melphalan and Ovarian-Neoplasms

This is the second update of the review first published in the Cochrane Database of Systematic Reviews in 2009, Issue 1. Epithelial ovarian cancer is diagnosed in over 200,000 women worldwide each year. Ten to 20% of women are diagnosed early, when there is still a good possibility of cure. The treatment of early-stage (stage I and IIa) disease involves surgery to remove the disease, often followed by chemotherapy (adjuvant chemotherapy). The largest clinical trials of adjuvant chemotherapy show an overall survival (OS) advantage with platinum-based chemotherapy; however the precise role and type of this treatment in subgroups of women with differing prognoses needs to be defined.. To undertake a systematic review of the evidence for adjuvant chemotherapy in early-stage epithelial ovarian cancer to determine whether chemotherapy following surgery offers a survival advantage over the policy of observation following surgery (with chemotherapy reserved for treatment of disease recurrence); and to determine if clinical subgroups of women with differing prognoses, based on histological subtype or completeness of surgical staging, have more or less to gain from adjuvant chemotherapy.. We performed an electronic search using the Cochrane Gynaecological Cancer Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 3), MEDLINE (1948 to March week 5, 2015), and EMBASE (1980 to week 14, 2015). We developed the search strategy using free-text and medical subject headings (MeSH). We also searched registers of clinical trials and citation lists of included studies for potentially relevant studies.. We included randomised clinical trials (RCTs) of women with early stage (I/IIa) epithelial ovarian cancer staged at laparotomy.. Two review authors independently extracted data and assessed study quality of included RCTs. We resolved any disagreements by discussion with a third review author. We used random-effects methods for all meta-analyses, including subgroup analyses.. The original version of this Cochrane review included five RCTs involving 1277 women. In this 2015 update, no new studies met the inclusion criteria but we included an additional paper with mature data (10-year follow-up) relating to a previously included study (ICON1).We included four studies in the meta-analyses and considered them to be at a low risk of bias. Most study participants (> 95%) had stage I ovarian cancer. Meta-analysis of five-year data from three studies indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (Hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53 to 0.93; 1008 women; 3 studies; I² statistic = 0%; high quality evidence). Likewise, meta-analysis of five-year data from four studies indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (HR 0.67, 95% CI 0.53 to 0.84; 1170 women, 4 studies; I² statistic = 0%; high quality evidence). These findings were robust over time, with 10-year HR estimates of 0.72 (95% CI 0.57 to 0.92; 925 women, 2 studies) and 0.67 (95% CI 0.53 to 0.83; 925 women, 2 studies) for OS and PFS, respectively (high quality evidence). The risk of death at 10 years follow-up favoured the adjuvant chemotherapy arm (0.76, 95% CI 0.62 to 0.94; 923 women, 2 studies; I² statistic = 0%), as did the findings for risk of progression at 10 years (RR 0.72, 95% CI 0.60 to 0.87; 925 women, 2 studies; I² statistic = 0%). Low quality evidence suggested that women with high-risk disease may have the most to gain from adjuvant chemotherapy. However, subgroup analyses could neither confirm nor exclude survival benefits in lower risk disease or in optimally staged disease. We found insufficient data to compare adverse events and long term risks between chemotherapy and observation groups.. High-quality evidence indicates that adjuvant platinum-based chemotherapy is effective in prolonging survival in women with early stage (FIGO stage I/IIa) epithelial ovarian cancer. It remains uncertain whether women with low- and intermediate-risk early stage disease will benefit as much from adjuvant chemotherapy as women with high-risk disease. Decisions to use adjuvant chemotherapy (AC) in these women should be mindful of this uncertainty, and the uncertainty regarding adverse events. Treatment of women with lower risk disease should be individualised to take into account individual factors.

Topics: Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Early Detection of Cancer; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Randomized Controlled Trials as Topic

Epithelial ovarian cancer is diagnosed in 4500 women in the UK each year of whom 1700 will ultimately die of their disease.Of all cases 10% to 15% are diagnosed early when there is still a good possibility of cure. The treatment of early stage disease involves surgery to remove disease often followed by chemotherapy. The largest clinical trials of this adjuvant therapy show an overall survival (OS) advantage with adjuvant platinum-based chemotherapy but the precise role of this treatment in subgroups of women with differing prognoses needs to be defined.. To systematically review the evidence for adjuvant chemotherapy in early stage epithelial ovarian cancer to determine firstly whether there is a survival advantage of this treatment over the policy of observation following surgery with chemotherapy reserved for treatment of disease recurrence, and secondly to determine if clinical subgroups of differing prognosis based on histological sub-type, or completeness of surgical staging, have more or less to gain from chemotherapy following initial surgery.. We performed an electronic search using the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 3), MEDLINE (1948 to Aug week 5, 2011) and EMBASE (1980 to week 36, 2011). We developed the search strategy using free-text and medical subject headings (MESH).. We selected randomised clinical trials that met the inclusion criteria set out based on the populations, interventions, comparisons and outcome measures.. Two review authors independently extracted data and assessed trial quality. Disagreements were resolved by discussion with a third review author. We performed random-effects meta-analyses and subgroup analyses.. Five randomised controlled trials (RCTs), enrolling 1277 women, with a median follow-up of 46 to 121 months, met the inclusion criteria. Four trials were included in the meta-analyses and we considered them to be at a low risk of bias. Meta-analysis of five-year data from three trials indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (1008 women; hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53 to 0.93). Likewise, meta-analysis of five-year data from four trials indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (1170 women; HR 0.67; 95% CI 0.53 to 0.84). The trials included in these meta-analyses gave consistent estimates of the effects of chemotherapy. In addition, these findings were robust over time (10-year PFS: two trials, 925 women; HR 0.67; 95% CI 0.54 to 0.84).Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy (HR for OS 1.22; 95% CI 0.63 to 2.37; two trials, 234 women) whereas those who had sub-optimal staging did (HR for OS 0.63; 95% CI 0.46 to 0.85; two trials, 772 women). One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 0.48; 95% CI 0.32 to 0.72) but not among those at low/medium risk (HR for OS 0.95; 95% CI 0.54 to 1.66). However, these subgroup findings could be due to chance and should be interpreted with caution.. Adjuvant platinum-based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having early (FIGO stage I/IIa) epithelial ovarian cancer. However, it may be withheld from women in whom there is well-differentiated encapsulated unilateral disease (stage 1a grade 1) or those with comprehensively staged Ib, well or moderately differentiated (grade 1/2) disease. Others with unstaged early disease or those with poorly differentiated tumours should be offered chemotherapy. A pragmatic approach may be necessary in clinical settings where optimal staging is not normally performed/achieved. In such settings, adjuvant chemotherapy may be withheld from those with encapsulated stage Ia grade 1 serous and endometrioid carcinoma and offered to all others with early stage disease.

Topics: Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Early Detection of Cancer; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Randomized Controlled Trials as Topic

Epithelial ovarian cancer kills about 1700 in the UK each year. Ten to fifteen percent of all cases are diagnosed early when there is still a good chance of cure. The treatment of early stage disease involves surgery to remove disease often followed by chemotherapy. The largest clinical trials of this adjuvant therapy show an overall survival (OS) advantage with adjuvant platinum based chemotherapy but the precise role of this treatment in sub-groups of patients with differing prognoses needs to be defined.. To systematically review the evidence for adjuvant chemotherapy in early stage epithelial ovarian cancer to determine; firstly whether there is a survival advantage of this treatment over the policy of observation following surgery with chemotherapy reserved for treatment of disease recurrence, and secondly; to determine if clinical sub-groups of differing prognosis based on histological sub-type or completeness of surgical staging, have more or less to gain from chemotherapy following initial surgery.. An electronic search was performed using the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2 2008), MEDLINE (1966 to 2008), EMBASE (1980 to 2008) and CancerLit. The search strategy was developed using free text and medical subject headings (MESH). This yielded a large number of article titles which were sifted down by two review authors to a limited number of articles, the full text versions of which were independently reviewed to select out clinical trials of direct and specific relevance to the review question. Hand searches of the clinical literature were conducted where appropriate to identify additional full-text papers or abstracts of other directly relevant clinical trials.. The review authors selected those clinical trials that met the inclusion criteria set out based on the populations, interventions , comparisons and outcome measures as detailed in the full text review.. Two review authors independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sub-group analyses were conducted.. Five randomised controlled trials (RCTs), enrolling 1277 women, with 46 to 110 months follow-up, met our inclusion criteria. These trials had low risk of bias. Meta-analysis of three trials with adequate data, assessing 1008 women, indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (hazard ratio (HR) 0.71; 95% CI 0.53 to 0.93). Likewise, meta-analysis of four trials with adequate data, assessing 1170 women, indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (HR 0.67; 95% CI 0.53 to 0.84). The trials included in these meta-analyses gave consistent estimates of the effects of chemotherapy.Sub-group analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy (HR for OS 1.22; 95% CI 0.63 to 2.37) whereas those who had sub-optimal staging did (HR for OS 0.63; 95% CI 0.46 to 0.85). One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 0.48; 95% CI 0.32 to 0.72) but not among those at low risk (HR for OS 0.95; 95% CI 0.54 to 1.66). However, these sub-group findings could be due to chance.. Adjuvant platinum based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having early stage epithelial ovarian cancer. However, even given the limits of sub-group analyses, there is strong evidence that optimal surgical staging identifies patients who have either little or nothing to gain from adjuvant chemotherapy. Taken together with the lack of a survival advantage seen in patients with "low-risk" cancers in the ICON1 trial, it appears safe to withhold adjuvant chemotherapy from optimally staged patients with well differentiated tumours.

Topics: Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Early Diagnosis; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms

Epithelial ovarian cancer is diagnosed in 4500 women in the UK each year of whom 1700 will ultimately die of their disease. Ten to fifteen percent of all cases are diagnosed early when there is still a good possibility for cure. The treatment of early stage disease involves surgery to remove disease often followed by chemotherapy. The largest clinical trials of this adjuvant therapy show an overall survival (OS) advantage with adjuvant platinum based chemotherapy but the precise role of this treatment in sub-groups of patients with differing prognoses needs to be defined.. To systematically review the evidence for adjuvant chemotherapy in early stage epithelial ovarian cancer to determine; firstly whether there is a survival advantage of this treatment over the policy of observation following surgery with chemotherapy reserved for treatment of disease recurrence, and secondly; to determine if clinical sub-groups of differing prognosis based on histological sub-type or completeness of surgical staging, have more or less to gain from chemotherapy following initial surgery.. An electronic search was performed using the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2008), MEDLINE (1966 to 2008), EMBASE (1980 to 2008) and CancerLit. The search strategy was developed using free text and medical subject headings (MESH).. The review authors selected those clinical trials that met the inclusion criteria set out based on the populations, interventions, comparisons and outcome measures.. Two review authors independently extracted data and assessed trial quality. Disagreements were resolved by discussion with a third review author. Random effects meta-analyses and sub-group analyses were conducted.. Five randomised controlled trials (RCTs), enrolling 1277 women, with 46 to 110 months follow-up, met the inclusion criteria. These trials had low risk of bias. Meta-analysis of three trials with adequate data, assessing 1008 women, indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (hazard ratio (HR) 0.71; 95% CI 0.53 to 0.93). Likewise, meta-analysis of four trials with adequate data, assessing 1170 women, indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (HR 0.67; 95% CI 0.53 to 0.84). The trials included in these meta-analyses gave consistent estimates of the effects of chemotherapy.Sub-group analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy (HR for OS 1.22; 95% CI 0.63 to 2.37) whereas those who had sub-optimal staging did (HR for OS 0.63; 95% CI 0.46 to 0.85). One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 0.48; 95% CI 0.32 to 0.72) but not among those at low risk (HR for OS 0.95; 95% CI 0.54 to 1.66). However, these sub-group findings could be due to chance.. Adjuvant platinum based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having early stage epithelial ovarian cancer. However, even given the limits of sub-group analyses, there is strong evidence that optimal surgical staging identifies patients who have either little or nothing to gain from adjuvant chemotherapy. Taken together with the lack of a survival advantage seen in patients with "low-risk" cancers in the ICON1 trial, it appears safe to withhold adjuvant chemotherapy from optimally staged patients with well differentiated tumours.

Topics: Antineoplastic Agents; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Early Diagnosis; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Randomized Controlled Trials as Topic

Topics: Antineoplastic Agents, Alkylating; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Survival Rate

Major advances in treatment for epithelial ovarian cancer have occurred over the last decade, giving hope to patients and families. Surgery remains a cornerstone of therapy. In early-stage epithelial ovarian cancer, a meticulous staging procedure should be performed to aid in determining patients who require appropriate adjuvant therapy and patients who can be monitored. The patient with advanced epithelial ovarian cancer significantly benefits from aggressive cytoreductive surgery and chemotherapy, affording the patient higher rates of complete response and partial response. In the new millenium, new therapeutic modalities should enhance the current response rates.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Female; Humans; Hysterectomy; Infusions, Parenteral; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Reoperation; Second-Look Surgery

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma; Clinical Trials as Topic; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Ovarian Neoplasms

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

The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the stan

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Melphalan; Ovarian Neoplasms; Paclitaxel; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate

Intraperitoneal radioactive chromic phosphate was administered to 69 patients with Stage I and II ovarian carcinoma who had undergone comprehensive surgical staging. Intestinal obstruction requiring surgical intervention occurred in four patients and was the most severe complication. Abdominal pain was the most common post-therapy complaint. Attention to time and technique of drug administration could minimize complications.

Topics: Adolescent; Adult; Aged; Chromium; Chromium Compounds; Female; Follow-Up Studies; Humans; Injections, Intraperitoneal; Melphalan; Middle Aged; Ovarian Neoplasms; Phosphates; Phosphorus Radioisotopes; Prospective Studies; Radiotherapy

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: Antimetabolites; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; DNA Repair; Drug Resistance; Female; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms

The symptomatology and outcome of three of our own cases with Melphalan overdose are presented. The literature regarding Melphalan overdose and its toxicity when given in normal and high doses is reviewed. Two of our cases with injection of less than 100 mg/m2 recovered from marrow aplasia within 3 weeks without major complications. The third patient died 6 days after injection of 290 mg/m2 Melphalan, probably due to cardiac arrhythmia before complete marrow failure had established. After intravenous application of more than 125 mg/m2 gastrointestinal side effects such as hemorrhagic diarrhea or even bowl perforation may be observed. These, together with a syndrome of inadequate ADH-secretion and electrolyte disturbances were the predominant clinical problems and the reasons for early death before infectious or bleeding complications due to prolonged marrow aplasia occur. Therapeutic measures are discussed. Due to the lack of a clinically useful antidote and detoxification method only symptomatic treatment is recommended. Colony stimulating factors such as GM-CSF G-CSF may improve the prognosis of moderate to severe Melphalan overdose.

Topics: Bone Marrow; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Overdose; Female; Humans; Infusions, Intravenous; Medication Errors; Melphalan; Middle Aged; Ovarian Neoplasms

Approximately 33% of women with invasive ovarian tumors present with what appears to be early epithelial ovarian cancer (FIGO Stages I and II) accounting for approximately 6000 new ovarian cancer cases each year in the United States. A better understanding of the natural history and patterns of spread of this disease has led to an increased awareness of the importance of thorough operative staging, cytoreductive surgery, and accurate determination of the extent of residual disease. These staging studies have documented frequent understaging of such patients. Results from such surgical staging studies indicate that only about 25% of women operated on in the United States have an initial surgical incision adequate to allow evaluation of the entire pelvis and abdominal cavity. As a result about 33% of patients thought to be free of disease at initial surgery have residual disease and in 75% the disease has spread intraabdominally. These studies have important implications for the design of future adjuvant trials. Fortunately, these accurate staging studies have defined groups of patients who require adjuvant treatment as well as those who do not. It is now apparent that certain groups of patients with Stage II and high-risk Stage I disease are at risk for failure throughout the abdominal cavity. Any form of adjuvant therapy, if it is to succeed, must obviously encompass this entire area. With this in mind, several prospective clinical trials have tested a variety of adjuvant approaches. Present evidence would suggest that systemic chemotherapy, intraperitoneal radioisotopes (32P) or whole abdominal irradiation have the potential to eradicate micrometastases throughout the area at risk. The need for adjuvant therapy is dependent upon the accuracy of initial surgical staging. If initial surgical evaluation was incomplete, the five year survival rates for Stage I (70%) and Stage II (40% to 50%) disease are poor enough that most investigators would advocate some sort of adjuvant therapy. However, comprehensive and accurate surgical staging will define subsets of ovarian cancer patients with such good prognoses (five year survival of 90% to 95%) that no adjuvant treatment is required. With the known risk of late second malignancies in ovarian cancer patients treated with long-term adjuvant chemotherapy, the identification of patients who do not require further treatment represents an advance. Accurate surgical staging coupled with proper adjuvant therapy designed

Topics: Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Melphalan; Ovarian Neoplasms; Prognosis

Pharmacokinetic modeling has suggested, and clinical investigations have confirmed, that intracavitary drug administration can result in a much greater drug exposure for the cavity into which the agent is instilled compared to the plasma. Both the safety and the efficacy of several agents administered individually or in combination have now been demonstrated. Several malignancies, in particular ovarian carcinoma and malignant mesothelioma, which remain confined to body cavities for much of their natural history, might be most rationally treated by the intracavitary treatment approach. Early clinical trials have demonstrated significant activity of intracavitary chemotherapy in both of these malignancies. Optimal drugs and dosages as well as appropriate scheduling for the various tumors involving body cavities remain to be defined. Whether or not combination intracavitary chemotherapy will significantly improve survival of patients with malignant disease confined to body cavities must await carefully controlled clinical trials comparing this treatment approach to standard systemically administered chemotherapy.

Topics: Absorption; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascitic Fluid; Bacterial Infections; Bleomycin; Cisplatin; Cytarabine; Diffusion; Doxorubicin; Drug Synergism; Female; Fluorouracil; Humans; Immunotherapy; Melphalan; Methotrexate; Mitomycins; Neoplasms; Ovarian Neoplasms; Peritoneal Cavity; Permeability; Pleura; Pleural Effusion; Radiation-Sensitizing Agents; Sclerosis; Streptozocin

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance; Female; Humans; Melphalan; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Tumor Stem Cell Assay

Significant and dramatic progress has been made in the diagnosis and treatment of women with ovarian carcinoma in the last 10 years, the results of which are now just being reflected in an increase in survival and cure rates. In early staged disease (Stage I and II) significant progress has been made concerning our understanding of the sites of subclinical metastasis when at surgery the tumor is clinically limited to the ovary or pelvis. A prospective study of 100 patients with Stages IA to IIB ovarian cancer who underwent restaging within 4 weeks of initial surgery will report this. Moreover, preliminary results of the first randomized therapeutic trials (melphalan versus observation; melphalan versus chromic phosphate [P-32]) in patients surgically staged and found to be Stage IA to IIB carcinoma will be discussed. For Stages IB to III, the 5-year survival rates comparing whole abdominal radiation by the moving strip technique to open field irradiation will be discussed. For advanced (Stage III and IV) ovarian carcinoma, the new techniques in debulking surgery will be illustrated. Finally, the significant progress in response rates, median duration of survival, disease-free survival, and 5-year survival rates made during the past 10 years will be presented. This will be done by comparing a unique group of 117 patients treated with melphalan alone, all of whom have been followed for 5 years or until death, to patients who received cisplatin combination chemotherapy--cyclophosphamide, hexamethylmelamine, Adriamycin (doxorubicin), and cisplatin (CHAD) or cisplatin, Adriamycin, and cyclophosphamide (PAC)--and have now been followed 3.4+ and 4+ years, respectively. What is clearly evident is that in the last decade there has been significant increase in response rates, median duration of survival, 3.4+-, 4+-, and 5-year survival rates and cure rates with the advent of debulking surgery and platinum-containing combination chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Radiotherapy; Time Factors

Topics: Alkylating Agents; Busulfan; Carcinoma, Bronchogenic; Carmustine; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Mechlorethamine; Melphalan; Neoplasms; Ovarian Neoplasms; Testicular Neoplasms

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

Topics: Altretamine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Estrogen Antagonists; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Progestins; Tamoxifen

Topics: Adenocarcinoma, Mucinous; Altretamine; Antineoplastic Agents; Carcinoma, Squamous Cell; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Prognosis

Poor survival rates of ovarian carcinoma have continued to be a cause of grave concern over decades and led to growing attention and alert in recent years. Promising results have already been recorded. More knowledge of important factors with relevance to prognosis has been helpful in unitising large-scale therapeutic studies for better comparability, a desire which had been unfulfilled in the past. Close interdisciplinary cooperation between gynaecologists, radiotherapists, and chemotherapists proved to be essential to optimum programmes of therapy. Persistent basic research for better understanding of biological behaviours of ovarian carcinomas and of so far unknown factors of prognosis and persistent efforts for earlier diagnosis of ovarian carcinoma are just as important. This is the only way to more effective control of the disease which still is, diagnostically and therapeutically, one of the major problems in gynaecology.

Topics: Carcinoma; Chlorambucil; Cyclophosphamide; Cystadenocarcinoma; Female; Humans; Melphalan; Mesonephroma; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Thiotepa

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: Adenocarcinoma; Castration; Chlorambucil; Cobalt Isotopes; Female; Humans; Hysterectomy; Melphalan; Ovarian Neoplasms

Topics: Carcinoma; Chlorambucil; Cyclophosphamide; Female; Genital Neoplasms, Female; Humans; Hysterectomy; Lymph Node Excision; Melphalan; Ovarian Neoplasms; Progestins; Radiotherapy, High-Energy; Thiotepa; Uterine Cervical Neoplasms; Uterine Neoplasms

Topics: Adenocarcinoma; Ascites; Carcinoma; Cyclophosphamide; Female; Fluorouracil; Humans; Injections, Intravenous; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Thiotepa

Topics: Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Thiotepa; Triaziquone; Vinblastine

The role of high-dose chemotherapy (HDCT) in epithelial ovarian cancer (EOC) remains controversial. This study was initiated to compare the efficacy and tolerability of HDCT as a consolidation approach in women with chemosensitive advanced EOC (FIGO stages IIC-IV). Patients who had achieved their first clinical complete remission after six cycles of conventional paclitaxel and carboplatin combination chemotherapy were randomly assigned to receive or not high-dose melphalan. The primary objective was to compare time to disease progression (TTP). A total of 80 patients were enrolled onto the trial. Patients who were randomized to receive HDCT were initially treated with cyclophosphamide 4 g/m(2) for PBPC mobilization. HDCT consisted of melphalan 200 mg/m(2). Of the 37 patients who were allocated to HDCT, 11 (29.7%) did not receive melphalan either due to patient refusal (n=5) or due to failure of PBPC mobilization (n=6). In an intent-to-treat analysis, there were no significant differences between the two arms in TTP (P=0.059) as well as in overall survival (OS) (P=0.38).

