapy is or is not advantageous. Findings obtained to date from the three studies indicate that patients completing two years of chemotherapy who are disease-free display a subsequent treatment failure rate that is no greater than that observed in untreated patients who survived two years without recurrence. Consequently, any advantage in disease-free survival observed at completion of therapy has been subsequently sustained for several years, suggesting this represents a real decrease rather than a postponement of treatment failure.

Topics: Age Factors; Aged; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymph Nodes; Melphalan; Methotrexate; Middle Aged; Prognosis

Topics: Age Factors; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Probability; Random Allocation; Tamoxifen

Stage II or III breast carcinoma patients were assigned to one of three adjuvant chemotherapy groups after mastectomy. The efficacy of melphalan, vs cyclophosphamide, fluorouracil, and prednisone (CFP), vs CFP plus BCG vaccine was compared in 173 patients treated for five days every six weeks for the first postoperative year. Tumor size, unfavorable local signs, extent of axillary nodal involvement, menopausal status, and participating hospital were considered in assigning patients to treatment groups. The median follow-up time was 26 months; 24.2% of the patients were studied for more than three years. Recurrent disease occurred in 31.6% of the patients in the melphalan group and in 13.4% and 13.2% in the other two groups. Six patients died of metastatic tumor; three others died of other causes. A favorable significant difference exists for polychemotherapy in prolonging disease-free interval in our series.

Topics: Antineoplastic Agents; BCG Vaccine; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Mastectomy; Melphalan; Neoplasm Staging; Postoperative Care; Prospective Studies

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Osteosarcoma

Topics: Affective Symptoms; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Libido; Mastectomy; Melphalan; Methotrexate

Topics: Antineoplastic Agents; BCG Vaccine; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Mycobacterium bovis; Neoplasm Metastasis; Postoperative Care; Semustine; Vincristine

Breast cancer patients participating in a prospective randomized clinical trial who were less than or equal to 49 years of age, had positive axillary nodes, and who received prolonged 1-phenylalanine mustard (L-PAM) as an adjuvant to mastectomy continue (after 4 years) to demonstrate a significantly greater disease-free survival (p = .007) than do patients who received placebo. Benefit was achieved in patients who were less than or equal to 39 years as well as those who were 40-49 years of age. Those in the younger age group showed a greater improvement in disease-free survival at 4 years relative to their controls (32% vs. 69%; p = .01) than did those in the older age group (48% vs. 61%; p = .09). When patients were examined relative to their nodal status, a highly favorable effect was found to have been achieved with L-PAM in those with 1-3 positive nodes (54% vs. 86%; p = .006). Results indicate that both age groups were benefited. When considered over time, they demonstrate that a relatively greater effect was achieved in the younger women. While L-PAM failed to significantly alter the disease-free survival of those with greater than or equal to 4 positive nodes a slightly better effect was achieved in the group less than or equal to 39 years. Since adjuvant chemotherapy has been found to be more effective in premenopausal than postmenopausal women, it has been presumed that decreased ovarian function, as a result of the chemotherapy, is responsible for the findings. To support or repudiate that concept, information regarding serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), as well as menstrual function, has been obtained from women receiving L-PAM or L-PAM plus 5-FU therapy. In contrast to findings relative to disease-free survival, ovarian function and menses were most affected in patients 40-49 years of age. Amenorrhea occurred in 73% of patients in that age group and in only 22% of those less than or equal to 39 years (p less than .001). Similarly, a significant increase in LH and FSH and a decrease in E2, all indicative of ovarian suppression, was observed only in the older group of patients. Thus, it is concluded that while ovarian suppression may account for some of the adjuvant chemotherapeutic effect in premenopausal women, the dichotomy of findings in younger and older premenopausal women relative to therapeutic response and ovarian function indicates that other factors could be responsible.

Topics: Adult; Age Factors; Breast Neoplasms; Clinical Trials as Topic; Female; Hormones; Humans; Lymphatic Metastasis; Melphalan; Menstruation; Middle Aged; Ovary; Remission, Spontaneous; Time Factors

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Lymphatic Metastasis; Melphalan; Middle Aged

Topics: Bone Marrow; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Melphalan; Menopause; Methotrexate; Vomiting

172 patients who had had mastectomy for breast cancer were treated by repeated adjuvant chemotherapy, either with phenylalanine mustard (P.A.M.) or a combination of cyclophosphamide, 5-fluorouracil, and prednisone (C.F.P.) with and without radiotherapy. Tumours recurred significantly more frequently and mortality tended to be higher in P.A.M.-treated patients than in patients on other treatment. The interval between surgery and disease recurrence was significantly shorter for P.A.M.-treated premenopausal but not postmenopausal patients than for patients of equivalent menstrual status treated with C.F.P. with or without radiation. The associations in premenopausal patients between the mode of treatment and both survival and the disease-free interval were significant before and after adjustment for variations between the treatment groups in the number of involved lymph nodes and the size of the primary tumour.

Topics: Adult; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Mastectomy; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Postoperative Care; Prednisone; Remission, Spontaneous; Time Factors

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged

The addition of levamisole, administered in adjunctive manner between the cycles of conventional high dose chemotherapy in patients with hormone resistant end state breast cancer substantially improved the survival of treated patients. Analysis of this double-blind study in 60 such patients suggests that improvement in remission status and survival is related to better tolerability of such cytotoxic therapy as regards both specific and nonspecific cytotoxicity. This improved tolerability enabled patients to receive higher doses of cytotoxic drugs over a shorter time period resulting in an improved remission rate and ultimate survival.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Levamisole; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Metastasis

Topics: Administration, Oral; Breast Neoplasms; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate

Topics: Adenocarcinoma, Mucinous; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukopenia; Lymphatic Metastasis; Mastectomy; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Thrombocytopenia

Chemotherapy once relegated to end stage patients has markedly improved with the use of combinations. Response rates with single agents have improved from 15 to 35%, to 50 to 70%, using combinations with an increase in complete response rates to about 25%. A series of four studies completed by the Eastern Cooperative Oncology Group over the past eight years typifies the improvement in response rates achieved by combinations as compared to single agents. Survival gain can be demonstrated for responders vs non-responders; however with current combinations, there is an apparent plateau in response rates (55 to 60%), durations of response (eight months) and survival for responders (18-22 months) as compared to survival of non-responders (six to eight months). Further improvement in response rates may occur by searching for new agents, combining hormonal and immunostimulation with chemotherapy or by sequencing non-crossresistant combinations. However, since most patients with breast cancer present with local or regional disease but go on to die of disseminated cancer, major improvements in survival are most likely to occur by treating this neoplasm as a systemic disease through cobmining effective local therapy with systemic treatments.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Estrogens, Conjugated (USP); Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Vincristine

Topics: Adult; Aged; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Survival; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Recurrence; Research Design

A randomized trial of Adriamycin (A) in combination with melphalan (M), (MA therapy), and in combination with M plus cyclophosphamide (C) (MAC therapy), was initiated in 40 evaluable patients with metastatic breast cancer. Twenty-two patients demonstrated an objective response to therapy: 9/20 to the MA regimen, and 13/20 to the MAC regimen. For the 22 responders, median duration of response is not yet achieved for either complete or partial responders, at 10 and 9 months, respectively. The addition of the two alkylating agents to Adriamycin was superior to the single alkylating agent addition, both in total response rate and in completeness of response. Maintenance therapy, after achieving the maximum cumulative dose of Adriamycin, was provided by cyclophosphamide plus methotrexate and 5-fluorouracil (CMF). In 19 patients completing induction and entering maintenance therapy, only one relapse has developed with maximun follow-up at 15 months.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Skin Neoplasms; Time Factors

Topics: Adult; Breast Neoplasms; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Lymphatic Metastasis; Melphalan; Middle Aged; Postoperative Care

A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy.

Topics: Adult; Aged; Antineoplastic Agents; Boston; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prospective Studies

Topics: Breast Neoplasms; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Lymph Node Excision; Mastectomy; Melphalan; Placebos; Thiotepa

Prolonged l-phenylalanine mustard (L-PAM) administration as an adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically positive axillary nodes was evaluated by a prospective, randomized, clinical trial. Treatment failures occurred in 22 per cent of 108 patients receiving placebo and 9.7 per cent of 103 women given L-PAM (p = 0.01). A statistically significant difference (p = 0.02) existed in favor of L-PAM relative to disease-free interval. In premenopausal women, the difference with respect to disease-free interval of treated and control groups was highly significant (p = 0.008). A treatment failure occurred in 30 per cent of premenopausal patients receiving placebo and 3 per cent of those treated with L-PAM (p = 0.008). Whereas a similar trend was observed in postmenopausal patients, the difference is not statistically significant. Thus, L-PAM has been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those who are premenopausal. Results were achieved with minimal undesirable side effects.

Topics: Bone Marrow; Bone Marrow Cells; Breast Neoplasms; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Lymph Nodes; Melphalan; Menopause; Middle Aged

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.

Topics: Adult; Body Temperature; Breast Neoplasms; Child; Colonic Neoplasms; Cyclophosphamide; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hyperthermia, Induced; Injections, Intravenous; Male; Melphalan; Neoplasms; Time Factors; Vincristine

Topics: Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Vincristine

Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages of carcinogenesis, including tumor initiation, promotion, and progression. Spices have been used for thousands of years and have many bioactive compounds with chemopreventive and chemotherapeutic properties. Curcumin has a multitude of beneficial biological properties, including anti-inflammatory and anticancer effects. This study investigated the effects of cotreatment with curcumin and the chemotherapeutic drug melphalan in cultured MDA-MB-231 breast cancer cells. When used alone, both curcumin and melphalan had a cytotoxic effect on breast cancer cells. Combined treatment with 11.65 µM of curcumin and 93.95 µM of melphalan (CURC/MEL) reduced cell viability by 28.64% and 72.43% after 24 h and 48 h, respectively. CURC/MEL reduced the number of colony-forming units and increased ROS levels by 1.36-fold. CURC/MEL alter cell cycle progression, induce apoptosis, and upregulate caspases-3, -7, and -9, in MDA-MB-231 cells. Cotreatment with curcumin and melphalan have anti-breast cancer cells effects and represent a promising candidate for clinical testing.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Curcumin; Female; Humans; Melphalan

Recently we developed a scalable scheme of synthesis of melphalan ester conjugate with 1,2-dioleoyl-. Herein we compared this new convenient in use formulation of MlphDG with parent drug Alkeran. Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion and lyophilized. Alkeran. Liposomes showed approximately two times lower acute toxicity and better tolerability than Alkeran. Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan therapy could be extended.

Topics: Animals; Antineoplastic Agents; Behavior, Animal; Breast Neoplasms; Cell Proliferation; Diglycerides; Dose-Response Relationship, Drug; Drug Compounding; Drug Screening Assays, Antitumor; Female; Liposomes; Male; Melphalan; Mice; Mice, Inbred C57BL; Molecular Structure; Prodrugs; Rats; Structure-Activity Relationship

Melphalan flufenamide (hereinafter referred to as "melflufen") is a peptide-conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal-derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA-MB231. The tumorigenic D492HER2 and MDA-MB231 cells were more sensitive than normal-derived D492 cells when treated with melflufen. Compared to the commonly used anti-cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA-MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13

Topics: Animals; Antineoplastic Agents, Alkylating; Breast Neoplasms; CD13 Antigens; Cell Line, Tumor; Chick Embryo; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; DNA Damage; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Leucyl Aminopeptidase; Melphalan; Phenylalanine; Signal Transduction; Tumor Suppressor p53-Binding Protein 1

Hepatic arterial infusion chemotherapy (HAIC) is an option for patients with liver-predominant metastatic breast cancer (LMBC), when no further systemic treatment is available. But systematic reports are limited. Here we conducted a retrospective analysis of LMBC patients treated at an expert center.. Individual patient data were retrieved from the clinical data base of the West German Cancer Center. Primary endpoints included hepatic response (RECIST), progression-free survival (PFS), overall survival (OS), and toxicity. A score based on LDH, AST, ALT and bilirubine was developed to estimate the hepatic metastasis load.. Data from 70 consecutive patients were included. All patients were heavily pretreated (median 7 treatment lines for LMBC). HAIC protocols included mitomycin/5-FU (70%), mitomycin (14.3%), melphalan (12.9%) and 5-FU (7.1%), with selection based on patient characteristics. Partial hepatic remission was obtained as best response in 14 patients (20.0%), stable disease in 27 patients (38.6%), and progressive disease in 29 patients (41.4%). Median PFS and OS from initiation of HAIC were 2 (range 0-10) and 7 months (range 1-37). Mainly hepatic and hematopoietic HAIC-related toxicities were observed; there was no treatment-related death. The hepatic metastasis score effectively separated two prognostic groups: Patients with a score <3 had significantly superior PFS (15 vs 7 weeks, p = 0.017) and OS (12 vs 5 months, p = 0.002).. HAIC offers a safe and effective salvage treatment strategy in heavily pretreated patients with LMBC and no further treatment options. The hepatic metastasis score may help to identify patients with sustained clinical benefit.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Melphalan; Middle Aged; Mitomycin; Retrospective Studies; Salvage Therapy

Studies evaluating chemotherapy high dose chemotherapy with autologous haematopoietic stem cell transplantation (HDC-ACSH) in the treatment of metastatic (MBC), locally advanced (LABC) and inflammatory (IBC) breast cancer have in common lack of biomarker information, in particular the HER2 status.. All consecutive female patients treated for breast cancer with HDC and AHSCT at Institut Paoli Calmettes between 2003 and 2012 were included. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: luminal, (HR+/HER2-), HER2 (HER2+, any HR) and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the IHC subtypes.. Three hundred and seventy-seven patients were included. For MBC, the TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI 11.76-44.4) compared to 44.64 months (95 % CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (P<0.01). For IBC, HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89 % (95 % CI 64-97) compared to 57 % (95 % CI 33-76) for the TN subgroup (HR 5.38, 95 % CI 1.14-25.44; P=0.034). For CSLA, luminal subgroup appeared to have the best prognosis with a 5-year OS of 92 % (95 % CI 71-98) against 75 % (95 % CI 46-90) for HER 2 subtype and 70 % (95 %CI 97-88) for TN subtype (P=0.301).. The HDC-ACSH does not change the prognosis value of IHC subtype in breast cancer patients.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autografts; Breast Neoplasms; Cancer Care Facilities; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Female; Genes, BRCA1; Genes, BRCA2; Genes, erbB-2; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Mitoxantrone; Prognosis; Retrospective Studies; Thiotepa

In this study, we have used melphalan (ML) as a model drug, used extensively for the treatment of breast cancer. Due to its remarkable haemolytic activity, clinical application of this drug is limited.. We incorporated the two synthesized PEGylated melphalan conjugates, viz. MLPEG 2000 and MLPEG 5000, separately into the medium molecular weight chitosan (CS)-based smart thermoreversible in-situ forming injectable hydrogel. Prepared hydrogels were evaluated for gelation time, rheological behaviour, drug release and stability.. Although PEGylated melphalan shows significant increase in aqueous solubility and decrease in haemolytic activity, it was loaded to hydrogel to improve dose frequency and local effect. Hydrogel comprising CS (3.22%, w/v) and glycerophosphate disodium salt (GP) (16%, w/v) showed consistent gelation time and retard the release of drug without compromising its stability. To underline the role of GP, conjugates were loaded into CS solution with and without the GP. Remarkably, absence of GP results in rapid initial burst with nearly complete drug release within 50 h, while addition of GP exhibited drug release up to 100 h.. Thus, this study highlighted the role of CS/GP thermoreversible injectable hydrogel for successful loading of PEGylated melphalan.

Topics: Antineoplastic Agents, Alkylating; Breast Neoplasms; Chemistry, Pharmaceutical; Chitosan; Delayed-Action Preparations; Glycerophosphates; Hemolysis; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Hydrogels; Injections; Melphalan; Rheology; Solubility; Temperature

Topics: Adult; Breast Neoplasms; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Immunoglobulin G; Lung Neoplasms; Melphalan; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Skin Neoplasms

Radiolabeled tyrosine analogues that have been successfully used in tumor imaging accumulate in tumor cells via an upregulated L-type amino acid transporter system. The anticancer drug melphalan is an L-type amino acid transporter substrate. Therefore, radiolabeled tyrosine analogues may have great potential in evaluating treatment responses to melphalan. In this study, a (99m)Tc-labeled tyrosine analogue, (99m)Tc tyrosine using N,N'-ethylene-di-L-cysteine (EC) as a chelator, was developed and its potential for noninvasively assessing tumors' early response to melphalan determined.. EC-tyrosine was synthesized in a three-step procedure and labeled with (99m)Tc. To assess cellular uptake kinetics, the percentage uptake of (99m)Tc-EC-tyrosine in the rat breast cancer cell line 13762 was measured. Planar imaging was performed in rats with 13762 cell-derived tumors. To determine the transport mechanisms of (99m)Tc-EC-tyrosine, a competitive inhibition study using L-tyrosine as an inhibitor was performed in vitro and in vivo. To assess tumors' response to melphalan, tumor-bearing rats were treated with different doses of melphalan, and planar imaging was performed 0 and 3 days after treatment. Immunohistochemical analyses were conducted to determine expressions of L-type amino acid transporter 1 and cellular proliferation marker Ki-67.. L-tyrosine significantly inhibited (99m)Tc-EC-tyrosine uptake in vitro and in vivo. Tumor volume decreased in a dose-dependent manner with melphalan, and tumor/muscle ratios of (99m)Tc-EC-tyrosine were significantly reduced in treated groups. Immunohistochemical data indicated that about 70% of tumor cells in the melphalan-treated groups underwent apoptosis, and the changes in tumor/muscle ratios reflected the decreased percentage of viable cells in treated tumors.. These findings suggest that (99m)Tc-EC-tyrosine has great potential for monitoring tumor response to melphalan in breast tumor-bearing rats.

Topics: Amino Acid Transport System y+L; Animals; Breast Neoplasms; Chelating Agents; Cysteine; Dose-Response Relationship, Drug; Female; Immunohistochemistry; Ki-67 Antigen; Melphalan; Neoplasm Proteins; Organotechnetium Compounds; Radionuclide Imaging; Rats; Rats, Inbred F344; Tissue Distribution; Treatment Outcome; Tyrosine

Melphalan (MEL) is a chemotherapeutic agent used in breast cancer therapy; however, MEL's side effects limit its clinical applications. In the last 20 years, resveratrol (RSV), a polyphenol found in grape skins, has been proposed to reduce the risk of cancer development. The aim of this study was to investigate whether RSV would be able to enhance the antitumor effects of MEL in MCF-7 and MDA-MB-231 cells. RSV potentiated the cytotoxic effects of MEL in human breast cancer cells. This finding was related to the ability of RSV to sensitize MCF-7 cells to MEL-induced apoptosis. The sensitization by RSV involved the enhancement of p53 levels, the decrease of procaspase 8 and the activation of caspases 7 and 9. Another proposed mechanism for the chemosensitization effect of MCF-7 cells to MEL by RSV was the cell cycle arrest in the S phase. The treatment with RSV or MEL increased the levels of p-Chk2. The increase became pronounced in the combined treatments of the compounds. The expression of cyclin A was decreased by treatment with RSV and by the combination of RSV with MEL. While the levels of cyclin dependent kinase 2 (CDK2) remained unchanged by treatments, its active form (Thr(160) -phosphorylated CDK2) was decreased by treatment with RSV and by the combination of RSV with MEL. The activity of CDK7, kinase that phosphorylates CDK2 at Thr(160), was inhibited by RSV and by the combination of RSV with MEL. These results indicate that RSV could be used as an adjuvant agent during breast cancer therapy with MEL.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Female; Humans; Immunoprecipitation; Melphalan; Resveratrol; Stilbenes

The role of post-therapeutic follow-up for breast cancer patients (pts) is open to debate. The aim of this study was to identify prognostic factors associated with the type of first event.. Data of 2,820 pts included in three adjuvant trials for node-positive breast cancer were used. Competing risk methodology was used to identify prognostic factors associated with time to first failure according to type of event.. After a median follow-up of 53 months, 732 pts had disease-related events (114 locoregional, 58 contralateral, and 560 distant metastasis). The prognostic factors associated with high locoregional recurrence were young age, number of positive lymph nodes and grade III. In multivariate analysis, the type of first event influenced post-relapse survival. Nottingham Prognostic Index identified three groups of pts at different risk of relapse.. Early relapse is rare in the first year after surgery and is associated with more aggressive disease. Using the Nottingham Prognostic Index, it is possible to identify pts at lower risks of relapse for whom it seems reasonable to limit the frequency of routine follow-up during the first years. For pts at higher risk of locoregional recurrence, regular follow-up should be maintained in order to detect potential curative events.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Docetaxel; Epirubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Lymph Nodes; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Prognosis; Randomized Controlled Trials as Topic; Taxoids; Treatment Failure

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Boronic Acids; Bortezomib; Breast Neoplasms; Cardiology; Diagnosis, Computer-Assisted; Drug Therapy, Combination; Evidence-Based Medicine; Female; Humans; Mammography; Medical Oncology; Melphalan; Multiple Myeloma; Prednisone; Pyrazines

It has been suggested that system L (LAT1/CD98hc) is up-regulated in cancer cells, including breast tumour cells, and is therefore a promising molecular target to inhibit or limit tumour cell growth. In view of this, we have examined the effect of BCH and other inhibitors of system L on the growth of MCF-7, ZR-75-1 and MDA-MB-231 cells. Treating cells with BCH markedly inhibited the metabolism of WST-1 in a dose-dependent fashion. Similarly, melphalan and D-leucine inhibited the growth of cultured breast cancer cells whereas MeAIB, an inhibitor of system A, was without effect. The effects of BCH and melphalan on cell growth were non-additive suggesting that both compounds were acting at a single locus. The results indicate that system L is required to maintain MCF-7, ZR-75-1 and MDA-MB-231 cell growth and support the notion that LAT1/CD98hc may be a suitable target to inhibit breast cancer progression.

Topics: Amino Acid Transport System L; Amino Acids, Cyclic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Fusion Regulatory Protein 1, Heavy Chain; Humans; Large Neutral Amino Acid-Transporter 1; Leucine; Melphalan

Design, synthesis, and cytotoxic activity of amidine derivatives of melphalan are described and structure-activity relationships are discussed. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 human breast cancer cells demonstrated that these compounds were more active than melphalan. Data from the ethidium displacement assay showed that these compounds were able to bind in the minor groove-binding mode in AT sequences of DNA. The cytotoxic properties of the amidine analogues of melphalan towards cultured human breast cancer cells correlate with topoisomerase II inhibitory properties but not with DNA-binding properties.

Topics: Amidines; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA; Drug Screening Assays, Antitumor; Ethidium; Humans; Inhibitory Concentration 50; Melphalan; Structure-Activity Relationship; Thymidine; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.

Topics: Amidines; Animals; Antineoplastic Agents, Alkylating; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Collagen; Dipeptidases; Distamycins; DNA Topoisomerases, Type I; DNA, Superhelical; Dose-Response Relationship, Drug; Humans; Integrin beta1; Melphalan; Molecular Structure; Netropsin; Receptor, IGF Type 1; Thymidine; Topoisomerase I Inhibitors

The present paper proposes to employ the cultured tumor cells of the breast and chick fibroblasts after long-term cultivation (for above 24 days) to determine their individual drug sensitivity and, as a criterion of cell damage, to use the percent of destruction of the cell layer formed in the wells 24 hours after drug insertion. It also presents the comparative results of tests of 2 cellular models that have been used to determine the in vitro sensitivity of the cells of breast cancer and chick fibroblasts to melfalan and its complex compound with copper acetylacetonate - MOK*M. At the same time, the cytotoxic activity of MOK*M and melfalan against tumor cells has been not shown to differ greatly (16.02+/-1.85 and 15.71+/-0.65% cell layer destruction, respectively), but the same activity of MOK*M against the model of intact cells (chick fibroblasts) was much less (15.23+/-1.97%) than that of melfalan (95.39+/-1.11%). The test system proposed by the authors is of certain informative value and it may be used for the determination of the individual sensitivity of tumor cells to antitumor drugs.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Cells, Cultured; Chick Embryo; Copper; Drug Screening Assays, Antitumor; Female; Fibroblasts; Humans; Melphalan; Organometallic Compounds; Tumor Cells, Cultured

Eukaryotic cells respond to DNA damage by activation of DNA repair, cell cycle arrest, and apoptosis. Several reports suggest that such responses may be coordinated by communication between damage repair proteins and proteins signaling other cellular responses. The Rad51-guided homologous recombination repair system plays an important role in the recognition and repair of DNA interstrand crosslinks (ICLs), and cells deficient in this repair pathway become hypersensitive to ICL-inducing agents such as cisplatin and melphalan. We investigated the possible role of the Rad51-paralog protein Xrcc3 in drug resistance. Xrcc3 overexpression in MCF-7 cells resulted in 1) a 2- to 6-fold resistance to cisplatin/melphalan, 2) a 2-fold increase in drug-induced Rad51 foci, 3) an increased cisplatin-induced S-phase arrest, 4) decreased cisplatin-induced apoptosis, and 5) increased cisplatin-induced DNA synthesis arrest. Interestingly, Xrcc3 overexpression did not alter the doubling time or cell cycle progression in the absence of DNA damage. Furthermore, Xrcc3 overexpression is associated with increased Rad51C protein levels consistent with the known interaction of these two proteins. Our results demonstrate that Xrcc3 is an important factor in DNA cross-linking drug resistance in human tumor cells and suggest that the response of the homologous recombinational repair machinery and cell cycle checkpoints to DNA cross-linking agents is intertwined.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cisplatin; DNA Repair; DNA-Binding Proteins; DNA, Neoplasm; Drug Resistance, Neoplasm; Female; Flow Cytometry; Genes, p53; Humans; Melphalan; Rad51 Recombinase; Receptor Cross-Talk; Recombinant Proteins; S Phase; Sister Chromatid Exchange

The microenvironment within solid tumors is slightly acidic, and manipulation of this extracellular acidity to cause intracellular acidification might be used to increase selective antitumor effects of some anticancer drugs. Potential mechanisms include inhibition of repair of DNA damage and inhibition of repopulation of tumor cells between successive courses of chemotherapy. Here, we evaluate the influence of extracellular pH (pHe) and of two agents that lead to intracellular acidification (cariporide and S3705) on toxicity of melphalan for two human breast cancer cell lines (MDA-MB231 and MCF7). Both the total number and number of colony-forming cells were evaluated during and after three sequential weekly drug treatments. Our results indicate the following: (a) Slow or absent repopulation after the first course of treatment that is influenced minimally by pHe. (b) Rapid repopulation after the second course of treatment that may be inhibited at low pHe. (c) Effects of low pHe following treatment with melphalan to increase cell kill. (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan. Although these results add to evidence that manipulation of intracellular pH within the acidic environment of solid tumors can influence the effects of chemotherapy, they are too small and inconsistent to warrant clinical evaluation.

Topics: Antineoplastic Agents, Alkylating; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chloride-Bicarbonate Antiporters; Culture Media; Guanidines; Humans; Hydrogen-Ion Concentration; Intracellular Fluid; Melphalan; Sodium-Hydrogen Exchangers; Sulfones; Time Factors

The transport of L-leucine by two human breast cancer cell lines has been examined. L-leucine uptake by MDA-MB-231 and MCF-7 cells was via a BCH-sensitive, Na+ -independent pathway. L-leucine uptake by both cell lines was inhibited by L-alanine, D-leucine and to a lesser extent by L-lysine but not by L-proline. Estrogen (17beta-estradiol) stimulated L-leucine uptake by MCF-7 but not by MDA-MB-231 cells. L-leucine efflux from MDA-MB-231 and MCF-7 cells was trans-stimulated by BCH in a dose-dependent fashion. The effect of external BCH on L-leucine efflux from both cell types was almost abolished by reducing the temperature from 37 to 4 degrees C. There was, however, a significant efflux of L-leucine under zero-trans conditions which was also temperature-sensitive. L-glutamine, L-leucine, D-leucine, L-alanine, AIB and L-lysine all trans-stimulated L-leucine release from MDA-MB-231 and MCF-7 cells. In contrast, D-alanine and L-proline had little or no effect. The anti-cancer agent melphalan inhibited L-leucine uptake by MDA-MB-231 cells but had no effect on L-leucine efflux. Quantitative real-time PCR revealed that LAT1 mRNA was approximately 200 times more abundant than LAT2 mRNA in MCF-7 cells and confirmed that MDA-MB-231 cells express LAT1 but not LAT2 mRNA. LAT1 mRNA levels were higher in MCF-7 cells than in MDA-MB-231 cells. Furthermore, LAT1 mRNA was more abundant than CD98hc mRNA in both MDA-MB-231 and MCF-7 cells. The results suggest that system L is the major transporter for L-leucine in both MDA-MB-231 and MCF-7 cells. It is possible that LAT1 may be the major molecular correlate of system L in both cell types. However, not all of the properties of system L reflected those of LAT1/LAT2/CD98hc.

Topics: Amino Acid Transport System y+; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Estrogens; Fusion Regulatory Protein 1, Light Chains; Fusion Regulatory Protein-1; Humans; Kinetics; Large Neutral Amino Acid-Transporter 1; Leucine; Melphalan

Increasing the drug concentration in tumors may produce massive tumoral response. By using a variety of hepatic vascular isolation techniques, high concentrations of chemotherapeutic drugs may be achieved in the hepatic vascular bed.. Complete percutaneous isolated hepatic perfusion (IHP) is feasible and safe.. Case series.. The hepatobiliary unit of a university hospital.. Ten patients with irresectable and chemoresistant hepatic tumors were eligible for study participation; 4 patients with hepatic metastases of breast cancer, gastric cancer, colorectal cancer, and cholangiocarcinoma were included.. Patients received 3 successive courses of chemotherapy by IHP. The first course was given at laparotomy, and the next 2 courses were given percutaneously. The interval between courses was 3 to 6 weeks. Each course involved IHP of the liver for 15 to 30 minutes, without oxygenation, with 1 to 3 boluses of melphalan (15 mg).. Morbidity and mortality.. Ten IHPs were performed (4 at laparotomy and 6 percutaneously). Concentrations of melphalan in the extracorporeal circulation were 10 times higher than those in the systemic circulation. Percutaneous IHPs had more leakage than those at laparotomy. However, hepatotoxicity was minimized. One patient experienced hepatic artery thrombosis, and 3 had severe neutropenia. Minor complications included ascites and pleural effusion. No deaths were observed 2 months after the last IHP. One partial response was observed (hepatic metastases of breast cancer).. Percutaneous IHP for intensive chemotherapy is less aggressive and less hepatotoxic than IHP at laparotomy and may be iterative.

Topics: Adenocarcinoma; Antineoplastic Agents; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cholangiocarcinoma; Colorectal Neoplasms; Fatal Outcome; Female; Humans; Laparotomy; Liver Neoplasms; Male; Melphalan; Middle Aged; Radiography, Interventional; Stomach Neoplasms

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Daunorubicin; Deoxycytidine; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Epirubicin; Female; Humans; Idarubicin; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Remission Induction; Taxoids; Thiotepa; Time Factors; Transplantation Conditioning; Treatment Outcome

This study was conducted to evaluate the efficacy of high-dose thiotepa, melphalan and carboplatin (TMCb) regimen in 27 patients undergoing autologous stem cell transplantation (ASCT) for metastatic breast cancer. A total of 27 patients with stage IV breast cancer underwent ASCT following thiotepa (500 mg/m(2)), melphalan (100 mg/m(2)) and carboplatin (1200-1350 mg/m(2)). Of 27 patients, 17 had refractory relapse, eight had responding relapse, and two had no evidence of disease (NED) at the time of transplant. In all, 11 patients had only bone disease, nine had bone plus visceral disease, three had only visceral disease, and two had locoregional recurrent disease. The median time from diagnosis to transplant was 1081 days (range 180-2341). Staging for evaluation of response was performed 4-6 months after transplantation. Five patients were not evaluable (NE) for response because of NED at transplant (n=2) or early death due to transplant-related complications (n=3) (two of viral pneumonia and one of regimen-related toxicity) occurring at a median of 4 days (range 11-46) post-transplant. One of the two patients who was NED at the time of transplant is still NED on day 760 post-transplant. Seven of 15 refractory (47%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft-tissue disease with at least improvement in bone lesions. Of 27 patients (37%),(10) are alive and progression-free, a median of 582 days (range 410-1380) after treatment, 6/17 (35%) with refractory disease and 4/10 (40%) with responsive disease. The probability of progression-free survival (PFS) for all patients was 0.50. The probabilities of PFS at 2 years for patients with refractory (n=17) and responsive (n=10) disease were 0.42 and 0.60, respectively. PFS at 2 years for the 14 patients who were NED or achieved CR/PR(*) following-HDC was 0.67. PFS at 2 years for patients who did not achieve CR/PR(*) following-DHC was 0.33. These preliminary data suggest that high-dose TMCb followed by autologous stem cell transplantation is an effective regimen for patients with advanced breast cancer and may be comparable to some previously used regimens.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Disease-Free Survival; Female; Graft Survival; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Thiotepa; Transplantation, Autologous; Treatment Outcome

Proline analogue of melphalan (Mel-pro) was synthesized as a prodrug susceptible to the action of ubiquitously distributed, cytosolic imidodipeptidase-prolidase [E.C.3.4.13.9]. Conjugation of melphalan (Mel) with proline (Pro) through imido-bond resulted in formation of a good substrate for prolidase. Cytosolic location of prolidase in neoplastic cell suggests that proline analogue of melphalan (Mel-pro) may serve as a prolidase convertible prodrug. We have compared several aspects of pharmacologic actions of Mel and Mel-pro in estrogen-independent breast cancer MDA-MB 231 cells. It has been found that Mel-pro is more effectively transported into the MDA-MB 231 cells, evokes higher cytotoxicity, similar inhibitory effect on DNA synthesis, lower inhibitory effect on collagen biosynthesis and reduces IGF-I receptor and MAPkinase expression in MDA-MB 231 cells, compared to Mel. The results suggest that targeting of prolidase as a Mel-pro-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dipeptidases; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Melphalan; Prodrugs; Proline

Complications of bone destruction occur in 10-29% of breast cancer patients with skeletal metastases. Palliative treatment consists of systemic chemotherapy, hormonal treatment, radiotherapy, and/or surgery in the case of (impending) fracture. A case is presented where isolated limb perfusion was applied for this indication.. A 43-year-old woman with extensive femoral metastases of breast cancer with impending fracture was treated with isolated limb perfusion (ILP) with melphalan. Radiotherapy had resulted only in pain reduction, and intramedullary fixation was opted against because stable fixation was considered not feasible due to the location of the metastases. ILP with high-dose melphalan (10-20 times the amount that can be administered systemically) under normothermic (37-38 degrees C) conditions, resulted in partial remission and reossification.. One year after ILP, until her death 2 years later, due to progressive metastases at other sites, the patient was able to bear weight again on her left leg.. In selected patients with symptomatic large bone metastases from breast cancer, and no other treatment options, ILP with melphalan may be used for successful palliation.

Topics: Adult; Antineoplastic Agents, Alkylating; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Drug Administration Schedule; Extremities; Female; Femoral Neoplasms; Fractures, Spontaneous; Humans; Melphalan; Palliative Care

Infectious complications were retrospectively analyzed in 129 transplants, performed in 90 patients, to identify characteristics that qualify breast cancer patients for outpatient-based PBSCT. Thirty-one cases (24%) did not develop fever. Of the remaining 98 cases, 84.7% developed fever during severe neutropenia. On univariate analysis, disease stages II-III, first PBSCT, mucositis grades II-IV and the use of two alkylators were associated with a higher risk of fever development. The latter two factors also affected fever occurrence on multivariate analysis. A longer median time to fever onset was observed in patients conditioned with single as compared to double alkylating agent-containing regimens (respectively 8th vs 6th day, P < 0.00001). As compared with metastatic breast cancer (MBC), high risk breast cancer showed a 2.3-fold increased risk of developing early fever during neutropenia (CI 2.3-3.8), remaining the only variable still significant on multivariate analysis (P = 0.0039). Combination antibiotic therapy was equivalent to single agent therapy. Patients suffering from microbiologically documented fever were at higher risk of undergoing second-line antibiotic therapy. In conclusion, MBC patients treated with a conditioning regimen containing only one alkylating agent and adequate prophylaxis for mucositis may qualify for outpatient-based PBSCT on the basis of a lower risk of infection.

Topics: Adult; Aged; Ambulatory Care; Anti-Bacterial Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Docetaxel; Drug Therapy, Combination; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infection Control; Infections; Inflammation; Melphalan; Middle Aged; Mitoxantrone; Mucous Membrane; Multivariate Analysis; Neutropenia; Paclitaxel; Patient Selection; Retrospective Studies; Risk; Taxoids; Thiotepa; Transplantation Conditioning

Prolidase [E.C.3.4.13.9] is ubiquitously distributed cytosolic egzopeptidase that is known to cleave imido-bond of some low molecular weight compounds coupled to L-proline. Previously we have found that conjugation of antineoplastic drug--melphalan (Mel) with proline (pro) through imido-bond resulted in formation of a good substrate for purified prolidase. Cytosolic location of prolidase in neoplastic cells suggests that proline analogue of melphalan (Mel-pro) may serve as a prolidase convertable pro-drug. We have compared several aspects of pharmacologic actions of Mel and Mel-pro in breast cancer MCF-7 cells. It has been found that Mel-pro is more effectively transported into the MCF-7 cells, evokes higher cytotoxicity, lower antimitotic activity and collagen-inhibiting activity, compared to Mel. The results suggest that targeting of prolidase as a pro-drug-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.

Topics: Antineoplastic Agents, Alkylating; Breast Neoplasms; Dipeptidases; Female; Humans; Melphalan; Prodrugs; Proline; Tumor Cells, Cultured

A preliminary analysis of our double high-dose chemotherapy with stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross-resistant studies, suggested that melphalan (M) adversely affected response to subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might affect response. We, therefore, constructed and examined preclinical models to determine whether prior exposure to M, in fact, adversely affected response to other therapy.. The purpose of the study was to determine whether the sequence of AAs, specifically the prior use of M, adversely affected response to subsequent treatment.. The methods employed were the following: (1) Human tumor cell lines rendered resistant by in vitro sequential exposure to five different AAs were developed. The resistant cell lines were examined for cross-resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer. (4) The double transplant model was developed in the mouse and the sequence of high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) studies of the various resistant tumor cell lines.. (1) The in vitro human tumor cells resistant to M were cross-resistant in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to other agents in only 10 to 20% of tests. (2) The in vivo studies of p388 indicated that resistance to M commonly crossed to other AAs and many non-AAs. (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs again indicated that M employed first markedly reduced responsiveness to subsequent treatment, particularly with AAs. (4) The double transplant model: again, M first markedly reduced response to other agents. (5) The in vitro resistant human tumor cell lines, particularly the breast cancer cell line MCF7, were found to contain high concentrations of glutathione S1 transferase gamma, which is consistent with that mechanism being responsible for resistance.. The sequence of alkylating agent treatment may substantially influence response. Melphalan, particularly, produces resistance that commonly crosses to the other AAs. Mechanistic studies indicate significant changes in glutathione S1 transferase, a known mechanism for broadly based resistance to AAs.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Breast Neoplasms; Carmustine; Cell Survival; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Mechlorethamine; Melphalan; Mice; Neoplasms, Experimental; Tumor Cells, Cultured

Multiple-cycle high-dose therapy with autologous hematopoietic progenitor cell (AHPC) support has been used to deliver dose-intensive therapy. We have used this approach as well as single-cycle high-dose therapy in treating patients with metastatic breast cancer. We present the outcomes of multiple-cycle high-dose therapies and compare them with those resulting from single-course high-dose therapies performed at a single institution. Fifty-five patients received 4 cycles of intensive chemotherapy with AHPC support. Three multicycle regimens were sequentially applied. Twenty patients were enrolled to receive 4 cycles of high-dose mitoxantrone, thiotepa, and cyclophosphamide. Nineteen subsequent patients received this regimen modified by the incorporation of paclitaxel. Sixteen patients received 2 cycles of high-dose melphalan, thiotepa, and paclitaxel and 2 cycles of mitoxantrone, thiotepa, and paclitaxel. The results of all 3 multiple-cycle therapies are compared with those of 55 contemporaneous patients with metastatic breast cancer who received a single course of high-dose cyclophosphamide and thiotepa or cyclophosphamide, cisplatin, and BCNU (carmustine) with hematopoietic cell rescue. Multiple-cycle therapy was associated with more infectious complications, increased transfusion requirements, and increased hospital admissions. However, there were no significant differences in outcomes between the groups. For 55 patients who received multiple-cycle therapy, the actuarial 3-year overall survival rate was 36% (95% confidence interval [CI] 23%-49%); freedom from progression and event-free survival were both 15% (CI 5%-25%). The median time to disease progression and median survival were 1.0 and 1.6 years, respectively. For the 55 patients who underwent a single course of high-dose therapy, the 3-year overall survival was also 36% (CI 18%-54%), whereas freedom from progression and event-free survival were both 19% (CI 7%-31%). The median time to progression and median survival were 0.8 and 2.2 years, respectively. Within the constraints of this patient population, the outcomes of 4 cycles of high-dose therapy with AHPC support were not superior to those resulting from single courses of high-dose therapy in the treatment of patients with metastatic breast cancer.