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents, Alkylating; Blood Transfusion, Autologous; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Lenograstim; Melphalan; Middle Aged; Ovarian Neoplasms; Recombinant Proteins; Survival Analysis; Time Factors

Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome.. One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%.. Seventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54).. This is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Paclitaxel; Stem Cell Transplantation; Time Factors; Treatment Outcome

The current study was performed to evaluate the efficacy and toxicity of a chemotherapy treatment using melphalan administered over a 24-h period with individual adapted dosing in advanced ovarian cancer. Melphalan was infused intravenously with an automatic infusion pump over a 24-h period. The schedule was repeated every 28 days for a maximum of 6 cycles. The initial administered dose was 25 mg/m(2). Drug adjustment was then made using a population approach, with the aim of constraining the overall area under the plasma concentration-time curve within 2.0-2.5 mg . h/l. A total of 96 courses of chemotherapy was administered. The toxicity profile did not differ greatly from that reported after a 1-h infusion and was acceptable in such a heavily pretreated patient population. Twenty-five patients were assessable for response and survival. Four (16%) partial responses were observed, which lasted 9, 10, 13 and 37 months, respectively. Three patients experienced stable disease during 8, 14 and 22 months, respectively. The 1- and 2-year survival rates were 18% and 6%, respectively. At the time of analysis, two patients remained alive with progressive disease at 22 and 37 months, respectively. In conclusion, melphalan administered over a 24-h period in platinum- and taxane-resistant ovarian cancer patients appeared to provide some clinical benefits with manageable toxicity. Based on these results, future studies comparing melphalan administered over a 24-h period and oral melphalan administrations will be scheduled.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Epithelium; Female; Humans; Infusions, Intravenous; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Treatment Outcome

Ovarian cancer is chemosensitive, but most patients with advanced disease die from tumor progression. As 25% of the patients can be cured by chemotherapy, it is reasonable to evaluate high-dose chemotherapy (HDCT). Forty-eight patients with untreated ovarian cancer were entered in a multicenter phase I/II trial of multicycle HDCT. Median age was 46 (19-59 years); International Federation of Gynecology and Obstetrics-stage was III in 79% and IV in 21%; 31% had residual disease >1 cm after surgery. Two courses of induction/mobilization therapy with cyclophosphamide (250 mg/m2) and paclitaxel (250 mg/m2) were used to collect peripheral blood stem cells. HDCT consisted of two courses of carboplatin (area under curve (AUC) 18-22) and paclitaxel followed by one course of carboplatin and melphalan (140 mg/m2) with or without etoposide (1600 mg/m2). Main toxicity was gastrointestinal. Limiting carboplatin to AUC 20 and eliminating etoposide resulted in manageable toxicity (69% without grade 3/4 toxicity). One patient died from treatment-related pneumonitis. At 8 years median follow-up, median progression-free-survival (PFS) and overall survival (OS) is 13.3 and 37.0 months. Five-years PFS and OS is 18 and 33%. Multicycle HDCT is feasible in a multicenter setting. A European phase III trial based on this regimen is evaluating the efficacy of HDCT.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Disease-Free Survival; Etoposide; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Treatment Outcome

The purpose of the present study is evaluation of the long-term efficacy of sequential abdominopelvic radiotherapy and melphalan in the management of ovarian carcinoma.. From 1970 to 1976, 94 women with stages I-III epithelial ovarian carcinoma enrolled in a prospective nonrandomized clinical trial were prescribed 20 Gy to the upper abdomen and 50 Gy to the pelvis followed by courses of melphalan (1 mg/kg/course). Primary endpoints were survival, recurrence, and toxicity.. There were 19 stage I, 25 stage II, and 50 stage III patients. For all stages, overall survival was 42% at 5 years, 30% at 10 years, and 17% at 25 years. Median follow-up of the survivors was 24 years. Disease-free survival was 48% at 5 years and remained at 45% from 10 to 25 years. All but two recurrences occurred within the first 27 months. No recurrence or treatment-related death occurred after 8 years. No recurrence was salvaged. All but one initial recurrence was within the peritoneal cavity. Of the 31 patients undergoing a second-look surgical procedure, 84% were free of tumor. Only 8% of patients recurred after a negative second look. Stage and the presence of palpable postoperative disease were significant prognostic factors. Disease-free survivals were 95% from 5 to 25 years for stage I, 70% at 5 years and 60% at 25 years for stage II, and 20% from 5 to 25 years for stage III (P < 0.0001). Although no patient with postoperative palpable tumor was cured, 25% lived beyond 2 years. Stage III patients without postoperative palpable tumor achieved a 47% 25-year disease-free survival. Acute toxicity was acceptable, and 98% of patients completed radiation therapy. Chronic toxicity included a 12% small bowel obstruction rate and a 3% fatal second malignancy/hematological toxicity rate (two cases of acute myelocytic leukemia, one case of thrombocytopenia).. The long-term disease-free survival obtained with abdominopelvic radiotherapy followed by single alkylating agent chemotherapy has not been exceeded by three subsequent decades of multiagent chemotherapy trials. Abdominal radiotherapy may be useful to consolidate complete responses following therapy multiagent chemotherapy, particularly with the upper abdominal dose escalation provided by intensity modulated radiation therapy and possibly in conjunction with chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease-Free Survival; Epithelial Cells; Female; Follow-Up Studies; Humans; Hysterectomy; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Treatment Outcome

Topics: Adult; Aged; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Pilot Projects

To evaluate the efficacy and safety of multiple cycles of high-dose carboplatin and paclitaxel and one consolidation cycle of high-dose melphalan with all cycles supported by hematopoietic stem cells and cytokine, in previously untreated patients with optimally debulked stage III epithelial ovarian cancer.. Patients had histologically documented epithelial ovarian cancer and optimal initial cytoreductive surgery. No prior chemotherapy was permitted. Adequate performance status, bone marrow, hepatic, and renal function was required. After being mobilized with cyclophosphamide 3 g/m(2), paclitaxel 300 mg/m(2), and filgrastim 5 microg/kg/day, peripheral blood stem cells (PBSC) were collected by leukapheresis. Patients received three cycles of carboplatin AUC 15 mg. min/ml iv, paclitaxel 250 mg/m(2), and PBSC with filgrastim every 28 days, followed by one cycle of melphalan 140 mg/m(2) and hematopoietic support.. Nine patients entered the trial and received all planned cycles of chemotherapy. Of the eight patients who consented to surgical reassessment upon completing therapy, four had residual small-volume macroscopic disease, three had microscopic residual disease, and one had pathologic complete response. The estimated probability of a pathologic complete response was 12.5% (95% confidence interval: 0.3-52.7%). Hematologic toxicity was severe but manageable. Eleven of 45 cycles (24.4%) resulted in hospital admission for neutropenic fever, dehydration +/- diarrhea, syncope, or shortness of breath and pain secondary to tense ascites.. The low pathological complete response rate did not justify toxicity; thus, the study was closed. High-dose chemotherapy as first-line treatment for epithelial ovarian cancer remains experimental and should be restricted to clinical trials.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Epithelial Cells; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Pilot Projects; Recombinant Proteins

The aim of this study was to assess the long-term impact of high-dose chemotherapy (HDC) as consolidation in a large series (n = 55) of advanced chemosensitive ovarian cancer patients who were optimally cytoreduced at time of first surgery or at interval debulking surgery (IDS). HDC consisted of carboplatin (600 mg/m(2) days 1 and 2), etoposide (450 mg/m(2) days 1 and 2) and melphalan (50 mg/m(2), days 3 and 4). The primary endpoint of the study was the assessment of time to progression (TTP) and overall survival (OS). In September 2000 the overall population had a median follow-up of 55 months (range 17--137) and a TTP of 35 months with a 5-year TTP rate of 35% (CI 95%: 21--49) whereas OS averaged 75 months with a 5-year OS of 59% (CI 95%: 45--73). In patients achieving optimal primary cytoreduction the median TTP was 44 months with a 5-year rate of 43% (CI 95%: 26--60). In the same series the 5-year OS rate was 62% (CI 95%: 45--79) (median OS = 75 months). In patients who were optimally cytoreduced at the time of IDS the median TTP was 25 months and the 5-year TTP rate was 22% (CI 95%: 3--41) and median OS was 46 months with a 5-year OS rate of 50% (CI 95%: 27--73). HDC with hematopoietic support could represent an effective approach for the treatment of advanced optimally cytoreduced ovarian cancer patients with chemosensitive disease. Patients who underwent IDS because of unresectable tumors at the time of first surgery had the greater survival benefit from HDC.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Female; Humans; Longitudinal Studies; Melphalan; Middle Aged; Ovarian Neoplasms; Survival Rate; Treatment Outcome

The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer.. Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0.. The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive.. With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Survival Rate; Topotecan

Ovarian cancer is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women. Despite improved surgical techniques as many as 20% of women with early stage disease will eventually relapse and die from their disease. The post-operative management of these women remains controversial. Here we present the long term follow-up data of our previously published study, as well as the incidence of second primary malignancies in these women.. Two hundred fifty-seven eligible patients with stage I, IIA 'high risk' ovarian carcinoma and IIB, IIIO (disease confined to pelvis) were randomized to either whole abdominal radiotherapy 2.250 rads in ten fractions (107 patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 patients) or intraperitoneal chromic phosphate 10-20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy.. Overall survival estimates at 10 years were: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P = 0.30). Relapse-free survival estimates at 10 years were: 50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm (P = 0.147). Long term follow-up has not demonstrated a significant difference between treatment arms. Second primary malignancies developed in 29 women (11%) after 2,229 person years of follow-up. This compares to 18.7 second primary malignancies which would have been expected in this group of age-matched controls and was statistically significant (P = 0.018). There was no significant difference in the total number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm (P = 0.06).. Long-term follow-up has not demonstrated a significant difference in overall or disease free survival between treatment arms. An excess of second primary malignancies (35%) was observed suggesting that lifelong surveillance is required in this population. Further research with newer treatment programs are needed to improve the cure rates in this population.

Topics: Antineoplastic Agents, Alkylating; Brachytherapy; Canada; Chromium Compounds; Combined Modality Therapy; Disease-Free Survival; Dose Fractionation, Radiation; Female; Humans; Melphalan; Neoplasm Staging; Neoplasms, Second Primary; Ovarian Neoplasms; Phosphates; Survival Rate; Time Factors

The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma.. Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase I study. In the first stage of the study, the doses of paclitaxel and cisplatin were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of intravenous melphalan was escalated in consecutive cohorts of 3-6 patients depending on toxicity. The planned dose escalation levels of melphalan were 6 mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225 mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival.. Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months.. The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Melphalan; Middle Aged; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Treatment Outcome

We performed a pilot phase II study to evaluate the potential for delivery of rapidly sequenced high-dose chemotherapy treatments rescued with autologous peripheral-blood progenitor cells (PBP) in patients with previously untreated, advanced ovarian cancer.. A single cycle of mobilization was used, primed with cyclophosphamide (CPA)/paclitaxel (Txl) and filgrastim (granulocyte colony-stimulating factor [G-CSF]), followed by three cycles of high-dose carboplatin (CBDCA)/Txl and one cycle of high-dose melphalan (MEL), each rescued by PBP. We then analyzed the outcome for a total of 56 consecutive patients treated with high-dose chemotherapy as part of this program.. In the phase II pilot, 21 patients were enrolled. There were no treatment-related deaths through 98 high-dose treatments, although 34 treatments were complicated by hospitalization, primarily for neutropenic fever. Seventy-six percent of patients experienced grade 3 to 4 gastrointestinal toxicity and 62% experienced grade 2 to 3 neuropathy. Five of 15 (33%) patients who underwent second-look surgery attained a pathologic complete response. In the overall analysis, 56 patients were reviewed. Forty-four patients were assessable for response by second-look surgery or clinical progression. Fifteen of 44 patients achieved a pathologic complete response (34%). The pathologic complete response rate in optimal-disease patients was 12 of 22 (55%), while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response.. The Gynecologic Oncology Group has initiated a pilot phase II trial of this approach in patients with optimally debulked stage III ovarian cancer. There is no evidence to support the use of this or other aggressive regimens outside of a clinical trial.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Paclitaxel; Survival Rate

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

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

Following surgical debulking, most patients with international Federation of Gynecology and Obstetrics (FIGO) Stage III or IV carcinoma of the ovary receive treatment with combination chemotherapy. However, the optimal postsurgical therapy for ovarian carcinoma remains to be defined.. To define better the role of initial therapy with a cisplatin-based chemotherapy regimen, the Eastern (Cooperative Oncology Group (ECOG) initiated a randomized, Phase III trial, EST 2878, comparing initial therapy with a single, orally administered alkylating agent, melphalan, versus a complex regimen employing cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD). Women who failed treatment with melphalan were crossed-over to treatment with CHAD minus the cyclophosphamide (HAD). Study endpoints included response to therapy, time to treatment failure, and overall survival.. Between October, 1978, and November, 1980, EST 2878 accrued 253 patients with advanced epithelial carcinoma of the ovary. There were 118 eligible patients initially treated with melphalan and 126 with CHAD. Two patients experienced lethal toxicities, including gastrointestinal hemorrhage (1 patient) and neutropenic sepsis (1 patient), and 22 patients experienced life-threatening toxicities, including hematologic toxicity (21 patients) and anaphylaxis (1 patient). Response to treatment and clinical complete response rates were higher in women receiving CHAD (60% and 38%, respectively) versus melphalan (42% and 21%, respectively) (P = 0.037 and P = 0.024, respectively), but these differences were confined to women older than 50 years of age. Likewise, time to treatment failure was significantly longer in women receiving CHAD (P = 0.014), but the difference was again confined to women older than 50 years of age and to women suboptimally debulked at the time of surgery. Survival did not differ between the two arms (median survivals of 17.5 months with initial melphalan therapy and 19.5 months with CHAD), probably because women treated initially with melphalan received salvage therapy with HAD). Twenty-three patients survived longer than 10 years. Among 18 long term survivors who had retrospective pathologic review, 8 had borderline tumors of the ovary.. In women with advanced ovarian cancer, initial therapy with a cisplatin-based combination chemotherapy regimen resulted in higher clinical complete response rates and longer time to failure compared with initial therapy with a single, oral alkylating agent; however, the benefits of this approach were confined to women older than 50 years of age at diagnosis, and there was no significant difference in survival.

Topics: Adult; Aged; Altretamine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cross-Over Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Survival Rate; Time Factors

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

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Transplantation, Autologous

The introduction of serotonin receptor (5-HT3) antagonists has improved the control of acute nausea and vomiting induced by cancer chemotherapy, but they seem to have little or no effect on delayed symptoms. Corticosteroids are known to reduce both acute and delayed nausea and vomiting. The aim of the present study was to test the hypothesis that a single high dose of dexamethasone (20 mg), a long-acting corticosteroid, given after cisplatin and in addition to ondansetron (8 mg three times a day), would enhance the control of both acute and delayed nausea and vomiting. A group of 104 chemotherapy-naive ovarian cancer patients, scheduled for at least three cycles of combination chemotherapy including cisplatin (50 mg/m2), were randomly allocated to receive either dexamethasone or placebo in addition to ondansetron. Two-thirds of the patients received doxorubin and melphalan on the day before cisplatin and 1/3 received doxorubicin immediately before cisplatin. Unexpectedly we found, in all three chemotherapy cycles, that patients receiving dexamethasone suffered from more delayed nausea and vomiting than patients receiving placebo. In patients with no acute nausea or vomiting, the boomerang effect of dexamethasone could be seen on the first day after chemotherapy. In a follow-up study on 5 patients not included in the randomized trial, dexamethasone induced a pronounced reduction in urinary cortisol excretion on the day after chemotherapy with a return to normal excretion on day 2. It is concluded that a single high dose of dexamethasone does not seem appropriate for controlling delayed nausea and vomiting.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Melphalan; Nausea; Ondansetron; Ovarian Neoplasms; Vomiting

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m2 + melphalan (M) 0.4 mg/kg was compared with A + M + cisplatin (C) 50 mg/m2 given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs. 50%, p < 0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p < 0.006) and in median survival time (26 months vs. 19 months, p = 0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage. Objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Cisplatin; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Neoplasm, Residual; Ovarian Neoplasms; Prognosis; Sweden

The primary aim was to induce a high number of pCR in early (FIGO IC, IIB + C) - and advanced (FIGO III-IV) - stage ovarian cancer with a surgery plus 4 cycles of cisplatin and melphalan (PAMP) regimen. The second objective was to prevent relapse with WAR in patients in remission after chemotherapy.. 218 eligible patients were treated after staging laparotomy with cisplatin 80 mg/sqm i.v. on day 1 and melphalan 12 mg/sqm i.v. on day 2 q 4 weeks. Response was verified by second-look laparotomy. WAR was carried out with the open field technique on a linear accelerator (daily dose: 1.3 Gy, total dose: 29.9 Gy) in patients with pathological or clinical CR or pathological PR with microscopical residual disease.. 146/218 patients (67%, 95% CI: 61%-73%) responded to PAMP: 56 (26%) achieved pCR, 24 (11%), cCR, 56 (26%) pPR and 10 (5%) cPR (c = clinical, p = pathological). Multivariate analyses revealed that in advanced stages (92 cases in remission), the achievement of pCR was the most important factor for longer time to failure (TTF) and survival. Only 51/118 (43%) patients in remission received WAR. Early-stage patients <= 55 years were more likely to have WAR than patients older than 55 years (77% vs. 23%; p = 0.02). Advanced-stage patients with cCR were less likely to be irradiated than patients with pCR or pPR (10% vs. 51%; p = 0.003). Toxicity of PAMP was acceptable with 10% of WHO grade 4 hematologic toxicity. Acute hematological toxicity of WAR caused interruption (33%) or incompleteness (33%) of irradiation in the majority of patients.. PAMP is an effective treatment for advanced ovarian cancer with a 67% response rate after 4 cycles. For the majority of patients in remission, WAR as a consolidation treatment was hardly feasible. For these patients new treatment modalities to consolidate remission are needed.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Feasibility Studies; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Radiotherapy; Remission Induction

From December 1983 through February 1992, a prospective study designed to determine the clinical course of patients with ovarian tumors of low malignant potential (LMP) was conducted by the Gynecologic Oncology Group (GOG).. This protocol was developed to evaluate the following (1) the biologic behavior of ovarian LMP tumors, (2) the effectiveness of melphalan chemotherapy in patients with clinically detectable residual disease after surgical staging and in patients whose tumors progress or recur after surgical therapy, and (3) the response rate to cisplatin in those who failed to respond to melphalan therapy. The study group consisted of 146 assessable patients with stage I serous LMP tumors. All of these women had the affected ovary (or ovaries) removed, and a complete staging operation was performed in each case. While 123 patients had a total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), 21 retained the uterus and one normal-appearing ovary and fallopian tube. No adjuvant chemotherapy or radiation therapy was administered to any patients in the stage I study group.. The median follow-up time was 42.4 months (range, 1.6 to 108). Thus far, no patient with a stage I ovarian serous LMP tumor has developed recurrent disease.. Stage I ovarian serous LMP tumors rarely, if ever, recur. Limited resection, after meticulous surgical exploration, is adequate therapy for women of reproductive age.

Topics: Adult; Aged; Cisplatin; Combined Modality Therapy; Cystadenocarcinoma, Serous; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prospective Studies; United States

Lower pre-chemotherapy night time cortisol excretion predicted more severe cisplatin induced nausea and vomiting in 42 ovarian cancer patients receiving ondansetron as a single antiemetic agent. Dexamethasone administration added to the antiemetic effect of ondansetron principally in patients who had low excretion of cortisol.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dexamethasone; Doxorubicin; Female; Humans; Hydrocortisone; Melphalan; Middle Aged; Ondansetron; Ovarian Neoplasms

The appropriate therapy for patients with localized (FIGO Stage I and II) ovarian cancer has been poorly defined for all age groups and particularly for the elderly. Few prospective randomized comparisons of adjuvant therapy after careful surgical staging have been performed. The Gynecologic Oncology Group (GOG) has performed a series of trials testing adjuvant treatment in carefully staged patients with early-stage ovarian cancer. Early trials included few elderly patients but the most recent trial (GOG 95) included 18% over the age of 65 years.. Comprehensive surgical staging defined by protocol is performed before randomization. Patients with predefined stages and histologies are included and the patients are randomized prospectively to receive either intraperitoneal phosphorus-32 or three monthly cycles of cyclophosphamide and cisplatin. Assessment of the value of this adjuvant therapy will depend on survival, disease-free survival, and relapse pattern differences between the two adjuvant therapies.. This is an ongoing clinical trial and insufficient numbers of patients have been randomized for definitive conclusions. There have been seven recurrences on both arms of the trial with a median time to recurrence of 14 months. There currently are no significant age differences between relapsed patients and disease-free patients. At this point, 12 elderly patients have been randomized to each of the arms of therapy.. Although no apparent survival differences exist for elderly patients in the most recent adjuvant chemotherapy trial of early ovarian cancer, the number of patients with cancer randomized and follow-up are insufficient to establish such a difference. Currently there is no evidence that elderly patients display a significant difference in relapse frequency or pattern.

Topics: Adult; Aged; Aged, 80 and over; Aging; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Phosphorus Radioisotopes; Prospective Studies

Two hundred twelve patients who underwent second-look laparotomy as part of their treatment for epithelial ovarian cancer were evaluated. Factors associated with positive second looks were initial stage, tumor grade, age, and residual disease (P less than 0.05). One factor not of significance was whether adjuvant therapy was platinum based. Initial stage only was associated with recurrence after a negative second look (P less than 0.001). When controlled for volume of disease no difference in survival between various salvage therapies could be demonstrated. Survival between patients with recurrence after negative second look and patients with microscopic residual disease was similar even though the former group was not treated until recurrence (P = 0.75). Second-look laparotomy does not improve survival with currently existing salvage modalities and should primarily be confined to those patients willing to participate in research protocols evaluating new second-line therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Laparotomy; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Retrospective Studies

From 1978 until 1988, 116 patients with epithelial ovarian cancer were entered onto one of three consecutive prospective clinical trials involving cisplatin-based combination chemotherapy. They had the following characteristics: (1) stage III or IV disease, (2) grade 2 or 3 tumors, and (3) optimally debulked tumors (residual disease < or = 2 cm). The purpose of the study was to investigate the influence of duration of chemotherapy on survival. The treatment plans were as follows: Trial 1, 12 cycles of cisplatin/melphalan (43 patients); Trial 2, 12 cycles of cisplatin/cyclophosphamide (24 patients); and Trial 3, 6 cycles of cisplatin/cyclophosphamide (49 patients). The total dose of cisplatin was 60 mg/m2 in the first trial and 50 mg/m2 in the second and third trials. Median survival times for the three groups were 58, 29, and 35 months, respectively (NS). Median progression-free survival (PFS) times were 37, 23, and 15 months, respectively (P = 0.0008). Combining patients from the first two trials, the median PFS for patients receiving 12 planned cycles of chemotherapy was 30 months versus 15 months for patients receiving 6 planned cycles (P = 0.0004). Using a forward stepwise Cox proportional hazard model, the use of 12 cycles of therapy and melphalan predicted increased PFS (P = 0.0001 and P = 0.0002, respectively). In view of these results, the lack of published data supporting the superiority of 6 over 12 cycles of chemotherapy, and the rather recent availability of less toxic maintenance therapy (i.e., carboplatin), we believe that a multiinstitutional trial comparing the 6-cycle regimen with more prolonged chemotherapy is justifiable.

Topics: Adult; Aged; Carboplatin; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Proportional Hazards Models; Prospective Studies; Time Factors

Ninety-three women with FIGO stage II epithelial ovarian carcinoma underwent comprehensive surgical staging and were randomized prospectively to therapy consisting of either intraperitoneal radioactive phosphorus or oral melphalan. No patient had gross residual disease at the time of randomization. Ten of the forty-five women treated with melphalan experienced severe bone marrow depression at some time during therapy and two women expired from leukemia. Four of the forty-eight women treated with intraperitoneal phosphorus required surgical reexploration for intestinal obstruction or bowel injury. Twenty-one women died of their disease. Survival was not statistically different between the two treatment arms. The 5-year actuarial survival was 78%.

Topics: Adolescent; Adult; Aged; Ascites; Carcinoma, Squamous Cell; Child; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Topics: Adenocarcinoma; Adult; Agranulocytosis; Anemia; Drug Evaluation; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leiomyosarcoma; Melphalan; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Biperiden; Cisplatin; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Female; Humans; Imidazoles; Lorazepam; Melphalan; Metoclopramide; Middle Aged; Ondansetron; Ovarian Neoplasms; Vomiting

The purpose of this study was to evaluate 5-year survival and 5-year progression-free survival in previously untreated patients with advanced ovarian cancer treated with single-agent melphalan in which very few patients underwent optimal debulking surgery (less than 2 cm residual) as compared with the patients treated with Cisplatin-based chemotherapy in which most patients underwent optimal debulking surgery. Significant increases in 5-year survival and 5-year progression-free survival were noted as we changed from the melphalan trial, in which only 14% underwent optimal debulking surgery, to PAC-H, in which 57% and the PAC trial in which 90%, respectively, underwent optimal debulking surgery. However, for those patients whose tumors were optimally debulked in the three trials, there were no statistically significant differences in median survival, median progression-free survival, 5-year survival, or 5-year progression-free survival in those patients treated with melphalan, PAC-H, or PAC. Without optimal debulking surgery, Cisplatin-based multiagent chemotherapy offered a small survival advantage. These results are similar to that reported by Gruppo Interregionale Cooperativo Oncologico Ginecologia, in which survival curves were identical for all the subgroups of chemotherapy regimens for those patients with residual disease less than 2 cm at the onset of chemotherapy whether they received (1) cyclophosphamide; (2) cyclophosphamide and Adriamycin; (3) cyclophosphamide, Adriamycin, and Cisplatin; (4) cyclophosphamide, Adriamycin, and hexamethylmelamine; (5) Cisplatin and cyclophosphamide; (6) low-dose Cisplatin; (7) high-dose Cisplatin; or (8) carboplatin.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Cisplatin; Combined Modality Therapy; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prospective Studies; Survival Analysis; Survival Rate

Forty-six patients with recurrent ovarian cancer were reoperated, and cancer samples for the subrenal capsule assay (SRCA) were collected from 23 of them, whereas this test was not done in the remaining 23 control patients. The SRCA was evaluable in 22 cases (96%). Taken together, no significant difference appeared in the 3 years' survival figures between the groups: seven of 22 patients (32%) with the evaluable SRCA and six of 23 control patients (26%) were alive. However, a further analysis of the data revealed that the SRCA guided the selection of chemotherapy only in 15 patients, whereas tumour samples were resistant to all cytostatics tested in six cases and toxic side-effects limited the clinical application of the test results in the remaining one case. Four of the 11 patients (36%) whose further chemotherapy was strictly chosen based on the SRCA and seven of the 24 patients (29%) whose treatment was based on physician's choice survived at least 3 years. Our conclusion is that the SRCA is of limited value in the selection of second-line chemotherapy in recurrent ovarian cancer.

Topics: Adult; Aged; Altretamine; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cystadenocarcinoma; Doxorubicin; Drug Screening Assays, Antitumor; Epirubicin; Female; Follow-Up Studies; Humans; Melphalan; Mice; Middle Aged; Ovarian Neoplasms; Subrenal Capsule Assay

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.

Topics: Adult; Aged; Altretamine; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Regression Analysis; Reoperation; Survival Rate

Intraperitoneal radioactive chromic phosphate was administered to 69 patients with Stage I and II ovarian carcinoma who had undergone comprehensive surgical staging. Intestinal obstruction requiring surgical intervention occurred in four patients and was the most severe complication. Abdominal pain was the most common post-therapy complaint. Attention to time and technique of drug administration could minimize complications.

Topics: Adolescent; Adult; Aged; Chromium; Chromium Compounds; Female; Follow-Up Studies; Humans; Injections, Intraperitoneal; Melphalan; Middle Aged; Ovarian Neoplasms; Phosphates; Phosphorus Radioisotopes; Prospective Studies; Radiotherapy

An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case-control study design, with three controls matched to each case of leukemia. Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Case-Control Studies; Chlorambucil; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia; Melphalan; Multicenter Studies as Topic; Neoplasms, Multiple Primary; Ovarian Neoplasms; Registries; Risk Factors; Thiotepa

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

Topics: Adult; Combined Modality Therapy; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Phosphorus Radioisotopes; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic

In a prospective, randomized, double-blind trial the combination betamethasone-dixyrazine was compared with high-dose metoclopramide as antiemetic treatment during combination chemotherapy (melphalan-doxorubicin and cisplatin) of ovarian carcinoma. Of 40 evaluable patients, 15 (38%) had previous experience with chemotherapy. Efficacy and side effects were recorded on patient and nurse questionnaires using the visual analog scale. Nausea and vomiting were prevented in 55% of the patients treated with melphalan-doxorubicin (Day 1) and in 36% of the patients treated with cisplatin (Day 2). Betamethasone-dixyrazine was superior to high-dose metoclopramide and prevented nausea in 76% compared to 32% during melphalan-doxorubicin therapy. Akathisia was noted in 21% and acute dystonic reactions in 2.6% during metoclopramide treatment but not in any case during betamethasone-dixyrazine therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Betamethasone; Cisplatin; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Metoclopramide; Nausea; Ovarian Neoplasms; Phenothiazines; Prospective Studies; Random Allocation

Two hundred fifty-seven eligible patients with stage I, IIA "high risk" ovarian carcinoma and IIB, IIIO (disease confined to pelvis), were randomized to either total abdominal radiotherapy (arm A) 2,250 rad in 20 fractions (107 patients), melphalan (arm B) 8 mg/m2/d X 4 every 4 weeks X 18 courses (106 patients), or intraperitoneal chromic phosphate (arm C) 10 to 20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy; arm A, 2,250 rad in ten fractions; and arms B and C, 4,500 rad in 20 fractions. Entry to arm C was discontinued early because of toxicity. In a multifactor analysis using proportional hazards models, no significant difference in survival was observed although there was a marginally significant difference in disease-free survival (P = .015) with arm B being superior to arm A. Stage (P less than .0001), grade (P less than .0001), and histology (P less than .008) were predictors of survival in the multifactor analysis. Performance status, age, and residual disease were significant predictors in the single factor analysis but were not predictive when correction was made for the effects of stage, grade, and histology. Five-year survival rates are 62% for arm A, 61% for arm B, and 66% for arm C. Median duration of follow-up is 8 years. Long-term complications of radiotherapy were seen in 19 patients on arm A, 11 on arm B, and 11 on arm C. Four patients who had received melphalan developed either a myelodysplastic syndrome or acute leukemia. Violations in covering the whole abdominal target volume were correlated with survival.

Topics: Chromium; Chromium Compounds; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Melphalan; Ovarian Neoplasms; Phosphates; Phosphorus Radioisotopes; Prognosis; Random Allocation

Between April 1981 and June 1985, 195 patients with ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) Stages IIB, IIC, III, and IV, entered a trial that consisted of surgery and chemotherapy with cisplatin (P) and melphalan (PAM) with or without hexamethylmelamine (HexaPAMP or PAMP regimens) every 4 weeks for 6 cycles. Because the intent was to study the outcome by treatment after evaluation of first-line chemotherapy, patients were evaluable only if the response was assessed by a second-look operation or if measurable disease progression was documented. One hundred fifty-eight patients (81%) were evaluable for response. Forty-five (28%) achieved pathologically confirmed complete remissions (pCR), and 24 of these patients received whole-abdominal radiation (WAR) for consolidation of response. Five patients with complete remission after WAR relapsed, as did nine of the 21 with complete remission who had not undergone WAR. The 3-year time to progression percentage (TTP +/- SE) from second-look operation was 70% +/- 7% for all patients who achieved pCR, 83% +/- 8% for those who received WAR, and 49% +/- 15% for those who did not receive WAR (this was not a randomized comparison). The 3-year TTP percentage for the 49 partial responders was 21% +/- 6%, identical for the 19 who had WAR and the 30 who had no radiation therapy. Additional or alternative methods for consolidation of pCR are needed since patients continue to relapse despite optimal initial response to therapy.

Topics: Abdomen; Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy

A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.

Topics: Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Random Allocation; Statistics as Topic

In October 1978, the Swedish Cooperative Ovarian Cancer Study Group started a randomized comparison of doxorubicin 40 mg/m2 and melphalan 0.4 mg/kg with melphalan 1 mg/kg every four weeks in International Federation of Gynecology and Obstetrics (FIGO) stages III and IV ovarian cancer of serous and anaplastic histology. One hundred sixty-eight patients entered the study, and 148 were evaluable at five years or longer. All had residual tumors larger than 10 cm, with appropriate stratification according to stage, histologic grade, and age. Definition of response was according to World Health Organization (WHO) criteria except that we required three months' regression of all clinically detectable tumors instead of one month. Seventy-three women treated with doxorubicin plus melphalan had a significantly higher response rate than 75 patients treated with melphalan alone (54.7 versus 26.7%; P less than .0001), median duration of response (13.0 versus 7.3 months; P less than .0057), and median survival time (18.5 versus 10.5 months; P less than .0001). Combined treatment produced significantly more complete remissions than single-agent therapy (30 versus 6.7%; P less than .001). At 60 months, ten patients were alive in the doxorubicin plus melphalan group, compared with three in the melphalan group. Temporary bone marrow depression was significantly more frequent in the melphalan-treated patients, but subjective side effects were the same in both groups.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cystadenocarcinoma; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Random Allocation; Sweden; Time Factors

Approximately 33% of women with invasive ovarian tumors present with what appears to be early epithelial ovarian cancer (FIGO Stages I and II) accounting for approximately 6000 new ovarian cancer cases each year in the United States. A better understanding of the natural history and patterns of spread of this disease has led to an increased awareness of the importance of thorough operative staging, cytoreductive surgery, and accurate determination of the extent of residual disease. These staging studies have documented frequent understaging of such patients. Results from such surgical staging studies indicate that only about 25% of women operated on in the United States have an initial surgical incision adequate to allow evaluation of the entire pelvis and abdominal cavity. As a result about 33% of patients thought to be free of disease at initial surgery have residual disease and in 75% the disease has spread intraabdominally. These studies have important implications for the design of future adjuvant trials. Fortunately, these accurate staging studies have defined groups of patients who require adjuvant treatment as well as those who do not. It is now apparent that certain groups of patients with Stage II and high-risk Stage I disease are at risk for failure throughout the abdominal cavity. Any form of adjuvant therapy, if it is to succeed, must obviously encompass this entire area. With this in mind, several prospective clinical trials have tested a variety of adjuvant approaches. Present evidence would suggest that systemic chemotherapy, intraperitoneal radioisotopes (32P) or whole abdominal irradiation have the potential to eradicate micrometastases throughout the area at risk. The need for adjuvant therapy is dependent upon the accuracy of initial surgical staging. If initial surgical evaluation was incomplete, the five year survival rates for Stage I (70%) and Stage II (40% to 50%) disease are poor enough that most investigators would advocate some sort of adjuvant therapy. However, comprehensive and accurate surgical staging will define subsets of ovarian cancer patients with such good prognoses (five year survival of 90% to 95%) that no adjuvant treatment is required. With the known risk of late second malignancies in ovarian cancer patients treated with long-term adjuvant chemotherapy, the identification of patients who do not require further treatment represents an advance. Accurate surgical staging coupled with proper adjuvant therapy designed

Topics: Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Melphalan; Ovarian Neoplasms; Prognosis

A randomized prospective therapy trial in patients with stage III optimal epithelial carcinoma of the ovary was accomplished by the Gynecologic Oncology Group. Therapy with melphalan or melphalan plus immuno-adjuvant, Corynebacterium parvum (C. parvum), was utilized as adjuvant treatment following surgical therapy. One hundred eight-five patients were eligible for evaluation with 87 patients in the melphalan group and 98 patients in the melphalan plus C. parvum group. The comparison of the treatment regimens showed no differences with respect to either progression-free interval or survival. However, it should be noted that a 50% 3-year survival was obtained. A group was identified, using four prognostic factors that had 80% survival at 3 years. Maximum size of the residual tumor, as well as performance status, was not prognostically significant. This study demonstrates a lack of efficacy of the addition of C. parvum to melphalan for this patient population.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Pilot Projects; Prognosis; Propionibacterium acnes; Prospective Studies; Random Allocation

We have evaluated the relation between alkylating agents and leukemic disorders in 3363 1-year survivors of ovarian cancer who were treated in five randomized clinical trials and at two large medical centers. Overall, 28 patients developed acute nonlymphocytic leukemia (expected, 1.2) and 7 developed preleukemia. A 93-fold increased risk for acute nonlymphocytic leukemia was seen in 1794 women treated with chemotherapy; the incidence of leukemic disorders was 7.7/1000 women per year. Risk was highest 5 to 6 years after the first treatment and appeared to decrease thereafter. The use of radiation therapy did not affect risk. The 10-year cumulative risk (mean +/- SE) of acquiring a leukemic disorder was 8.5% +/- 1.6% after treatment with any alkylating agent, 11.2% +/- 2.6% after treatment with melphalan, and 5.4% +/- 3.2% after cyclophosphamide treatment. A dose-response relationship was apparent in 605 women receiving melphalan and suggested in 333 women receiving cyclophosphamide. Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide. These data indicate that choice of chemotherapeutic agent and drug dosage may influence significantly the risk for long-term adverse effects of cancer therapy.

Topics: Acute Disease; Adult; Aged; Cyclophosphamide; Dose-Response Relationship, Drug; Epidemiologic Methods; Female; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Preleukemia; Probability; Time Factors

The combinations of triethylenethiophosphoramide and methotrexate (TM) and cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil (CAF) were compared, both as sequential and fixed rotational treatments for advanced ovarian cancer, with L-phenylalanine mustard (L-PAM). Treatment with CAF produced a higher response rate (25% complete responses plus 31% partial responses) than treatment with L-PAM (15% complete responses plus 18% partial responses). A fixed rotation of TM and CAF resulted in longer survival (median of 15 months and 75th percentile of 27 months) than sequential treatment with TM initially, followed by CAF upon failure (median of 12 months and 75th percentile of 22 months). The fixed rotation of TM and CAF also increased progression-free survival (median of 12 months and 75th percentile of 24 months) over that achieved by initial treatment with TM (median of 6 months and 75th percentile of 15 months) or L-PAM (median of 9 months and 75th percentile of 21 months). Most patients (96%) on the fixed rotation were treated with both TM and CAF. Fewer patients (62%) on the sequential schedule with TM actually received both combination regimens, and even fewer patients (37%) beginning on CAF ever crossed over to TM. Patient age of 50 years or younger was a favorable prognostic factor for response, survival, and time to first treatment failure (progression-free survival). Disease Stage IIIA or IIIB, surgery including a bilateral salpingo-oophorectomy plus hysterectomy, and treatment within 6 months of initial diagnosis were favorable predictors for both survival and time to first treatment failure. Ambulatory performance status and well-differentiated disease were favorable prognostic factors for survival. Patients with unevaluable disease failed later than those with evaluable disease who, in turn, failed later than patients with measurable disease.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Prospective Studies; Random Allocation; Thiotepa

A randomized chemotherapy trial is forthwith reported on, in which therapy A (vincristine/ifosfamide/tegafur) was compared with therapy B (fluorouracil/trofosfamide/methotrexate/melphalan). Both patient groups received trofosfamide and oral progesterone as maintenance treatment until the end of the second therapy year. Forty-six patients were randomized into group A, 63 into group B. The evaluation of the survival curves suggests a division of the patients into 3 groups with different mortality risks.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Germany, West; Humans; Ifosfamide; Melphalan; Methotrexate; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Random Allocation; Tegafur; Vincristine

As part of a randomized trial evaluating several treatment programs in the management of poor prognosis, early stage ovarian cancer, 53 patients were randomized to receive a combination of pelvic external beam radiation, 4000 rad plus 10-20 millicuries of radioactive chromic phosphate given intraperitoneally. Only 35 patients (66%) actually received the chromic phosphate. The other 18 did not enter this phase of treatment for a variety of reasons documented in this report. Ten (29%) of the 35 patients receiving the full course of treatment had significant long term side effects with the median time to onset of symptom being 9 months after the chronic phosphate was given. There were no treatment-related deaths. The complications could not be related to the dose of the isotope, the technique of administration, nor any other definable predisposing factors. This combination is not recommended for further study.

Topics: Brachytherapy; Chromium; Chromium Compounds; Female; Humans; Melphalan; Ovarian Neoplasms; Phosphates; Phosphorus Radioisotopes

The results of a randomized trial, stratified according to age and stage of disease, in 140 patients with ovarian cancer are presented. The drug, levamisole, or a placebo was given as adjuvant to cytotoxic chemotherapy for 12 months after maximal surgical reduction of tumor. Because of severe side effects, levamisole treatment was discontinued in 8 of 69 patients (marked neutropenia in 5, severe skin rashes in 3). There were no significant differences in the survival curve and mean duration of survival between levamisole-treated and placebo-treated groups during the 4 years of follow-up, except for patients with Stage II disease. Among these latter patients, the survival rate became progressively much lower in the levamisole-treated group and the difference reached statistical significance after the second year of follow-up (P less than 0.01). In view of the inconclusive evidence that levamisole provides a beneficial effect (in fact, there is concern of a deleterious effect) and the serious side effects, the drug should not be used in patients with ovarian cancer.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Follow-Up Studies; Humans; Levamisole; Melphalan; Middle Aged; Neutropenia; Ovarian Neoplasms; Placebos; Random Allocation

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

A prospective randomized study was conducted in women with suboptimal (greater than or equal to 3 cm residual) Stage III, Stage IV, and recurrent ovarian adenocarcinoma to determine if combination chemotherapy is more effective than melphalan alone in achieving remission and improving survival. Of 233 evaluable patients with measurable disease, there were 64 treated with melphalan alone, of whom 20% achieved a clinical complete response and 17%, a partial response. Of the 97 patients receiving melphalan plus hexamethylmelamine, 28% achieved complete response compared with 32% of 72 patients given Adriamycin plus cyclophosphamide. The partial response rates for the combinations were 24% and 17%, respectively. The effect of these treatments was assessed in an additional 136 evaluable patients without measurable disease by progression-free interval and duration of survival. After statistically adjusting for distribution of cell type and grade, the clinical complete response rate for Adriamycin and cyclophosphamide (32%) in measurable cases was significantly higher (P = 0.04) than for melphalan alone. However, this combination did not improve median survival (12.3, 13.5, and 14.2 months, respectively, for M, M + H, and A + C). None of the other parameters showed a statistically significant advantage for combination chemotherapy, but the combinations caused more hematologic and gastrointestinal toxicity.

Topics: Adenocarcinoma; Adult; Aged; Altretamine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Prognosis; Random Allocation; Triazines

From May 1978 until November 1980, 169 previously untreated patients with advanced epithelial ovarian cancer were entered into a prospective randomized clinical trial comparing the combination of hexamethylmelamine, Adriamycin, and cyclophosphamide (HAC) to a combination of melphalan and cis-platinum. Eleven patients were excluded from analysis and another 5 patients were excluded from response analysis. Of 153 patients evaluable for response, there were 47, or 30.7%, complete responders (all determined surgically), 6 partial responders, and 100 nonresponders. The response rate for the HAC group was 31% and for the melphalan-platinum group was 37.8%. The overall response rate was 34.6%. Residual tumor diameter (less than or greater than 2 cm) exerted a statistically significant effect on response--47.8 vs 24.4%. Of the 47 complete responders, 7, or 14.9%, have relapsed, with the median duration of remission of 44+ months. Of the 158 patients evaluable for survival, 90 patients have died, with a median survival time of 27.9 months (HAC = 26.4 months, melphalan-platinum = 29.6 months). Age, FIGO stage, histologic grade, and residual disease all exerted a significant effect on survival time. Second-line therapy in the treatment failures was of no benefit. Hematologic toxicity was greater in the melphalan-platinum group. Gastrointestinal toxicity was severe in both groups. Other toxicities were minor and infrequent.

Topics: Adult; Altretamine; Anemia; Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukopenia; Melphalan; Middle Aged; Ovarian Neoplasms; Prospective Studies; Random Allocation; Thrombocytopenia

A prospective randomized trial was carried out in 153 patients with stage III malignant epithelial tumours for comparing the effects of irradiation or combination of chemotherapy and irradiation on prognosis and operability. No significant differences between these two treatment modalities were found. Of the patients primarily considered inoperable were 41 per cent operated upon after preoperative treatment. Minimum residual disease (0 to less than or equal to 2 cm) occurred in 38 per cent of the primarily operated and in 31 per cent of those operated upon after preoperative treatment. Preoperative irradiation in primarily inoperable patients enabled more effective surgical measures at relaparotomy. The size of the residual tumour after surgery and the tumor grade influenced the survival.

Topics: Carcinoma; Clinical Trials as Topic; Female; Humans; Laparotomy; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Radiotherapy Dosage; Random Allocation

A multimodality treatment program has been applied to ovarian carcinoma at the Johns Hopkins Hospital since August 1975. Forty-nine patients were subdivided into 23 patients with maximally resected Stage III micrometastatic, and 26 patients with significant retained disease, 20 with Stage III macrometastatic and 6 with Stage IV. After initial pilot studies, those patients with minimally retained disease entered a randomized prospective study. Antiovarian antiserum was used in one arm of the study; in both study arms colloidal P-32, delayed split whole abdominal irradiation, and maintenance melphalan were used. For the 23 patients with micrometastatic disease the cumulative survival and survival without evidence of disease at four years is 78 and 34% respectively. Twenty-six patients with macrometastatic disease were treated with or without intraperitoneal antiserum and multiagent chemotherapy; their cumulative one year survival is 50%. The lack of significant toxicity of intraperitoneal antiovarian antiserum and the results of multimodality therapy indicate the feasibility of this therapeutic approach to further improve ovarian cancer therapy.

Topics: Adenocarcinoma, Mucinous; Altretamine; Antibodies, Neoplasm; Carcinoma; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Ovarian Neoplasms; Ovary; Phosphorus Radioisotopes; Prospective Studies; Random Allocation

A prospective randomized trial for comparing the effects of chemotherapy and radiotherapy on survival in malignant epithelial ovarian tumours was carried out during the years 1975-1978 in 142 (90%) of a total material of 157 patients in Stage I and Stage II of this disease. Stratification was done according to the state of the tumour capsule and the type of histology found in Stages Ia and Ib. Two types of randomized treatment were given: A. Patients with no extracystic excrescences and intact tumour capsule with mucinous tumours in Stages Ia and Ib were given Melphalan or were not treated, while those with non mucinous tumours were given Melphalan or radiotherapy; B. All of the other patients with tumours in Stage I and Stage II were treated with radiotherapy alone, or were irradiated in combination with Melphalan treatment. Both of these treatment groups had about the same rates of 2- and 5-year survival. It was seen that the histological grade and the amount of residual tumour left at surgery are important prognostic factors. Postoperative treatment does not seem to improve cases of well differentiated, early mucinous tumours in Stage Ia. Acceptable results were obtained, however, irrespective of histological type, in early Stage I, moderately differentiated tumours treated with Melphalan or radiation therapy, and in well- or moderately differentiated tumours in Stage I or Stage IIa using irradiation alone or in combination with chemotherapy. Stages IIb and IIc, and all poorly differentiated tumours in Stages I and II, require more aggressive treatment.

Topics: Adenocarcinoma, Mucinous; Adult; Castration; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Postoperative Care; Prospective Studies; Radiotherapy Dosage; Random Allocation

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

Topics: Acute Disease; Adult; Aged; Alkylating Agents; Animals; Chlorambucil; Clinical Trials as Topic; Female; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Ovarian Neoplasms; Random Allocation; Risk

Thirty-eight patients with an advanced ovarian cancer (FIGO stage III and IV) were randomly allocated to treatment, either with melphalan (M) or a combination of adriamycin, 5-fluorouracil and cyclophosphamide (CAF) to determine the effect on survival. Actuarial survival of the two treatment groups was the same but the combination was more toxic.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Random Allocation

Two consecutive studies were undertaken in patients with advanced adenocarcinoma of the ovary to compare melphalan, adriamycin and 5-fluorouracil (MAF) with cyclophosphamide, adriamycin and 5-fluorouracil (CAF). Twenty-one patients received MAF and 19 received CAF. The objective response rate was 35% for MAF and 62% for CAF patients, and complete remission occurred in 23% of MAF, and in 56% of CAF, patients. These differences were not statistically significant. In both groups, complete remission had a statistically significant and favourable influence on survival. Toxic effects were predominantly haemopoietic and gastrointestinal, MAF having a significantly greater thrombocytopenic potential than CAF, but over-all tolerance was good on both protocols. MAF and CAF are comparable and effective combinations for the treatment of advanced ovarian cancer, but do not demonstrate superiority to single alkylating agent therapy or to other combinations. This emphasizes the continuing need for well designed randomized trials comparing single alkylating agents with combinations of known active agents.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Carcinoma; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

The objectives of the initial surgical procedure in patients with common epithelial carcinomas of the ovary are determination of the intraabdominal extent of the cancer and the reduction of tumor masses to the smallest residuum before initiating further therapy. Since ovarian cancer is a disease of the entire abdominal cavity, biopsy of selected sites will often detect unsuspected involvement by microscopic foci of metastatic carcinoma. Tumor-reductive surgery resulting in a small tumor residuum before initiating chemotherapy is thought to improve the changes for inducing a complete response. The retroperitoneal operative approach enhances the surgeon's effort to remove tumor bulk. Between July 1, 1972, and September 1, 1978, 104 patients with FIGO Stage III or IV carcinomas of the ovary were treated with melphalan. The conditions of 38 patients were evaluated by second-look laparotomy. This analysis attempts to define tumor-reductive surgery and relates the outcome of the results of the operative procedure to patients treated with melphalan.

Topics: Adult; Carcinoma; Clinical Trials as Topic; Female; Humans; Laparotomy; Lymphatic Metastasis; Melphalan; Methods; Middle Aged; Ovarian Neoplasms; Prospective Studies; Random Allocation

The results of a national clinical trial to compare combination and sequential chemotherapy for stage III or IV ovarian cancer are reported. Of the 253 patients from 16 centres across Canada who were admitted to the trial 13 were excluded from the analysis. All the patients were observed for 2 to 5 years from entry into the trial. There were no differences in response to therapy or in survival between the patients treated with melphalan followed by 5-fluorouracil and then by methotrexate in high dosage and the patients treated with the same agents in combination. Patients with minimal residual disease after resection of stage III ovarian cancer had a good prognosis. Other favourable prognostic factors were age (less than 55 years), performance status (90% or 100% on the Karnofsky scale) and histologic grade of the tumour.

Topics: Adult; Aged; Antineoplastic Agents; Canada; Carcinoma; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms

The purpose of this study was to determine the efficacy of single and multiple drug chemotherapeutic regimens in the treatment of patients with advanced or recurrent, Stage III and IV, ovarian epithelial carcinoma. Patients were randomly assigned to one of four treatment regimens postoperatively, or at the time of recurrence: Regimen I--Melphalan (MEL) 0.2 mg/kg/day for five days every four weeks; regimen II--MEL as in Regimen I plus 5-fluorouracil (FU) 15 mg/kg/day for five days every four weeks; regimen III--MEL and FU as in regimen II plus dactinomycin (AC) 0.5 mg daily for five days every four weeks; and regimen IV--Cytoxan (CY) 7 mg/kg/day, FU 8 mg/kg/day and AC 0.5 mg/day for five days every four weeks. Four hundred and twenty-seven patients were in the study, 314 of whom are evaluable for progression-free interval (PFI), survival, and toxicity: 102 in regimen I, 80 in regimen II, 83 in regimen III, and 49 in regimen IV. Of these, 293 were considered evaluable for response. Because of excessive toxicity, entry of patients to regimen IV was discontinued midway through the study. The overall toxicity was quite high but was most severe in regimen II and IV where 16 toxicity deaths were recorded. The complete and partial response rate with Melphalan alone was 29.2%. This response rate was not enhanced by the addition of FU or FU and AC and not substantially different than the response rate of AC, FU, and CY.

Topics: Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Erythrocyte Count; Female; Fluorouracil; Humans; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platelet Count; Prognosis; Time Factors

Topics: Altretamine; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Triazines

The histologic grade of epithelial ovarian tumors was found to be a major prognostic factor for survival in patients with advanced (stage III-IV) disease. In addition, a grading system based on cytologic detail (modified Broders' grades I-IV) identified groups with a differential response to chemotherapy. The overall improvement in survival observed with combination chemotherapy was related primarily to an increased survival of patients with grade II and III lesions. Although the survival of patients with grade I lesions was markedly better than for patients with grade IV lesions, in neither case was it influenced by the choice of single-agent or combination chemotherapy. In prospective clinical trials in advanced disease, modified Broders' grades should be included as a separate stratification factor.

Topics: Altretamine; Cell Differentiation; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Prognosis

Topics: Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Remission, Spontaneous; Time Factors

Topics: Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Organothiophosphorus Compounds; Ovarian Neoplasms; Remission, Spontaneous

Topics: Antigens, Neoplasm; Carcinoembryonic Antigen; Drug Therapy, Combination; Female; Humans; Immune Sera; Male; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Peritoneal Neoplasms; Phosphorus Radioisotopes; Radiotherapy Dosage

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Altretamine; Antineoplastic Agents; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Prospective Studies

Fifty-seven patients referred to Roswell Park Memorial Institute between 1971-1975 with Stage III or IV epithelial ovarian cancer treated with prior radiation therapy were randomly allocated to treatment with melphalan, 5-fluorouracil (5-Fu) plus melphalan (FUME), actinomycin-D plus 5-fluorouracil plus melphalan (ACFUME), actinomycin-D, or 5-fluorouracil plus cyclophosphamide (ACFUCY). These patients receiving 5-FU plus melphalan had longer median duration of survival with better quality of life. Combination chemotherapeutic agents effected significantly. better responses (P less than 0.05) than single agent chemotherapy. The ACFUME and ACFUCY combinations resulted in higher incidence of severe and life-threatening toxicity. Patients showing complete response had maximum median duration of survival.

Topics: Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; New York; Ovarian Neoplasms; Prospective Studies; Quality of Life; Thrombocytopenia

The age adjusted death rate for ovarian cancer has remained unchanged for the past 20 years. Recent data obtained by staging ovarian cancer patients with lymphangiography and peritoneoscopy demonstrated that many patients with apparently localized disease actually have occult dissemination within the abdomen. These new staging techniques plus the determination of the histologic grade of anaplasia may permit a more precise determination of a patient's prognosis and therefore better design of therapeutic stategy. Radiotherapeutic techniques are being adapted to attempt to treat some areas of occult disease. Numerous single chemotherapeutic agents are capable of producing objective tumor responses. Preliminary data suggest that combination chemotherapy can increase the objective response rate above that seen with single agents. Longer follow-up is necessary to determine whether combination chemotherapy can prolong survival.