Topics: Adjuvants, Pharmaceutic; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Infections; Melphalan; Middle Aged; Mitoxantrone; Paclitaxel; Survival Rate; Thiotepa; Time Factors; Transplantation, Autologous

The aim of the present study was to evaluate the correlation between the number of CD34+ cells transfused and the duration of hypoplasia, and the relationship between various CD34+ subsets (CD34+/33-; CD34+/38-; CD34+/ HLA-DR-; CD34+/Thy-1+) and engraftment kinetics in a series of patients with breast cancer treated with high doses of thiotepa and melphalan.. We treated 42 consecutive patients: 19 in an adjuvant context (>= 4 positive axillary nodes) and 23 for metastatic disease. A combination of thiotepa 600 mg/m(2) and melphalan 140-160 mg/m(2) was administered as the conditioning regimen. All patients received peripheral blood progenitor cells (PBPC) and growth factors for hematopoietic rescue.. In univariate analysis, we found a significant relationship between the number of CD34+ cells reinfused and the time to hematologic recovery and the duration of hospital stay. We observed an inverse correlation between the number of CD34+ cells reinfused and the units of platelets transfused. Cox multivariate analysis confirmed that the number of CD34+ cells reinfused is the most effective predictor of time to hematologic recovery. CFU-GM resulted to be a better predictor of the duration of hospitalization.. We found a significant relationship between the number of PBPC reinfused and the time to hematologic recovery after high doses of thiotepa and melphalan. In our experience, the numbers of subsets of CD34+ cells infused did not give compared additional information to that provided by the total number of CD34+ cells infused.

Topics: Adult; Analysis of Variance; Antigens, CD34; Breast Neoplasms; Female; Graft Survival; Hospitalization; Humans; Melphalan; Middle Aged; Mouth Mucosa; Platelet Transfusion; Stomatitis; Thiotepa

To determine the effect of glutamine suspension on mucositis associated with the administration of high-dose preparative regimens for bone marrow transplantation.. We performed a retrospective analysis of 21 consecutive patients receiving high-dose paclitaxel and melphalan as the preparative regimen for autologous peripheral blood stem-cell transplantation for metastatic breast cancer between January 1997 and December 1997. Glutamine suspension was given as swish-and-swallow administration every four hours around the clock starting day-7, for a total dose of 24 g/d.. The group given oral glutamine suspension demonstrated significantly fewer days of mucositis and a lower maximum grade of mucositis. The treatment group also had fewer days of parenteral morphine for pain relief. The group that did not receive glutamine required an average of 5.22 days of patient-controlled analgesia (PCA) morphine; the glutamine group did not require PCA morphine. The total days of narcotic pain relief were decreased in the glutamine group; however, this did not reach statistical significance. Qualitatively, the patients in the glutamine group had less oral ulceration and bleeding, and were able to tolerate liquids sooner than those in the nonglutamine group. Patients tolerated the glutamine suspension well.. This study showed that around-the-clock administration of oral glutamine may decrease both the severity and duration of mucositis associated with high-dose bone marrow transplant preparative regimens. The decrease in severity and duration of mucositis translated into reduced parenteral narcotic use. A prospective, randomized, controlled trial is needed to determine future applications of glutamine in the support of patients undergoing high-dose chemotherapy.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Bone Marrow Transplantation; Breast Neoplasms; Gastrointestinal Diseases; Glutamine; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Paclitaxel; Retrospective Studies; Suspensions; Transplantation, Autologous

Quantitative expression of neutrophil CD11b/CD18 following chemotherapy (either conventional dose consolidation chemotherapy or high dose chemotherapy with autologous stem cell transplantation) was investigated during the early recovery phase (neutrophil count 0. 5-1.0x109/l) and at full recovery (neutrophil count 1.0-2.5x109/l) following treatment. CD11b/18 expression was normal in stem cell transplantation supported patients during both early and full neutrophil recovery. By contrast CD11b/CD18 expression was markedly decreased in patients who received chemotherapy without stem cell support. These results suggest that recovery of neutrophil count may not always coincide with recovery of neutrophil function and that G-CSF stimulated peripheral stem cell transplantation enhances neutrophil function post chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; CD18 Antigens; Combined Modality Therapy; Cytarabine; Etoposide; Female; Filgrastim; Gene Expression Regulation, Leukemic; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Macrophage-1 Antigen; Male; Melphalan; Middle Aged; Neoplasm Proteins; Neutropenia; Recombinant Proteins; Remission Induction

Autologous peripheral stem cell transplantation (APSCT) is increasingly used for various hematologic malignancies and solid tumors. The objective of this study was to analyze the immune reconstitution after APSCT and see if there was any correlation with diagnosis, age, type of high-dose therapy, CD34(+) selection of the autograft and double vs single APSCT.. Lymphocyte subset recovery was studied in 46 consecutive patients with hematologic malignancies and breast cancer, who underwent APSCT. Eleven patients with multiple myeloma received tandem autografts. Thirty-one patients were given total body irradiation (TBI) as part of the high-dose treatment. Eighteen patients received a CD34(+) selected graft. The percentage and absolute numbers of lymphocyte populations, T-cells (CD2(+), CD3(+)), B-cells (CD19(+)), NK cells (CD56(+ )CD3(-) and CD16(+)CD3(-)) and T-cell subpopulations (CD4(+), CD8(+), CD4(+)CD45RA(+), CD4(+ )CD45RO(+), CD4(+)DR(+), CD8(+ )CD45RO(+), CD8(+)DR(+)), were monitored with flow cytometry during the first year after APSCT.. The total B-cell (CD19(+)) and T-cell (CD3(+)) counts were reconstituted to normal levels 2-4 months after APSCT. All patients had a low CD4/CD8 ratio during the observation period, related to both a low number of CD4(+) cells and elevated numbers of CD8(+) cells. The low number of CD4(+) cells was due to a persistently low level of naive CD4(+)CD45RA(+) cells. A high proportion of the CD8+ cells displayed a phenotype compatible with activated T-cells (CD8(+)DR(+)) up to 10 months after autografting. The number of NK cells (CD56(+)3(-) or CD16(+)3(-)) reached normal values within one month post-transplant. No single variable, such as diagnoses, age, TBI as part of the high-dose treatment, tandem autografting or CD34(+) selection of the graft, influenced the immune or hematopoietic reconstitution and no correlation with documented infectious complications was found.. Despite heterogeneity of diseases, age, initial treatment and high-dose regimens, lymphocyte subset analysis did not reveal any differences in hematopoietic or immune reconstitution. All patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplant, caused by a persistent increase of CD8(+) lymphocytes and a constant reduction of CD4(+) lymphocytes, making the patients susceptible to infections for a prolonged period of time post-transplant.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carmustine; Cell Lineage; Combined Modality Therapy; Cytarabine; Disease Susceptibility; Female; Graft Survival; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphocyte Count; Lymphocyte Subsets; Lymphopenia; Male; Melphalan; Middle Aged; Podophyllotoxin; Sweden; Transplantation Conditioning; Transplantation, Autologous

The type of regimen used might result in mobilization of phenotypically and functionally different CD34(+) cells. We compared the phenotype of CD34(+) cells in leukapheresis products of three homogeneous groups: I, healthy individuals treated with granulocyte colony-stimulating factor (G-CSF) alone (n = 13); II, patients mobilized with G-CSF following chemotherapy (n = 16); and III, patients mobilized with G-CSF after high-dose chemotherapeutic pretreatment (n = 24). Multiparameter flow cytometry was performed for CD34(+) subpopulation analysis and focused on adhesion molecules, differentiation markers and megakaryocytic markers relevant for stem cell homing, with special reference to the importance of L-selectin expression. Regimens I and II led to higher numbers of mobilized CD34(+) cells (mean 468 x 10(6) and 491 x 10(6) CD34(+) cells per leukapheresis procedure respectively) than regimen III (mean 41 x 10(6) CD34(+) cells per leukapheresis procedure). Both the expression of L-selectin and CD54 on CD34(+) cells was significantly lower in group III, as was the percentage of megakaryocytic (CD41(+)) progenitors. A higher percentage of primitive (CD38(-) and/or HLA(-)DR(-)) CD34(+) cells was found in group III, correlating with a higher clonogenicity of the CD34(+) cells. However, when comparing the CD34(+)_ subpopulations that were also positive for L-selectin, there was no significant difference between the three regimens. A similar approach for the megakaryocytic CD34+ population resulted in an even worse quality of regimen III: 5.1% of CD34(+) being CD41(+)/L-selectin(+) compared with 9.2% and 8.9% in regimens I and II respectively. We concluded that the phenotypes of the CD34(+) cells in the G-CSF (group I) and G-CSF-chemotherapy (group II) regimens are similar, whereas the phenotype of the CD34(+) cells mobilized in the high-dose regimen (group III) displayed features that might negatively influence homing of the cells. Future studies will be directed towards regimens that will lead to the mobilization of a higher amount of CD34(+) cells with a phenotypically favourable phenotype.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Filgrastim; Flow Cytometry; Fluorouracil; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Immunophenotyping; Intercellular Adhesion Molecule-1; L-Selectin; Leukapheresis; Megakaryocytes; Melphalan; Multiple Myeloma; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Stem Cells; Vincristine

Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Caspase 3; Caspases; Doxorubicin; Enzyme Activation; Fluorouracil; Glutathione Transferase; Humans; Melphalan; Membrane Glycoproteins; Paclitaxel; Recombinant Fusion Proteins; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dexamethasone; Doxorubicin; Fatal Outcome; Female; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Melphalan; Middle Aged; Multiple Myeloma; Myasthenia Gravis; Prednisone; Radiography; Vincristine

Twenty-six patients with breast cancer who had relapsed after previously receiving high-dose chemotherapy and autologous hematopoietic cell support received a second course of high-dose cytoreductive therapy and autologous hematopoietic cell support as salvage therapy. Several different high-dose therapy regimens were employed for the second transplant, including a radiolabeled immunoconjugate. Two patients died of treatment-related complications. The remaining 24 patients relapsed a median of 126 (range 22-635) days after salvage transplant. All have since died. The median survival after salvage transplant was 362 (range 31-931) days. We conclude that second courses of high-dose therapy as salvage treatment are generally well-tolerated but their efficacy is modest. Alternative treatment strategies are needed for these patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Life Tables; Melphalan; Middle Aged; Neoplasm Metastasis; Paclitaxel; Salvage Therapy; Survival Analysis; Treatment Outcome

The purpose of this study was to determine the effectiveness of second mobilization strategies in patients who yielded < 2.5 x 10(6) CD34+ PBSC/kg after initial mobilization. Repeat mobilization attempts were made with chemotherapy and G-CSF (n = 61) or G-CSF alone (n = 58) in patients who failed initial mobilization with chemotherapy and G-CSF (n = 92) or G-CSF alone (n = 27). A median of 0.27 x 10(6) CD34+ cells/kg per apheresis was collected after the second mobilization, compared with 0.16 with initial harvests (p = 0.0001). Forty-eight percent achieved a target CD34+ cell dose > or = 2.5 x 10(6)/kg when harvests from the first and second mobilizations were combined. Fifteen of 17 patients (88%) with > or = 1.5 x 10(6) CD34+ cells/kg harvested after first mobilization had > or = 2.5 x 10(6) CD34+ cells/kg collected when first and second harvests were combined, as compared with 42 of 102 (41%) achieving < 1.5 x 10(6) CD34+ cells/kg with first PBSC harvests (p = 0.0001). Second mobilizations with chemotherapy and G-CSF or G-CSF alone resulted in similar CD34+ cell yields. Toxicities of second mobilizations were comparable with those of first mobilizations. Seventy-nine patients (66%) received high-dose chemotherapy with PBSC support, with recovery of neutrophils and platelets in a median of 11 and 15 days, respectively. Transplant-related mortality was 4%, and event-free survival at 2 years was 0.34. It was concluded that second mobilization attempts in patients who fail to achieve > or = 2.5 x 10(6) CD34+ cells/kg on initial mobilization were successful in 48% of patients. G-CSF alone was as effective as chemotherapy plus G-CSF in mobilizing CD34+ cells and was associated with less morbidity.

Topics: Adult; Antigens, CD; Antigens, CD34; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cytapheresis; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging

L-buthionine-S,R-sulfoximine (L-S,R-BSO) was enriched for the active L-buthionine-S-sulfoximine (L-S-BSO) diastereomer. Comparative analysis was performed to determine if this enriched form possessed an increased capacity to deplete glutathione (GSH), and to inhibit the proliferation of tumor cell lines and fresh human tumor samples. Increased activity was observed for the enriched preparation of L-S-BSO in direct proportion to its increased L-S-diastereomeric percentage. Significant antitumor activity towards melanoma, breast and ovarian carcinoma specimens was noted, with the greatest activity directed against malignant melanoma. The activity of BSO on melanoma specimens was found to be correlated with their melanin content, suggesting that free radicals generated during melanin synthesis may become cytotoxic after GSH-dependent scavenging has been eliminated by BSO treatment. The antimelanoma activity of melphalan and BCNU were found to be significantly enhanced in combination with L-S-BSO. With respect to the mechanism of L-S-BSO synergy with alkylators, L-S-BSO treatment of M14 and ZAZ human melanoma cell lines resulted in decreased GSH levels and glutathione S-transferase (GST) activity. Western and Northern blot analyses indicated that GST-mu was the predominant isozyme downregulated after L-S-BSO treatment. Both M14 and ZAZ cell lines selected for resistance to L-S-BSO also showed decreased levels of GST-mu expression. However, in drug free media GST enzyme activity returned to pre-treatment levels without altering the BSO-resistance status of the cell lines. We conclude that L-S-BSO may be an active agent in the treatment of melanoma, and that it may enhance alkylator activity on melanoma through depletion of GSH and down-regulation of GST expression. Purified L-S-BSO should be explored clinically as an active agent for the treatment of melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Buthionine Sulfoximine; Carmustine; Down-Regulation; Drug Resistance; Enzyme Inhibitors; Female; Glutamate-Cysteine Ligase; Glutathione Transferase; Humans; Melanins; Melanoma; Melphalan; Ovarian Neoplasms; Tumor Cells, Cultured

5-Oxo-L-prolinase (5-OPase) (EC 3.5.2.9) links the synthesis and metabolism of glutathione (GSH) in the gamma-glutamyl cycle. Previous studies showed that L-2-oxothiazolidine-4-carboxylate (OTZ), a 5-oxo-L-proline analog that is metabolized by 5-OPase, can preferentially decrease the cellular GSH levels in vivo in rat mammary tumors and sensitizes the tumors to the alkylating agent melphalan. The present study investigated the biochemical mechanism of this effect in a human breast cancer cell line, MCF7. We found that OTZ decreased the GSH levels in MCF7 cells. When the cells were treated with OTZ plus melphalan, the cytotoxicity of melphalan was increased as compared with that of melphalan alone, and this effect could be reversed by the addition of glutamate, which is the product of 5-OPase reaction and a critical substrate in GSH synthesis. We concluded that OTZ increases melphalan toxicity by limiting glutamate production from 5-OPase for GSH synthesis. We also observed that the expression of 5-OPase in the stably transfected MCF7 cells decreased the cellular GSH contents, sensitized the cells to melphalan toxicity, and diminished the sensitizing effect of OTZ. Furthermore, exposure to the GSH-depleting agent buthionine sulfoximine led to increased expression of 5-OPase in both MCF7 cells and the peripheral blood mononuclear cells of patients. These results indicate a critical interaction between cellular GSH levels and 5-OPase activity that could be important in GSH modulation in therapeutic settings.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Synergism; Glutathione; Humans; Melphalan; Pyroglutamate Hydrolase; Pyrrolidonecarboxylic Acid; Thiazoles; Thiazolidines; Tumor Cells, Cultured

Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal kinase activity via aggregation-mediated activation of tumor necrosis factor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, we demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a major role in mediating the apoptotic effects of UV-irradiation. UV-irradiation and TNF alpha acted in a synergistic manner to induce apoptosis. UV-irradiation stimulated the aggregation-mediated activation of TNFR1 which was coupled with activation of caspase 8, the most proximal caspase in TNF alpha signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at different levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was specific for UV-irradiation since neither CrmA nor the dominant negative FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induced apoptosis. Cisplatin and melphalan, the UV-mimetic agents known to elicit UV-type DNA damage, also induced apoptosis but differed from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these findings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not sufficient to activate the membrane TNFR1. Based on our results we propose that the plasma membrane initiated events play a predominant role in mediating UV-irradiation-induced apoptosis and that UV-irradiation appears to engage the apoptotic axis of TNFR1 and perhaps those of other membrane death receptors to transduce its apoptotic signals.