Topics: Alkylating Agents; Altretamine; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Laparoscopy; Lymphatic Metastasis; Lymphography; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Clinical Trials as Topic; Drug Evaluation; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

Topics: Altretamine; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Thiotepa

Appreciating the past reports of effectiveness for various therapeutic modalities in ovarian cancer, the Gynecologic Oncology Group activated eight protocols. Three involved epithelial lesions with randomized multimodality trials alone or in combination. The other protocols were devoted to registration of rare tumor case reports. Conclusions are still difficult to reach due to inconsistencies in pathologic diagnoses and deficiencies in radiation therapy, chemotherapy and surgery inherent in the initial phases of group development by diverse specialist in oncology. Adjuvant therapy for early cancer seems to have no advantage. Single drug, melphalan therapy may be as effective as multi-drug, irradiation or combined drug-irradiation therapy and less toxic. For the rare tumors, preliminary results suggest therapeutic advantage for at least one triple drug program in malignant teratoma. With the lessons of the past, it is anticipated that new studies briefly described herewith may be more effectively applied.

Topics: Altretamine; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Melphalan; Ovarian Neoplasms; Propionibacterium acnes; Radiotherapy Dosage

One hundred and eight patients with Stage III or IV epithelial ovarian cancers were randomly allocated to treatment with either melphalan or the combination of Actinomycin-D, 5-fluorouracil, and cyclophosphamide (ACFUCY). Those patients receiving the ACFUCY combination had a higher objective response rate and a statistically significantly lower progression rate. The ACFUCY combination gave a higher incidence of severe toxicity.

Topics: Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

Topics: Cyclophosphamide; Drug Resistance; Female; Humans; Melphalan; Ovarian Neoplasms; Risk; Thrombocytopenia; Thrombophlebitis

A search for improved forms of systemic chemotherapy in advanced ovarian carcinoma has resulted in two prospective trials at the Medicine Branch National Cancer Institute. The first trial compared high-dose, split-course intravenous cyclophosphamide with conventional treatment with an oral alkylating agent, melphalan [also called L-phenylalanine mustard (PAM)]. While both regimens were essentially equal in therapeutic efficacy, the former was considerably more toxic and the latter was therefore preferred. The second trial employed a 4-drug combination (5-fluorouracil, methotrexate, cyclophosphamide, and hexamethylmelamine); the results indicated a higher overall response rate (85%) and a higher complete remission rate (31%) with the combination therapy than with the PAM therapy, although the study is short and the observations are preliminary.

Topics: Altretamine; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Humans; Maryland; Melphalan; Methotrexate; National Institutes of Health (U.S.); Ovarian Neoplasms; Prospective Studies; United States

The effectiveness of melphalan, hexamethylmelamine, and 5-fluorouracil was compared in the treatment of patients with advanced ovarian cancer. Patients responded the best to hexamethylmelamine, which, however, was associated with considerable neurotoxicity. Patients responded the worst to 5-fluorouracil, which occasionally induced severe gastrointestinal toxicity. Patients treated with melphalan continued to demonstrate the response rate reported for several years in the literature. Melphalan seemed the best choice as a second-line drug. It induced not only the longest survival rate among patients, but also the only two complete responses as a second-line drug. Hexamethylmelamine has shown no activity as a third-line drug to date.

Topics: Adult; Altretamine; Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

In an attempt to improve the response rate and hopefully the survival rate in women with advanced ovarian adenocarcinoma, three new modalities of therapy for ovarian adenocarcinoma were undertaken in 97 women. Sequential therapy consisted of surgery followed by chemotherapy, second-look laparotomy, and subsequent whole abdominal radiation. Eight women exhibiting a complete clinical response to chemotherapy were subjected to this treatment. However, only one woman (12%) is surviving without evidence of tumor recurrence. Concomitant therapy consisted of external radiation and single alkylating agent chemotherapy in 23 women. Again, the survival was poor: a 5-year survival of 8% without tumor recurrence. The third treatment modality consisted of a randomized study of 66 patients in whom single agent therapy with melphalan was compared with multiple agent therapy consisting of cyclophosphamide, dactinomycin, and 5-fluorouracil. In those women with stage III and IV serous adenocarcinoma of the ovary, a 63% response rate was obtained in patients receiving triple chemotherapy as compared to a 45% response rate in those receiving melphalan. Moreover, 40% of the group given triple chemotherapy exhibited a complete response as compared to only 18% in the group given melphalan.

Topics: Adenocarcinoma; Alkylating Agents; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Thiotepa

The therapeutic effects of adriamycin and of melphalan in patients with advanced carcinoma of the ovary were tested in a prospective randomized study. Complete and partial remission occurred in eight of 19 patients treated with adriamycin and in four of 20 patients given melphalan. The difference, however, is not statistically significant. The median duration of complete and partial remissions was slightly longer after treatment with melphalan than with adriamycin. The number of cycles required to produce the initial regression state was less in the patients in the group given adriamycin as compared with those in the group treated with melphalan. No cross resistance was observed between the two drugs. These data indicate that, in patients with carcinoma of the ovary, the therapeutic efficacy of adriamycin is competitive with that of the most effective conventional agents, such as melphalan.

Topics: Adenocarcinoma; Carcinoma; Clinical Trials as Topic; Doxorubicin; Drug Evaluation; Endometriosis; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Remission, Spontaneous

Considerable progress is being made in the chemotherapy of some gynecologic cancers. A random study comparing postoperative irradiation therapy with chemotherapy shows the two to be equally effective. Chemotherapy has the advantages of added safety and of being much less expensive for the patient. Postoperative chemotherapeutic treatment with VAC of patients with embryonal carcinoma of the ovary can prevent recurrence of this frequently fatal tumor. In some patients with advanced embryonal carcinoma of the ovary, chemotherapy with VAC may produce permanent remissions. Combined irradiation and chemotherapy and vincristine and actinomycin-D may be curative for some patients with advanced sarcomas in the pelvis or abdomen. This treatment combination is associated with severe complications; however, some are preventable.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Pelvic Neoplasms; Sarcoma; Teratoma; Vincristine

One hundred and forty-nine patients with early cancer of the ovary who were suitable for postoperative radiotherapy were treated in a random study in which the efficacy of whole abdominal irradiation with additional irradiation to the pelvis was compared to that of chemotherapy with melphalan. The number of patients without evidence of disease at 2 years indicates that both treatments give similar results. However, the survivals among patients with stage I ovarian cancer showed an improvement for women treated with irradiation, survivals among patients with stage II ovarian cancer showed only a minor difference between women treated with irradiation and those treated with chemotherapy, and survivals among patients with stage III ovarian cancer improved for women treated with chemotherapy. The complications resulting from both treatments differed greatly. Melphalan was well tolerated; it caused serious bone marrow depression in only one patient. The blood counts of all patients after completing their prescribed chemotherapy promptly returned to normal levels. Seven patients treated with irradiation developed small bowel injury requiring surgery. Six of these patients, however, were treated with irradiation to the pelvis followed by strip irradiation to the entire abdomen. Since this treatment plan probably gives excessive doses of irradiation to the pelvis, it has been discontinued.

Topics: Adolescent; Adult; Aged; Bone Marrow; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy

One hundred and forty-nine patients with early cancer of the ovary who were suitable for postoperative radiotherapy were treated in a random study in which whole abdominal irradiation with additional treatment to the pelvis was compared to chemotherapy with Melphalan. The number of patients without evidence of disease at 2 yr seems to show that the results of treatment are similar. When the Berkson-Gage method of projection is used, however, the survival rate in stage I is apparently improved with irradiation; there is only a minor difference in the results of the two methods in stage II, and survival rates are improved for patients with stage III disease who were treated with chemotherapy. The complications of treatment in this study were quite different. Melphalan was well tolerated, and only one patient had serious bone marrow depression as a result of this treatment. All had prompt recovery of blood counts to normal after completing the prescribed chemotherapy. Seven patients treated by radiotherapy developed a small bowel injury which required surgery. Six of these were treated with irradiation to the pelvis followed by strip irradiation to the entire abdomen. This treatment plan probably gives excessive doses of irradiation to the pelvis and has been discontinued. This type of complication is much less frequent with the other sequence of treatment--strip irradiation to the whole abdomen and subsequent treatment to the pelvis. The cost to the patient of the two treatment programs varied considerably. Patients who received irradiation had the added expense of living in Houston for the duration of treatment. Patients treated with chemotherapy were often seen a 2- or 3-mo intervals and had their chemotherapy supervised by their personal physician.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Female; Humans; Melphalan; Ovarian Neoplasms; Postoperative Care; Radiotherapy

Twenty-four fully staged, previously untreated patients with advanced ovarian carcinoma were prospectively randomized to either intensive intravenous cyclophosphamide or conventional oral Melphalan therapy. The median durations of initial remissions (5 and 6 mo) and the median durations of survival (15 and 14 mo) were similar for the two regimens but the toxicity of the intensive regimen was excessive. Followup indicates that long term disease free survivals are possible in those patients who achieve complete remissions on chemotherapy alone as three of the four patients achieving complete remission in the present study remain free of disease with a median survival in excess of 30 mo. High dose intensive alkylating agent therapy in the manner used in the present study fails to enhance the response to chemotherapy and produces unacceptable toxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Administration, Oral; Cyclophosphamide; Cystadenocarcinoma; Dose-Response Relationship, Drug; Female; Humans; Injections, Intravenous; Laparoscopy; Melphalan; Ovarian Neoplasms; Remission, Spontaneous; United States

Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However, elucidating its pharmacokinetic behavior and preparing it for administration are challenging since it undergoes spontaneous hydrolysis. In this study, melphalan is transformed into a macromolecular prodrug by copolymerizing with p-dioxanone. The hydrophobicity of copolymer chains protects melphalan from hydrolysis. Poly(p-dioxanone-co-melphalan; PDCM) is electrosprayed and converted into nanoparticles (PDCM NPs) with diameters of ~300-350 nm to facilitate its intracellular delivery. UPLC-MS and HPLC are applied to verify and monitor the release of melphalan from PDCM NPs. PDCM NPs could suppress the proliferation of SKOV-3 cells. The IC50 of 4.3% melphalan-containing PDCM-3 NP was 70 mg/L, 72 h post administration. These suppression characteristics not only affected by the degradation and then the extracellular release of melphalan from PDCM NPs, but also the uptake via phagocytosis phenomenon in SKOV-3 cells. As revealed by flow cytometry, phagocytosis is a first-order process. Once phagocytosed, PDCM NPs are digested by lysosomes, causing a rapid release of melphalan into the cytoplasm, which ultimately causes suppression of SKOV-3 cell proliferation. Finally, the in vivo antitumor effects of PDCM NPs are verified in xenograft ovarian carcinoma. After a 20-day treatment, the tumor growth rate of the PDCM-3 NP group was (266 ± 178%) which was lower than those in the free melphalan group (367 ± 150%) and control group (648 ± 149%). Besides, significant tissue necrosis and growth suppression were observed in animals administered injections of PDCM NPs. Furthermore, the in vivo tracing results of Nile red-labeled PDCM NPs demonstrated that PDCM-3 NPs might be phagocytosed by macrophages and then taken to adjacent lymph nodes, which is a way of prevention or early treatment of lymphatic metastasis of tumors.

Topics: Animals; Cell Line, Tumor; Dioxanes; Drug Carriers; Female; Humans; Macrophages; Male; Melphalan; Mice; Mice, Nude; Nanoparticles; Ovarian Neoplasms; Particle Size; Phagocytosis; Polymers; Prodrugs; Xenograft Model Antitumor Assays

Definite diagnosis of metastasis from unknown primary depends on a comprehensive immunohistochemical investigation of tumor specimen. Accurate identification of the origin site usually helps a lot in choosing the most appropriate treatment. Molecular characterization provides more chance of a cure. Echoing modern medical development, BRCA1/2 mutations have been correlated with high efficiency of poly(adenosine diphosphate-ribose) polymerase inhibitors in ovarian cancer. While a previous case report demonstrated a surprising cure of platinum-resistant ovarian cancer with BRCA2 mutation by orally administered melphalan.. A 53-year-old Taiwanese woman's malignant pleural effusion was diagnosed to be a metastasis from an occult cancer in female genital organ by diligent pathological study despite absence of image evidence. She resolutely refused intravenously administered chemotherapy. After failure of anti-estrogen tamoxifen, orally administered melphalan achieved excellent complete remission. Pathogenic homozygous BRCA1 and BRCA2 mutations were later detected in tumor cells by next-generation sequencing. The same BRCA2 mutation exists in a heterozygous status in the germline deoxyribonucleic acid.. This is so far the second report of long-term remission of advanced female genital organ cancer with BRCA mutations achieved by orally administered melphalan. BRCA1/2 mutations and even all "BRCAness" of malignancy, at least ovarian cancer and ovarian-related cancers, probably not only correlate with high efficacy of poly(adenosine diphosphate-ribose) polymerase inhibitors but also lead to a high-potential cure by orally administered melphalan. We recommend that clinical trials that test this assumption be carefully designed and sophisticatedly performed.

Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Female; Genes, BRCA1; Genes, BRCA2; Humans; Melphalan; Middle Aged; Neoplasms, Unknown Primary; Ovarian Neoplasms; Pleural Effusion, Malignant

Antitumor efficiencies of cytostatics dioxadet, cisplatin, mitomycin C, melphalan, and paclitaxel after a single intraperitoneal or intravenous injection in doses of 1.5, 4, 1.5, 2, and 5 mg/kg, respectively, were studied on the model of transplanted ovarian tumor in 124 rats. The antitumor effects were evaluated by the increase in median survival. Dioxadet, cisplatin, and melphalan injected intraperitoneally significantly prolonged the lifespan median - by 79, 88, and 114%, respectively, and were in fact ineffective, when injected intravenously. Intraperitoneal mitomycin C prolonged lifespan median by just 35%, intravenous - by 152%. Paclitaxel injected intraperitoneally and intravenously prolonged the lifespan median by 45 and 81%, respectively.

Topics: Adenocarcinoma, Papillary; Animals; Antineoplastic Agents; Ascites; Cisplatin; Female; Injections, Intraperitoneal; Injections, Intravenous; Melphalan; Mitomycin; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Rats; Survival Analysis; Treatment Outcome; Triazines

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cytoreduction Surgical Procedures; Disease-Free Survival; Drug Evaluation, Preclinical; Female; Humans; Hyperthermia, Induced; Injections, Intraperitoneal; Melphalan; Mice; Mice, SCID; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Peritoneal Neoplasms; Phenylalanine; Xenograft Model Antitumor Assays

The study or antitumor effects of dioxadet, cisplatin, melphalan, paclitaxel, mitomycin C, cyclophosphamide and gemcitabine at intraperitoneal (i.p.) and intravenous (i.v.) administration as monochemotherapy and polychemotherapy in a rat model of ascitic ovarian cancer was carried out in 244 female Wistar rats. Ovarian cancer was transplanted i.p. at a number of 1 x 10(7) tumor cells. The drugs were administered once in 48 hours after ovarian cancer transplantation i.p. or i.v. for monotherapy--in maximum tolerated doses, for i.p. polychemotherapy--in half doses from maximum tolerated doses. Antitumor effects of the treatment were estimated in increase in median survival time (MST) compared to control rats who were administered saline i.p. At i.p. administration dioxadet, cisplatin and melphalan increased MST by 79%, 88% and 144%, respectively, while at i.v. administration these drugs didn't affect MST. Mitomycin C and paclitaxel had stronger antitumor action at i.v. administration increasing MST by 152% and 81%, respectively, while at i.p. administration these drugs increased MST by 35 and 45%, respectively. Combinations dioxadet + cisplatin, dioxadet + cyclophosphamide and dioxadet + paclitaxel at i.p. administration increased MST by 305%, 277% and 133%, respectively, and had additive antitumor action compared to mono-effects of these drugs. Gemcitabine and combination dioxadet + gemcitabine at i.p. administration didn't significantly affect survival of rats with ovarian cancer. Intraperitoneal monochemotherapy and polychemotherapy could be more effective in the treatment of peritoneal carcinomatosis from ovarian cancer compared to systemic administration of the drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Deoxycytidine; Female; Gemcitabine; Infusions, Intravenous; Infusions, Parenteral; Maximum Tolerated Dose; Melphalan; Mitomycin; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Rats; Rats, Wistar; Triazines

DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the 'unhooking' step is common to all ICLs.. Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment.. Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line specific. Real time PCR studies highlighted differences in the damage response to melphalan and cisplatin following equi-ICL forming doses.. These data suggest that the mechanisms by which melphalan and cisplatin-induced ICLs are 'unhooked' in vitro are distinct, and the mechanisms of clinical acquired resistance involving repair of ICLs, are drug specific.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Deoxycytidine; DNA; DNA Damage; DNA Repair; DNA Replication; Drug Resistance, Neoplasm; Female; Gemcitabine; Histones; Homologous Recombination; Humans; Melphalan; Multiple Myeloma; Ovarian Neoplasms; Rad51 Recombinase; Signal Transduction

Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Carcinoma; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Time Factors; Treatment Outcome

In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-omega-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by (1)H, (31)P, (13)C NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl(3) solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5-bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated.

Topics: Antineoplastic Agents; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Nitrogen; Ovarian Neoplasms; Phosphorylation; Piperidones; Structure-Activity Relationship; Thiophenes

Clear cell carcinoma of the ovary is an aggressive tumor characterized by relative chemoresistance and a poor prognosis. The purpose of this study was to review our experience with recurrent clear cell carcinoma of the ovary to evaluate its responsiveness to systemic cytotoxic and hormonal agents.. All patients diagnosed with clear cell carcinoma of the ovary seen at our institution between 1990 and 2002 were identified and their medical records reviewed. Eligibility criteria were: 1) primary diagnosis of clear cell carcinoma of the ovary, 2) measurable recurrent disease, 3) treatment of recurrent disease with 1 or more systemic regimens, and 4) adequate clinical information. End points were clinical response, progression-free survival, and overall survival.. Fifty-one patients treated for recurrent clear cell carcinoma were identified. The patients received a total of 105 regimens (344 cycles of therapy). Among patients with platinum-sensitive disease (n=22 regimens), 2 patients (9%) had partial responses to retreatment with carboplatin plus paclitaxel, and 4 (18%) had stable disease. Among patients with platinum-resistant disease (n=83 regimens), only 1 patient (1%) had a partial response - to gemcitabine - and 1 patient had stable disease in response to 2 different regimens-paclitaxel and gemcitabine. The median progression-free survival was 8 months, and the median overall survival was 18 months.. Our findings suggest that recurrent clear cell carcinoma of the ovary is particularly chemoresistant. A continued search for more active, targeted agents is warranted.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Cyclophosphamide; Docetaxel; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Taxoids

Topics: Antineoplastic Agents; Carboplatin; Cisplatin; Female; Humans; Infusions, Parenteral; Injections, Intraperitoneal; Melphalan; Oncology Nursing; Ovarian Neoplasms; Paclitaxel; Peritoneal Cavity; Risk Factors

Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5'-Aza-2'-deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity, synergy, or competition was observed with MIS and rapamycin, AzadC, doxorubicin, cisplatin, and paclitaxel, suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone. These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity.

Topics: Animals; Anti-Mullerian Hormone; Apoptosis; Azacitidine; Cell Line, Tumor; Decitabine; Drug Resistance, Neoplasm; Female; Glycoproteins; Humans; Immunoglobulin G; Melphalan; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Receptors, Peptide; Receptors, Transforming Growth Factor beta; Testicular Hormones; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Melphalan; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Survival Analysis; Treatment Outcome

We are reporting on a case of platinum-refractory low-grade ovarian cancer responding to treatment with an allogeneic bone marrow transplantation from an unrelated donor.. The 37-year-old patient received a preparative regimen consisting of fludarabine 25 mg/m(2) on days -6, -5, -4, -3 and -2, melphalan 70 mg/m(2) on days -3 and -2, and thymoglobulin 2 mg/kg on days -3, -2 and -1. An unrelated HLA-compatible bone marrow was infused on day 0. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. The patient demonstrated complete donor chimerism. Serial CT scans of the abdomen and pelvis over the following 15 months showed a slow regression of the malignant lesion.. Engraftment of an unrelated donor marrow was achieved in a patient with ovarian cancer and induced a tumor response. This suggests the presence of a graft-versus-tumor effect in ovarian cancer. Further study is underway.

Topics: Adult; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Drug Resistance, Neoplasm; Female; Graft vs Tumor Effect; Humans; Melphalan; Ovarian Neoplasms; Vidarabine

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Melphalan; Ovarian Neoplasms; Paclitaxel

BBR3464 is a trinuclear platinum complex that exhibits a potent cytotoxicity and efficacy against cisplatin-resistant tumors. To better understand the determinants of cellular resistance to BBR3464, we selected a resistant ovarian carcinoma cell line after exposure to the complex. The resistant cells (A2780/BBR3464) exhibited a high level of resistance to the selecting agent, but a marginal cross-resistance to cisplatin. Although cellular accumulation of BBR3464 was similar in parental and in resistant cells, DNA platination was decreased in A2780/BBR3464 cells, suggesting a reduced drug accessibility to DNA. This behavior reflected a partial drug inactivation at cytoplasmic level, as a consequence of increased levels of nucleophilic molecules including metallothioneins and human neurofilament low, but not glutathione. A2780/BBR3464 cells also exhibited a reduced susceptibility to apoptosis, which was consistent with reduced expression of Bax, and an alteration of DNA mismatch repair system, as reflected by lack of expression of MLH1 and PMS2, which could impair the recognition/repair of DNA lesions. Whereas both platinum drugs induced G2/M arrest in the parental cells, BBR3464, but not cisplatin, caused a late G1 arrest of resistant cells. Cisplatin induced an appreciable increase of p21(WAF1) levels in both models, in contrast to BBR3464 that produced a substantial upregulation of p21(WAF1) only in parental cells. An inverse relationship with p21(WAF1) modulation was found for CHK1 in parental cells treated with both agents and in resistant cells treated with cisplatin. This pattern of response is consistent with a regulatory loop involving p53 and p21(WAF1) at G2 checkpoint. In contrast, no modulation of CHK1 was found in A2780/BBR3464 treated with the triplatinum compound. These findings, indicating a different activation of regulatory pathways at DNA damage checkpoints in response to cisplatin and BBR3464, support an altered ability of resistant cells to recognize or tolerate sublethal lesions induced by BBR3464.

Topics: Antineoplastic Agents; Apoptosis; Base Pair Mismatch; Carmustine; Checkpoint Kinase 1; Cisplatin; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA Adducts; DNA Damage; DNA Repair; DNA, Neoplasm; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; G1 Phase; Glutathione; Humans; Melphalan; Metallothionein; Organoplatinum Compounds; Ovarian Neoplasms; Paclitaxel; Protein Kinases; Tumor Cells, Cultured

A large number of drugs have been used to treat recurrent ovarian cancer, yet there are few data that guide the physician's choice. Typically, the decision to re-treat with platinum-based therapy depends on the progression-free interval. However, the optimum agent for the treatment of platinum-resistant or refractory disease is not defined. In this study, we investigated the efficacy of oral melphalan in patients who have platinum refractory or resistant disease. A retrospective analysis was performed on 22 patients with ovarian carcinomas who had relapsed within 6 months of their platinum-based chemotherapy and were treated with oral melphalan. No objective responses were seen and the median overall survival was 3 months from commencement of therapy. Although the treatment was generally well tolerated, only two of the 22 patients managed to complete the planned six cycles of treatment. At the time of analysis, only two patients were alive. Other nonplatinum compounds have demonstrated response rates in the region of 20% in similar patient populations and it is unlikely that any positive responses could have been missed by chance (95% CI 0-15.4). The results of this study serve to eliminate oral melphalan as a treatment option in patients with platinum-resistant or refractory ovarian carcinoma.

Topics: Administration, Oral; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Ovarian Neoplasms; Platinum Compounds; Retrospective Studies; Treatment Outcome

The purpose of this study was to determine the response to melphalan in patients with recurrent epithelial ovarian cancer after platinum-based therapy. This retrospective observational study analyzed 10 patients with recurrent epithelial ovarian carcinoma treated with melphalan between August 1995 and April 2001. All had received primary platinum-based therapy. Nine of the 10 patients had chemosensitive disease. All but one patient had received one or more second-line therapies prior to melphalan. The median time to recurrence after first-line therapy was 26 months (range, 3-68). Treatment with melphalan resulted in 2 (20%) complete responses and 1 (10%) partial response (response rate, 30%; 95% CI 8%, 65%). The median progression-free interval after initiation of melphalan therapy was 8 months (range, 3-23). The most common side effects were grade I thrombocytopenia (20% of courses) and grade II leukopenia (18% of courses). The use of melphalan as palliative chemotherapy in patients with recurrent ovarian cancer results in response rates similar to those reported with other more expensive agents. Melphalan at the doses reported here has a favorable toxicity profile.

Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Female; Humans; Melphalan; Neoplasm Recurrence, Local; Ovarian Neoplasms; Palliative Care; Platinum Compounds; Retrospective Studies; Salvage Therapy; Survival Analysis

to determine the outcome of epithelial ovarian cancer in patients registered with the European Group for Blood and Marrow Transplantation (EBMT).. A retrospective analysis was performed on 254 patients with advanced or recurrent disease, median age 46 years (14-63) from 39 centres treated between 1982 and 1996. Only 25% of patients were known to have no or microscopic disease after initial surgery; in approximately 20% the disease status was unknown, the remainder had macroscopic disease.. One hundred five patients received high-dose chemotherapy in complete or very good partial remission, twenty-seven in second remission and the remainder in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86%) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 vs. 14 months; P = 0.0001). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 vs. 9 months; P = 0.005). With a median follow-up of 76 months from diagnosis the median disease-free and overall survival in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months.. High-dose chemotherapy has a potential benefit for patients in remission. The results support the conduct of randomised studies to determine whether there is a real value from this treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Carcinoma; Disease-Free Survival; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Registries; Retrospective Studies

The importance of dose intensity has been suggested in ovarian carcinoma. We retrospectively evaluated the long-term results of melphalan-based high-dose chemotherapy (HDC) with hematopoietic rescue in a unicentric series of 33 patients with advanced ovarian cancer sensitive to first-line chemotherapy. Before HDC, treatment with debulking surgery and platinum-based chemotherapy was followed by second-look operation (SLO). HDC consisted of melphalan (n = 8), melphalan and cyclophosphamide (n = 9), or melphalan, etoposide and carboplatinum (n = 16). Toxicity was mainly hematological. One death occurred from infection during aplasia. With a median follow-up of 60 months after intensification, the 5-year progression-free survival (PFS) rate was 29% and the 5-year overall survival (OS) rate was 45%. Survival differed significantly according to tumor status at SLO. Women with microscopic or macroscopic disease at SLO, ie with a pathological partial response to first-line therapy (PPR), had survivals of 7% at 5 years, similar to other salvage therapies. Better results were obtained in the 20 women with a complete pathological response (PCR) at SLO with 43% 5-year PFS (median, 51 months) and 75% 5-year OS (median not reached). In conclusion, melphalan-based HDC with hematopoietic rescue had an acceptable toxicity in patients with chemosensitive advanced ovarian cancer. In situations of salvage therapy for patients in PPR, this treatment was not effective in long-term analysis. On the contrary, long-term results were favorable in patients with PCR, suggesting further prospective randomized studies comparing HDC and other consolidation treatments should be undertaken in this particular situation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Cystadenocarcinoma; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Laparotomy; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Reoperation; Retrospective Studies; Survival Rate; Time Factors; Transplantation, Autologous

Combination chemotherapy with hexamethylmelamine (hexalen, altretamine, hexastat), 100 mg, thrice a day, per os, 14 days (out of a 28-day course) and sarcolysin, 15 mg, per os, during the first 5 days of the course, was received by 24 patients with primary advanced tumors of the ovaries, prior to or after cytoreductive surgery. Total apparent response to chemotherapy among 19 patients of the study group was 47.2%, clinically significant (plus stabilization)--94.5%, without significant untoward side-effects (vomiting--19%; leukopenia degree II-III--33% and thrombocytopenia--19%). The drug proved an active component of combination therapy for advanced ovarian carcinoma.

Topics: Adult; Aged; Altretamine; Antineoplastic Agents, Alkylating; Carcinoma; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Retrospective Studies; Treatment Outcome

Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects of TNF combined with various cytotoxic agents in a model consisting of a human ovarian cancer cell line containing endogenous wild-type p53 (wtp53) and sublines that were made drug resistant against various cytotoxic agents by transfection of several forms of mutated p53 (mtp53). Using the microculture tetrazolium assay, the cytotoxic effects of TNF alone, the cytotoxic agents VM-26, melphalan, cisplatin, vinblastine, paclitaxel, and mitoxantrone, plus the combined effects of 10 ng/ml TNF added 30 min before various concentrations of the cytotoxic agents were established. Compared with the control cell line (A2780/cmv), two cell lines transfected with mtp53 (A2780/m248 and A2780/m273) showed increased resistance against several cytotoxic agents but also an enhanced sensitivity to TNF. Interaction of TNF with the cytotoxic drugs was additive in the drug-sensitive control cell line as well as in the drug-resistant sublines. However, because of the increased sensitivity of A2780/m248 to TNF at the dose used for the combinations, the combination of TNF with several cytotoxic drugs reduced the level of resistance in A2780/m248 compared with the control cell line A2780/cmv. In conclusion, this study shows that addition of TNF can ameliorate resistance to cytotoxic agents in a subline that is drug-resistant because of mutated p53. This reduction in resistance by TNF is not due to synergistic interaction, but to collateral sensitivity to TNF.

Topics: Antineoplastic Agents; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Genes, p53; Humans; Melphalan; Mitoxantrone; Mutation; Ovarian Neoplasms; Paclitaxel; Teniposide; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Vinblastine

Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment.. We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups.. Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia.. Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Case-Control Studies; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Leukemia; Logistic Models; Melphalan; Middle Aged; Ovarian Neoplasms; Risk Factors

Exposure of A2780 human ovarian tumor cells to a low concentration of melphalan in vitro for 7 days resulted in the development of melphalan resistance. This resistance was not a stable characteristic of the cells since it was lost after 2 weeks in culture in the absence of drug. The melphalan-resistant cells exhibited significant cross-resistance to cisplatin but only minor cross-resistance to doxorubicin. The resistant cells had elevated levels of glutathione-S-transferase activity and mRNA. Exposure of the cells to the ethacrynic acid resulted in a decrease in enzyme activity as well as a reversal of their drug-resistant phenotype, indicating that the enzyme is involved in the resistance. When ethacrynic acid was present during the 7-day exposure of the cells to melphalan, the development of drug resistance was prevented. This system may serve as a useful preliminary step in screening for agents which can prevent the development of chemotherapy-induced drug resistance in human cancer.

Topics: Antineoplastic Agents, Alkylating; Blotting, Northern; Drug Resistance, Neoplasm; Ethacrynic Acid; Female; Glutathione Transferase; Humans; Melphalan; Ovarian Neoplasms; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30 h) was significantly higher after sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml x h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11 h after solid exposure versus 20 h after sequential doses) and intracellular concentrations 5-6 h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.

Topics: Adenocarcinoma; Antineoplastic Agents, Alkylating; Cell Count; Cell Survival; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Humans; Melphalan; Ovarian Neoplasms; Tumor Cells, Cultured

Irradiation of advanced ovarian cancer has been performed during the years 1976-1984 with six-field technique. Results of this treatment in a long follow-up have never before been evaluated.. Seventy-five patients with stage IIb-IV of invasive ovarian cancer have been treated with a combination of surgery, radiotherapy and chemotherapy. The results of the treatment were compared with 98 patients treated during the year 1991-1992 with surgery and chemotherapy only.. After controlling for the differences in background factors between the groups considered, there was still a significantly better survival rate for the patients treated with radiotherapy.. The results suggest that the role of radiotherapy in advanced ovarian cancer should be investigated in a prospective randomized trial.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chi-Square Distribution; Cisplatin; Dose Fractionation, Radiation; Doxorubicin; Female; Follow-Up Studies; Humans; Life Tables; Longitudinal Studies; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Ovarian Neoplasms; Proportional Hazards Models; Prospective Studies; Radiotherapy Dosage; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Survival Rate

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

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Thiotepa; Transplantation, Autologous; Treatment Outcome

Exposure of A2780 human ovarian tumor cells to a low concentration of melphalan in vitro for 7 d results in the development of melphalan resistance, which is dependent on elevated cellular levels of glutathione and glutathione S-transferase. The inclusion of selenite (at concentrations as low as 0.2 microM) during the exposure to melphalan completely prevented the development of resistance. Selenite did not prevent the melphalan-induced increase in glutathione, but it did prevent the increase in the activity of glutathione S-transferase. It also prevented the increase in the expression of the glutathione S-transferase gene, suggesting that this may be the mechanism by which it prevents the development of melphalan resistance. The results of this in vitro study suggest that selenite may prove to be useful in preventing the development of drug resistance in vivo.

Topics: Antineoplastic Agents, Alkylating; Blotting, Northern; Cell Division; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Glutathione Transferase; Humans; Melphalan; Ovarian Neoplasms; RNA, Messenger; Sodium Selenite; Tumor Cells, Cultured

DNA repair has been proposed to be an important determinant of cancer cell sensitivity to alkylating agents and cisplatin (DDP). Nucleotide excision repair (NER), which represents one of the most important cellular DNA repair processes able to remove a broad spectrum of DNA lesions, is involved in the recognition and repair of the crosslinks caused by DDP and melphalan (L-PAM). In this study, the mRNA levels of the different genes involved in NER (ERCC1, XPA, XPB, XPC, XPD, XPF) were examined in a panel of eight different human cancer cell lines, together with the overall DNA repair capacity using a host cell reactivation assay of a damaged plasmid. A statistically significant correlation was observed between the relative expression of XPA/XPC (P < 0.05) and ERCC1/XPC (P < 0.05) mRNAs. No correlation was found between the DDP and L-PAM IC50S and the relative mRNA expression of the tested NER genes. When the overall cellular DNA repair capacity was studied, carcinomas seemed to have a higher repair activity than leukaemias; but this repair DNA activity correlated neither with the mRNA expression of the different NER genes nor with DDP and L-PAM IC50S. These data seem to suggest that even if the NER pathway is an important determinant for the cytotoxicity of alkylating agents, as demonstrated by the extremely high sensitivity to alkylating agents in cells lacking this repair system, other factors have to play a role in regulating the cellular sensitivity/resistance to these antitumour drugs.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blotting, Northern; Cisplatin; Colonic Neoplasms; DNA Repair; Female; Gene Expression; Humans; Leukemia; Melphalan; Neoplasms; Ovarian Neoplasms; Tumor Cells, Cultured

The benzoyl nitrogen mustard derivative of distamycin A, tallimustine, belongs to a new class of alkylating agents, known as DNA minor groove alkylating agents. It alkylates adenine N3 with high sequence specificity, causing no alkylation of guanine N7, the main site of alkylation of clinically used nitrogen mustards such as L-PAM. The present study investigated the in vivo antitumour activity of a combination of tallimustine and melphalan (L-PAM). Two murine tumours were used: i.p. (intraperitoneally) transplanted L1210 leukaemia and i.m. (intramuscularly) transplanted M5076 ovarian reticulum cell sarcoma (M5). In L1210, which is only marginally sensitive to tallimustine, the combination of tallimustine 3 mg/kg i.p. with L-PAM 10 mg/kg i.p. was as effective as 20 mg/kg L-PAM, which is the maximum tolerated dose. In M5, which is sensitive to both drugs, the combination was superior to either drug alone. The results suggest that the combination of tallimustine and L-PAM--or possibly in general, minor groove alkylators and major groove alkylators--may be therapeutically advantageous and therefore should be investigated clinically.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Distamycins; Female; Leukemia L1210; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Transplantation; Nitrogen Mustard Compounds; Ovarian Neoplasms; Survival Rate

A series of 53 patients with poor-prognosis epithelial ovarian cancer treated with high-dose chemotherapy (HDC) followed by hematopoietic rescue was retrospectively studied from the day of diagnosis for toxicity and long-term survival analysis.. Patients were treated with surgery followed by cisplatin combination chemotherapy. After second-look operation (SLO), HDC was administered: 23 patients received melphalan (140 mg/m2 on day 1) and 30 patients received a combination of carboplatin (400 mg/m2 on days 1 to 4) and cyclophosphamide (1.6 g/m2 on days 1 to 4). After HDC, autologous stem-cell transplantation was performed for hematologic support.. One patient died of cardiac failure after HDC, but the acute toxicity was acceptable for the other patients. With a median follow-up of 81.5 months, the 5-year overall survival rate for the 53 patients was 59.9% and the disease-free survival (DFS) rate at 5 years was 23.6%. Twenty-four patients (45.3%) were alive, 12 with no evidence of disease and 12 with recurrent disease. The best results were achieved in 19 patients with pathologic complete response at SLO (74.2% 5-year overall survival; 32.8% 5-year DFS).. HDC followed by autologous stem-cell support is a well-tolerated therapeutic approach for patients with poor-prognosis ovarian carcinoma. In this report, the 59.9% survival of 53 patients at 5 years must be compared to the 20% to 30% 5-year survival observed after conventional therapy. These results should be confirmed by an ongoing prospective randomized trial.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Retrospective Studies; Salvage Therapy; Survival Analysis; Treatment Outcome

We investigated the effect of pharmacological modulators on the cytotoxic activity of melphalan and cisplatin in human ovarian cystadenocarcinoma cells sensitive (OAW42) or resistant (OAW42MER) to bifunctional alkylating agents. By filter elution experiments we observed a reduced accumulation and a faster repair of melphalan-induced DNA interstrand cross-links in the OAW42MER resistant cells than in the OAW42 parental, sensitive cells. Moreover, resistant cells were characterized by an increased level of mRNA encoding enzymes involved in the nucleotide excision repair pathway, such as ERCC (excision repair cross complementing)1 and ERCC2. Among the modulators used, the topoisomerase I inhibitor topotecan was able to increase melphalan cytotoxic activity in sensitive and resistant cell lines. Topotecan also positively modulated cisplatin activity, although to a variable extent in the two cell lines, as a function of treatment schedule. The energolytic compound lonidamine markedly enhanced the cytotoxicity of melphalan and cisplatin, with a potentiating effect in the OAW42MER resistant cells almost 2-fold that of in the OAW42 sensitive cells. No significant potentiation was observed by using calcium channel blockers, such as verapamil and nimodipine. Conversely, an increase in melphalan cytotoxic activity was determined by flunarizine in OAW42MER resistant cells and, to a lesser extent, in OAW42 sensitive cells. However, the calcium blocker failed to modulate cisplatin activity in both cell lines.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blotting, Northern; Calcium Channel Blockers; Cell Survival; Cisplatin; Culture Media; Cystadenoma; Drug Resistance, Neoplasm; Female; Flunarizine; Humans; Melphalan; Nimodipine; Ovarian Neoplasms; RNA Probes; RNA, Neoplasm; Tumor Cells, Cultured; Verapamil

Multidrug resistance (MDR) in human cancer cells is multifactorial. Previously, we reported on the association between expression of P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRP), and the lung resistance protein (LRP) with the MDR phenotype in the NCI panel of 60 human cancer cell lines used for in vitro anticancer drug screening. Eight cell lines from this panel, manifesting widely divergent levels of in vitro drug resistance were chosen to investigate the role of MRP and LRP expression at the molecular level. LRP mRNA levels, as determined by ribonuclease protection assay, varied significantly among the 8 cell lines, and correlated closely with in vitro drug resistance to both MDR and non-MDR related drugs. LRP mRNA expression was determined to be a stronger correlate of drug sensitivity than protein expression. In contrast, MRP mRNA levels were not significantly correlated with drug sensitivity. The rates of newly transcribed LRP or MRP mRNA did not correlate with mRNA levels, indicating that mRNA stability or other features of processing may be important in regulation of LRP and MRP mRNA levels. Using Southern blot analysis, LRP gene amplification was shown not to be associated with LRP overexpression. These data suggest that LRP expression may be an important determinant of the MDR phenotype in cell lines intrinsically resistant to cancer chemotherapeutic agents.

Topics: Amsacrine; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cell Nucleus; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Resistance, Multiple; Female; Glycoproteins; Humans; Kidney Neoplasms; Leukemia; Lung Neoplasms; Melphalan; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; Phenotype; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles

Previous studies have demonstrated that melphalan-resistant human ovarian tumor cells exhibit a higher degree of sensitivity to the cytotoxic effects of selenite in vitro than comparable drug-sensitive cells (P.B. Caffrey, G.D. Frenkel, Selenite cytotoxicity in drug resistant and non-resistant human ovarian tumor cells, Cancer Res. 52 (1992) 4812-4816; P.B. Caffrey, G.D. Frenkel, The development of drug resistance by tumor cells in vitro is accompanied by the development of sensitivity to selenite, Cancer Lett. 81 (1994) 59-65). We have now examined the sensitivity of drug-resistant tumors to selenite in vivo. A2780 human ovarian tumor cells, or their melphalan-resistant derivative (A2780ME) cells were injected subcutaneously into nude mice and the resulting tumors were found to be melphalan-sensitive and -resistant, respectively, in vivo. Treatment with selenite (2 mg/kg Se s.c.), which had no overt toxic effect on the animals, resulted in a significant decrease in the rate of growth of the melphalan-resistant tumors, but not on the rate of growth of the drug-sensitive tumors. Thus, melphalan-resistant ovarian tumors are also more sensitive to selenite treatment in vivo.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Mice; Mice, Nude; Ovarian Neoplasms; Sodium Selenite; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Cell Cycle; Cisplatin; DNA Fragmentation; Dose-Response Relationship, Drug; Doxorubicin; Female; Flow Cytometry; Humans; In Situ Nick-End Labeling; Melphalan; Ovarian Neoplasms; Time Factors; Tumor Cells, Cultured

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

The sensitivity of tumor cells to lysis by natural killer (NK) and interleukin-2 (IL-2)-activated killer (LAK) cells was studied in three ovarian carcinoma cell lines (2780.9S, SKOV-3, and CHOAUXB1), four multidrug-resistant (MDR) variants, and a melphalan-resistant line. The antitumor activity of LAK cells was evaluated both by 51Cr release and by conjugate formation assays. Four of four P-glycoprotein-positive (P-gp+) MDR ovarian carcinoma cell line variants were lysed by human LAK cells to a greater extent than were their drug-sensitive counterparts. In contrast, a melphalan-resistant ovarian carcinoma cell line that does not overexpress P-gp (P-gp-) did not exhibit an increased susceptibility to LAK cells relative to its parental cell line. Two of the four P-gp+ MDR ovarian carcinoma cell line variants were tested for human NK cell susceptibility and this was found to be unchanged or decreased. The P-gp+ MDR ovarian carcinoma cell line 2780.AD645 showed a higher frequency of tumor cell binding to LAK cells than did the drug-sensitive parental line. A monoclonal antibody (mAb) against a cell surface epitope of P-gp, MRK16, used at 1 microgram/ml, enhanced the LAK susceptibility of P-gp+ MDR ovarian carcinoma cell lines. However, when incubation with 10 micrograms/ml MRK-16 antibody (Ab) was followed by 12.5 micrograms/ml F(ab')2 goat anti-mouse (GAM) immunoglobulin (Ig), the increased LAK susceptibility of P-gp+ MDR cell lines was inhibited. These data strongly suggest that P-glycoprotein-positive MDR ovarian carcinoma cells not only are targets for LAK cells, but are more sensitive than their drug-sensitive parental lines. This is in contrast to their susceptibility to NK cells, which is low to start with and remains unchanged or even decreased in MDR cells. It is postulated here that P-gp or associated changes result in a greater frequency of effector-target cell binding, leading to increased LAK cell cytotoxicity.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma; CHO Cells; Cricetinae; Cytotoxicity, Immunologic; Drug Resistance, Multiple; Female; Humans; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Melphalan; Ovarian Neoplasms; Tumor Cells, Cultured

A2780 and COLO-316 ovarian adenocarcinoma cell lines were exposed to 1.0 mM 1-octanol for 12 hr in order to evaluate the potential effects of inhibition of gap junction-mediated intercellular communication (GJIC) on cellular responses to the chemotherapeutic drug melphalan. Other cellular endpoints relevant to drug-resistance mechanisms which were monitored after treatments included cellular glutathione levels, glutathione S-transferase activity, mitochondrial membrane potential, and plasma membrane lipid mobility. In cells which were sensitive to melphalan, octanol enhanced melphalan toxicity in the GJIC-competent (A2780/S) but not GJIC-incompetent (COLO-316/S) sensitive cells. Although octanol increases plasma membrane lipid mobility in A2780/S and COLO-316/S, it appears that enhancement of A2780/S sensitivity to melphalan may be due to inhibition of GJIC. In melphalan-resistant cells (A2780/R and COLO-316/R), 1.0 mM octanol treatment for 12 hr combined with melphalan reversed the resistance of the cells to the drug. Therefore, alterations in cellular glutathione metabolism and effects on the plasma membrane in addition to uncoupling of GJIC may be involved in sensitizing communication-competent and communication-incompetent resistant cells because COLO-316/R lacks gap junction-mediated intercellular communication. Further, analysis of mitochondrial membrane potential provided an index of acquired drug resistance and the efficacy of melphalan and combined octanol/melphalan toxicity.

Topics: 1-Octanol; Adenocarcinoma; Cell Communication; Drug Resistance; Female; Gap Junctions; Glutathione; Glutathione Transferase; Humans; Melphalan; Membrane Fluidity; Membrane Potentials; Mitochondria; Octanols; Ovarian Neoplasms; Tumor Cells, Cultured

Tallimustine or N-deformyl-N-[4-N-N,N-bis(2-chloroethylamino)benzoyl], a distamycin-A derivative (FCE 24517), is a novel anti-cancer agent which alkylates N3 adenine in the minor groove of DNA. The cell-cycle phase perturbations induced by the drug were investigated and compared with those caused by melphalan (L-PAM) in SW626 human ovarian-cancer cells. By coupling bromodeoxyuridine (BUdR) immunoreaction with biparametric flow-cytometric (FCM) analysis, we investigated the cell-cycle phase perturbation induced by tallimustine or L-PAM, considering separately the cells which, during the 1-hr treatment, were in the S phase or in G1-G2/M phases of the cell cycle. L-PAM delayed the S-phase progression of cells exposed to the drug when they were in S phase, with a consequent accumulation of cells as soon as they reached the G2 phase. In contrast, the S-phase cells treated with tallimustine were not perturbed during the DNA-synthesis phase progression, and were blocked in G2 only after they had passed through the G1/S transition of a new cell cycle. In cells which were in G1 or G2/M phases during drug treatment, tallimustine and L-PAM caused similar accumulation in G2. The differences in the cell-cycle perturbation caused by tallimustine and L-PAM may well be related to the different DNA damage the 2 drugs produced. These findings emphasize the different properties of DNA-minor-groove alkylating agents and conventional ones.

Topics: Alkylating Agents; Bromodeoxyuridine; Cell Cycle; Distamycins; DNA; DNA, Neoplasm; Female; Flow Cytometry; Humans; In Vitro Techniques; Melphalan; Nitrogen Mustard Compounds; Nucleic Acid Conformation; Ovarian Neoplasms; Tumor Cells, Cultured

The effects of selenite on cell viability and proliferation in a line of drug-sensitive human ovarian tumor (A2780) cells were compared with its effects on a melphalan-resistant derivative of these cells (A2780-ME) which had been developed in vitro (Hamilton et al. (1985) Biochemical Pharmacol., 34, 2583-2586). With the A2780-ME cells there was a 50% decrease in the number of viable cells (i.e. which exclude Trypan Blue dye) after exposure to less than 100 microM selenite for 6 h. In contrast, exposure to more than 300 microM selenite was required to achieve the same effect in the parent line. Similarly, exposure to 10 microM selenite resulted in a 50% decrease in A2780-ME cell proliferation, whereas this treatment had only a small inhibitory effect on proliferation of the parent cells. Thus, the development of melphalan resistance in vitro was accompanied by the development of selenite sensitivity. Pre-exposure of the two cell types to buthionine sulfoximine eliminated the difference in their intracellular glutathione levels, as well as most of their differential sensitivity to selenite. Furthermore, the two cell types did not exhibit a difference in sensitivity to selenodiglutathione, the product of the reaction of selenite with glutathione. Thus, the increase in intracellular glutathione, which has been shown to be responsible for the development of drug resistance in these cells is also responsible for the development of selenite sensitivity.

Topics: Cell Division; Drug Resistance; Female; Glutathione; Humans; Melphalan; Organoselenium Compounds; Ovarian Neoplasms; Sodium Selenite; Tumor Cells, Cultured

The incidence of ovarian cancer has been increasing gradually over the last 25 years. The presenting symptoms are non-specific and, in many cases, there is extensive intraabdominal spread at the time of diagnosis. Diagnosis is based on abdominal ultrasonography followed by laparotomy for tumor classification and extensive excision. Assay of CA125 can be a useful diagnostic tool for post-menopausal women, and for determining the response to treatment. Routine screening for ovarian cancer is not feasible. The most important prognostic factor is tumor extension. In early stages, chemotherapy does not improve the prognosis in "low-risk" patients, and its value in high-risk patients remains to be determined. In patients with advanced-stage ovarian carcinoma, platinum derivatives are the reference drugs. The high toxicity of cisplatin has led to the development of carboplatin, which has similar activity but virtually no nephrotoxicity, neurotoxicity or ototoxicity. Carboplatin is currently considered as the cytostatic drug of choice, as it can be given at higher doses which may improve the survival time. The possible indications for intraperitoneal chemotherapy remain to be determined. Secondary laparotomy should not be used, except in clinical trials. Taxol (paclitaxel), a new cytostatic agent that prevents mitosis through an original mode of action, is currently undergoing evaluation.