Topics: Adaptor Proteins, Signal Transducing; Antigens, CD; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Carrier Proteins; Caspase 10; Caspase 8; Caspase 9; Caspases; Cell Membrane; Cisplatin; DNA Damage; DNA Repair; DNA, Neoplasm; Enzyme Activation; Fas-Associated Death Domain Protein; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Melphalan; Mitogen-Activated Protein Kinases; Neoplasm Proteins; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Serpins; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Ultraviolet Rays; Viral Proteins

The use of circulating progenitor cell support following high-dose chemotherapy for malignancies decreases but does not entirely abolish platelet transfusion requirement. We investigated the feasibility of supporting the posttransplant thrombocytopenic phase exclusively with autologous platelets collected by apheresis and cryopreserved.. 25 patients underwent plateletpheresis during the platelet rebound occurring after high-dose cyclophosphamide. Autologous platelets were cryopreserved in 5% dimethylsulfoxide, thawed and transfused during the aplastic phase after the myeloablative regimen whenever clinically required.. A single plateletpheresis was carried out in all patients, allowing the harvest of a platelet concentrate with a mean value of 7.7 x 10(11) platelets. No significant procedure- or transfusion-related side effects were recorded. Mean platelet recovery after freezing and thawing was 63% and the mean number of platelet reinfused was 4.8 x 10(11); 23 of 25 patients were fully supported with autologous platelets.. Plateletpheresis performed in our selected group of patients was found to be a safe and effective procedure to collect large amounts of autologous platelets; the numbers obtained proved to be sufficient for the transfusion demand of almost all patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Blood Preservation; Blood Transfusion, Autologous; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Methotrexate; Platelet Transfusion; Thiotepa; Thrombocytopenia

We studied the efficiency of indirect tumor cell purging via enrichment of CD34+ hematopoietic progenitor cells from leukapheresis products (LP) in breast cancer patients based on immunomagnetic selection of CD34+ cells. Detection of tumor cells was made by immunocytochemical staining. In addition, we evaluated the capacity of cytokeratin 19 (CK19)- and a novel epidermal growth factor receptor (EGF-R)-specific reverse transcriptase-polymerase chain reaction (RT-PCR) for monitoring tumor cell depletion. LP from 13 breast cancer patients were analyzed. Twenty-three CD34 selection procedures were performed. A median of 1.4 x 10(10) total nucleated cells ([TNC] range, 0.88 to 3.5 x 10(10)) with a median CD34 purity of 2.5% (range, 0.4% to 6.3%) were entered into the selection procedure. Immunomagnetic CD34 enrichment resulted in a median purity of 83.3% (range, 45% to 95.4%) and a median recovery of 73.2% (range, 22% to 95%). Retransfusion of CD34-selected cells after high-dose chemotherapy resulted in a rapid and sustained hematologic recovery, reaching an absolute neutrophil count of 500/microL at day +10 and platelet count of 20,000/microL at day +11. Tumor cell depletion was quantified by immunocytochemical detection of CK19-positive cells. By this method, a median tumor cell depletion of 1.9 log (range, 0.7 to > 3 log) could be demonstrated. Immunocytochemical detection of tumor cells was more sensitive than RT-PCR, yielding positive results in 81% of LP (17 to 21) versus 58% positive LP (10 of 17). However, EGF-R-based RT-PCR was much more sensitive than CK19-based RT-PCR (10 of 17 v 1 of 17). Despite highly efficient CD34 selection, tumor cells were still detectable after CD34 enrichment using immunocytochemistry and EGF-R-specific RT-PCR. Thus, this novel EGF-R-specific RT-PCR appears to be of value as an additional method to detect contaminating breast cancer cells within LP.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cisplatin; DNA, Complementary; DNA, Neoplasm; Epirubicin; ErbB Receptors; Etoposide; Evaluation Studies as Topic; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunoenzyme Techniques; Immunomagnetic Separation; Keratins; Leukapheresis; Melphalan; Middle Aged; Neoplasm Proteins; Neoplastic Cells, Circulating; Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transplantation Conditioning

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Topics: Adult; Aged; Arm; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Male; Mastectomy; Melanoma; Melphalan; Middle Aged; Respiratory Function Tests; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Combined Modality Therapy; Drug Resistance; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Prognosis; Survival Rate; Thiotepa; Transplantation, Autologous

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Doxorubicin; Female; Fluorouracil; Humans; Hypoxia; Melphalan; Mitomycin

Abnormalities in the p53 tumor suppressor gene have been shown to affect cellular processes related to cell cycle control and gene amplification. In this study we compare the status and function of wild-type p53 in MCF-7 breast cancer cells with sublines selected for resistance to chemotherapeutic agents having different mechanisms of action. Sublines that were resistant to melphalan, pyrazafurin, mitoxantrone, etoposide and PALA all retained expression of wild-type p53. Methotrexate-resistant MCF-7 cells were unusual heterozygotes that expressed a wild-type and dominant, in-frame p53 deletion mutant and the doxorubicin-resistant cells expressed only mutant p53. Analysis of the G1 checkpoint after treatment with ionizing radiation revealed that the pyrazafurin-, melphalan- and mitoxantrone-resistant cells arrested strongly in G1. The etoposide- and PALA-resistant cells had an intermediate G1 arrest phenotype and the methotrexate- and doxorubicin-resistant cells had a minimal G1 arrest phenotype. mRNA and protein analyses of downstream effector genes, including P21CIP1/Waf1, mdm2, Gadd 45 and the retinoblastoma protein, did not entirely differentiate sublines having a strong versus intermediate G1 arrest phenotype. Neither the p53 status nor the strength of the G1 arrest could be correlated with cell survival after ionizing radiation. When drug-sensitive MCF-7 cells were treated with the same chemotherapeutic agents, p53 and p21CIP1/Waf1 levels increased between 2- and 14-fold. Together these data suggest that other cellular factors likely play a role in overcoming the inhibitory effects of ionizing radiation on p53 in drug-resistant breast cancer cells.

Topics: Amides; Antineoplastic Agents; Aspartic Acid; Blotting, Western; Breast Neoplasms; Cell Cycle; Clone Cells; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Drug Resistance, Neoplasm; Enzyme Inhibitors; Etoposide; Female; Flow Cytometry; Gene Expression; Genes, p53; Humans; Immunohistochemistry; Melphalan; Mitoxantrone; Neoplasm Proteins; Nuclear Proteins; Phosphonoacetic Acid; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Pyrazoles; Ribonucleosides; Ribose; Tumor Cells, Cultured; Tumor Suppressor Protein p53

The cytotoxic activity of bendamustine hydrochloride was evaluated against human ovarian and breast carcinoma cell lines including cell lines resistant to cisplatin and doxorubicin in vitro. The relative degree of resistance to bendamustine hydrochloride was lower in all cell lines compared with cyclophosphamide, melphalan and BCNU, suggesting only incomplete cross-resistance. Furthermore lower levels of resistance were also observed in all breast cancer cell lines when bendamustine hydrochloride was compared with cisplatin. Bendamustine hydrochloride also presents good activity in cell line MCF 7 AD, which is approximately 80-fold resistant to doxorubicin compared with MCF 7. Basic glutathione levels and activity of glutathione-S-transferase showed no correlation to the IC50 values for bendamustine hydrochloride in the cell lines. When given at equitoxic concentrations, bendamustine hydrochloride consistently induced more DNA double-strand breaks than melphalan, cyclophosphamide or BCNU. In addition, removal of DNA double-strand breaks induced by bendamustine hydrochloride was relatively slow with the majority of DNA double-strand breaks still being detectable after 24 h. These findings indicate differences in the interaction between bendamustine hydrochloride and DNA, and may explain the lack of complete cross-resistance between bendamustine hydrochloride and the other alkylating agents.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Breast Neoplasms; Carmustine; Cisplatin; Cyclophosphamide; DNA Damage; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Tumor Cells, Cultured

Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration.. Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support.. Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively.. Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Thiotepa; Transplantation, Autologous

Human breast carcinoma (MCF7-MLNr) cells resistant to the bifunctional drugs L-phenylalanine mustard (L-PAM, 5-fold resistance), mechlorethamine (9-fold), cisplatin (3-fold), and BCNU (3-fold) were used to investigate the role of DNA repair in the development of resistance to alkylating agents. We have previously shown that neither L-PAM transport and metabolism nor glutathione-associated enzymes were altered in MCF7-MLNr cells, compared to the sensitive cells MCF7-WT. This study shows that treatment of pRSV-CAT plasmid with L-PAM at concentrations up to 1 microM proportionally inhibit the expression of chloramphenicol acetyl transferase (CAT) activity, while higher concentrations abolished CAT activity. pRSV-CAT reactivation was significantly increased when plasmid was transfected into MCF7-MLNr cells, compared to MCF7-WT cells. This indicates that resistant cells have more efficient capacity to recognize and repair L-PAM induced DNA damage. The mRNA expression of DNA nucleotide excision repair genes ERCC1, XPD (ERCC2), XPB (ERCC3), and polymerase beta was found to be similar in both the MCF7-WT and MCF7-MLNr cells. Western blot analysis also reveals no difference in the expression of ERCC1, AP endonuclease, poly (ADP-ribose) polymerase, and alkyl-N-purine-DNA glycosylase proteins. The lack of correlation between enhanced host cell reactivation capacity in resistant cells, and the expression of these specific DNA repair genes suggests that proteins encoded by these genes are not rate limiting steps for resistance to bi-functional alkylating drugs in human breast cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents, Alkylating; Blotting, Northern; Blotting, Western; Breast Neoplasms; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Plasmids; Tumor Cells, Cultured

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinogens; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Ethmoid Sinus; Female; Fluorouracil; Follow-Up Studies; Humans; Leiomyosarcoma; Mastectomy, Modified Radical; Melphalan; Methotrexate; Neoplasms, Second Primary; Paranasal Sinus Neoplasms

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Radiation-Induced; Manitoba; Melphalan; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasms, Second Primary; Postoperative Care; Radiotherapy, Adjuvant; Time Factors

We have demonstrated previously decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan (MelR MCF-7). Cross-resistance studies of MelR MCF-7 cells revealed that this cell line was 6.7-fold cross-resistant to methotrexate, but only 2-fold resistant to trimetrexate. Methotrexate transport studies in MelR MCF-7 cells showed a 2-fold decrease in initial methotrexate uptake and a 2-fold decrease in the Vmax for methotrexate uptake in the resistant cells. Methotrexate resistance in MelR MCF-7 cells was also associated with a decrease in non-effluxable methotrexate following incubation with radiolabeled drug for 24 hr. Characterization of intracellular methotrexate after accumulation for 24 hr demonstrated decreased levels of free methotrexate in MelR MCF-7 cells. Analysis of methotrexate polyglutamate formation in MelR MCF-7 cells indicated that the decrease in non-effluxable, non-protein-bound methotrexate was associated with a 3-fold decrease in higher order methotrexate polyglutamate formation. No difference was noted in folylpolyglutamate synthetase activity between the resistant and parental cell lines. Therefore, the observed decrease in methotrexate polyglutamate formation in MelR MCF-7 cells appeared to result from decreased availability of substrate. There was no evidence of any alteration in the amount of the catalytic activity of dihydrofolate reductase in MelR MCF-7 cells compared with parental MCF-7 (WT MCF-7) cells; moreover, the binding affinity of dihydrofolate reductase for methotrexate and the percentage of protein-bound methotrexate were similar in both cell lines. In addition, the total amounts of thymidylate synthase protein and thymidylate synthase catalytic activity in MelR MCF-7 cells were unchanged. Thus, acquired methotrexate resistance in MCF-7 cells selected for resistance to melphalan appears to result from down-regulation of methotrexate uptake.

Topics: Breast Neoplasms; Cell Line; Drug Resistance, Multiple; Humans; Melphalan; Methotrexate; Multienzyme Complexes; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Trimetrexate

Relapse after high-dose alkylating agent therapy continues to be an important clinical issue. To begin to understand the characteristics of cells surviving alkylating agent exposure human MCF-7 breast carcinoma cells were exposed to a range of concentrations of melphalan or cis-diamminedichloroplatinum(II) and cell survival determined by colony formation over a time course of 4 weeks. When antitumor alkylating agent exposure killed 3-4 logs of cells as determined by surviving fraction after 1 week of colony formation a progressive increase in surviving fraction was evident over the 4-week course of the experiment. Many attached single cells with abnormal morphology were evident in these dishes; however, the colonies which arose over the 4-week observation time were made up of cells morphologically indistinguishable from the control cells. Cell cycle patterns in the cultures exposed to high concentrations of the antitumor alkylating agents indicated a block in G2/M but by 4 weeks post-drug exposure most had returned to a normal exponential growth pattern. When MCF-7 cells or human SW2 small cell lung cancer cells were exposed to a concentration of melphalan or cis-diamminedichloroplatinum(II) that killed 1-2 logs of cells followed by exposure to a concentration range of the same drug for 24 h or 7 days later resistance to the second drug exposure was evident in both cell lines. Using [14C]melphalan the uptake of the drug into MCF-7 cells pre-treated was compared. Decreased drug uptake did not appear to be a factor in resistance to melphalan observed upon re-exposure to the drug. The potential clinical implications of these findings is discussed.

Topics: Breast Neoplasms; Cell Cycle; Cell Size; Cell Survival; Cisplatin; Drug Resistance; Humans; In Vitro Techniques; Lung Neoplasms; Melphalan; Time Factors; Tumor Cells, Cultured

Clinical trials combining paclitaxel with other active chemotherapy agents are currently underway. In vitro preclinical studies may assist in the selection of appropriate drug combinations or sequences for clinical investigation. We have used clonogenic cell survival assays and DNA flow cytometry to examine the effect of paclitaxel combined with melphalan, thiotepa, or cisplatin on the survival and cell-cycle parameters of human lung A549 and breast MCF-7 adenocarcinoma cells. A549 and MCF-7 cells were incubated with paclitaxel for 24 h, followed by a 1 h exposure to cisplatin, melphalan, or thiotepa. Both cell types were also incubated with cisplatin or an alkylator for 1 h followed by a 24 h paclitaxel exposure. When the paclitaxel exposure preceded either melphalan, thiotepa, or cisplatin, the cytotoxicity was additive for both cell lines tested. When cisplatin or alkylator exposure was given prior to the paclitaxel, cytotoxicity was also additive in MCF-7 cells. However, cisplatin or alkylators were antagonistic to paclitaxel cytotoxicity when they preceded the paclitaxel exposure in A549 cells (e.g., 2% survival with 100 nM paclitaxel vs. 7% survival with cisplatin and paclitaxel). Cell-cycle analysis revealed that exposure to 100 nM paclitaxel for 24 h blocked a majority of the cells into the G2/M phase (> or = 80% for A549 cells, 60-65% for MCF-7 cells). However, exposure to alkylators before incubation in paclitaxel reduced the proportion of A549 but not MCF-7 cells in G2/M--e.g., exposure to 30 micrograms/ml cisplatin prior to paclitaxel exposure caused only 25% of A549 and 55% of MCF-7 cells to block in G2/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Death; Cisplatin; DNA, Neoplasm; Drug Administration Schedule; Flow Cytometry; Humans; Lung Neoplasms; Melphalan; Paclitaxel; Thiotepa; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Etoposide; Feasibility Studies; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Melphalan; Multiple Myeloma; Neoplasm Metastasis; Retroviridae; Transfection; Transplantation, Autologous; Whole-Body Irradiation

An in vitro model of acquired melphalan resistance was developed by serial incubation of an MCF-7 human breast cancer cell line in increasing concentrations of melphalan. The resulting derivative cell line, Me1R MCF-7, was 30-fold resistant to melphalan. Uptake studies demonstrated decreased initial melphalan accumulation in Me1R MCF-7 cells. Inverse-reciprocal plots of initial melphalan uptake revealed a 4-fold decrease in the apparent Vmax of Me1R MCF-7 compared with WT MCF-7 (516 amol cell-1 min-1 vs 2110 amol cell-1 min-1 respectively) as well as a decrease in the apparent Kt (36 microM vs 70 microM respectively). Two amino acid transporters have previously been identified as melphalan transporters: system L, which is sodium-independent and inhibited by 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH), and system ASC which is sodium dependent and unaffected by BCH. At low concentrations of melphalan (3-30 microM), 1mM BCH competition eliminated the differences between the two cell lines, thus implicating an alteration of the system L transporter in the transport defect in the resistant cells. Me1R MCF-7 cells were also evaluated for glutathione-mediated detoxification mechanisms associated with melphalan resistance. There was no difference between Me1R MCF-7 and WT MCF-7 in glutathione content, glutathione-S-transferase activity and expression of pi class glutathione S-transferase RNA. In addition, buthionine sulfoximine did not reverse melphalan resistance in Me1R MCF-7 cells. Therefore, Me1R MCF-7 cells provide an in vitro model of transport-mediated melphalan resistance in human breast cancer cells.

Topics: Amino Acid Transport Systems; Amino Acids; Amino Acids, Cyclic; Breast Neoplasms; Carrier Proteins; Dose-Response Relationship, Drug; Drug Resistance; Glutathione; Glutathione Transferase; Humans; Melphalan; Time Factors; Tumor Cells, Cultured

In this study we describe the effects of tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites on the toxicity of a range of drugs to human breast and lung cancer and to Chinese hamster ovary cell lines, determined using a tetrazolium-based semi-automated colorimetric assay. Vinblastine resistance was completely abolished in an mdr1-transfected lung cancer cell line (S1/1.1), indicating that P-glycoprotein-mediated multidrug resistance can be fully reversed by anti-oestrogens. A substantial (14- to 39-fold) enhancement of vinblastine toxicity to highly multidrug-resistant (MCF-7Adr) cells expressing P-glycoprotein was also observed in the presence of tamoxifen, toremifene and their metabolites, while m-amsacrine, cisplatin and melphalan toxicity was unaffected.

Topics: Amsacrine; Animals; Breast Neoplasms; Cell Survival; CHO Cells; Cisplatin; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance; Humans; Lung Neoplasms; Melphalan; Tamoxifen; Toremifene; Tumor Cells, Cultured; Vinblastine

Conventionally in vitro cytotoxicity assays are performed as single-end-point determinations. To compensate for the diversity of growth rates among different cell lines in this report we describe a computerized kinetic chemosensitivity assay based on quantification of biomass by staining cells with crystal violet. As a prerequisite four human breast cancer cell lines (MDA-MB-231, MCF-7, T-47-D and ZR-75-1) were characterized with regard to oestrogen and progesterone receptor content, modal chromosome number and proliferation kinetics depending on the number of passages in culture. With prolonged time in culture for ZR-75-1 exposed to various concentrations of cisplatinum a dose-related increase in drug effect was observed. Owing to a correction of the T/C values for the initial cell mass (at the time when drug is added) a sharp distinction between cytostatic and cytocidal drug effects becomes obvious in plots of corrected T/C values versus time of incubation. The influence of the untreated control on the corrected T/C values and possible time courses of theoretical inhibition profiles (reflecting cytostatic, transient cytotoxic or cytocidal drug effects as well as development of resistance) and their relationship to the corresponding growth curves of drug-treated cells are discussed. Chemosensitivity assays with diethylstilbestrol dipropionate, tamoxifen, melphalan, cisplatinum, vinblastine, Adriamycin and 5-fluorouracil prove the theoretical considerations to be true for MDA-MB-231, MCF-7, T-47-D and ZR-75-1 human breast cancer cell lines in practice.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Division; Cisplatin; Diethylstilbestrol; Drug Screening Assays, Antitumor; Female; Fluorouracil; Gentian Violet; Humans; Kinetics; Melphalan; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Receptors, Progesterone; Tumor Cells, Cultured; Vinblastine

The clinical and pathologic findings in a 53-year-old woman who developed a uterine adenosarcoma following an adenomyoma are described. During the interval between the diagnosis of adenomyoma and the subsequent diagnosis of adenosarcoma, the patient developed breast carcinoma and received adjuvant chemotherapy that included tamoxifen. The possible stimulatory effects of this drug upon the patient's pre-existing adenomyoma are discussed in view of reports of tamoxifen-associated endometrial carcinoma and uterine sarcomas developing in the setting of estrogen excess.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Transformation, Neoplastic; Combined Modality Therapy; Doxorubicin; Endometriosis; Female; Fluorouracil; Humans; Melphalan; Menopause; Middle Aged; Tamoxifen; Uterine Neoplasms; Wilms Tumor

Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line.

Topics: Amino Acid Sequence; Animals; Anthraquinones; Antineoplastic Agents; Breast Neoplasms; Cell Membrane; Cell Survival; Cisplatin; Doxorubicin; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Melphalan; Methotrexate; Molecular Sequence Data; Oligopeptides; Orchiectomy; Pituitary Gland; Prostatic Neoplasms; Rats; Receptors, LHRH; Structure-Activity Relationship; Tumor Cells, Cultured

High-dose cyclophosphamide can be used to obtain haematological stem cells from the peripheral blood. In this paper we analyse the dynamics of appearance of cells with these characteristics, together with the impact of this drug on the immunological system. Cyclophosphamide seems to possess immunomodulating effects even at high doses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Female; Hematopoietic Stem Cells; Humans; Immune System; Melphalan; Middle Aged

Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail.. We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy).. The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg.. Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

Topics: Aged; Alkylating Agents; Breast Neoplasms; Case-Control Studies; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Melphalan; Middle Aged; Myelodysplastic Syndromes; Radiotherapy; Radiotherapy Dosage; Risk

A rare case of lambda light chain disease with bilateral breast involvement is described. A complete regression after a new chemotherapy combination (peptichemio + teniposide + dexamethasone) was obtained. A previous treatment with prednisone + melphalan was ineffective.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dexamethasone; Humans; Immunoglobulin lambda-Chains; Male; Melphalan; Multiple Myeloma; Peptichemio; Podophyllotoxin; Prednisone; Remission Induction; Time Factors

A retrospective analysis of prognostic factors in 214 consecutive node-positive (N+) operable breast cancer patients, receiving Melphalan + 5-fluorouracil adjuvant chemotherapy between 1980 and 1984 was performed. Median follow-up was 95 months. Actuarial disease-free interval (DFI) and survival (S) were determined according to age, menopausal status, histology, size of primary tumor (T), multifocality, tumor location, hormonal receptor status, number of N+, size of N+, tumor spread in axillary fat, and interval between surgery and onset of adjuvant chemotherapy. On univariate analysis two factors were prognostic for DFI and S: number of N+ and T size. A comparison between traditionally classified T1 and T2 patients revealed no significant difference, but when the cut-off point was shifted from 2 cm to 3 cm, T size represented a highly significant prognostic factor. In patients with T less than or equal to 3 cm 5-year DFI was 54% and 5-year S was 76%, while in patients with T greater than 3 cm the respective values were 23% (p less than 0.001) and 41% (p less than 0.001). These significant DFI and S differences persisted after adjustment for number of N+ by bivariate analysis. Multivariate analysis supported the importance of T greater than 3 cm as a strong adverse predictor. Four adverse variables, T greater than 3 cm, number of N+ greater than or equal to 4, multifocality, and tumor spread in axillary fat were used to divide our patients into three subsets with significantly different DFI: Group I, with none of the above factors; Group II, with only one factor present; and Group III, with more than one factor present (5 years DFI 66%, 45%, and 21%, respectively; p less than 0.001).