Topics: Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Cisplatin; Female; Humans; Injections, Intraperitoneal; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Prognosis; Risk Factors; Survival Analysis

We have previously obtained, by exposure to near continuous increasing concentrations of cisplatin, a panel of human ovarian cancer cell lines that exhibit a wide range of primary resistance to the drug (9- to > 400-fold). These cells had strikingly increased (4- to 50-fold) levels of glutathione (GSH) as compared with the drug-sensitive cells of origin (A. K. Godwin et al., Proc. Natl. Acad. Sci. USA, 89: 3070-3074, 1992). Utilizing this panel of resistant cell lines, we evaluated cross-resistance to classical alkylating agents, natural product drugs, and irradiation. We observed that cross-resistance to carboplatin paralleled that of cisplatin, culminating in approximately 250-fold resistance. Similarly, melphalan cross-resistance continued to increase to > 400-fold and again paralleled the primary cisplatin resistance. Cell lines with low to very high levels of resistance to cisplatin are 8- to 850-fold resistant to the epipodophyllotoxin derivative etoposide. Cross-resistance is also observed for other natural product drugs, including Adriamycin (approximately 80-fold), mitoxantrone (approximately 440-fold), and taxol (approximately 40-fold). Cross-resistance to irradiation is, however, modest (< 2-fold). The cells with the greatest primary resistance to cisplatin most commonly had the highest cross-resistance to the other drugs examined. The cross-resistance to the natural product category drugs was found not to be mediated by the products of either the multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes based on lack of coordinate increased expression or amplification of these genes as assessed by Northern and Southern blot analyses. Furthermore, verapamil failed to markedly increase drug sensitivity. Although there was no indication that these natural product drug efflux pumps were operative, we observed decreased doxorubicin accumulation in these cell lines cross-resistant to natural products. In addition, alternations in DNA topoisomerase II mRNA levels, which have been observed in a variety of human tumor cell lines selected in vitro for resistance to etoposide or teniposide, were not detected. Only intracellular levels of GSH correlated with cross-resistance to these diverse anticancer agents and partial loss of resistance was associated with a marked decrease in glutathione levels. In the absence of alternative mechanisms, we speculate that the very broad clinically relevant cross-resistance seen in this model

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carboplatin; Carrier Proteins; Cell Line; Cell Survival; Cisplatin; DNA Topoisomerases, Type II; Doxorubicin; Drug Resistance; Female; Gene Expression; Glutamate-Cysteine Ligase; Humans; Melphalan; Membrane Glycoproteins; Mitoxantrone; Ovarian Neoplasms; RNA, Messenger; Tumor Cells, Cultured

The chromosomes of 111 ovarian cancer patients were studied in G- and C-banded slides from peripheral blood lymphocyte (PBL) cultures for chromosome damage caused by chemotherapy and radiotherapy and for asymmetry of the constitutive heterochromatin of chromosomes 1, 9, and 16. We also monitored the survival of these patients to determine whether any secondary neoplasia induced by the therapy and report the findings of our investigations. Melphalan (MEL) was the only drug used in single-drug chemotherapy. The incidence of chromosome abnormalities in melphalan-treated cells (25%) was higher than in the control group (17%). The incidence of structural changes was also higher (10.5%) in the MEL-treated group than in controls (6%). After treatments with combinations of drugs, the incidence of structural changes remained at the same level (11%). In the patients receiving combined treatment with MEL and radiation, the rate of structural changes increased dramatically (24%). The overall rate of chromosome aberrations in this group was also higher (50%). Combination of two or more drugs and radiation produced only 14% structural chromosome changes. The overall rate of chromosome aberrations was also low (20%) in this group. Of 111 patients studied, only 33 were alive 6 years after initiation of the study. Of the surviving patients, eight had rearranged chromosomes in the first analysis. After 5 years, new blood samples were collected from these patients and chromosome analyses showed abnormal karyotypes in all eight patients. All chromosome abnormalities in the second analysis were completely unrelated to those in the first analysis, however. Whether the chromosome changes in the second analysis were due to therapy or to other unknown factors could not be determined. Data on C-banding and the distribution of inversions indicated that 91% of the patients had C-band heteromorphisms of chromosomes 1, 91% had heteromorphisms of chromosome 9, and 69% had heteromorphisms of chromosome 16. Furthermore, inversions were observed in chromosome 1 (41% of patients), chromosome 9 (28% of patients), and chromosome 16 (5% of patients).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Chromosome Aberrations; Chromosome Deletion; Chromosome Inversion; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 9; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Heterochromatin; Humans; Karyotyping; Melphalan; Methotrexate; Middle Aged; Mitomycins; Neoplasms, Second Primary; Ovarian Neoplasms; Radiotherapy; Translocation, Genetic; Vincristine

Topics: Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents; Bone Marrow Transplantation; Carboplatin; Combined Modality Therapy; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melphalan; Ovarian Neoplasms; Platelet Count; Prospective Studies

Pharmacokinetically guided administration of melphalan was investigated during a pilot study in patients with advanced ovarian adenocarcinoma. The schedule involved a fixed dose on day 1 (7.9 mg) followed by a second dose on day 2, calculated on the basis of pharmacokinetic data to achieve a target area under the concentration-time curve (AUC). 20 courses of intravenous melphalan were administered to 7 patients. AUC, standardised to 1 mg/m2, ranged between 4.3 and 8.9 (mg/l) min. In 12 fully evaluable courses, less than 15% deviation from the target AUC was found, showing that AUC monitoring was possible by means of the test dose. Pharmacodynamic effects showed a positive correlation with melphalan AUC. Myelosuppression appeared at 47 (mg/l) min and grade 3 or 4 haematological toxicities were observed in 4 cycles, associated with AUC values ranging between 86 and 112 (mg/l) min. Relative leucocyte decreases were well correlated with AUC values.

Topics: Adenocarcinoma; Aged; Bone Marrow; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Melphalan; Middle Aged; Ovarian Neoplasms; Pilot Projects

We initiated in February 1982 a pilot study of high dose melphalan (HDM) and ABMT as consolidation treatment for ovarian carcinoma. Eleven patients entered into this study; 6 patients received HDM and ABMT (group 1), 5 patients received HDM in combination with flash abdominal radiotherapy followed by ABMT (group 2). Two of 6 group 1 patients and 3 of 5 group 2 patients are still alive with NED more than 3 years after ABMT (58+, 72+, 37+, 39+, 43+) and are hopefully cured. Main toxicity was haematological, we have not observed any death related to therapy. HDM and ABMT compared favorably with other consolidation treatments (abdominopelvic radiotherapy or IP chemotherapy) and merits a larger evaluation.

Topics: Abdominal Neoplasms; Adult; Bone Marrow Diseases; Bone Marrow Transplantation; Combined Modality Therapy; Cystadenocarcinoma; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Ovariectomy; Prognosis; Remission Induction; Transplantation, Autologous

The role of glutathione (GSH) and GSH-S-transferase (GST) activity in modulating the cytotoxicity of four platinum drugs and melphalan was evaluated in eight human ovarian carcinoma cell lines. The cell lines were established from solid and ascitic tumours from pretreated and untreated patients, and showed a wide spectrum of sensitivity to several platinum II and platinum IV drugs; cisplatin, carboplatin, CHIP and tetraplatin. Intracellular glutathione concentration measured in the cell lines showed a significant (P = 0.05) correlation with IC50 values for cisplatin (r = 0.91), carboplatin (r = 0.87) and CHIP (r = 0.88). The correlation between GSH levels and IC50 values for melphalan (r = 0.76) or tetraplatin (r = 0.60) was not as significant. GST activity showed no correlation with IC50 values, for the four platinum drugs. To determine the significance of the elevated GSH concentration in the refractory cell lines, the effect of D,L-buthionine-S, R-sulfoximine (BSO) mediated GSH depletion on platinum drug cytotoxicity was examined in one of the most sensitive (CH1) and two of the least sensitive (relatively resistant; SKOV-3, HX/62) cell lines. Comparison was made with the effect of GSH depletion on melphalan cytotoxicity in these three lines. These lines were differentially sensitive to BSO, with the two most platinum drug resistant lines being more tolerant to BSO than the sensitive CH1 line. Depletion of cellular GSH, ranging between 61 and 88%, had a differential effect on the sensitivity to PtII vs PtIV drugs in the three cell lines: cytotoxicity of the PtIV drugs, tetraplatin and CHIP, was substantially enhanced in both the resistant and sensitive cell lines; in contrast, the cytotoxicity of the PtII drugs, cisplatin and carboplatin, was only significantly increased in one of the two relatively resistant lines (SKOV-3) and in the sensitive (CH1) line after GSH depletion. Moreover the dose modification factor (DMF) for the PtII agents were lower than those for PtIV agents in the three cell lines. The dose modification factor for tetraplatin after BSO treatment was similar to that observed for melphalan in all three cell lines. In the SKOV-3 cell line extending the BSO pretreatment period to 48 h from 24 h marginally reduced the cytotoxicity of cisplatin, whereas the cytotoxicity of the other three drugs remained similar to that observed after 24 h BSO pretreatment. In contrast, extending the BSO treatment to 24 h after drug exposure potentiated the

Topics: Carboplatin; Cell Line; Cisplatin; Female; Glutathione; Glutathione Transferase; Humans; Melphalan; Organoplatinum Compounds; Ovarian Neoplasms

DNA damage was evaluated by flow cytometric (FCM) analysis of cells treated with L-phenylalanine mustard (L-PAM) and stained with anti-DNA monoclonal antibody (MAb) F7-26. DNA damage was rapidly repaired, as indicated by the loss of DNA immunoreactivity after removal of L-PAM. Two types of drug combinations were found to inhibit DNA repair. Combinations containing inhibitors of DNA polymerase (ara-C, aphidicolin) or these inhibitors and hydroxyurea inhibited DNA repair in A2780/PAM and A549 cells. The inhibition of DNA repair by combinations of DNA-damaging agents thioTEPA or cisplatin and DNA polymerase inhibitors is a novel observation based on the specificity of DNA damage assay with MAb F7-26. Combinations containing thioTEPA or cisplatin inhibited DNA repair in A549 but not in A2780/PAM cells. Drug combinations which inhibited DNA repair also significantly enhanced cell killing by L-PAM. Cell survival in cultures treated with L-PAM and efficient inhibitors was 2 to 3 orders of magnitude lower than was expected for additive survival. ThioTEPA and cisplatin play a dual role in combination chemotherapy by inducing DNA damage and inhibiting repair of DNA damage. FCM analysis of DNA repair may be a useful component of drug evaluation and could be applied to determine cell-type specific sensitivity to inhibitors of DNA repair.

Topics: Alkylating Agents; Antineoplastic Agents; Aphidicolin; Cell Line; Cell Survival; Cisplatin; Cytarabine; Diterpenes; DNA Damage; DNA Repair; Female; Humans; Lung Neoplasms; Melphalan; Nucleic Acid Synthesis Inhibitors; Ovarian Neoplasms; Thiotepa

Alkylating agents have been used individually and in combination to treat epithelial ovarian carcinoma. In this study, the cytotoxicity of 7 alkylating agents has been measured using a serial dilution clonogenic assay. When individual agents were evaluated, markedly different activity was observed against several ovarian cancer cell lines. Among 4 cell lines tested, OVCA 432 was the most sensitive to cisplatin, thiotepa and melphalan. When alkylating agents were used in combination against OVCA 432, synergistic activity was observed with cisplatin and each of several other alkylating agents including thiotepa, melphalan, 4-hydroperoxycyclophosphamide (4HC) and carboplatin. The combination of cisplatin and thiotepa also exerted synergistic activity against the OVCA 420, 429 and 433 cell lines, but had only additive or subadditive activity against the NIH:OVCAR-3 cell line. Sequential treatment of tumor cell lines with the different alkylating agents was as effective as simultaneous treatment. Synergistic anti-tumor activity in cell culture is consistent with clinical observations that alkylating agents in combination appear more effective than single agents for treatment of advanced epithelial ovarian cancer. In addition, our study suggests that cisplatin in combination with thiotepa, 4HC or melphalan might prove useful for high-dose therapy with autologous bone-marrow support.

Topics: Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cell Division; Cisplatin; Cyclophosphamide; Drug Synergism; Female; Humans; Melphalan; Ovarian Neoplasms; Thiotepa; Tumor Cells, Cultured

Topics: Buthionine Sulfoximine; Cell Nucleus; Drug Resistance; Female; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms; Tumor Cells, Cultured

The effect of L-phenylalanine mustard (L-PAM) on heterogeneous cell populations containing sensitive and resistant cells was evaluated by flow cytometric analysis of DNA damage. Cell cultures were treated with L-PAM for 1 h, fixed, and stained with anti-DNA monoclonal antibody which detects DNA damage induced by alkylating agents. DNA damage was significantly lower in sensitive A2780 cells cocultured with resistant A549 or A2780/PAM cells than in A2780 cells grown separately. Decrease of DNA damage in sensitive cells did not occur when sensitive and resistant cells were grown in common medium without direct contact. Transfer of drug resistance in cocultures was prevented by phorbol ester which is known to inhibit metabolic cooperation via cell junctions. Treatment of cocultures with buthionine sulfoximine increased DNA damage in resistant cells and prevented decrease of DNA damage in sensitive cells. Glutathione (GSH) content in A2780 cells cocultured with A549 cells was significantly higher than GSH content in A2780 cells grown separately. We conclude that decreased response of sensitive cells in cocultures was induced by contact transfer of GSH from GSH-rich resistant cells to sensitive cells. Intercellular transfer of drug resistance demonstrated by analysis of DNA damage was confirmed by colony formation assay. Treatment with L-PAM and Adriamycin killed all cells in A2780/MDR and A549 cultures. Coculture of these lines survived combination treatment because transfer of GSH to multidrug-resistant cells from GSH-rich A549 cells induced resistance to L-PAM and Adriamycin in a single cell. The presence of 2% A549 cells increased resistance of A2780/MDR cells to L-PAM. Phorbol ester eliminated resistance of coculture to combination treatment. Metabolic cooperation between cell subsets with different mechanisms of drug resistance induced resistance to treatment with drugs of different classes (multiclass drug resistance). Inhibition of cell cooperation may improve the response of tumors to combination chemotherapy.

Topics: Antimetabolites; Buthionine Sulfoximine; Cell Communication; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; DNA; DNA Damage; Drug Resistance; Female; Flow Cytometry; Glutathione; Humans; In Vitro Techniques; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms; Tetradecanoylphorbol Acetate

Topics: Adult; Carcinoma; Combined Modality Therapy; Female; Humans; Melphalan; Ovarian Neoplasms

The antitumor activity of delta 7-prostaglandin A1 (delta 7-PGA1) or delta 12-prostaglandin J2 (delta 12-PGJ2) on human ovarian cancer cell lines resistant to cisplatin (CDDP), doxorubicin (ADR), and L-phenylalanine mustard (l-PAM) was studied in vitro. A2780AD, A2780 (parent cells of A2780AD), 2008DDP, and 2008 cells (parent cells of 2008DDP) were used. The antitumor activities of the drugs were defined with 50% inhibitory concentration (IC50) estimated from growth inhibition curves, which were obtained by an indirect colorimetric method. Drug-resistance ratios obtained from IC50 values, by comparing A2780AD and A2780 cells, were 62.5 for ADR, 4.6 for CDDP, 4.9 for l-PAM, 1.5 for delta 7-PGA1, and 1.8 for delta 12-PGJ2. Those obtained by comparing 2008DDP and 2008 cells were 1.1 for ADR, 16.0 for CDDP, 2.9 for l-PAM, 2.3 for delta 7-PGA1, and 3.2 for delta 12-PGJ2. Thus some human ovarian cancer cells resistant to ADR, CDDP, and l-PAM remain sensitive to antitumor PGs.

Topics: Antineoplastic Agents; Cisplatin; Doxorubicin; Drug Screening Assays, Antitumor; Female; Humans; Melphalan; Ovarian Neoplasms; Prostaglandin D2; Prostaglandins A; Tumor Cells, Cultured

The metallothionein content of ovarian tumours is considerably higher than that found in normal ovaries (greater than 100-fold differences in mean values, P less than 0.001). There was no difference between the metallothionein content of tumours from patients who had completed chemotherapy, usually with a regimen containing a platinum drug, and tumours from untreated patients. Similarly, the level of metallothionein was not influenced by response to therapy, age, stage, histology, or tumour cell differentiation state. These data do not support the hypothesis that metallothionein content is a major determinant of tumour sensitivity in ovarian cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Ifosfamide; Melphalan; Metallothionein; Middle Aged; Ovarian Neoplasms; Ovary

High linear energy transfer (LET) fast neutrons for the local control of advanced head and neck tumours are currently being evaluated at several centres. Fast neutrons are believed to produce more direct, and less OH mediated damage than photons, and consequently be less affected by intracellular thiol levels. Chemoresistant tumours with elevated thiol levels may therefore be more effectively controlled by fast neutron therapy than by photons. The "in vitro" radiation response of melphalan sensitive and resistant human ovarian tumour cell lines has demonstrated that melphalan resistance confers a 1.5-fold level of cross-resistance to photons, primarily attributable to a 2-fold decrease in the alpha component in the resistant OAW42/MER cell line. Pretreatment of the melphalan-resistant line with the thiol depleting agent buthionine sulphoximine (BSO) restored the magnitude of alpha to a value similar to that in the chemosensitive cell line. The survival curves of these cell lines following neutron irradiation were near exponential, with similar values of alpha. This study has demonstrated that melphalan resistant tumour cells are cross-resistant to photon irradiation, but not to fast neutrons. The mechanism of cross-resistance has yet to be determined, but glutathione (GSH) appears to be involved.

Topics: Fast Neutrons; Female; Humans; Melphalan; Ovarian Neoplasms; Radiation; Radiation Tolerance; Tumor Cells, Cultured

We retrospectively evaluated the feasibility and antitumour efficacy of high dose melphalan (HDM) followed by autologous marrow rescue in 35 patients with common epithelial ovarian cancers. All patients initially had advanced disease (FIGO III-IV) and received HDM after extensive surgery and a median of 6 cycles of cis-DDP containing regimens CAP or CHAP. All, except three patients who showed evidence of progression, had a second surgical exploration before high dose chemotherapy. Melphalan was given at a dosage greater than or equal to 140 mg/m2 followed 24 h later by autologous marrow rescue. Severe but reversible aplasia and mucositis were the most common toxicities: three patients died from the procedure, two from infection and one from secondary leukaemia. HDM was effective in 75% of evaluable patients; this was evidence of activity in patients who failed to respond to first line chemotherapy. The duration of response was short, particularly for patients treated with progressive disease at the time of high dose chemotherapy rather than in partial or complete remission. With a median follow-up of 23 months (range 8-54) after high dose chemotherapy, 19 patients are alive (15 with non-progressive disease) with a projected survival of 47% between 2 and 5 years.

Topics: Adult; Bone Marrow Transplantation; Carcinoma; Dose-Response Relationship, Drug; Female; France; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Retrospective Studies; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Ovarian Neoplasms

Thirty-one patients with stage I epithelial ovarian carcinoma were treated during 1981 and 1985. Fourteen cases were stage Ia, two stage Ib and fifteen stage Ic. Twenty-eight cases had at least a TAH with BSO. Postoperatively, twenty-one patients received melphalan as adjuvant chemotherapy (mean of 11 courses). There were 8 patients who received no adjunctive therapy. One patient had radiation treatment and the remaining one received hormonal treatment. Eighty-seven per cent (27 out of 31) of tumors were of borderline type or well differentiated, four were moderately well differentiated. Poorly differentiated tumor was not observed in our series. The follow-up (31 patients) ranged from 0-82 months with a median of 52 months. The overall 5-year survival was 95.4 per cent. There was one reported death whose tumor was stage Ic grade 1 and who had received melphalan postoperatively. No serious adverse effects were noted among patients who received melphalan.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Thailand

DNA damage in the cells sensitive and resistant to alkylating agents was determined by flow cytometry analysis of cells stained with anti-DNA monoclonal antibody (MOAB) F7-26. MOAB F7-26 interacted with single-stranded regions in alkylated DNA, and the binding of antibody to the cells increased in proportion to the decrease in cell viability. Development of resistance to L-phenylalanine mustard (L-PAM) in A2780 cells was associated with decreased immunoreactivity of DNA with MOAB F7-26. Fluorescence was significantly lower in resistant cells than in sensitive cells, and the difference in the binding of MOAB between two cell types increased with the dose of L-PAM. The enhancement of L-PAM cytotoxicity to resistant cells by buthionine sulfoximine and hyperthermia was accompanied by a proportional increase of MOAB F7-26 binding to DNA. The same relative potential of sensitization regimens was established by cell survival and MOAB staining. The time course of DNA repair established by decrease of MOAB binding after L-PAM removal was similar in sensitive and resistant cells. Resistance of A2780 cells to L-PAM was associated with low initial level of DNA damage and with decreased cytotoxicity per unit of damage. We conclude that resistant cells could be distinguished from sensitive cells by staining with MOAB F7-26 and that the sensitization of resistant cells could be quantitatively predicted by flow cytometry analysis of MOAB binding.

Topics: Alkylating Agents; Antibodies, Monoclonal; Buthionine Sulfoximine; Cell Line; Cell Survival; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance; Female; Flow Cytometry; Humans; Kinetics; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms; 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

Patients with epithelial ovarian carcinoma (OVCA) and positive second-look operation (SLO) have a poor short-term prognosis. Treatment after SLO is still controversial and pilot studies are justified in an attempt to improve survival of these patients. As OVCA is known to be a chemosensitive tumor, it seems logical to treat these patients with high-dose chemotherapy with the support of an autologous bone marrow transplantation. Fourteen patients underwent primary surgery with tumor debulking followed by cis-platinum-based chemotherapy. SLO was performed in each patient and was microscopically positive in five and macroscopically positive with secondary debulking in nine. All patients were treated after SLO with high-dose melphalan (HDM), 140 mg/m2, and autologous bone marrow support. HDM was well tolerated, with a median time to granulocyte recovery of 21 days. There was no death due to treatment toxicity. The mean follow-up after SLO is 43 months. Five patients (35.7%) are disease free at 30 to 60 months after SLO with no further treatment and, thus, a good quality of life. Four patients are alive with recurrent disease. Five patients died of OVCA; actuarial 3-year survival is 64%. This therapeutic procedure is well tolerated and seems to provide long-term survival for patients with no complete response after first-line chemotherapy. Therefore, it might also be applied to patients at high risk of recurrence after a negative SLO.

Topics: Adenocarcinoma; Adult; Bone Marrow Transplantation; Carcinoma; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoiesis; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Pilot Projects; Reoperation

Nineteen patients with recurrent epithelial ovarian cancer who had responded to initial cisplatin-based combination chemotherapy were re-treated with cisplatin-based therapy. The median disease-free interval, as measured from the last cycle of primary chemotherapy to the diagnosis of relapse, was 26.3 months (range 5-81 months). Eighteen of the 19 patients had measurable disease at the time of relapse. Nine patients had a clinical complete response to the cisplatin-based re-treatment, and nine patients had a partial response (surgically documented in one case). The overall response rate to secondary cisplatin-based chemotherapy was therefore 100% in patients with measurable disease. Toxicity of re-treatment was acceptable. The median progression-free survival, as measured from the diagnosis of relapse to the time of disease progression, was 10.6 months (range 4-24 months). The median survival from diagnosis of relapse was 19.3 months (range 5-39 months). At the time of analysis, three patients were alive without evidence of disease, four were alive with tumor, and 12 were dead of cancer. These data suggest that re-induction with cisplatin-based chemotherapy should be considered for patients who develop recurrent disease after favorable responses to primary cisplatin-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Remission Induction

Forty-six patients with early (Stage I and II) ovarian cancer referred as free of residual disease after primary surgery, selected for high-risk features, were treated with adjuvant single-agent alkylating therapy comprising either intravenous cyclophosphamide (1 g/m2) in 36 patients, or oral melphalan (0.2 mg/kg daily for 5 days) in eight. Cyclophosphamide was repeated every 3 weeks for 10 cycles and melphalan every 6 weeks for 12 cycles. With a median follow-up of 36+ months, 18 patients have relapsed. The actuarial 5-year relapse-free survival was 48% and the overall 5-year survival was 54%; median survival was 84 months. Pretreatment FIGO stage was the single most important predictor of relapse-free and overall survival duration. For patients with Stage IA and IB tumours the 5-year actuarial relapse-free survival was 89%; for patients with stage IC and II (all substages), the 5-year relapse-free survival was 24% (P = 0.001). For this latter group adjuvant single alkylating agent therapy was not adequate and alternative therapeutic regimens are required. The problem of suboptimal primary surgical staging is also addressed.

Topics: Administration, Oral; Cyclophosphamide; Female; Humans; Injections, Intravenous; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Ovary; Postoperative Care; Prognosis

The hypothesis that in vitro chemosensitivity testing could predict clinical outcome was tested in women with ovarian cancer. Short-term drug effects on DNA and RNA metabolism (by inhibition of 3H-thymidine and 3H-uridine incorporation) were measured in primary cultures of tumor cells. In vitro inhibitory effects were found with the four drugs tested: cisplatin, adriamycin, melphalan, and methotrexate. From data based on impaired RNA and/or DNA metabolism (greater than or equal to 20% inhibition), correct prediction of "sensitivity" was 79% and that of "resistance" was 84%. An analysis of the predictive value of both assays, used singly or together, revealed a high specificity but moderate sensitivity; the best positive predictive value (94%) was obtained when both RNA and DNA metabolisms were impaired. Our results support the idea that two subsets of patients who are being considered for cytotoxic chemotherapy can be selected; those who may benefit from treatment and those who may not, regardless of the drugs tested in vitro or used in vivo.

Topics: Antineoplastic Agents; Cisplatin; DNA, Neoplasm; Doxorubicin; Drug Screening Assays, Antitumor; Female; Humans; In Vitro Techniques; Melphalan; Methotrexate; Ovarian Neoplasms; RNA, Neoplasm; Tumor Cells, Cultured

Forty-one patients with epithelial ovarian tumors of low malignant potential are discussed. Twenty-three patients presented with Stage I, four with Stage II and 14 with Stage III disease. All patients with Stage I disease were solely treated surgically. Twelve patients with Stage II and III disease also received postoperative chemotherapy. Four of ten patients had persistent disease at second look laparotomy. Chemotherapy was not used in six patients with Stage II and III disease when the tumor was considered to have been removed completely. Forty of the 41 patients are currently alive and free of disease at two to nine years of follow-up study. Vigorous and, at times, multiple surgical procedures remain the primary treatment of ovarian tumors of low malignant potential.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cyclophosphamide; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Peptichemio; Reoperation; Retrospective Studies

In vivo mutations at the locus for hypoxanthine phosphoribosyl transferase (hprt) were studied in 6-thioguanine (TG)-resistant T-lymphocyte clones from healthy male and female subjects and ovarian carcinoma patients treated with melphalan. Southern blot analysis of 108 clones showed alterations in 14% (4/29) of the clones from healthy males, 4.3% (2/47) of the clones from healthy females and 3.1% (1/32) of the clones from melphalan-treated patients. 2 of the 7 abnormal clones had a total deletion of the hprt gene; the others had partial deletions. Karyotype analysis of 82 clones revealed 1 clonal abnormality in 29 mutant clones from healthy males (3.6%). Loss or structural aberration of 1 X-chromosome occurred in 6% of the clones from healthy females. The frequency of karyotypic abnormalities (excluding those affecting one of the X-chromosomes) was significantly higher in clones from patients (37%) as compared to healthy females (5.9%). No aberration was found to affect the hprt locus at Xq27 in any of the 82 clones studied.

Topics: Blotting, Southern; Carcinoma; Chromosome Aberrations; Chromosome Disorders; Clone Cells; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Karyotyping; Melphalan; Mutation; Ovarian Neoplasms; T-Lymphocytes

Melphalan is widely used in the chemotherapeutic treatment of an ovarian cancer. Bone marrow depression, nail change, hypersensitivity, chronic pulmonary fibrosis, and nausea and vomiting, are the side effects reported as a result of the toxicity of Melphalan. So far as we know, renal toxicity caused by Melphalan has not been reported in the past literature. A case of acute renal failure induced by Melphalan in a patient with 3rd stage ovarian cancer is presented in this paper. This therefore is the first report of renal toxicity caused by Melphalan.

Topics: Acute Kidney Injury; Adenocarcinoma, Mucinous; Aged; Female; Humans; Kidney; Melphalan; Ovarian Neoplasms

Interdisciplinary protocols for management of advanced adenocarcinoma of the ovary have resulted in prolonged patient survival. A subset of patients is emerging in whom central nervous system (CNS) relapse occurs even following negative second-look procedures (SLP). Seven of 342 eligible patients entered in a National Cancer Institute of Canada Trial for Ovarian Cancer, from February 1, 1980 to March 31, 1984, had CNS relapse. All patients received adriamycin and cisplatin. SLP was performed in 5 patients, 3 of whom were complete responders (CR). Two additional patients failed to complete their chemotherapy and had progressive pelvic disease. The median age of these 7 patients was 57 years, their overall survival time was 28 months, compared with an average age of 58 years and survival of 21.6 months, for the entire group. Two patients had prolonged survival after their CNS relapse; 1 patient lived 26 months, and the other, who underwent craniotomy for primary management of the metastasis survived 18 months. Confirmation of metastatic disease was obtained in 4 of the 7 patients. The results of this study suggest that management of CNS involvement in adenocarcinoma of the ovary should be determined by overall performance status even in the presence of generalized disease.

Topics: Adenocarcinoma; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Humans; Melphalan; Meningeal Neoplasms; Middle Aged; Ovarian Neoplasms

Topics: Buthionine Sulfoximine; Cell Survival; Cisplatin; Female; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms; Tumor Cells, Cultured

Melphalan (L-PAM) pharmacokinetics were investigated in nine ovarian cancer patients before and after cisplatin (DDP) treatment. When L-PAM was given 24 h before DDP, the elimination half-life (t 1/2 beta), plasma clearance (Clp), and volume of distribution (Vd beta) of L-PAM were, respectively: 46.4 +/- 6.7 min, 20.5 +/- 3.7 l/m2, and 306.8 +/- 34.4 ml/min per square meter. When L-PAM was inoculated 24 h after DDP, t 1/2 beta, Clp, and Vd beta were 47.5 +/- 6.3 min, 20.4 +/- 2.8 l/m2, and 322.0 +/- 54.1 ml/min per square meter. Thus, DDP pretreatment does not significantly affect L-PAM pharmacokinetics. Regression analysis showed a significant correlation between the L-PAM elimination rate constant (beta) and renal function assessed by creatinine clearance. One patient who received this sequence of treatment for six courses showed a threefold decrease of L-PAM Clp after the last treatment. The reported high myelotoxicity of the combination of DDP and L-PAM when DDP was given 24 h before L-PAM cannot be attributed to DDP-induced changes in L-PAM kinetics but might to some extent be related to a loss of renal function consequent to many courses of treatment.

Topics: Adult; Aged; Cisplatin; Female; Humans; Injections, Intravenous; Melphalan; Metabolic Clearance Rate; Middle Aged; Ovarian Neoplasms

Fifty-five ovarian cancer patients treated with melphalan during 1968-1978 were followed during 309 person years and studied with cytogenetic analyses. During the clinical follow-up 7 patients developed a new primary solid tumour. The excess risk of developing new primary solid tumours in patients treated with melphalan was statistically significant (p less than 0.05) and the relative risk corresponded to 3.0. Patients developing a new solid tumour showed a similar pattern of chromosome aberrations in the peripheral lymphocytes to that previously shown for the whole cohort.

Topics: Cells, Cultured; Chromosome Aberrations; Female; Humans; Lymphocytes; Melphalan; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange

Although the human tumor clonogenic assay (HTCA) is extremely reliable in determining clinical correlations, it is a complicated process requiring considerable time in order to obtain results. Thus, an experimental study on cytopathologic observation (cytologic assay) and comparative evaluation between it and HTCA were performed in order to establish a more rapid and accurate drug sensitivity test. Materials included Colon 26, a cell line established in our department, malignant effusion and surgical specimens. In carrying out HTCA according to the Hamburger-Salmon method, the cell suspension samples following exposure to anti-tumor agents (MMC, L-PAM, ADM, CDDP) were cultivated in test tubes for 3-8 hours and stained by the Papanicolaou and Giemsa methods. According to Tokita's criteria, when cellular changes showed as nuclear pyknosis and nuclear destruction were found to have increased significantly in comparison with a control group, the cells were judged to be sensitive. Very similar and parallel results were obtained between HTCA and cytologic assay in this study, with a significant correlation. Cytologic assay was proved to be an easy, rapid and accurate method for testing drug sensitivity and its clinical application can be expected in the future.

Topics: Animals; Antineoplastic Agents; Cisplatin; Colonic Neoplasms; Colony-Forming Units Assay; Cytological Techniques; Doxorubicin; Drug Evaluation, Preclinical; Female; Humans; Melphalan; Mice; Mitomycin; Mitomycins; Ovarian Neoplasms; Tumor Stem Cell Assay

Several large cohorts of patients treated with alkylating agents served as a means to review the clinical and pathologic features of 55 cases of myelopathic disorders that resulted. The incidence was 1.8% overall and consisted of five patients (9.9%) who developed bone marrow hypoplasia or aplasia, 15 (27.2%) who developed a myelodysplastic syndrome, and 35 cases of acute myeloid leukemia (62.9%). The median time to recognition of MPD was 14 months, following cessation of chemotherapy. The distribution of the treatment-related MDS cases was different than "de novo" MDS with a high percentage of RAEB-T, and with the treatment related AMLs, there were a higher percentage of patients with FAB M6 (erythroleukemia), and no cases of FAB M3 (hypergranular promyelocytic). The median survival of all patients was very brief.

Topics: Adolescent; Adult; Aged; Alkylating Agents; Anemia, Aplastic; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Female; Gastrointestinal Neoplasms; Humans; Infant; Karyotyping; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Ovarian Neoplasms

Human ovarian cancer cell lines with stable cisplatin resistance have been developed by chronic exposure of the parent cisplatin-sensitive A2780 line to increasing concentrations of cisplatin. 2780CP8 (CP8 refers to this cell line's growth in medium containing 8 microM cisplatin) has several clonal cytogenetic abnormalities but lacks homogeneously staining regions or double-minute chromosomes. It has a significantly greater monolayer growth rate, cloning efficiency in agarose, and total glutathione content compared to the A2780 line, but similar activities of several glutathione-dependent enzymes. The 2780CP8 subline is 7.3-fold resistant to cisplatin compared to the A2780 line, as well as cross-resistant to irradiation and melphalan. It is not cross-resistant to Adriamycin, but this develops with increased cisplatin resistance (14-fold) obtained by further cisplatin exposure of 2780CP8. Of the cisplatin analogues tested which are of current clinical interest, carboplatin, iproplatin, and tetraplatin, only the latter is more cytotoxic than cisplatin in the A2780 and 2780CP8 lines. The 2780CP8 subline is also cross-resistant to these analogues in the relative order carboplatin greater than iproplatin greater than tetraplatin (most to least cross-resistant). Treatment of a highly cisplatin resistant cell line (2780CP70) with either melphalan or cisplatin was associated with a significant increase in [3H]thymidine incorporation into DNA in the presence of 10 mM hydroxyurea compared with the parent sensitive cell line which showed essentially no capacity to repair DNA damage by these drugs. A2780 and its cisplatin-resistant cell lines may thus be useful in studying drug resistance mechanisms, in screening new drugs for activity (especially against drug resistant tumors), and in formulating induction and salvage therapies for ovarian cancer.

Topics: Antineoplastic Agents; Carboplatin; Cell Line; Cell Survival; Cisplatin; DNA Repair; Drug Resistance; Female; Glutathione; Humans; Melphalan; Organoplatinum Compounds; Ovarian Neoplasms; Structure-Activity Relationship

Forty-nine patients classified after surgery and complete non-surgical restaging as "no residual disease" were treated with adjuvant chemotherapy. Thirty-nine patients had ovarian carcinoma and 10 borderline tumors. All patients had geographic inaccessibility. Domiciliary treatment with melphalan at the dose of 10 mg/day p.o. for 5 consecutive days every 4 weeks for 12 cycles was used. Within 6 months from the end of adjuvant treatment a second restaging with peritoneoscopy and peritoneal cytology was performed. The median administered dose of melphalan was 575 mg. No patient with a borderline tumor relapsed. Nine patients with ovarian carcinoma relapsed (23%): 4/10 at stage II-III and 5/29 (17%) at stage I. The relapse-free survival at 96 months was 77% for stage I patients and 73% for all patients. The overall survival was 87% for stage I patients and 81% for all patients. Mild myelo-depression was evident in 65% of patients. No case of acute nonlymphocytic leukemia was observed.

Topics: Combined Modality Therapy; Female; Humans; Melphalan; Omentum; Ovarian Neoplasms; Postoperative Care; Postoperative Period; Prognosis; Prospective Studies

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

The development of acquired resistance to alkylating agents frequently limits the effectiveness of chemotherapy in the treatment of ovarian cancer. While the resistance to alkylating agents is multifactorial, the association of drug resistance with elevations in glutathione (GSH) is of potential clinical relevance since there exist pharmacologic means to lower intracellular GSH levels. We have used in vitro and in vivo models of human ovarian cancer to demonstrate that selective inhibition of GSH synthesis with L-buthionine-S,R-sulfoximine (L-BSO) leads to a lowering of GSH levels and an increase in cytotoxicity of the alkylating agent melphalan. In the human ovarian cancer cell line NIH:OVCAR-3, derived from a patient clinically refractory to alkylating agents, L-BSO resulted in a 3.6-fold enhancement of melphalan cytotoxicity. This cell line was also adapted for intraperitoneal growth in athymic nude mice. In this in vivo model, in which the mice die of massive ascites and intraabdominal carcinomatosis, L-BSO given orally in drinking water for 5 days decreased GSH levels in the tumor cells by 96% compared to a 79 and 86% reduction in GSH levels in the bone marrow and gastrointestinal mucosa respectively. Lowering of GSH levels with BSO was not accompanied by an increase in lethality for melphalan in non-tumored nude mice. However, in tumor-bearing nude mice, a single melphalan (5 mg/kg) treatment following GSH depletion with L-BSO was markedly superior to treatment with melphalan alone, producing a 72% increase in median survival time. Furthermore, L-BSO treatment of human bone marrow cells prior to melphalan exposure had little effect on melphalan toxicity as assessed in a CFUc-GM assay. These results suggest that treatment with the GSH synthesis inhibitor BSO may preferentially enhance the cytotoxic effects of alkylating agents against human ovarian cancer and overcome acquired resistance.

Topics: Animals; Buthionine Sulfoximine; Colony-Forming Units Assay; Drug Resistance; Drug Synergism; Female; Glutathione; Histocytochemistry; Humans; Melphalan; Methionine Sulfoximine; Mice; Mice, Nude; Ovarian Neoplasms

Fifty-three patients treated between 1974 and 1981 were analyzed to establish the relationship between myelosuppression, tumor response, and survival in the treatment of advanced ovarian carcinoma, Stage III-IV, with melphalan alone or a melphalan-doxorubicin combination. The total response rate was 34% and the 5-year survival rate was 24.5%. Responders had significantly higher performance status and hemoglobin values at the start of chemotherapy. During chemotherapy the mean nadir values of leukocytes and thrombocytes were identical for responders and nonresponders and the degree of myelosuppression measured in this way did not predict the probability of tumor response or survival. The bone marrow of nonresponders seemed to be more active, judging from a tendency towards higher leukocyte and thrombocyte cell counts before the individual chemotherapy courses than in responders. Dose reduction and interval prolongation seemed to worsen the prognosis with regard to tumor response and long-term survival. Combination chemotherapy with melphalan-doxorubicin was superior to single drug therapy with melphalan with regard to bone marrow toxicity, tumor response rate and survival. The most important single prognostic factor at the start of chemotherapy was the performance status (Karnofsky's index). Myelosuppression per se did not improve the prognosis with regard to tumor response or survival in this series.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Platelets; Doxorubicin; Female; Hemoglobins; Humans; Leukocyte Count; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis

Three cell lines resistant to adriamycin, melphalan and cisplatin were established in vitro from human ovarian cancer cell line A2780. Each subline showed a resistance to its inducing drug of 75-fold in the case of adriamycin, 6-fold in the case of melphalan and 11-fold in the case of cisplatin. However, all of these sublines showed collateral sensitivity to bleomycin. Approximately a 2-fold higher susceptibility to bleomycin was observed generally. The biochemical mechanisms of this collateral sensitivity are not clear at present, but the higher concentration of glutathione in these resistant tumor cell lines might be related to the high susceptibility of these resistant cells to bleomycin.

Topics: Bleomycin; Cell Line; Cisplatin; Colony-Forming Units Assay; Doxorubicin; Drug Resistance; Female; Glutathione; Humans; Melphalan; Mutation; Ovarian Neoplasms; Tumor Stem Cell Assay

Thirty-six patients with advanced/recurrent epithelial ovarian carcinoma were treated with a combination of hexamethylmelamine, cyclophosphamide, adriamycin, and cis-platinum. In the group of 23 previously untreated patients, 10 of 12 (83%) with measurable disease had objective responses (7 complete, 3 partial). The median survival of the 23 patients exceeded 18 months. After approximately 1 year of chemotherapy, 9 patients with no clinical evidence of disease had a 'second look' laparotomy; 6 of these patients were disease-free. Two of the 6 patients with surgically documented complete responses had bulky (greater than 5 cm) disease prior to initiation of chemotherapy and remained disease-free at 22 and 50 months. One of the 6 patients relapsed 5 months after a negative second look. The other patients were alive and disease-free at 18, 46, and 51 months. Only 4 of 13 melphalan-resistant patients (31%) demonstrated an objective response to the 4-drug combination. The median survival was 13 months.

Topics: Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Reoperation

Cytogenetic studies were carried out on peripheral lymphocytes from cancer patients at different times after therapy with melphalan. The frequency of sister chromatid exchange (SCE) was increased markedly shortly after treatment, and then declined to near pretreatment levels over a four-week period. In-vitro studies showed that the SCE frequency induced by melphalan is reduced slowly in resting G0 lymphocytes and considerably faster in mitogen-stimulated G1 cells. The results demonstrate that measurement of SCE is useful for the study of newly-induced chromosome damage in melphalan-treated cells, but is less suitable for the detection of persistent, cytogenetic alterations long after therapy. The frequency of chromosomal aberrations in a cohort of 50 patients with ovarian carcinoma was increased for up to ten years after melphalan therapy. The predominant aberrations were chromosomal translocations, marker chromosomes and cells with multiple, complex rearrangements. The frequency distribution of chromosomes involved in aberrations was studied in cells from some of the patients. An overrepresentation of chromosomes 8 and 9 was found in these cells, whereas the X chromosome was overrepresented in cells from control subjects. An increased frequency of chromosomal rearrangements was found in long-term cultures of T-lymphocytes from three of the patients, indicating that these aberrations are compatible with cell survival and proliferation. Seven patients in the cohort developed a second, primary tumour during the observation time. The frequencies and types of aberrations in these patients were similar to those of the other patients in the cohort.

Topics: Carcinoma; Cell Division; Cell Survival; Chromosome Aberrations; Chromosomes; DNA Damage; Female; Humans; In Vitro Techniques; Karyotyping; Lymphocytes; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange; Thrombocytopenia; Time Factors

Three cases of advanced epithelial ovarian carcinoma Stage III-IV which could not be submitted to classical surgical and oncological treatment (BSO-TH) are presented. After a year of chemotherapy a complete remission was observed. Myometrial and myocervical micrometastases were found in a specimen from the hysterectomy, carried out during second-look, that was negative. These micrometastases, when they are present, apparently show a different chemosensitivity, as compared with other metastasis localization. The causes of this phenomenon are analyzed.

Topics: Female; Humans; Hysterectomy; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

We have investigated the role of glutathione in determining the macromolecular binding and cytotoxicity of cisplatin (DDP) and melphalan (LPAM) in human ovarian carcinoma cells and DDP-resistant L1210 mouse leukemia cells. Glutathione reacted avidly with DDP in normal saline with a bimolecular rate constant of 16.2 M-1 hr-1. Glutathione had no effect on the rate of hydrolysis of LPAM, consistent with the SN1-like reaction mechanism of LPAM. Glutathione protected calf thymus DNA and bovine serum albumin from DDP platination and LPAM alkylation. Glutathione also protected nuclei isolated from human ovarian carcinoma cells from DDP platination. The importance of intracellular glutathione in determining the cytotoxicity of DDP and LPAM was assessed by depletion of glutathione with buthionine sulfoximine in three cell types. Exposure to 0.5 mM buthionine sulfoximine for 20-28 hr depleted glutathione to levels that were 10-20% of control levels. COLO 316 and 2008 human ovarian carcinoma cells, and ZCR9 mouse leukemia cells were all sensitized to LPAM cytotoxicity by this level of glutathione depletion. The dose modification factors, defined as the IC50 control cells/IC50 depleted cells, were: 2.6 +/- 0.5 for COLO 316 cells, 1.6 +/- 0.1 for 2008 cells, and 2.1 +/- 1.1 for ZCR9 cells. In contrast, glutathione depletion had a minimal effect on DDP cytotoxicity in these cells with dose modification factors of: 1.2 +/- 0.2 for COLO 316 cells, 0.8 +/- 0.3 for 2008 cells, and 1.1 +/- 0.1 for ZCR9 cells. The differential potentiation of DDP and LPAM cytotoxicity by glutathione depletion in these cells, despite the similar protection that glutathione affords macromolecules from drug binding, suggests that there are fundamental differences in the intracellular interaction of these electrophilic drugs with glutathione.

Topics: Animals; Cell Line; Cell Nucleus; Cisplatin; DNA; Female; Glutathione; Humans; Kinetics; Leukemia L1210; Melphalan; Mice; Ovarian Neoplasms; Serum Albumin, Bovine

Thirty-one patients with histologically confirmed FIGO Stage II adenocarcinoma of the ovary were prospectively treated in two sequential studies: 3000 rad of whole abdominal radiation therapy over 6 weeks by an open field technique followed by 2000 rad pelvic boost over 2 weeks (group 1, 16 patients, 1972-1974) or 5000 rad of pelvic radiation therapy over 5 weeks followed by a year of melphalan chemotherapy at a dose of 0.2 mg/kg/day for 5 days every 4 weeks (group 2, 15 patients, 1975-1982). Abdominal radiation included the entire peritoneal cavity and both diaphragms; the liver was not shielded. Only 2 patients had residual disease greater than 2 cm. No group 1 patients underwent pretherapy restaging laparoscopy prior to radiation or second look laparotomy after treatment. Eighty percent of group 2 patients underwent restaging laparoscopy (10) or staging laparotomy (2) prior to radiation. All group 2 patients underwent second look procedures if no evidence of disease. No patient developed intestinal complications secondary to radiation requiring surgery. Eighty-one percent of group 1 patients and to date 40% of group 2 patients developed recurrences. Size of residual disease prior to radiation, histologic grade, and substage (IIA, B, or C) did not correlate with recurrences. Five-year estimated survival was 40 and 50% for groups 1 and 2, respectively. Three thousand rad of wole abdominal radiation plus 2000 rad pelvic boost or 5000 rad pelvic radiation plus melphalan did not appear to improve survival over surgery alone. The role of radiation therapy in Stage II ovarian cancer remains unclear.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Combined Modality Therapy; Enteritis; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Radiation Injuries; Radiotherapy

6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule.

Topics: Analysis of Variance; Bone Marrow; Colony-Forming Units Assay; Female; Humans; In Vitro Techniques; Melanoma; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Structure-Activity Relationship; Tumor Stem Cell Assay

A new in vitro chemosensitivity test was developed from comparative studies on the cytotoxicity of anticancer drugs against human tumor tissues xenografted into nude mice and their cultivated cells in vitro. Half a gram of the material was sufficient to examine the sensitivity of the tissues to 10 kinds of potential anticancer drugs and the results were obtained within 24 hours. The test was applied to all of 20 patients with advanced ovarian cancer. The predictive accuracy was 58% in 12 evaluable patients. This response rate was higher than those of conventional combination chemotherapy with or without cisplatin and adriamycin. Individual ovarian cancers showed different sensitivities to the drugs. These results indicate that heterogeneity of sensitivity to anticancer drugs exists among individual ovarian cancers and that our new type of in vitro chemosensitivity test is useful for selecting the most effective drugs for each individual type of ovarian cancer.

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Child; Cisplatin; Colony-Forming Units Assay; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Nimustine; Nitrosourea Compounds; Ovarian Neoplasms; Tumor Stem Cell Assay

A multidrug resistance phenotype is frequently observed in animal and human cell lines selected for in vitro resistance to a single chemotherapeutic agent. Overexpression of a highly conserved cell-surface glycoprotein (P-glycoprotein) is consistently associated with this phenotype in these mutant lines. A monoclonal antibody against P-glycoprotein was used to examine tumor samples from five patients with advanced ovarian cancer for evidence of P-glycoprotein overexpression. High levels of P-glycoprotein were detected in samples from two patients suggesting that a multidrug resistance mutation may also occur in ovarian cancer. This finding has broad implications for the understanding of nonresponse to chemotherapy in a variety of human neoplasms, and may provide a rational explanation for failure of chemotherapy in treatment of advanced ovarian cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cisplatin; Cyclophosphamide; Cystadenocarcinoma; Doxorubicin; Drug Resistance; Female; Genetic Markers; Glycoproteins; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Phenotype

A case of primary malignant mixed mesodermal tumor (MMMT) of the ovary arising de novo in a post-menopausal multiparous female is reported. The tumor contained heterologous elements in the form of cartilage and fat in addition to carcinosarcomatous areas. Post-operatively, single-agent chemotherapy was administered and up to the time of reporting the patient has been alive and well. Because of the rarity of these tumors the proper treatment remains a dilemma. The differential diagnosis of MMMT of ovary and teratocarcinoma is considered, as the two are confused frequently.

Topics: Carcinosarcoma; Diagnosis, Differential; Female; Humans; Melphalan; Middle Aged; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Teratoma

Lymphoblastoid cell lines (LCLs) were established from 83 patients with ovarian cancer by transformation of peripheral B lymphocytes with Epstein-Barr virus. Comparing the melphalan resistance of different groups of LCLs using the mean Do obtained from clonogenic survival assays, LCLs from melphalan-treated patients were significantly more resistant than LCLs from patients not treated with this drug. However, prior treatment of the patient with ionizing radiation was not associated with increased in vitro resistance of the LCL to this agent. In melphalan-treated patients where LCLs were established serially, the melphalan Do increased after further melphalan treatment in vivo and decreased when no further treatment was given. No correlation was found between age of donor and LCL resistance to any of the above agents. A group of 15 LCLs previously established from non-tumour donors was less resistant to melphalan than the LCLs from patients with ovarian cancer. In a group of 29 patients with advanced disease in whom the clinical response was known, LCL resistance to melphalan appeared to be associated with poor clinical response to cross-linking agents. These results suggest that B cell populations undergo long term, but not necessarily permanent, increases in resistance to melphalan.

Topics: B-Lymphocytes; Cell Line; Cell Survival; Cell Transformation, Viral; Cells, Cultured; Chlorambucil; Cross-Linking Reagents; Dose-Response Relationship, Drug; Drug Resistance; Female; Herpesvirus 4, Human; Humans; Melphalan; Ovarian Neoplasms; Prognosis; Time Factors

From 1980 to 1984 fifty-four patients with advanced ovarian carcinoma after operation and concluding chemotherapy with alkeran (n = 7) or cis-platin/alkeran +/- hexamethylmelamine (n = 47) as well as second-look laparotomy received follow-up radiotherapy either with the moving-strip technique (n = 35) or later the open-field technique (n = 19). 32 patients in CR received radiation therapy. 15 patients in CR are without relapse after undergoing open-field radiation therapy and a mean observation period of 25 months. At this point of time 5 of 17 patients had relapses under the moving-strip radiation treatment. The frequency of the relapses is apparently due to the very long periods of radiation and numerous interruptions in treatment. If residual tumors were present at the begin of ray therapy, a CR could only be achieved in cases where the previous monotherapy was with alkeran.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Reoperation

From January 1978 to October 1982, 47 patients with histological diagnosis of epithelial cancer of the ovary received peptichemio (PTC) at a dose of 70 mg/m2 (maximum, 120 mg total) every 15 days. Forty-two patients are now evaluable: 27 with stage III and 15 with stage IV disease. All patients but four with stage IV disease had been pretreated and had received at least one drug combination (median, three drugs per patient, including alkylating agents). Before the administration of PTC, the tumor extension in the abdomen was carefully assessed in all patients: ten patients had residual tumor less than 2 cm in diameter, while 32 patients had tumor greater than 2 cm in diameter. Objective responses were obtained in ten patients (23.8%): six complete remissions and one partial remission were observed in stage III patients and one complete remission and two partial remissions were observed in stage IV patients. Of the ten responding patients, eight had tumors less than 2 cm in diameter before receiving PTC. The median duration of response was 16 months. The most frequent side effects were myelosuppression and phlebosclerosis. Bone marrow depression was a common finding after the third course in heavily pretreated patients. Accordingly, in these patients a schedule interval of 3 weeks should be more appropriate. Since most of the responders were in the "small tumor" category, PTC appears to be an active drug in patients with ovarian cancer having small tumors (less than 2 cm). On the other hand, the response rate in a nonselected population of patients remains to be clearly defined with further studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma; Drug Eruptions; Female; Humans; Leukocyte Count; Melphalan; Middle Aged; Nausea; Ovarian Neoplasms; Peptichemio; Platelet Count; Vomiting

Human epithelial ovarian tumours were successfully established as xenografts in nude mice in 54% of cases. An evaluation of the biological characteristics of tumours propagated in nude mice was carried out and the functions investigated included morphology, growth kinetics, cellular DNA content, cell surface antigen expression and sensitivity to chemotherapy. To allow a more detailed study of the influence of ploidy on biological behaviour, xenografted tumour with varying degrees of aneuploidy and tumours with a common ancestry but different ploidies were also established. Although this is a highly selective model system favouring the growth of biologically aggressive tumours the xenografts, in general, reflect many of the characteristics of the tumours from which they were derived and are likely to provide a useful model for investigating the biology of ovarian cancer.