Topics: Breast Neoplasms; Chemotherapy, Adjuvant; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Middle Aged; Prognosis; Retrospective Studies

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Topics: Animals; Antineoplastic Agents; Aziridines; Breast Neoplasms; Cell Division; Cell Line; Drug Screening Assays, Antitumor; Female; Humans; Leukemia L1210; Leukemia, Experimental; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Structure; Neoplasms, Experimental; Quinazolines; Sarcoma, Experimental; Structure-Activity Relationship

A combination of mitomycin C, vindesine and melphalan was administered to 33 patients with heavily pretreated refractory breast cancer. The overall response rate was 27% with a mean duration of more than 10.2 months. A stabilization with a mean duration of 5.1 months was seen in 56% of cases, while 20% of patients progressed. Gastrointestinal toxicity, mostly grade 1 or 2 nausea/vomiting was seen in 85% of cases, grade 1 or 2 leukopenia in 60% of patients, and grade 1 or 2 thrombocytopenia in 42%. Considering the good compliance of this regimen and the poor prognosis of patients with refractory advanced breast cancer, this combination can be useful as a palliative treatment of breast carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Melphalan; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Palliative Care; Vindesine

Failure of anti-cancer agents to reach all clonogenic cells at cytotoxic concentrations is recognized as an important form of resistance in solid tumours. Subcutaneously implanted mammary adenocarcinoma 16/C was used to evaluate the intratumour distribution of five alkylating, bioreductive alkylating and intercalating agents and two radiation sensitizers. The agents were classified according to their in vivo distribution in well- and poorly-perfused tumour regions, as delineated by lissamine green. The classifications were: (1) distribution in direct proportion to the vascular supply; (2) uniform distribution to well- and poorly-perfused tumour regions; and (3) preferential retention in the poorly-perfused tumour regions. Our current state of knowledge did not allow reliable prediction of the classification based on chemical structure or mechanism of action.

Topics: Adenocarcinoma; Alkylating Agents; Animals; Antineoplastic Agents; Antipyrine; Biological Transport; Breast Neoplasms; Carbon Radioisotopes; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Melphalan; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Transplantation, Heterologous

Available information suggests that individuals with breast cancer gain weight during adjuvant treatment and that this weight gain may be associated with poor prognosis. Exploration of the factors which affect weight gain may aid in developing weight control interventions for these patients. To determine the factors which are associated with weight gain, 32 women undergoing adjuvant chemotherapy were followed over 2 years from the beginning of adjuvant treatment. Measures of psychologic functioning and self-reports of exercise levels and eating were assessed every 2 months during the course of treatment. Sixty-nine percent of the women gained weight over treatment, resulting in a significant weight gain for the group as a whole. Weight gain was correlated positively with several psychologic measures but not with assessed biologic measures. A multiple-regression equation using psychologic/behavioural measures of emotional discharge, logical analysis, affective regulation, interpersonal sensitivity, average number of symptoms, and obsessive compulsiveness accounted for 58% of the variance in overall weight gain. At 2 years of follow-up, 27 women had gained weight for an average of 6.03 kg. The coping style of logical analysis emerged as a significant predictor of disease recurrence, accounting for 28% of the variance in weight gain at 2 years. The results are discussed in terms of identification of women likely to gain weight during adjuvant treatment, directions for future research, and development of interventions to control weight gain.

Topics: Adaptation, Psychological; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Melphalan; Methotrexate; Middle Aged; Prednisone; Recurrence; Regression Analysis; Social Support; Vinblastine; Weight Gain

Several cell lines resistant to alkylating agents possess increased activity of glutathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the glutathione redox system may affect cellular sensitivity to alkylators. We report that the (-.)enantiomer of gossypol is a potent and selective inhibitor of GST alpha and GST pi isozymes, and that in combination with buthionine sulfoximine (BSO), causes the enhanced modulation of alkylator resistance in two drug resistant cell lines with increased GST activity. The use of (-)gossypol alone had no effect on the 2-5-fold resistance of MCF-7 Adr and Walker resistant cells to chlorambucil, melphalan and BCNU. Cellular depletion of glutathione with BSO resulted in a 2-4-fold modulation of cell sensitivity to these alkylators. However, the combination of (-)gossypol with BSO resulted in a markedly greater modulation of alkylator sensitivity than with either inhibitor alone. Therefore, the complementary inhibition of glutathione and GST by BSO and (-)gossypol, respectively, produced a synergistic modulation of alkylator cytotoxicity in these drug resistant cell lines. The favorable clinical pharmacokinetics of (-)gossypol suggest its further evaluation for use in combination with BSO and alkylating agents in clinical trials.

Topics: Alkylating Agents; Animals; Breast Neoplasms; Buthionine Sulfoximine; Carcinoma 256, Walker; Carmustine; Cell Division; Cell Line; Chlorambucil; Cisplatin; Drug Antagonism; Drug Resistance; Glutathione Transferase; Gossypol; Humans; In Vitro Techniques; Isomerism; Melphalan; Methionine Sulfoximine; Rats

Human anti-mouse antibody (HAMA) response was determined in the serum of 67 patients who received subcutaneously administered radiolabelled murine monoclonal antibodies (MoAb) (50 micrograms-3 mg) for immunolymphoscintigraphy and of 10 patients with advanced colorectal cancer who received murine MoAb-N-acetyl melphalan (MoAb-N-AcMEL) conjugates (amount of MoAb ranged from 120 mg/m2 body surface area to 1000 mg/m2 body surface area) as therapy. A pre-existing low level of apparent human anti-mouse antibody reactivity could be detected in the serum of normal subjects and patients prior to administration of murine MoAb. Subcutaneous administration of low doses of murine MoAb, as used in immunolymphoscintigraphy, was associated with a low incidence (4/67 or 6%) of elevated HAMA response; the use of F(ab')2 fragments was associated with the development of elevated HAMA response in one of three patients. By contrast, therapy with hepatic artery infusion of murine MoAb-N-AcMEL conjugates in three repetitive daily doses (each infusion lasting 2 h) elicited elevated HAMA responses in 10/10 (100%) patients, usually 1-3 weeks after the start of therapy. The HAMA response of patients in the therapy group was higher than those in the immunolymphoscintigraphy study and the use of steroids did not prevent the development of the HAMA response. Further administration of MoAb-N-AcMEL conjugates to a patient, who had already developed HAMA, led to 'serum sickness'-type symptoms and a transient reduction in the HAMA titres. The elevated HAMA response was polyclonal, containing increased levels of both immunoglobulin M and G (IgM and IgG) and was directed against mouse-specific determinant, the isotype (presumed to be the Fc portion), the F(ab')2 and the 'idiotype' of mouse immunoglobulins.

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Breast Neoplasms; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Epitopes; Humans; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Immunotoxins; Infusions, Intra-Arterial; Injections, Subcutaneous; Lymphatic Metastasis; Melphalan; Mice; Radionuclide Imaging; Time Factors

Pulmonary function tests (standard vital capacity, SVC; total lung capacity, TLC; forced expiratory volume in 1 second-forced vital capacity ratio, FEV1/FVC; carbon monoxide transfer factor, DLCO) were prospectively evaluated in patients (median age 25 years, 13-52 years; median follow-up 20 months, 6-51 months) with Hodgkin's disease (15 patients), non-Hodgkin's lymphoma (9 patients), and inflammatory breast cancer (3 patients) treated with sequential high-dose therapy comprising the following phases over approximately 2 months: a) cyclophosphamide (7 g/m2); b) vincristine (1.4 mg/m2), methotrexate (8 g/m2), and cisplatinum (120 mg/m2) or etoposide (2 g/m2); c) total body irradiation (TBI; 12.5 gy, 5 fractions over 48 hours), intravenous melphalan (120-180 mg/m2), and transplantation of autologous peripheral blood and/or bone marrow hematopoietic stem cells. Within 2 months after transplantation, 12 patients also received 25 Gy radiotherapy boost to mediastinum and clavicular regions. In vivo dosimetry evaluations of fractionated TBI treatments showed that mean radiation dose absorbed by lungs was 12.18 Gy (97.4% of TBI dose). Despite such a high radiation dose, we observed only transient and subclinical decrease of SVC, TLC, and DLCO. The decrease of SVC, TLC, and DLCO was more evident and prolonged in patients receiving radiotherapy boost. All parameters progressively recovered to normal values within 2 years after transplantation. In contrast, FEV1/FVC remained within normal limits in all patients, thus demonstrating the absence of obstructive ventilatory changes. In addition, no interstitial pneumonia was observed.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Italy; Lung; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Prospective Studies; Pulmonary Gas Exchange; Total Lung Capacity; Transplantation, Autologous; Whole-Body Irradiation

Curative treatment regimens for leukemias, lymphomas, and testicular cancer have been based on laboratory observations of a clear relationship (generally linear-log) between increasing doses of chemotherapeutic agents and tumor cytotoxicity and on recognition of the need for combination chemotherapy to avoid the emergence of drug resistance. Chemotherapeutic agents have been selected for combinations based on cytotoxic activity, different mechanisms of action (to avoid cross-resistance), and different dose-limiting toxicities (to avoid additive toxicity). The ideal combinations use the highest tolerable doses of active non-cross-resistant agents to minimize the potential for drug resistance and achieve optimum cytotoxicity. Dose escalation is often limited by myelosuppression. Hematologic stem cell support from bone marrow or peripheral blood allows the administration of significantly higher doses of chemotherapy. In 1977, Thomas and colleagues in Seattle reported that 13 of 100 patients who underwent bone marrow transplantation for relapsed acute leukemia were disease-free 1 to 4.5 years later. Today, almost 50% of selected patients with acute myelogenous leukemia who undergo transplantation with human leukocyte antigen-matched sibling donor marrow during first remission are cured. Between 20% and 50% of lymphoma patients who undergo transplantation after failing conventional treatment have survived; those whose disease is responding to standard-dose therapy at the time of transplant have the best prognosis. Conditioning regimens that are sufficiently cytoreductive are not currently available for patients with solid tumors. The diversity of solid tumors makes it likely that a variety of regimens will be required. In a sequence of laboratory and clinical studies, we have constructed and evaluated a regimen comprising 6 g/m2 of cyclophosphamide, 500 mg/m2 of N,N',N''-triethylenethiophosphoramide (thiotepa), and 800 mg/m2 of carboplatin. The response rate in women with measurable breast cancer was 81%. While profound myelosuppression was noted, organ toxicity has been rare. This regimen, designed to exploit the principles of curative cancer chemotherapy, is associated with low morbidity and high cytoreductive efficacy. The regimen is currently being evaluated in a phase II trial in patients with previously untreated metastatic breast cancer who are responsive to conventional-dose chemotherapy. Of 29 patients entered in the study, only one has died of toxici

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Carmustine; Cisplatin; Cyclophosphamide; Drug Evaluation; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Thiotepa

Two drug-resistant variants of the human breast cancer cell line MCF-7 have been shown previously to exhibit radiation resistance associated with an increase in the size of the shoulder on the radiation survival curve. In the present study, glutathione (GSH) depletion was achieved by exposure of cells to buthionine sulfoximine (BSO) with, in some cases, additional treatment with dimethyl fumarate. Levels of GSH in the adriamycin-resistant subline MCF-7 ADRR are initially lower than in the other two sublines and are depleted to a greater extent by exposure to BSO. Wild-type MCF-7 cells are not sensitized by GSH depletion when irradiated under aerated conditions but are sensitized under hypoxic conditions to an extent which is related to the level of GSH depletion. In contrast both the drug-resistant sublines (MCF-7 ADRR and the melphalan-resistant line MCF-7 MLNR) are radiosensitized by GSH depletion under both aerated and hypoxic conditions. It is hypothesized that in the case of the MCF-7 ADRR cell line, which expresses high levels of the GSH-associated redox enzyme systems, GSH-S-transferase and GSH-peroxidase (GSH-Px), radiosensitization results when GSH-Px is inhibited in GSH-depleted cells. The reasons for radiosensitization of aerated MCF-7 MLNR cells cannot be explained on this basis, however, and other factors are being examined.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line; Cell Survival; Dose-Response Relationship, Radiation; Doxorubicin; Drug Resistance; Female; Glutathione; Humans; In Vitro Techniques; Melphalan

Patients receiving high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) may experience life-threatening hemorrhagic myocarditis. The authors investigated whether HDC was associated with an acquired platelet defect. Platelet aggregation and release were evaluated after HDC in ten patients with either metastatic breast carcinoma or melanoma. Platelets underwent shape change and a primary wave of aggregation. High-dose chemotherapy was associated with the inhibition of secondary aggregation of platelets induced by adenosine diphosphate (ADP), arachidonic acid, prostaglandin H2 (PGH2) analog (U44619), and collagen. Although electron microscopic study of the platelets revealed normal morphologic features with an adequate number of dense bodies and alpha-granules, release of adenosine triphosphate (ATP) from dense granules was less than 20% of normal. The acquired platelet defect occurred before development of thrombocytopenia. Aggregation of platelets from normal volunteers was not inhibited by either the addition of the chemotherapeutic agents, chemotherapy metabolites, or the patients' sera. In conclusion, HDC induces an acquired abnormality in platelet secretion and aggregation which may contribute to the development of hemorrhagic complications after ABMT.

Topics: Adenosine Triphosphate; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Platelet Disorders; Blood Platelets; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Cyclophosphamide; Female; Hemorrhage; Humans; Male; Melanoma; Melphalan; Middle Aged; Myocarditis; Platelet Aggregation

Fourteen patients with refractory metastatic breast cancer were treated with high dose chemotherapy and autologous hematopoietic stem cell rescue. All patients received cyclophosphamide (7.5 g/m2 over 3 days) and thiotepa (150-225 mg/m2 over 3 days), three patients in addition received melphalan (4.5 mg/kg), and seven patients received carmustine (150-562 mg/m2). Toxicities included pancytopenia, infection, hemorrhagic cystitis, skin rash, nausea, vomiting, diarrhea, and mucositis. There was one toxic death secondary to sepsis and ventricular tachycardia. The overall response rate was 77% including a 15% complete response rate. The overall median survival for all patients was 6.0 months (range 2-22 months). The median survival for nonresponders was 3.5 months. The median duration of response was 89 days (range 40-262). In our experience high dose chemotherapy with autologous stem cell reinfusion produces a high response rate in refractory breast cancer. However, because of the short duration of response and overall survival, we feel this type of therapy should be utilized earlier in the course of disease.

Topics: Adult; Breast Neoplasms; Carmustine; Cell Survival; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cells; Humans; Melphalan; Middle Aged; Neoplasm Staging; Thiotepa

Topics: Breast Neoplasms; Cell Division; Cell Line; Cell Survival; Cyclooxygenase Inhibitors; Female; Humans; Indomethacin; Melphalan; Methotrexate; Tumor Cells, Cultured

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.

Topics: Adult; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Mitoxantrone; Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Stomach Neoplasms

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

Topics: Amino Acid Sequence; Animals; Breast Neoplasms; Cell Membrane; Chlorambucil; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Melphalan; Molecular Sequence Data; Ovulation; Pituitary Gland; Prostatic Neoplasms; Rats; Receptors, LHRH

Alkalating chemotherapeutic agents are frequently implicated in the development of acute non-lymphocytic leukemia. A case report illustrates the danger of administering a prolonged course of adjuvant chemotherapy with Melphalan following mastectomy for breast cancer.

Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Humans; Leukemia, Myelomonocytic, Acute; Melphalan; Middle Aged; Risk Factors; Time Factors

236 patients with various advanced malignant solid tumors treated by combined chemotherapy with routine doses of cisplatin (DDP) from 1980 to 1986 are presented. According to different doses of cisplatin everyday, the patients were divided into 4 groups: 1. 20 mg/day x4-5, 80 cases; 2. 30 mg/day x3-5, 91 cases; 3. 40 mg/day x3-4, 37 cases; 4. 50 mg/day x2-3, 28 cases. Each group was repeated for 3 weeks. The effect and toxicity were analysed and compared with 22 cases treated by single DDP in 1975. The response (CR + PR) rate was 39.2% in 194 evaluated patients. The response rate was similar in group 20 mg and single DDP (29.2% and 27.3%). The response rate was lower than that of group 30 mg, 40 mg, and 50 mg (43.4%, 42.4%, and 50%) (P less than 0.05). The remissions in various groups were not significantly different. The toxicity of combined chemotherapy was not severe. 91.1% of patients had nausea and vomiting. There was no statistical difference in the various groups. Bone marrow suppression was less in single DDP group than that of combined chemotherapy group, (P less than 0.05). DDP 30 mg-50 mg 1/d x5-3 was better than HD-DDP in some patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasms; Procarbazine; Testicular Neoplasms; Vincristine

The aim of the present investigation was to determine whether the administration of a third year of tamoxifen, following 2 years of L-phenylalanine mustard, 5-fluorouracil and tamoxifen, would benefit women with primary breast cancer. The data at 5 years indicate that in patients receiving a third year of tamoxifen treatment, a significant prolongation in disease-free survival occurs, when compared to patients who receive only 2 years of tamoxifen. This benefit is limited to patients older than 49 years of age, and is not apparent in women younger than 50. It is concluded that an additional year of tamoxifen therapy, following the completion of chemotherapy prolongs both disease-free survival and actual survival in node-positive, 'tamoxifen-responsive' patients.

Topics: Adult; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Tamoxifen; Time Factors

A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Sarcoma; Transplantation, Autologous

In a prior National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant study, the addition of the antiestrogen tamoxifen to chemotherapy with melphalan and fluorouracil adversely affected survival in several patient subsets, suggesting an antagonistic drug interaction. To investigate this possibility, we studied the interaction of tamoxifen and other antiestrogens with several cytotoxic drugs in cultured human breast cancer cell lines. Clinically relevant concentrations of tamoxifen and melphalan reduced colony survival of estrogen receptor (ER)-positive breast cancer cells when used alone in a colony-forming assay. However, pretreatment of cells with tamoxifen followed by exposure to melphalan resulted in antagonism, with more colonies surviving treatment with the combination than with melphalan alone. Identical effects were seen using several other triphenylethelene antiestrogens. An antagonistic interaction was observed even with a brief preincubation with tamoxifen that had no effect on cell proliferation, indicating that antagonism was not due to tamoxifen's known cell kinetic effects. Tamoxifen even antagonized melphalan cytotoxicity in ER-negative breast cancer cells and in cultured liver cells. An additive drug interaction occurred when melphalan was combined with pharmacologic concentrations of estradiol or medroxyprogesterone acetate, but antagonism was also observed with dexamethasone. Tamoxifen also antagonized the cytotoxicity of fluorouracil in these cells. However, an additive interaction occurred when the antiestrogen was combined with doxorubicin or 4-hydroxy-cyclophosphamide, an alkylating agent that is transported into the cell by a different carrier-mediated mechanism than melphalan. To avoid potential antagonism in the clinic, combinations of tamoxifen with melphalan and/or fluorouracil should be avoided.

Topics: Breast Neoplasms; Cell Cycle; Cell Survival; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Estrogen Antagonists; Fluorouracil; Humans; Melphalan; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured

Resistance to the cytotoxic effects of alkylating agents is a major limitation to their clinical efficacy. Although a number of animal and human tumor cell models have been developed to study this problem, it has proven difficult to achieve very high levels of resistance to alkylating agents in vitro. This is consistent with the recent clinical evidence that alkylator resistance can be overcome by dose escalations of less than 10-fold. A number of mechanisms of alkylator resistance have been described, more than one of which may occur in the same model. This paper describes a human breast cancer cell subline selected for 3-fold resistance to melphalan and cross-resistant to other alkylators in which only one of the previously described mechanisms of resistance, enhanced removal of DNA interstrand cross-linking, is demonstrable. Northern blot analysis using the human incisional repair gene ERCC-1 cDNA demonstrated that this particular gene product is not the altered function in these cells, so the molecular characterization of the observed enhanced repair is pending. Because these cells are also cross-resistant to radiation and to adriamycin and epipodophyllotoxin, they may represent a clinically relevant model in which to examine the role of DNA repair of lesions resulting from alkylators and other cytotoxic agents.

Topics: Blotting, Northern; Breast Neoplasms; Cell Division; Cross-Linking Reagents; DNA Damage; DNA Repair; Drug Resistance; Glutathione; Glutathione Transferase; Humans; Melphalan; RNA, Messenger; Tumor Cells, Cultured

Chromosome lesions detected in lymphocytes from 14 patients previously treated with melphalan, a bifunctional alkylating agent, have been analyzed on R-banded preparations. In comparison to controls, there was no significant increase of chromatid-type lesions, but chromosome-type lesions were quite frequent, affecting 21.5% of metaphases, on the average. Reciprocal translocations represent 54%, unbalanced translocations 15%, deletions 19% and inversions 6% of all rearrangements. Most of these would not have been detected without the use of chromosome banding. The distributions of affected chromosomes and chromosome bands were not random. Almost all imbalances resulting from rearrangements lead to losses but not to gains. The distribution of the abnormal chromosomes has been compared to that observed in controls and in in vitro experiments, and to the characteristic pattern of malignant cells from patients affected by secondary acute leukemia (ANLL).

Topics: Breast Neoplasms; Chromosome Aberrations; Chromosome Banding; Chromosome Deletion; Chromosome Inversion; Humans; Lymphocytes; Lymphoma; Melphalan; Translocation, Genetic

Adding Fluosol-DA and carbogen breathing to treatment with various anticancer drugs can result in a significant enhancement of tumor growth delay compared to the drug and air breathing. The optimal conditions for tumor response depend upon the drug, oxygenation level and duration, and perfluorochemical emulsion dosage. In this study, representative chemotherapeutic agents from several classes were tested in a tumor growth delay assay in combination with various doses of Fluosol-DA under conditions of normal aeration, carbogen breathing either for 1-2 hours or 6 hours, or with hyperbaric 100% oxygen (3 atmospheres) breathing for 1 hour to determine whether the antitumor activity of these drugs would be improved.

Topics: Animals; Antineoplastic Agents; Bleomycin; Breast Neoplasms; Carbon Dioxide; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Combinations; Fibrosarcoma; Fluorocarbons; Fluorouracil; Humans; Hydroxyethyl Starch Derivatives; Male; Melphalan; Methotrexate; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasm Transplantation; Neoplasms; Organoplatinum Compounds; Oxygen; Tumor Cells, Cultured

Fifteen patients with advanced breast cancer who had achieved either a good partial or a complete response to conventional chemotherapy were selected to receive intensification treatment with high-dose melphalan 140-200 mg/m2 (HDM). All patients received autologous bone marrow rescue. All patients experienced marked haematological toxicity, and most experienced moderate or mild gastrointestinal side effects. There were three treatment-related deaths. Of twelve assessable patients eleven have relapsed; median time to relapse after HDM is 7 months. Nine of these eleven have died from recurrent breast cancer. Of the three patients remaining alive, only one is disease-free, at 18 months after HDM. Analysis of the pattern of metastatic relapse suggests that recurrence was due to failure of HDM to eradicate residual disease in the patient, rather than reinfusion of viable tumour cells. Treatment intensification with HDM has not succeeded in prolonging survival in patients already in good remission.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Evaluation Studies as Topic; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neutropenia

The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is often-limited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%-90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.

Topics: Breast Neoplasms; Cell Line; Doxorubicin; Drug Interactions; Drug Resistance; Fluorouracil; Humans; Melphalan; Methotrexate; Perhexiline; Tamoxifen; Tumor Stem Cell Assay; Vinblastine

We compared the effects of defined medium, fetal bovine serum (FBS) and human serum (HuS) on the growth and responses to chemotherapeutic agents of human breast cancer cells in primary culture. Normal and tumor tissues were dissociated to small aggregates and single cells and seeded onto collagen-gel-coated wells in defined medium or medium supplemented with 5% FBS or 5% HuS. In all cases examined, defined medium and medium containing HuS were superior to medium containing FBS in supporting growth of both normal and tumor cell cultures. However, cultures in defined medium showed an initial cell loss. Cells from the same tumor cultured in different media varied in their responses to chemotherapeutic agents. In light of these results, medium supplemented with HuS, which promoted attachment of these cells in culture and stimulated their growth, should be the most appropriate nutrient environment for determining the effects of therapeutic agents on cells as it most closely resembles the in vivo situation. Because there were also variations in growth rates and chemosensitivities of tumor cells cultured in different human serum samples, we suggest that optimal conditions in which to culture these cells include the serum of the patient whose tumor is removed. This serum may provide host factors that influence cell growth and interact with exogenous factors.

Topics: Animals; Antineoplastic Agents; Blood; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cattle; Cell Division; Cells, Cultured; Culture Media; DNA; Doxorubicin; Epithelium; Female; Fetal Blood; Fluorouracil; Humans; Melphalan; Microscopy, Electron

In carcinoma of the breast the disease stage at diagnosis determines therapy and is closely related to prognosis. To date no single biochemical marker of disseminated breast cancer has been described although beta 2 microglobulin values in the serum have been suggested as a discriminant between localized and systemic disease. Using a new method of beta 2 microglobulin estimation, we carried out a prospective study of levels in 53 patients with breast cancer who were studied repetitively over a 2 yr period. No relationship could be determined between beta 2 microglobulin values and the stage of the disease. Moreover beta 2 microglobulin levels, even when elevated, did not predict early metastasis. Repeated beta 2 microglobulin estimations during treatment of metastatic disease had limited usefulness in that patients with responsive disease usually showed a fall in beta 2 microglobulin, whereas there was generally no change in non-responsive patients. These changes were, however, often within the normal range and seemed to offer a marginal improvement in assessment.

Topics: beta 2-Microglobulin; Breast Neoplasms; Female; Humans; Melphalan; Neoplasm Staging; Time Factors

Fifty-nine patients received 61 courses of cyclophosphamide, cisplatin, and carmustine combined. The phase I study consisted of seven dose escalations. Dose levels 5 and 6 also included the attempted addition of melphalan at 40 and 80 mg/m2. The maximum tolerated dose for the three-drug combination was 5620 mg/m2 of cyclophosphamide, 165 mg/m2 of cisplatin, and 600 mg/m2 of carmustine. The dose-limiting toxic effect was fatal veno-occlusive disease of the liver in two of five patients treated at the highest dose level. Veno-occlusive disease of the liver was fatal in two of 40 patients treated at Dose level 4, the maximum tolerated dose. The median time to recovery of polymorphonuclear leukocyte counts to greater than 500/microliters and platelet counts to transfusion independence greater than 20,000/microliters was 19 and 22 days, respectively, after marrow reinfusion. Other toxic effects observed included postdischarge pulmonary toxicity, which appeared to respond to prednisone therapy. Thus, this combination of alkylating agents can be combined at close to the transplant dose of each individual agent. The response rate was high despite considerable prior treatment in most patients. Of 16 evaluable patients with breast cancer, 15 responded (six complete responses). Of six evaluable patients with sarcoma, six responded (one complete response). While patients with melanoma had had no prior treatment, 11 of 17 patients responded (65%). There are currently three patients who are disease-free. Two patients with melanoma were rendered disease-free by excisional biopsy of the only remaining nodule after good partial response, and a patient with metastatic breast cancer remains disease-free after a complete response at 36+ months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Hematologic Diseases; Humans; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Statistics as Topic

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Colonic Neoplasms; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Levamisole; Lung Neoplasms; Melphalan; Neoplasms; Postoperative Care; Stomach Neoplasms

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Female; Humans; Mammary Neoplasms, Experimental; Melphalan; Neoplasms, Experimental; Neoplasms, Multiple Primary; Ovarian Neoplasms; Rats

Osteonecrosis (aseptic or avascular necrosis of bone) is an entity with many causes that can occur at a variety of sites. It is a known complication of corticosteroid therapy, either alone or combined with other drugs in the treatment of malignancy. Osteonecrosis associated with chemotherapy that does not include corticosteroids is rare; three such cases have been reported in the English literature. One received cyclophosphamide alone, another vinblastine and bleomycin, while the third received cyclophosphamide, methotrexate, and 5-fluorouracil. The authors report a 40-year-old woman who had a left radical mastectomy in 1978 and a right radical mastectomy in 1980 for infiltrating ductal adenocarcinoma of the breasts. She received melphalan following the first surgery and a combination of doxorubicin, cyclophosphamide, and 5-fluorouracil after the second operation. In 1984 she noted pain in both knees that slowly increased in severity. A bone scan revealed increased periarticular activity in the medial and lateral femoral condyles of both knees compatible with bilateral osteonecrosis. There was no evidence of metastatic carcinoma on the bone scan. The patient was treated surgically with drilling and autologous bone grafting. A bone biopsy at the time of surgery revealed osteonecrosis but no metastatic adenocarcinoma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cyclophosphamide; Doxorubicin; Female; Femur; Fluorouracil; Humans; Melphalan; Osteonecrosis; Radiography

We report in a 40 year-old woman a bifocal mammary and vertebral plasmocytoma attended by surgery and "preventive" chemotherapy. Eight years later, an acute and apparently non secondary myeloblastic leukemia is observed without sign of diffuse myelomatosis. Plasma cell tumors of the breast are uncommon. Eleven cases have been published, combining solitary plasmocytoma and infiltration occurring in multiple myeloma.

Topics: Adult; Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Neoplasms, Multiple Primary; Plasmacytoma; Spinal Neoplasms; Time Factors

We have devised a method utilizing a monoclonal antibody-toxin conjugate (LICR-LON-Fib75/abrin A-chain) for ridding bone marrow of infiltrating breast cancer cells to rescue patients with autologous bone marrow following high dose therapy. Initially we examined the activity of this conjugate in vitro. Five of seven human breast cancer cell lines were killed following exposure at 10(-8) M for 2 h; this concentration only reduced bone marrow colony formation to 83% (range, 50-100%) of control bone marrow. We then examined the pattern of bone marrow recovery after high dose melphalan (200 mg/m2) in patients with advanced breast cancer who were in remission following combination chemotherapy. To do this we compared the time of recovery of the blood count in three patients who received treated marrow and seven who received untreated marrow. Mean time to recovery of the peripheral white count (greater than 1.5 X 10(9)/liter) was 16.7 days (treated) and 18.3 days (untreated), respectively. Mean time to recovery of peripheral platelet count (greater than 50 X 10(9)/liter) was 23.7 days (treated) and 18.9 days (untreated), respectively. Patients continued in remission for 1-greater than 14 mo after high dose melphalan, and remission duration was similar in patients who received treated (6.2 mo) and untreated (7.3 mo) bone marrow. These findings indicate that treatment of bone marrow with LICR-LON-Fib75/abrin A-chain conjugate does not significantly impair bone marrow recovery, and it is, therefore, possible to rescue breast cancer patients with bone marrow that has been cleansed of infiltrating cancer cells. This may have an application in patients with poor-risk primary breast cancer who have micrometastases and who may benefit from intensive therapy, but it has minimal application in patients with more advanced disease.

Topics: Abrin; Antibodies, Monoclonal; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Cell Line; Female; Humans; Melphalan; Neoplasm Metastasis; Tumor Stem Cell Assay

A clinical evaluation of peptichemio (40-45 mg/m2/day for 3 days every 3-4 weeks) was conducted in 32 patients with advanced breast cancer, 28 of whom were evaluable for both toxicity and response. The overall response rate was 18% (one complete remission and four partial remissions), with a median duration of 4 months (range, 2-6). The major side effects were cumulative myelotoxicity, phlebitis, mild nausea, and vomiting. A posttreatment heparin infusion was used to prevent phlebitis.

Topics: Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Heparin; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombophlebitis

A review and update of published studies on estrogen receptor (ER) and progesterone receptor (PgR) as prognostic factors in breast cancer support the following conclusions. In stage I breast cancer, the lack of ER seems to be the most important factor for predicting earlier recurrence and poorer survival. In stage II breast cancer, PgR content appears to be better than ER content in predicting disease-free survival and PgR content is as important as ER content in predicting overall survival. The benefits of adjuvant endocrine therapy are better predicted by the presence or absence of PgR than by the presence or absence of ER. Measurement of proliferative activity (S-phase DNA) by thymidine labeling or flow cytometry and of aneuploidy by flow cytometry also provides prognostic information. The strong correlations between tumor receptor content, percent S-phase cells, and aneuploidy suggest that these measurements in concert might identify a subset of stage I breast cancer patients at increased risk for recurrence, who would thus be potential candidates for adjuvant therapy.

Topics: Adult; Breast Neoplasms; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

Pulse in vitro thymidine labeling index (TLI) was used to measure proliferative activity in 757 infiltrative breast carcinomas. The TLI varied from 0.00% to 35.6%, and the frequency distribution was positively skewed, with a mean of 7.1% and a median of 5.2%. The TLI was negatively correlated with the age of the patient and content of estrogen and progesterone receptors and was positively correlated with the size of the carcinoma and the degrees of nuclear anaplasia, necrosis, and inflammatory cellular infiltrate. The TLI did not correlate with the number of axillary lymph node metastases. The TLI of locally advanced carcinomas were elevated significantly. Evaluation of the clinical course in a series of 278 patients showed that the TLI is a prognostic indicator independent of stage and estrogen receptor content. Patients with negative axillary lymph nodes who had TLI above the median had more than twice the probability of relapse within 4 years as patients with TLI below the median. Similar results have been reported by Silvestrini et al. The TLI can be used to select and identify high-risk patients and to stratify patients for trials of adjuvant therapy. The DNA index and the percent of nuclei with S-phase DNA content estimated by flow cytometry hold promise as prognostic indicators but have not been as well studied as the TLI.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Carcinoma in Situ; Cell Cycle; DNA, Neoplasm; Epithelium; Evaluation Studies as Topic; Female; Flow Cytometry; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Thymidine; Tritium

A search for significant pathological prognostic variables for 10-year disease-free survival was performed in women enrolled in protocol 4 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) who were treated by radical mastectomy. Pathological assessment of the number of lymph nodes with metastatic involvement (0, 1-3, or 4+) is the principal factor. Women with tumors measuring less than 2 cm had statistically significant better survival than those with larger cancers. This association was independent of nodal status, but the magnitude of difference was only 15%. A pattern of germinal center predominance in regional lymph nodes and high histological grade adversely influenced disease-free survival in patients without nodal metastases. A high histological grade and tumor size of 2 cm or more similarly affected disease-free survival in patients with metastases in 4 or more nodes. Although no statistically significant factors were found that might predict treatment failure or success in the patients with 1-3 positive nodes, trends relating to histological grade and tumor size were observed. The presence of more than 13 positive nodes indicated patients who would fail by 10 years, after surviving for 5 years, whereas type 1, 2, and 4 "scar" cancers were favorable indices. Favorable response to chemotherapeutic agents used in clinical trials by the NSABP was significant in patients with poorly differentiated cancer but not in those with well-differentiated cancer (grades 1 and 2). This relationship prevailed in both older (greater than or equal to 50 yr) and younger (less than or equal to 49 yr) women.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Female; Fluorouracil; Humans; Lymph Nodes; Mastectomy; Melphalan; Methotrexate; Middle Aged; Prognosis

Two women are described in whom, on the basis of prior therapy for breast cancer and the presence of painful, lytic bone lesions, an initial diagnosis of metastatic breast cancer was made. Further evaluation established the diagnosis of multiple myeloma in both patients. Neither had evidence of recurrent breast cancer. These cases indicate that women with a history of breast cancer in whom lytic bone lesions develop without evidence of extraskeletal metastases should have the diagnosis of multiple myeloma excluded.

Topics: Agammaglobulinemia; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Breast Neoplasms; Diagnosis, Differential; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Radiography

The effect of known chemotherapeutic programs in patients with breast cancer who developed metastasis during or after adjuvant chemotherapy with L-PAM plus 5-FU (PF) were studied. Thirteen patients failed while receiving adjuvant therapy at 3-22 months from the time therapy started. Three patients failed 6-28 months after 2 years of therapy. Thirteen patients received PF followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) at the time of progression on PF. Of these, ten received Adriamycin and vincristine (AV) at the time of progression on CMF. The response to CMF was 7%. No patient responded to AV after progression on CMF. Two of three patients treated with AV after failure on PF did respond, but both for only 6 months. This suggests that adjuvant therapy may render the tumor less responsive to further chemotherapy. Since most patients failed while on adjuvant therapy, this may indicate a poor prognosis regardless of the agents used.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Tamoxifen; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Tamoxifen

Adherence to the dose or the need for dose reduction and the duration of treatment intervals were determined retrospectively for 1446 chemotherapy courses in 291 patients with malignant lymphoma and breast cancer. In patients over 60 years of age treated with the COP and COPP regimes there was a significantly higher frequency of deviation from the standard regime than in younger patients; a similar situation was seen in patients with breast cancer. The cause in the elderly patients was presumably due to the higher incidence of non-oncological diseases. In a group treated using the CHOP-scheme there was no difference in comparison with the reference group. In this group patients with severe pre-existent diseases were excluded before treatment. The results indicate that age itself is not a major risk factor for a combination chemotherapy. Pre-existent diseases play a substantial role in the toxicity of cytostatics.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Fluorouracil; Humans; Lymphoma; Male; Melphalan; Methotrexate; Middle Aged; Multiple Myeloma; Prednisolone; Prednisone; Procarbazine; Risk; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Prednisone; Vincristine

The effect of the antiestrogen tamoxifen on the cytocidal activity and uptake of melphalan in human breast cancer cells was investigated. A clonogenic assay was used to obtain dose-survival curves of estrogen receptor-positive MCF-7 cells and of estrogen receptor-negative Evsa T cells following treatment with melphalan and/or tamoxifen. Isobolograms derived from these dose-survival curves were concave downward, suggesting that the drug interaction was antagonistic. The effect of tamoxifen on melphalan uptake by breast cancer cells was evaluated at steady-state conditions. Thin-layer chromatography revealed that the intracellular level of free intact melphalan (mean +/- S.E.) in control cells was 6.47 +/- 1.21 fmoles/cell and that in cells treated with tamoxifen was 3.60 +/- 0.35 fmoles/cell; this 44% reduction in cellular melphalan was statistically significant (P = 0.006). Thus, the antagonistic cytocidal effect of melphalan and tamoxifen against breast cancer cells appeared to be due to inhibition of melphalan uptake at the steady state by the antiestrogen. Further investigation revealed that tamoxifen inhibited unidirectional melphalan influx in human breast cancer cells both by the sodium-independent system L and by the sodium-dependent system ASC. Tamoxifen also appeared to stimulate melphalan efflux from human breast cancer cells. The first-order rate constant K for melphalan efflux from control cells was 0.085 +/- 0.008 and that from cells treated with tamoxifen was 0.129 +/- 0.005; the difference was highly significant (P less than 0.001). Therefore, the antagonistic effect of tamoxifen on the uptake and cytocidal activity of melphalan in breast cancer cells appeared to be due to inhibition of melphalan influx and stimulation of drug efflux.

Topics: Breast Neoplasms; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Melphalan; Receptors, Estrogen; Tamoxifen

Weight gain during adjuvant chemotherapy has been reported by several authors. Because increased body weight at diagnosis is associated with an increased risk of disease recurrence, we have assessed the prevalence of weight gain in a series of patients receiving adjuvant treatment, as well as the association of weight gain with type of treatment and risk of recurrence. We first assembled an inception cohort of 237 patients who had all undergone pretreatment evaluation and treatment at one institution, and had already been followed for at least 12 months. Body weight at the start and completion of treatment was recorded, as was type of treatment and status at last followup. Ninety-six percent of patients gained weight during treatment and none lost weight (mean increase 4.3 kg). Weight gain was strongly associated with treatment, and was least in patients receiving single agent chemotherapy, greatest in patients treated with ovarian ablation and prednisone, and intermediate in those receiving combination chemotherapy. There was no association between weight gain and disease recurrence.

Topics: Adult; Aged; Body Weight; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prognosis; Risk

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.

Topics: Adenocarcinoma; Amino Acids; Amino Acids, Cyclic; Animals; Biological Transport; Bone Marrow; Breast Neoplasms; Cell Line; Cell Survival; Chromatography, Thin Layer; Colony-Forming Units Assay; Culture Media; Female; Humans; Kinetics; Melphalan; Mice; Neoplasms

Four cases of acute myelodysplastic-non-lymphocytic leukemia secondary to cytotoxic agents were reported. Primary diseases were breast cancer (1 patient), ovarian cancer (2 patients) and multiple myeloma (1 patient). All except one (with multiple myeloma) were in clinical remission of their primary diseases. Common cytotoxic agent used was melphalan. Median total drug dose and median latent period from diagnosis of primary diseases were 1299 mg and 63 months respectively. None with the exception of one received specific treatment. All died except one who is in a very poor condition. Survival from the diagnosis of hematologic diseases ranged from 3-9 months. Clinical features, cytogenetic findings, pathogenetic mechanism and risk of the disease were briefly discussed.

Topics: Acute Disease; Adult; Breast Neoplasms; Chromosome Aberrations; Female; Humans; Leukemia; Leukemia, Radiation-Induced; Melphalan; Middle Aged; Multiple Myeloma; Ovarian Neoplasms; Radiotherapy

One hundred and thirty three specimens from mammary and ovarian adenocarcinoma and from melanoma were cultured according to an agar/agar clonogenic assay. Melanoma and ovarian cancers exhibited a 70 per cent rate of success for culture; 50 per cent of the mammary adenocarcinomas were successfully cultured. Fifty-nine ovarian cancers were cultured in order to test the in vitro effectiveness of Cisplatinum and Adriamycin. Thirty percent of cultured tumors gave rise to relevant chemograms. The chemoresistance measured in vitro was correlated to the ineffectiveness of the patient's treatment. In contrast, we were unable to predict chemosensitivity. Taking into account the technical difficulties encountered in these assays, human tumor clonogenic assays cannot at present be proposed as a routine procedure in the prediction of the effectiveness of chemotherapeutic treatments. Nevertheless, they must be developed in order to determine the spectrum of activity of new antineoplastic agents on various human tumors.

Topics: Adenocarcinoma; Agar; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cisplatin; Colony-Forming Units Assay; Cyclophosphamide; Doxorubicin; Drug Resistance; Female; Humans; Melanoma; Melphalan; Ovarian Neoplasms; Tumor Stem Cell Assay

Oestrogen receptors were measured in the primary breast tumours of 508 patients and progesterone receptors in those of 486 patients. Survival from mastectomy was significantly longer in patients with receptor-positive tumours. There was no significant difference between patients with receptor-positive and receptor-negative tumours in the relapse-free interval, but survival from first relapse was longer in patients with receptor-positive tumours. Axillary node status and tumour size indicated the probability of relapse but did not influence the length of survival after relapse. Response to tamoxifen or ovarian ablation was known in 65 of the 137 patients who relapsed. Survival from first relapse was significantly longer in patients who both responded to hormone therapy and had receptor-positive tumours. Patients who did not respond to hormone therapy and had receptor-positive tumours had the same survival characteristics as those with receptor-negative tumours who did not respond.

Topics: Breast Neoplasms; Female; Follow-Up Studies; Humans; Mastectomy; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

Fifty-seven patients with metastatic breast carcinoma have been treated with mitomycin C (10 mg/m2 IV 6-weekly), melphalan (6 mg/m2 PO X 3 days, 3-weekly), and methotrexate (35 mg/m2 IV 3-weekly) to assess the efficacy and toxicity of this regimen. Of 48 evaluable patients 19 (40%) responded for a median period of 5 months and 12 (25%) had stabilisation of disease. Of the 12 patients previously treated with adriamycin only one responded, whereas 18 of the 36 patients without previous chemotherapy responded. Although healing of bone metastases was infrequent control of hypercalcaemia was commonly seen. Generally the treatment was well tolerated and treatment was stopped in only five patients because of toxicity. Cumulative marrow toxicity was observed but was not a significant problem in the first 6 months of treatment. Mitomycin C, melphalan, and methotrexate (MMM) appears to provide an effective, well tolerated chemotherapy combination for metastatic breast carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Melphalan; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Palliative Care

Topics: Agar; Animals; Biopsy; Breast Neoplasms; Cell Survival; Colonic Neoplasms; Colony-Forming Units Assay; Culture Techniques; Female; Humans; Male; Melanoma; Melphalan; Mice; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Tumor Stem Cell Assay

A 47-year-old woman developed a unique myeloproliferative disorder 36 months after receiving adjuvant chemotherapy postoperatively for breast carcinoma. Her bone marrow and peripheral blood exhibited many of the myelodysplastic changes commonly observed in treatment-linked leukemia. In addition, there was striking marrow and blood eosinophilia and eosinophilic infiltration in multiple organs. She also developed a poorly differentiated lymphocytic lymphoma which responded to therapy. Her myeloproliferative disorder, with marked eosinophilia, continued to progress, however, and she died shortly after its diagnosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Eosinophilia; Female; Humans; Lymphoma, Non-Hodgkin; Mastectomy; Melphalan; Middle Aged; Myeloproliferative Disorders; Prednisone; Vincristine

Thirty patients with histologically proven node-positive early breast cancer (Stage II) were treated by total mastectomy and axillary clearance and adjuvant chemotherapy regimens including melphalan for 1 year. These patients were studied sequentially, at 3-month intervals, for up to 2 years to assess effects of cytotoxic drugs on immune function, and to determine whether any changes in immune function were related to recurrence. All indices were in the normal range before chemotherapy. The most marked and long-lasting effects of chemotherapy were on numbers of circulating T-cells and B-cells. Mean counts +/- one standard error (X 10(6)/ml) for T-cells before and 12 months after stopping chemotherapy were 1.537 +/- 0.118 and 0.874 +/- 0.120 (P less than 0.01), and for B-cells 0.345 +/- 0.060 and 0.207 +/- 0.030 (P less than 0.01). Functional indices of T-cell and B-cell competence were less compromised than values for cell counts and, in contrast, recovery occurred either during or within 3 months of stopping chemotherapy. This held for both T-cell function measured by delayed-type hypersensitivity (DTH) responsiveness to five recall antigens and mitogenic responsiveness to phytohemagglutinin, and for B-cell function measured by titration of blood group isohemagglutinins. After 4 years the 30 subjects were divided into groups according to whether there was recurrence of cancer (14) or no recurrence (16); the only index predictive of recurrence was depression of DTH to recall antigens. Thus it was found that cytotoxic chemotherapy with melphalan appears to cause long-lasting depression of cell counts but only short-lasting depression of functional indices of immunocompetence, and that levels of immunologic indices during chemotherapy are mostly nonpredictive of recurrence of cancer. The results prompt some caution in the use of adjuvant chemotherapy, at least with melphalan.

Topics: Adult; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; B-Lymphocytes; Breast Neoplasms; Combined Modality Therapy; Female; Humans; Immunity, Cellular; Immunity, Innate; Isoantibodies; Mastectomy; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Pilot Projects; T-Lymphocytes; Time Factors

The measurement of estrogen and progesterone receptors in human breast cancer provides useful markers for predicting response to endocrine therapy. In human breast cancer, about 90% of unresponsive tumors and 60-80% of tumors responsive to endocrine therapy can be predicted by receptor measurement. Hormone-dependency of breast cancer easily disappears, and endocrine therapy for hormone-dependent cancer markedly encourages disappearance. Since very useful non-steroidal antiestrogens have been synthesized recently, the usefulness of drug-based endocrine therapy for breast cancer has become more important compared with brought about by surgical therapy. To improve the effectiveness of endocrine therapy for hormone-dependent cancer, the proliferation of hormone-independent cancer cells developing from hormone-dependent cancer cells during endocrine therapy should be inhibited. For inhibition, chemotherapy combined with the endocrine therapy and adjuvant endocrine therapy seem to be useful methods for the future.

Topics: Animals; Breast Neoplasms; Female; Fluorouracil; Humans; Melphalan; Mice; Neoplasms, Hormone-Dependent; Rats; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

Topics: Animals; Antineoplastic Agents; Axilla; Breast Neoplasms; Castration; Combined Modality Therapy; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Male; Mastectomy; Melphalan; Menopause; Mice; Neoplasm Staging; Prognosis; Tamoxifen

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Topics: Adolescent; Adult; Aged; Bone Marrow Transplantation; Breast Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Evaluation Studies as Topic; Female; Gastrointestinal Diseases; Humans; Male; Melanoma; Melphalan; Middle Aged; Neuroblastoma; Neutropenia; Sarcoma, Ewing; Thrombocytopenia; Time Factors

Natural killer (NK) cell activity and antibody-dependent (K) cell activity were studied sequentially in 30 patients with early node-positive breast cancer entered into an adjuvant chemotherapy trial. The drugs used were melphalan, and melphalan with methotrexate, given for 12 months. Estimations were made 3-monthly during chemotherapy, and then at 15 and 24 months to assess recovery. Mean values for NK-cell activity during chemotherapy were significantly lower than the mean pre-chemotherapy baseline value at all time-points from 3 to 15 months, but there was recovery by 24 months. Mean values for K-cell activity during chemotherapy did not appear to differ from the mean pre-chemotherapy value, but variability in individual values was high. Over a 4-year follow-up period, a comparison of 16 patients who did not develop recurrent breast cancer with 14 who did showed that NK-cell activity was significantly lower in the latter group 12 months after the start of chemotherapy.

Topics: Antibody-Dependent Cell Cytotoxicity; Breast Neoplasms; Cytotoxicity, Immunologic; Drug Therapy, Combination; Female; Humans; Killer Cells, Natural; Long-Term Care; Melphalan; Methotrexate; Recurrence

Therapy of solid and hematologic tumors with alkylating agents appears to increase the frequency of acute non-lymphocytic leukemia (ANLL), as indicated by the cases reported in the literature. The carcinogenetic mechanism of alkylating agents seems related to their ability to damage DNA, and this is supported by the findings of multiple cytogenetic abnormalities in these patients. We report a case of ANLL secondary to therapy with melphalan, which was utilized on an adjuvant basis for breast cancer. ANLL developed 24 months after chemotherapy was discontinued. Results of the cytogenetic analysis in our patient showed multiple rearrangements and marker chromosomes. Among these was a large metacentric chromosome, identified in 6 of 8 karyotypes, in the size range of group A, which probably resulted from a translocation t(7;14) (7qter leads to 7p11::14p11 leads to 14qter). The natural history of the underlying disease and of the ANLL in our patient and data from chromosomal analysis seem to confirm the hypothesis that alkylating agents are potentially leukemogenic in man, probably through genetic damage. This possibility should be considered when such cytotoxic drugs are used in an adjuvant setting.

Topics: Breast Neoplasms; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Melphalan; Middle Aged

The possible influence of histologic grade, necrosis and size of invasive breast cancers on the five year survival rate of women treated in NSABP clinical trials with regimens of L-PAM (P) and L-PAM + 5-FU (PF) and for four years in those receiving L-PAM + 5-FU + methotrexate (PMF) was investigated. Generally, all regimens effected an increased survival when compared to controls that did not receive adjuvant therapy. However, this favorable response was statistically more pronounced in those women whose cancers were histologically evaluated to be poorly differentiated (histologic grade 3) and exhibited four or more regional axillary nodal metastases. Patients whose cancers were associated with 1-3 nodal metastases were not found to exhibit statistically significant responsiveness to any regimen regardless of tumor grade. Possible reasons for this dichotomy are presented. Tumor necrosis, although paralleling the results noted with histologic grade, failed to further discriminate patients who might respond to chemotherapeutic agents. Tumor size was not found to be a consistently significant indicator of chemotherapeutic responsiveness. Generally, the PF and PMF regimens were more effective than P alone in those patients exhibiting a response. These findings indicate the importance of identifying subsets of patients with breast cancer not only from a biologic but also therapeutic perspective.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Middle Aged; Prognosis

Serum vitamin A and retinol-binding protein (RBP) concentrations were measured in patients comprising 53 myeloma and 28 epithelial cell cancer cases. Vitamin A levels in these patients were found to be significantly lower than those in the 30 healthy subjects, the effect being more marked in the patients with cancer of epithelial origin. The serum concentrations of retinol-binding protein (RBP) fell in parallel with vitamin A in the epithelial cancer patients, while the RBP concentrations remained unaffected in the patients with myeloma, suggesting that the underlying factor for resulting low vitamin A levels may be different in these two groups of patients.

Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Retinol-Binding Proteins; Urinary Bladder Neoplasms; Uterine Neoplasms; Vitamin A

Tumour cells from 7 patients with ovarian carcinoma and from 22 different human tumour xenografts representing a wide range of histological sub-types have been examined for multicellular spheroid forming ability. Spheroid formation was limited to cells derived from xenografts. Of the 22 lines tested, 5 formed spheroids capable of growth in isolation. There was no clear relationship between histological type and spheroid-forming ability. The plating efficiency of tumour cells obtained from spheroids was always greater than for the cells obtained from the dissociated tumour of origin and was in some cases as much as 6-fold greater. Spheroid growth was nearly exponential for 4 cell lines. Volume growth delay was used to investigate the activity of melphalan, adriamycin, the Vinca alkaloids, CCNU and cisplatin. Differences between lines in drug response broadly reflected patient and in vivo xenograft response.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Aggregation; Cell Division; Cell Line; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Lomustine; Lung Neoplasms; Melphalan; Mice; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Transplantation, Heterologous; Vinca Alkaloids

A combination of AMSA and peptichemio was evaluated in patients with advanced breast cancer refractory to conventional chemotherapy. Of 33 evaluable patients, five patients (15%) achieved partial remission, two patients (6%) had less-than-partial remission, nine patients (27%) had stable disease, and seventeen patients (52%) had progressive disease. The median duration of response was 6 months (range: 3-8 months). The median duration of stable disease was 5 months (range: 2-7 months). Myelosuppression was the dose-limiting toxicity. This combination of AMSA and peptichemio did not result in an improved response rate or duration of remission compared to the previous experience with single-agent therapy with either of these agents.

Topics: Adult; Aged; Aminoacridines; Amsacrine; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leukopenia; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombocytopenia

Fifteen patients with clinical primary inflammatory carcinoma of the breast were treated with initial chemoimmunotherapy between September 1974 and May 1977. The protocol was a combination of Adriamycin, vincristine, 5-fluorouracil, and methotrexate given by I.V. push, and melphalan per os. Thermographic cooling was taken as the criterion of operability. Initial chemotherapy was resumed after surgery up to a total of ten courses and followed by maintenance chemotherapy for a minimum of one year. Immunotherapy using I-BCG-F. Pasteur was routinely associated with the antimitotic agents. The median survival for our 15 patients has not been reached and exceeds 56 months. These results correspond to an obvious therapeutic benefit compared with recent attempts in which similar chemoimmunotherapy protocols were used; this benefit seems to be the consequence of the adaptation of the length of initial chemotherapy to the data given by plate-thermography.

Topics: Aged; Antineoplastic Agents; BCG Vaccine; Breast Neoplasms; Carcinoma; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Thermography; Time Factors; Vincristine

Ultrasonic energy can generate controlled, local hyperthermia (42 degrees C--43 degrees C), and ultrasonic hyperthermia results in increased cytotoxicity of chemotherapeutic drugs for the treatment of cancer. Human breast (MX-1) and lung (LX-1) tumors implanted subcutaneously in athymic nude mice were treated with a single application of ultrasonic (670 kHz, peak intensity of 5 watts/cm2) hyperthermia (43.0 degrees C +/- 0.5 degrees C) for 30 minutes in combination with suboptimal doses of cyclophosphamide, melphalan, or procarbazine. Delays in the tumor growth rate and temporary tumor regression were observed. Comparison of the tumor growth rate with single modalities, ie, drug or hyperthermia alone, shows evidence of synergistic effects of the combination of ultrasonic hyperthermia and melphalan on MX-1 and of hyperthermia and procarbazine on LX-1 tumors.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Drug Synergism; Female; Hot Temperature; Humans; Lung Neoplasms; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Procarbazine; Transplantation, Heterologous; Ultrasonic Therapy

Topics: Adjuvants, Pharmaceutic; Adult; Aminoglutethimide; Antineoplastic Agents; Breast Neoplasms; Castration; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Hypophysectomy; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Receptors, Estrogen; Tamoxifen

A clonogenic assay of long-term breast cancer cell cultures in vitro has been developed to provide a highly reproducible method with which to quantitate tumor cell killing by hormones and/or cytotoxic chemotherapeutic agents. Monolayer cultures of estrogen receptor-positive MCF-7 human breast cancer cells and of estrogen receptor-negative Evsa T cells are harvested by treatment with 0.01% trypsin:0.02% EDTA in Hanks' balanced salt solution. Cell suspensions are treated with drug or hormone in serum-free medium for 1 hr at 37 degrees; treated cells are washed, plated, and cultured for approximately 14 days; and colonies consisting of greater than or equal to 30 cells are counted. Compared to estrogen receptor-positive cells, estrogen receptor-negative cells were 2-fold more sensitive to melphalan but were conversely 1.9-fold more resistant to Adriamycin; these differences were statistically significant (p less than 0.001). Thus, response to cytotoxic chemotherapeutic agents appeared to be independent of estrogen receptor status. For cells treated with diethylstilbestrol, the dose of drug or hormone reducing the surviving cell fraction to 1/e (DO) for estrogen receptor-positive cells was 2.27 nmol/ml, and that for estrogen receptor-negative cells was 2.80 nmol/ml; this difference was not statistically significant. However, with tamoxifen therapy, the DO for estrogen receptor-positive cells was 0.601 nmol/ml, and that for estrogen receptor-negative cells was 3.64 nmol/ml; this 6-fold greater degree of resistance to tamoxifen of estrogen receptor-negative cells was highly significant (p less than 0.001). Treatment of cells for 24 hr with 17 beta-estradiol stimulated proliferation not only of estrogen receptor-positive cells but also of estrogen receptor-negative cells. However, estradiol at concentrations up to 200 microM had no apparent cytocidal activity, as measured by the clonogenic assay. Furthermore, treatment of MCF-7 cells simultaneously with estradiol and either diethylstilbestrol or tamoxifen failed to reverse the cytocidal activity of those two agents. These findings suggest that, in the clonogenic assay described herein, diethylstilbestrol and tamoxifen may kill human breast cancer cells by an independent mechanism of action and that the cytocidal activity of diethylstilbestrol and the proliferative effect of 17 beta-estradiol appear to be independent of estrogen receptor status.

Topics: Breast Neoplasms; Cell Line; Cell Survival; Cells, Cultured; Clone Cells; Diethylstilbestrol; Dose-Response Relationship, Drug; Doxorubicin; Estradiol; Female; Humans; Kinetics; Melphalan; Receptors, Estrogen; Tamoxifen

Forty patients with metastatic breast cancer were treated with a combination of continuous 5-day infusion vinblastine and peptichemio. All patients had received prior therapy with 5-fluorouracil, adriamycin, cyclophosphamide and methotrexate. Vinblastine was given at a dose of 1.2 mg/m2/day for 5 days. Following completion of the 5-day infusion vinblastine, peptichemio was given as a rapid I.V. injection at a dose of 60 mg/m2. Ten partial responses (30%) were observed among the 33 evaluable patients with a median time to treatment failure of 6 months. Myelosuppression, predominantly granulocytopenia, was the major toxicity resulting from this combination. The response rate of this combination is not better than that observed with continuous 5-day infusion vinblastine alone.

Topics: Adult; Aged; Agranulocytosis; Breast Neoplasms; Drug Therapy, Combination; Female; Humans; Infusions, Parenteral; Melphalan; Middle Aged; Peptichemio; Vinblastine

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Pulmonary Fibrosis; Radiotherapy; Remission, Spontaneous

As the observation times of current studies using adjuvant chemotherapy in the treatment of operable stage II breast cancer lengthen, the probability of significantly reducing the high risk of developing metastases associated with this stage of the disease is also increasing and should be reflected in improved cure rates. The theoretical basis, prerequisites and presently available results for adjuvant chemotherapy of breast cancer are discussed. Adjuvant combination chemotherapy provides better results than monochemotherapy with Alkeran. While earlier results suggested that adjuvant chemotherapy is especially effective in premenopausal women, newer studies and analyses indicate that appropriate dosage and consistent administration of chemotherapy are of decisive importance. Exact determination and documentation of the tumor stage, and especially the regional lymph node status, is the most important factor in determining the indication for adjuvant chemotherapy. Adjuvant chemotherapy is still best with many unsolved problems. These include the duration, necessary intensity based upon risk factors, and short- and long-term side effects.

Topics: Adult; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Middle Aged; Neoplasm Metastasis; Prednisone; Risk; Vincristine

The results of treatment of 110 out-patients with breast metastases, using various repeated schemes of chemotherapy, are discussed. The results and recommendations may be integrated with the procedures of selection of schemes of breast metastasis treatment. Good tolerance, virtual absence of side--effects and complications (e. g. persistent leukopenia) were observed. Integration of the new scheme with antibiotic treatment (carminomycin and adriamycin) is suggested.

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisolone; Time Factors; Vincristine

A study was made on the recovery of the bone marrow after adjuvant chemotherapy given to 30 post-mastectomy patients with stage II breast cancer treated with either melphalan or melphalan and methotrexate at 6-weekly intervals for 1 year. Counts of peripheral blood cells were made serially during treatment and then for a further 2 years after stopping chemotherapy. Mean counts for all cell types fell during chemotherapy and recovery was long-delayed. Thus 24 months after chemotherapy, mean counts for total leucocytes and platelets were significantly lower than mean pretreatment counts and counts for a normal female population, and the count for neutrophils was significantly lower than the count before treatment; after 24 months mean counts for lymphocytes were not significantly depressed. Melphalan was assumed to be the agent responsible. Slow haematological recovery after cessation of adjuvant chemotherapy with one particular regimen points to the need for including long-term post-chemotherapy observation of the bone marrow in the assessment of adjuvant chemotherapy programmes.

Topics: Antineoplastic Agents; Blood Cell Count; Breast Neoplasms; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukocyte Count; Lymphatic Metastasis; Mastectomy; Melphalan; Methotrexate; Platelet Count

This report summarizes the present status of the proposed use of WR-2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid) acid) in radiotherapy and/or chemotherapy. This drug selectively concentrates in normal tissues, both in vivo and in vitro, but is passively absorbed by virtually all of the solid tumors which have been studied. In vivo this drug can increase the resistance to radiation or alkylating agents (nitrogen mustard, cis-platinum, cyclophosphamide, and L-phenylalamine mustard) by factors of up to 3, while leaving the solid tumors to suffer the full effects of either treatment.

Topics: Alkylating Agents; Amifostine; Animals; Breast Neoplasms; Cyclophosphamide; Humans; In Vitro Techniques; Mechlorethamine; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Organothiophosphorus Compounds; Platinum; Rabbits; Radiation-Protective Agents; Rats; Time Factors

Topics: Age Factors; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Prognosis

Evidence is presented that melphalan uptake by MCF-7 human breast cancer cells and peripheral blood lymphocytes from normal human subjects is an active process involving 2 amino acid carriers. Quantitative differences were observed in drug transport between the 2 cell types. Cell/medium distribution ratios of melphalan at equilibrium conditions were approx. 4-fold higher in breast cancer cells than in lymphocytes. The transport capacity, Vmax, for both carrier systems was at least 50-fold greater in MCF-7 cells than in lymphocytes, whereas the Michaelis constants were similar. These findings, in part, provide a rational basis for the use of melphalan in the chemotherapy of breast cancer.

Topics: Amino Acids; Biological Transport; Breast Neoplasms; Carrier Proteins; Cells, Cultured; Drug Interactions; Kinetics; Lymphocytes; Melphalan; Sodium

Two patients developed acute bone marrow cancer following mastectomy and institution of alkylating agents as adjuvant chemotherapy. An aneuploid condition was observed in both cases, along with involvement of chromosomes 11 and 12 in structural rearrangements. Subsequent studies of 18 patients who had or had not received such therapy showed no evidence of chromosomal aberrations. However, the long-term effect of adjuvant chemotherapy in cancer patients is still of concern until additional information becomes available.

Topics: Adult; Aged; Bone Marrow; Breast Neoplasms; Chromosome Aberrations; Female; Humans; Melphalan; Middle Aged; Pancytopenia

Topics: Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Humans; Lymphoma; Melphalan; Multiple Myeloma; Neoplasm Metastasis; Palliative Care; Prednisone; Vincristine

Chemotherapy employed in the treatment of metastatic breast cancer effectively palliates the disease. Response rates to combination chemotherapy are high (greater than 50%); response durations, however, are still very short (less than 1 year). Future investigations must focus on the development of alternate maintenance regimens to improve response duration. Other areas for future study include the use of immunotherapy in conjunction with chemotherapy and the combination of chemotherapy and endocrine manipulation.

Topics: Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Prednisone; Vincristine

The hormonal features of the menstrual cycle determined by measurement of serum LH, FSH, oestradiol, progesterone and prolactin were normal in thirteen breast cancer patients clinically disease free and not taking anti-tumour therapy. Results of similar studies during seven menstrual cycles in four patients on an adjuvant therapy programme of L-phenylalanine mustard (L-PAM) + 5-flurouracil (5-FU) also had normal hormonal characteristics after three to fourteen courses of chemotherapy. Amenorrhoea with elevated gonadotrophins occurred after seven courses of chemotherapy in one 48-year-old woman. Adjuvant chemotherapy does not appear to result in major alterations in hormone secretion during menstrual cycles of women who continue to menstruate while on therapy.

Topics: Adult; Breast Neoplasms; Estradiol; Female; Fluorouracil; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Melphalan; Menstruation; Middle Aged; Progesterone; Prolactin

Topics: Breast Neoplasms; Female; Humans; Melphalan; Neoplasm Metastasis

Topics: Adult; Age Factors; Aged; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Ovary; Prednisone; Recurrence

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Melphalan; Ovarian Neoplasms; Premedication

Prolonged L-Phenylalanin mustard Administration and combination chemotherapy as on adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically axillary nods. Lead to improvement of results. L-PAM and CMF have been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those who are premenopausal. In our trial no improvement of results could be observed by administration of Chlorambucil, Cyclophosphamide and 5-FU. Experience with both single-drug and combination chemotherapy has shown that the benefit of these treatments, as judged by the disease-free intervall, is restricted largely to premenopausal patients. This suggest that the therapeutic effect is due, at least to cytotoxic suppression of endocrine function. Therefore further prospective trial in this field are necessary.

Topics: Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Cyclophosphamide; Fluorouracil; Humans; Melphalan; Methotrexate; Thiotepa

Topics: Aged; Breast Neoplasms; Diagnostic Errors; Female; Humans; Leukemia, Myeloid, Acute; Mastectomy; Melphalan

Topics: Adult; Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Mastectomy; Melphalan; Recurrence

New concepts and treatments currently available for adjuvant studies are illustrated by a review of ongoing studies sponsored by the National Cancer Institute. More thorough information is needed on immunotherapeutic agents to allow more rationale in the use of these agents. Solid bases to properly select drugs or drug combinations for adjuvant purposes are being established. However, dose-schedule and duration of treatment are still to be defined. Strategies directed at prolonging the benefit of surgical adjuvant chemotherapy remain to be planned. Progress continuously achieved with immunotherapy and chemotherapy should rapidly broaden the spectrum of tumour types to be included in adjuvant studies.

Topics: Antineoplastic Agents; Breast Neoplasms; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Dianhydrogalactitol; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lung Neoplasms; Male; Melphalan; Methotrexate; Neoplasms; Osteosarcoma; Rectal Neoplasms

Topics: Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Hormones; Humans; Immunotherapy; Mastectomy; Melphalan; Methotrexate; Neoplasm Metastasis

Topics: Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Mastectomy; Melphalan; Postoperative Care; Pregnancy; Pregnancy Complications

Topics: Adenocarcinoma; Adult; Aged; Bone Marrow; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Recurrence

Plasma oestradiol-plus-oestron (E2 + E1), follicle-stimulating hormone (F.S.H.), luteinising hormone (L.H.), androstenedione (A2), and dehydroepiandrosterone sulphate (D.S.) were measured in 33 breast-cancer patients before and after adjuvant chemotherapy. Before treatment the plasma E2 + E1, A2, and D.S. levels were significantly higher and the L.H. and F.S.H. lower in the 16 premenopausal patients than in the 17 postmenopausal patients. After 6 mo of adjuvant chemotherapy the premenopausal patients, 11 of whom had become amenorrhoeic, showed striking reductions in plasma E2 + E1 and A2 and elevations in plasma L.H. and F.S.H. Further changes were evident after 12 mo of treatment. Plasma-A2 fell after chemotherapy in the postmenopausal group; the other hormones were unchanged. The beneficial effects of adjuvant chemotherapy for breast cancer may result, in part, from suppression of ovarian function.

Topics: Adult; Aged; Androstenedione; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Dehydroepiandrosterone; Drug Therapy, Combination; Estradiol; Estrone; Female; Fluorouracil; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Middle Aged; Ovary; Vincristine

Topics: BCG Vaccine; Breast Neoplasms; Female; Humans; Immunity, Cellular; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Techniques; Immunosuppression Therapy; Immunotherapy; Lymphocytes; Mastectomy; Melphalan; Postoperative Care; Skin Tests; T-Lymphocytes

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Fluorouracil; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Methotrexate; Thiotepa

Topics: Breast Neoplasms; Female; Humans; Mastectomy; Melphalan; Methotrexate

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Menopause; Methotrexate; Postoperative Care; Prednisone; Vincristine

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Therapy, Combination; Female; Humans; Lomustine; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Nitrosourea Compounds; Prednisone

Topics: Adenocarcinoma; Adenocarcinoma, Scirrhous; Age Factors; Aged; Breast Neoplasms; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma

Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Cyclophosphamide; Female; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Pregnancy; Thiotepa; Trophoblastic Neoplasms; Uterine Neoplasms

Hormonal manipulation and chemotherapy used as adjuvants to surgery are aimed at controlling systemic micro-metastases from breast cancer. Primary hormonal manipulation consists of oophorectomy (for premenopausal women) or hormone administration. Hormone receptors, which are sometimes present in tumors, are now being measured and tested for their predictive value as to which tumors will respond to manipulation. Systemic chemotherapy has been used for years, but no drug that is specific against mammary tumors has yet been discovered. New drugs or combinations of older drugs are constantly being tested. To acquire a good data base for future decisions, systemic chemotherapy should be administered and patients followed up according to carefully constructed protocols.

Topics: Breast Neoplasms; Castration; Doxorubicin; Drug Therapy, Combination; Female; Hormones; Humans; Melphalan; Thiotepa

Topics: Breast Neoplasms; Humans; Immunity; Melphalan; Multiple Myeloma

Topics: Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Methotrexate; Neoplasm Recurrence, Local; Risk

Topics: Antibodies, Neoplasm; Breast Neoplasms; Cell Division; Female; Humans; Immunity; Kinetics; Lymph Nodes; Lymphatic System; Melphalan; Neoplasm Metastasis; Research Design

A wide variety of approaches are being applied to the therapy of breast cancer. Treatment begins with a biopsy followed by mastectomy to remove the primary tumor. The risk category must be determined and, at present, an axillary dissection appears to be required; in the future, tumor cell markers may replace the role of an axillary dissection in the determination of risk category (TORMEY et al., 1975). If the nodes are positive, adjuvant chemotherapy and possibly immunotherapy should be considered. A positive estrogen receptor assay suggests that patients may also benefit from endocrine treatments. If it is negative, the chances of responding to hormonotherapy are very limited, except, perhaps, for anti-estrogens (McGUIRE, et al., 1975). Adjuvant therapy for patients with negative nodes is not recommended at this time; this view may have to be modified as the results of current adjuvant studies become available. We have at hand the means to improve the cure rate of patients with breast cancer. We are getting better diagnostic methods and find more patients with negative nodes. We know more about the primary treatment and have systemic modalities that are effective in the adjuvant situation. The immediate problem is to learn how to put these treatments together, and this task has been undertaken by on-going clinical trials. We are anticipating the results with optimism.

Topics: Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Methotrexate; Prognosis; Time Factors

Topics: Breast Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Time Factors; Vincristine

Topics: Breast Neoplasms; Female; Humans; Mastectomy; Melphalan; Postoperative Care; Thiotepa

Immunological function was studied in 48 patients before, during and after cancer treatment, using cutaneous tests, spontaneous rosettes test and the PHA and PWM lymphocyte stimulation tests. Chemotherapeutic drugs were used individually or in combination for 5 days a month and were preceeded by a cellular synchronization using Vincristine (1 mg/m2/day). When treatment was discontinued, we observed in 30 patients increased rates of spontaneous rosettes and of thymidine uptake. We noticed in several cases that the cutaneous tests became positive even if they were negative before and during treatment. The I.O.P. appeared 5 days after chemotherapy was discontinued and lasted 8 to 12 days. The topography of the neoplasm had no influence on the I.O.P. Failure to manifest I.O.P. is not indicative of a negative response of the tumor to chemotherapy (9 positive responses to chemotherapy out of 18 patients without I.O.P.) But the I.O.P. was a fairly constant feature in patients with positive response to chemotherapy and with favorable prognosis (28/30).

Topics: Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immune Adherence Reaction; Liver Neoplasms; Lung Neoplasms; Lymphocyte Activation; Melphalan; Methotrexate; Neoplasms; Ovarian Neoplasms; Thiotepa; Vincristine

Topics: Breast Neoplasms; Female; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Menopause; Thiotepa

Topics: Antineoplastic Agents; Breast Neoplasms; Busulfan; Carcinogens; Cyclophosphamide; Humans; Leukemia, Myeloid; Lung Neoplasms; Melphalan; Methotrexate; Neoplasms; Pancreatic Neoplasms; Rectal Neoplasms; Triaziquone; Urinary Bladder Neoplasms

Topics: Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Prognosis; Vincristine

Topics: Breast Neoplasms; Humans; Lymphatic Metastasis; Mastectomy; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Female; Humans; Lymphatic Metastasis; Melphalan; Middle Aged

Topics: Adult; Age Factors; Aged; Breast Neoplasms; Contraceptives, Oral, Hormonal; Family; Female; Humans; Mastectomy; Maternal Age; Medical Records; Melphalan; Menopause; Middle Aged; Neoplasm Metastasis; Parity; Pregnancy

Topics: Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Vincristine

Topics: Breast Neoplasms; Female; Humans; Melphalan; Radiotherapy

Although breast cancer presents as localized disease and is treated with local modalities, i.e. surgery and radiotherapy, patients die with metastatic disease. For patients with positive nodes, the recurrence rates are well known. It is this group of patients who should receive more aggressive treatment. Chemotherapeutic regimens are available that cause responses in patients with advanced disease in the range of 20% to 65%, with about 15% complete responses The current paper deals with the application of several chemotherapeutic regimens at the time of surgery in those patients at high risk. The preliminary results indicate a significant decrease in the recurrence rates. Additional studies combining chemotherapy and hormonal procedures are mentioned.

Topics: Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prednisone

Topics: Adenine Nucleotides; Adenosine Diphosphate; Amidines; Antibiotics, Antineoplastic; Bleomycin; Blood Platelets; Breast Neoplasms; Bronchial Neoplasms; Cyclophosphamide; Doxorubicin; Firefly Luciferin; Fluorouracil; Glyoxal; Hodgkin Disease; Humans; Hydrazones; Leukemia; Luciferases; Lymphocytes; Melphalan; Methotrexate; Neoplasms; Nephelometry and Turbidimetry; Plasmacytoma; Platelet Aggregation; Vinca Alkaloids

Topics: Alabama; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Mastectomy; Melphalan; Methotrexate; Middle Aged; Surveys and Questionnaires; Thiotepa

Topics: Adenocarcinoma; Autoimmune Diseases; Autopsy; Bone Marrow; Breast Neoplasms; Female; Humans; Immunoglobulin G; Leukemia; Melphalan; Middle Aged; Multiple Myeloma

This work discusses the experience of one surgical team in the Third Surgical Unit at the Republican Teaching Hospital, Baghdad, from 1967 to 1970. 112 patients with advanced malignant lesions in various parts of the body were dealt with. In 84, the intra-arterial route was adopted; in the remaining, systemic administration of cytotoxic agents either singly or in combination was employed. The results are reported in terms of subjective and objective response, and the various complications are discussed.

Topics: Antineoplastic Agents; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Iraq; Male; Melphalan; Methotrexate; Mouth Neoplasms; Podophyllin; Stomach Neoplasms; Urogenital Neoplasms

Topics: Adult; Breast Neoplasms; Carcinosarcoma; Female; Humans; Mastectomy; Melphalan; Neoplasm Metastasis; Toxins, Biological

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Antimetabolites; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Chlorambucil; Choriocarcinoma; Cyclophosphamide; Female; Fluorouracil; Hodgkin Disease; Humans; Hydrazines; Intestinal Neoplasms; Melphalan; Methotrexate; Multiple Myeloma; Ovarian Neoplasms; Pregnancy; Thiotepa; Vinblastine

Topics: Breast Neoplasms; Female; Humans; Melphalan

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Culture Techniques; Flavonoids; Fluorouracil; HeLa Cells; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methods; Mitomycins; Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Female; Hodgkin Disease; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms; Palliative Care; Stomach Neoplasms; Thiotepa

Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Melphalan; Middle Aged

Topics: Abdominal Neoplasms; Angiography; Breast Neoplasms; Geriatrics; Gold; Humans; Injections; Iodine Isotopes; Leukemia; Lymphatic Metastasis; Lymphatic System; Lymphography; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Methotrexate; Neoplasms; Radioisotopes; Radionuclide Imaging; Retroperitoneal Neoplasms; Scandium; Thiotepa; Yttrium

Topics: Breast Neoplasms; Carcinoma, Bronchogenic; Dysgerminoma; Female; Gastrointestinal Neoplasms; Hodgkin Disease; Humans; Liver Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Ovarian Neoplasms; Sarcoma

Topics: Breast Neoplasms; Dysgerminoma; Female; Follicle Stimulating Hormone; Hexestrol; Humans; Melphalan; Neoplasms; Ovarian Follicle; Ovarian Neoplasms; Pharmacology; Pituitary Diseases; Pituitary Gland; Progesterone; Rats; Research; Thiotepa

Topics: Aziridines; Breast Neoplasms; Cyclophosphamide; Female; Humans; Melphalan; Neoplasms; Ovarian Neoplasms; Surgical Procedures, Operative; Thiotepa; Triethylenemelamine

Topics: Adenine; Bone Marrow Transplantation; Breast Neoplasms; DNA; Female; Folic Acid; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Neoplasms; Ovarian Neoplasms; Perfusion; Sarcoma; Thiotepa; Triethylenemelamine

Topics: Adenofibroma; Animals; Breast Diseases; Breast Neoplasms; Fibroadenoma; Humans; Hypertrophy; Mammary Glands, Animal; Mammary Glands, Human; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Melphalan; Pharmacology; Rats; Research; Toxicology

Topics: Antineoplastic Agents; Aziridines; Breast Neoplasms; Cell Nucleus; Coloring Agents; Cyclophosphamide; Female; Hodgkin Disease; Humans; Hyperplasia; Hypertrophy; Mathematics; Melphalan; Ovarian Neoplasms; Pathology; Staining and Labeling; Thiotepa; Triethylenemelamine; Uterine Neoplasms; Vaginal Smears

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Humans; Mammary Neoplasms, Experimental; Melphalan; Phenylalanine