Topics: Animals; Antigens, Neoplasm; Antigens, Surface; Cisplatin; DNA, Neoplasm; Female; Graft Survival; Humans; Interphase; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium bovis; Neoplasm Transplantation; Ovarian Neoplasms; Ploidies; Transplantation, Heterologous

There are no conclusive studies on the value of adjuvant chemotherapy in radical resected ovarian carcinoma. General reflections including parameters, toxicity and formation of a secondary tumor suggest forgoing adjuvant therapy of stages Ia to IIa. The survival rate of all other stages is below 50%. A therapy would seem necessary. Only general recommendations can be made due to lack of conclusive trials.

Topics: Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Ovariectomy; Prognosis

Forty evaluable patients with advanced epithelial cancers of the ovary received chemotherapy. Twenty-seven previously untreated patients underwent a 1:1 randomization between a combination of Cytoxan, Hexamethylmelamine, and Fluorouracil (CHF) versus a single agent, L-phenylalanine mustard (L-pam). Thirteen patients previously treated with other therapies received CHF as a second-line therapy. Eighty-five percent of the patients receiving triple therapy were responders, versus 57% in the single agent group. Fifty percent of the CHF group had a complete response versus 17% in the L-pam group (p = 0.09). All patients with complete resection of less than 2 cm residual disease at primary surgery were responders, regardless of the type of therapy. Response in these patients is defined in terms of disease-free interval. The importance of maximal surgical resection in management of these cancers is discussed. Five of eight patients treated with CHF undergoing second-look operations had no evidence of disease. One of three L-pam treated patients had no evidence of disease at second-look surgery. Six of 13 patients (46%) had partial response to CHF as a second-line drug.

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Random Allocation; Time Factors

High-dose intraperitoneal chemotherapy is a current developmental approach in the treatment of advanced ovarian cancer. Considerable pharmacologic data have been obtained on the intraperitoneal X time product for a number of agents administered by this route. We used the human tumor cloning assay (HTCA) to compare the activities of both standard and experimental agents used for intraperitoneal treatment. In vitro dose-survival curves were constructed for each drug over a two-log range of concentrations using fresh ovarian cancers from more than 50 patients. The mean concentration X time product (CXT) achievable in the intraperitoneal space after high-dose intraperitoneal drug administration was divided by the corresponding ID50 value (concentration of drug in vitro associated with 50% survival of tumor colonies) for each agent to calculate in vivo CXT: in vitro ID50 ratios. Using this approach, the standard agents, melphalan, cisplatin, and 5-FU were predicted to have similar efficacies by intraperitoneal administration, but doxorubicin and mitomycin were significantly inferior. Of the drugs tested, the new agent mitoxantrone was associated with the most favorable CXT to ID50 ratio and is, therefore, predicted to be particularly promising for intraperitoneal administration.

Topics: Anthraquinones; Antineoplastic Agents; Cisplatin; Colony-Forming Units Assay; Cytarabine; Doxorubicin; Female; Fluorouracil; Humans; Infusions, Parenteral; Melphalan; Mitomycin; Mitomycins; Mitoxantrone; Ovarian Neoplasms; Peritoneal Cavity; Tumor Stem Cell Assay

Seventy-six evaluable patients with ovarian carcinoma stages FIGO IIb, IIc, III, and IV, either received cis-platin (P) (80 mg/m2 iv. day 1), melphalan (PAM) (12 mg/m2 i.v. day 2) and hexamethylmelamine (HEXAPAMP) (135 mg/m2 orally days 8 to 21) or the same dose of cis-platin and melphalan but no hexamethylmelamine (PAMP) every four weeks. In 24 patients (32%) a surgically ascertained CR was achieved. 16 of these received follow-up radiation treatment to the whole abdomen. At present 19 patients are without relapse (average time 24 months). The trial has not been concluded. Particularly no predictions can be made on the value of follow-up radiation therapy in obtaining long-term remission rates.

Topics: Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis

One hundred ten patients with advanced ovarian carcinoma (Stages IIIA, IIIB, and IV) were evaluated for survival. They received as first treatment one of the following regimens: melphalan (L-PAM) (41 patients), cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF) (16 patients), cyclophosphamide plus doxorubicin plus 5-fluorouracil (CAF) (17 patients), cyclophosphamide plus doxorubicin plus hexamethylmelamine plus cisplatin (CHAD) (13 patients, thiotepa plus methotrexate (TM) with fixed rotation with CAF (TM/CAF) (17 patients), and 6 patients received other chemotherapy as first treatment. There was no significant difference in survival time with the various treatment arms despite differences in response rates. Patients with Stage IIIA had significantly longer survival than those with Stages IIIB and IV (P less than 0.01). Patients with good performance status (PS 0) had significantly better survival than those with poor performance status (PS 3-4) (P less than 0.02). At this time the improved response rates on combination chemotherapy has not given improved survival rates, and disease stage and performance status remain of prime importance in survival prediction.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Random Allocation; Retrospective Studies; Time Factors

This report presents 13 patients with epithelial ovarian neoplasms of low malignant potential. Ten patients had serous tumors, 1 had a mucinous tumor, and 2 had endometrioid tumors. Two had Stage I disease, 4 had Stage II disease, and 7 had Stage III disease. All were treated with melphalan. Second-look laparotomy was performed in 11 patients and 1 patient required subsequent exploratory laparotomy. None achieved histologic confirmation of cure. Five patients continued treatment with melphalan and underwent third-look laparotomy with findings of persistent disease. Seven patients are alive without clinically detectable evidence of disease. Four patients died of their disease and 2 patients died of melphalan-induced acute leukemia.

Topics: Adult; Aged; Combined Modality Therapy; Epithelium; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Reoperation

A patient with ovarian carcinoma who subsequently developed the paraneoplastic syndrome of cerebellar degeneration is presented. The literature is reviewed and possible explanations of the phenomenon are discussed.

Topics: Abdominal Neoplasms; Adenocarcinoma, Papillary; Autopsy; Cerebellar Diseases; Combined Modality Therapy; Female; Humans; Melphalan; Middle Aged; Neurologic Examination; Ovarian Neoplasms; Paraneoplastic Syndromes; Physical Therapy Modalities; Thiamine

Topics: Buthionine Sulfoximine; Cell Line; Cell Survival; Cisplatin; Doxorubicin; Drug Resistance; Drug Synergism; Female; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms

At the UCSD Cancer Center several chemotherapeutic agents have been evaluated for safety and clinical utility when delivered by the intraperitoneal route. Both melphalan and cytarabine have demonstrated a major pharmacokinetic advantage for peritoneal cavity exposure to drug compared to that of the plasma when these agents are administered directly into the abdominal cavity. In addition, limited clinical efficacy for both agents has been demonstrated. In one experimental system cisplatin and cytarabine have shown significant concentration-dependent synergy. As intraperitoneal drug delivery allows one to administer extremely high concentrations of chemotherapeutic agents to tumors localized to the abdominal cavity, this therapeutic approach is perhaps the optimal method for producing clinically relevant concentration-dependent drug synergy. Patients with refractory ovarian carcinoma and other tumors principally confined to the peritoneal cavity have demonstrated subjective and objective improvement following intraperitoneal therapy with a cisplatin-cytarabine-based chemotherapeutic regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cytarabine; Digestive System Neoplasms; Doxorubicin; Drug Evaluation; Female; Humans; Infusions, Parenteral; Male; Melphalan; Middle Aged; Ovarian Neoplasms; Peritoneal Cavity

Drug resistance is a major problem in the treatment of ovarian cancer. We have developed human ovarian cancer cell lines with varying degrees of resistance and sensitivity to cisplatin, melphalan, and doxorubicin. The steep dose-response relationships in other lines support the rationale for high-dose therapy either by intraperitoneal or systemic administration of drugs. The demonstration that some of the resistant cell lines have a decreased accumulation of doxorubicin and that resistance in these lines can be reversed by a calcium channel blocker has led to a clinical trial of verapamil plus doxorubicin in refractory ovarian cancer patients. It has also been demonstrated that resistance to cisplatin and melphalan is associated with increased levels of glutathione. Pharmacologic depletion of glutathione with buthionine sulfoximine, an inhibitor of glutathione synthesis, increases the cytotoxicity of melphalan and cisplatin in drug sensitive and resistant cell lines.

Topics: Antineoplastic Agents; Cell Line; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Female; Glutathione; Humans; Hypertonic Solutions; Melphalan; Ovarian Neoplasms; Tumor Stem Cell Assay; Verapamil

Topics: Animals; Cell Line; Cell Survival; Cisplatin; Clone Cells; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Humans; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Thymidine; Time Factors; Vinblastine

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

Since 1981 we have received 50 tumor samples from 10 different sites; over half were breast or ovary. Of the 27 that were considered suitable for cloning, 11 produced colony formation and 6 of these were drug tested. One ovarian granulosa cell tumor and its xenograft (V7) were tested against several cytotoxic agents. During a period of 16 months, sensitivity to cisplatin was relatively stable but sensitivity to vinblastine was markedly changed when the original tumor cells and original cells stored in liquid nitrogen were compared with xenograft cells. These changes may be related to patient treatments prior to tumor sample collection. This xenograft V7 exhibited chromosome karyotype and iso-enzyme Glucose-6-phosphate dehydrogenase consistent with it being of human origin. Gross histology of original tumor and xenograft were similar. Chemosensitization in vivo of a breast xenograft (Hx99) to melphalan by misonidazole was investigated. Misonidazole at a total dose of 0.5 g/kg given prior to melphalan (14 mg/kg) was an effective chemosensitizer.

Topics: Animals; Antineoplastic Agents; Bleomycin; Cisplatin; Colony-Forming Units Assay; Drug Synergism; Etoposide; Female; Granulosa Cell Tumor; Humans; Melphalan; Methotrexate; Mice; Misonidazole; Neoplasm Transplantation; Neoplasms; Ovarian Neoplasms; Transplantation, Heterologous; Tumor Stem Cell Assay; Vinblastine

Sixty-eight patients with "advanced ovarian carcinoma" were entered into an ongoing phase-II trial for remission induction with cis-platinum (DDP) 80 mg/m2 i.v. on day 1 followed by forced saline diuresis, melphalan (L-PAM) 12 mg/m2 i.v. on day 2 and hexamethylmelamine (HMM) 130 mg/m2 p.o. X 14 days from days 8-21 in six monthly cycles following operative resection and/or staging. Fifty-one patients were evaluable for response, ten had not completed six courses and could not be assessed, two patients died early (one probably of toxicity), and five patients refused treatment and follow-up. Thirty-Two patients had serous, endometrioid or undifferentiated carcinomas of the ovary. Of these, 11 (35%) achieved a pathologically proven complete remission (CR), five (16%) were NED after second-look (residual disease in ovary or removed omentum with all other biopsies and cytology washings negative), eight (32%) achieved a partial remission (PR), and three (12%) had progressive disease. None of the seven patients with clear-cell carcinoma and none of the three patients with Mullerian tumor of the ovary responded. Six of nine patients with tumors of uncertain origin or proven metastasis to ovary did not respond to treatment. These preliminary results indicate that advanced ovarian carcinomas form a heterogeneous group of recognizable neoplastic diseases with striking variation in response to treatment.

Topics: Adenocarcinoma; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Evaluation; Female; Humans; Melphalan; Middle Aged; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Prognosis; Reoperation

Four human ovarian carcinoma xenografts were established and maintained in immune-suppressed mice. Cells obtained from these xenografts were exposed in vitro to melphalan, JM8, and cisplatin; cell survival following a 1-h exposure was measured using a soft-agar colony assay. A similar dose-response curve was obtained with melphalan for each of the four xenografts, despite previous treatment with an alkylating agent in two of the patients from whom the xenografts originated. Cell survival was also compared after JM8 and cisplatin exposure in each individual xenograft. It was found to be similar for each tumour when the concentrations of JM8 used were 10-fold greater than those of cisplatin. Early clinical studies in which JM8 has been shown to be effective in the treatment of ovarian carcinoma support the view that xenograft tumours may have a role in phase-II screening of new cytotoxic agents.

Topics: Animals; Antineoplastic Agents; Carboplatin; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Melphalan; Mice; Neoplasm Transplantation; Organoplatinum Compounds; Ovarian Neoplasms; Transplantation, Heterologous

The results of chemotherapy (frequency and duration of remission) of 237 cases of primary and 119-recurrent serous cystadenocarcinoma of ovaries are discussed.

Topics: Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Cystadenocarcinoma; Female; Humans; Melphalan; Neoplasm Recurrence, Local; Ovarian Neoplasms; Prognosis; Thiotepa; Time Factors; Triazines

The Authors refer their own experience on a planned prospective study of integrated chemosurgical treatment in advanced epithelial ovarian cancer. Repetitive surgery interspersed with non cross resistant schedules of chemotherapy can achieve more than 60% of complete responses with an expected five years survival rate dependent on the residual disease after primary and especially second operation. In particular residual neoplasia larger than five centimeters after the first laparotomy or larger than two centimeters left behind at second laparotomy constitutes the worst prognostic index.

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Prospective Studies; Reoperation

One hundred and fifty patients with malignant ovarian tumors were treated in the Cancer Institute Hospital between 1949 and 1977. Most (103; 68.7%) of the patients had simple primary ovarian cancer. A retrospective study was performed in these 103 patients to investigate the relationship between the 5-year survival rate and the clinical stage and primary treatment. The 103 patients were classified according to FIGO criteria. The survival rates for stages I, II, III and IV were 73.7%, 50.5%, 17.4% and 0%, respectively. As the primary treatment, operations were performed on 92 of the 103 patients. To conclude, of primary importance in the treatment of ovarian cancer is the surgical, complete as possible removal of the tumors. Postoperatively, radiotherapy and chemotherapy should be used. Recently, second look operations have come into wider use. General procedures for the surgical and postoperative treatment of progressive ovarian cancer have been established. Although surgical procedures for the treatment of early ovarian cancer have also been established, there are no consistent procedures for postoperative treatment. Since the incidence of ovarian cancer is increasing, the development of appropriate methods for early diagnosis and treatment of this carcinoma is eagerly awaited.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Castration; Combined Modality Therapy; Doxorubicin; Female; Humans; Hysterectomy; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy Dosage; Reoperation; Tegafur

Chemotherapy using adriamycin with cyclophosphamide, and cyclophosphamide with hexamethylmelamine or with alkeran causes no significant reduction in the total lymphocyte count, in the percentage subpopulations of T cells and B cells or in mononuclear cell cytotoxicity in patients with Stage II carcinoma of the ovary during their first course of chemotherapy.

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Cyclophosphamide; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Doxorubicin; Female; Humans; Leukocyte Count; Lymphocytes; Melphalan; Ovarian Neoplasms; T-Lymphocytes; Time Factors

We reviewed the clinical records of 32 patients with granulosa cell tumor of the ovary treated at the Wisconsin Clinical Cancer Center (WCCC) between 1970 and 1982. Eleven of these patients were treated with one or more chemotherapeutic regimens, yielding a total of 22 treatment trials. Objective response was observed in 7 of 17 evaluable treatment trials (41%). The response to chemotherapy could not be assessed in five treatment trials due to the concomitant administration of radiotherapy. We conclude that granulosa cell tumor of the ovary is responsive to chemotherapy. However, the optimal chemotherapeutic regimen for this rare neoplasm remains to be established on the basis of prospective clinical trials.

Topics: Adult; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Granulosa Cell Tumor; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prednisone; Retrospective Studies; Vincristine

The effectiveness of alkylating agents in the treatment of ovarian cancer is limited by the frequent development of drug resistance. In order to examine the mechanisms of resistance and potential ways in which this resistance could be overcome, we have developed a human ovarian cancer cell line, 1847ME, resistant to the bifunctional amino acid nitrogen mustard, melphalan. A 4-fold higher concentration of melphalan was required to produce an equivalent reduction in tumor colony formation in 1847ME cells as compared to the parent melphalan-sensitive line A1847. The magnitude of resistance in 1847ME was similar to that observed in the cell lines NIH:OVCAR-2, NIH:OVCAR-3, and NIH:OVCAR-4 which were derived from ovarian cancer patients clinically resistant to alkylating agents. There was no detectable difference in melphalan uptake between A1847 and 1847ME. The cellular content of the inactive dihydroxy melphalan metabolite, however, was two times greater in 1847ME compared to A1847. Levels of the principal intracellular thiol, glutathione, were found to be 2-fold greater in 1847ME than in A1847, and to be similarly elevated in the OVCAR lines. Depletion of glutathione by incubation of the cells in cystine-free medium or in the presence of the specific inhibitor of glutathione synthesis, DL-buthionine-S,R-sulfoximine, was accompanied by a marked increase in melphalan cytotoxicity. Doses of DL-buthionine-S,R-sulfoximine which were only minimally cytotoxic were associated with complete reversal of the induced resistance to melphalan in 1847ME. Synergism between melphalan and DL-buthionine-S,R-sulfoximine was also demonstrated in the OVCAR cell lines derived from previously treated ovarian cancer patients. The reversal of induced resistance to melphalan by modulation of glutathione levels is of potential clinical relevance. In addition, these cell lines provide a useful model system in which to study further the mechanisms of alkylating agent resistance in human tumors.

Topics: Buthionine Sulfoximine; Cell Line; Cell Survival; Cystine; Drug Resistance; Drug Synergism; Female; Glutathione; Humans; Kinetics; Melphalan; Methionine Sulfoximine; Ovarian Neoplasms

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

Variables associated with a negative second-look laparotomy in patients with stage III epithelial ovarian carcinoma are analyzed. Fifty-six patients were clinically free of disease after systemic chemotherapy and were subjected to second-look laparotomy to assess tumor status. Eighteen of these patients (32.1%) had no evidence of malignancy. Eight (14.3%) additional patients with no gross evidence of disease at laparotomy had microscopic persistence; five of these had disease documented in the pelvic or para-aortic lymph nodes. Significant variables associated with a histologically and cytologically negative second-look operation were low tumor grade (P less than .01), the use of cis-platinum containing combination chemotherapy (P less than .01), patient age less than or equal to 50 years (P less than .02), small residual tumor (less than 0.5 cm) before chemotherapy (P less than .05), and metastatic tumor less than or equal to 10 cm before initial cytoreduction (P less than .05). Patients treated with six to nine cycles of combination chemotherapy had the same probability of a negative second-look laparotomy as those treated with ten to 12 cycles. Multivariate discriminate analysis indicated that patients with low tumor grade, those receiving cis-platinum containing combination chemotherapy, and those with minimal residual tumors (less than 0.5 cm) after primary cytoreductive surgery correctly classify second-look status in 78.6% of patients. Until a nonsurgical method of monitoring subclinical disease is available, a through second-look laparotomy, including a pelvic and para-aortic lymphadenectomy, should be performed.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cystadenocarcinoma; Female; Follow-Up Studies; Humans; Laparotomy; Lymph Node Excision; Lymphatic Metastasis; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Reoperation

Topics: Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melphalan; Ovarian Neoplasms; Random Allocation

Melphalan (L-PAM) was compared to (C) cyclophosphamide, (M) methotrexate, and (F) 5-fluorouracil (CMF) in 413 patients with advanced ovarian carcinoma. L-PAM was given 3.5 mg/m2 twice daily for 5 days every 5 weeks. CMF doses were: C, 400 mg/m2; M, 15 mg/m2; and F, 400 mg/m2 IV on days 1 and 8 every 28 days. Three hundred seventy-five patients have been analyzed (L-PAM, 190; CMF, 185). One hundred fifty-three patients (41%) had measurable disease, 109 (29%) had evaluable disease, and 113 (30%) had nonmeasurable, nonevaluable disease. Response rates for patients with measurable and evaluable disease combined were similar: L-PAM, 32/130 (24%) (15% complete response); CMF, 47/132 (35%) (18% complete response). Patients with Stage IV measurable disease had a greater response rate to CMF, 22/52 (42%) versus L-PAM, 6/39 (15%). Survival and time to treatment failure were similar for both treatment regimens. Survival was improved in responders. Medians are: complete response, 28.1 months; partial response, 12.3 months; and no response, 6.7 months. Disease stage, performance status and age were identified as important prognostic variables for both survival and time to treatment failure.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Probability; Random Allocation; Time Factors

Acute nonlymphocytic leukemia developed in a 57-year-old woman following adjuvant therapy with melphalan for ovarian carcinoma. Maturation of differentiating marrow myeloid and erythroid precursors was megaloblastic. The serum vitamin B12 level was low, and Schilling test revealed vitamin B12 malabsorption correctable with intrinsic factor. Megaloblastic maturation of the marrow cells was converted to normoblastic following treatment with vitamin B12 and folic acid. However, blast cells persisted in the marrow, and cytogenetic analysis revealed aneuploidy and trisomy 18. In contrast to the marrow blast cells, there was a decline in circulating blast cells following vitamin replacement, suggesting that these cells were capable of maturation but required vitamin B12 for this purpose.

Topics: Acute Disease; Anemia, Pernicious; Bone Marrow; Cell Division; Cystadenocarcinoma; Female; Folic Acid; Hemoglobins; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Topics: Adult; Aged; Ascites; Ascitic Fluid; Bone Marrow Diseases; Colonic Neoplasms; Female; Humans; Infusions, Parenteral; Kinetics; Laparotomy; Male; Melphalan; Middle Aged; Models, Biological; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Stomach Neoplasms

Chromosome aberrations were studied in peripheral lymphocytes from 50 patients treated with melphalan against ovarian carcinoma. The chromosome analyses were carried out 4-132 months (mean 57 months) after the end of melphalan therapy. Most of the patients were studied several times during four years. The mean frequency of cells with chromosome and chromatid aberrations was 5.4% in the patients and 2.3% in an untreated control group. The highest aberration frequency (average 18%) was found in a patient who later developed gastric carcinoma. The dominating types of aberrations in the patients were chromosome exchanges occurring as single marker chromosomes or as multiple chromosome rearrangements. These types of aberrations were found in only 0.3% of the control cells as compared to 3.8% of the patient cells. Patients with a high total dose of melphalan (above 420 mg) and a long duration of the therapy (average 22.5 months) had a higher frequency of cells with aberrations (6.3%) than patients with a lower total dose (below 420 mg) and a shorter therapy (12 months) (4.2%). No additive effect of radiation therapy was observed on the aberration frequency.

Topics: Adult; Aged; Chromosome Aberrations; Dose-Response Relationship, Drug; Female; Humans; Lymphocytes; Melphalan; Middle Aged; Ovarian Neoplasms; Stomach Neoplasms; Time Factors

Topics: Carcinoma; Female; Humans; Immunotherapy; Interferons; Melphalan; Ovarian Neoplasms; Propionibacterium acnes

The paper presents the results of intratumoral chemotherapy of 32 cases of single metastases of stage III-IV ovarian cancer into the Douglas pouch. The metastases were detected at different stages after primary treatment. Thiotepa, cyclophosphamide, sarcolysin and methotrexate were administered in 81.2, 9.4, 6.2 and 3.1% of cases, respectively. A clinically-significant effect was recorded in 14 out of 32 cases (43.7%); tumor process was arrested in 15 cases (46.9%); treatment failed in 3 cases (9.4%). Toxic side-effects were less frequent and pronounced than in patients given standard systemic monochemotherapy.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cystadenocarcinoma; Douglas' Pouch; Endometriosis; Female; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Thiotepa

Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, we obtained an M5 subline resistant to CTX (M5-CTX-16R). Median survival times were approximately 29 and 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively, whereas in M5-CTX-16R it ws 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation, and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 hr after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 hr and at subsequent times, no cytokinetic pertubation was evident in M5-CTX-16R, whereas in M5 marked accumulation of cells in G2-M was observed at 48, 72, 96, and 120 hr. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil, and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea, and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.

Topics: Animals; Antineoplastic Agents; Carmustine; Cell Cycle; Cell Line; Cyclophosphamide; Dacarbazine; Drug Resistance; Female; Lymphoma, Large B-Cell, Diffuse; Melphalan; Mice; Mice, Inbred C57BL; Ovarian Neoplasms

Between 1970 and 1980, 50 patients with carcinoma of the ovary were treated sequentially with six courses of IV phenylalanine mustard (L-PAM), second look surgery, and radiotherapy using the strip technique. Seven patients had advanced Stage I disease and six patients had Stage II disease; all of these patients are alive and well with no evidence of disease (NED) with a mean survival of five years. Thirty-seven patients had Stage III disease: ten of these patients did not respond to L-PAM (26%); 17 patients had a partial response (48%), and four of these (22%) are alive with NED and a mean survival of five years; ten patients (26%) had a complete response to L-PAM and all are alive and well with a mean survival of five years. The presence of a minimal tumor burden after the initial surgery, a mixed histology, a low-grade differentiation, suppression of leukocyte count to below 2000/mm3 after the first course of chemotherapy, and a complete response to L-PAM, were all factors that contributed to the probability of a long-term survival. Tumors responding to L-PAM and then recurring also responded to a combination of cisplatin and adriamycin, and hexamethylmelamine.

Topics: Adult; Aged; Carcinoma; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Radiotherapy, High-Energy; Time Factors

Topics: Adult; Aged; Altretamine; Cisplatin; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms

A cell line, NIH:OVCAR-3, has been established from the malignant ascites of a patient with progressive adenocarcinoma of the ovary after combination chemotherapy with cyclophosphamide, Adriamycin, and cisplatin. OVCAR-3 grows as a cobblestone-like monolayer with foci of multilayering, is tumorigenic in athymic mice, clones in agarose, and has an abnormal karyotype which includes a homogeneous staining region and a double minute chromosome. The cultured cells and xenografts contain cytoplasmic androgen- and estrogen-binding macromolecules with the specificity of the respective steroid hormone receptors. These components have sedimentation coefficients of 7 to 9S in low-salt sucrose-density gradients, have dissociation constants of 250 and 9.6 pM, and are present at concentrations of 30 and 28 fmol/mg cytosol protein characteristic of androgen and estrogen receptors, respectively. OVCAR-3 is resistant in vitro to clinically relevant concentrations of Adriamycin (5 X 10(-8) M), melphalan (5 X 10(-6) M), and cisplatin (5 X 10(-7) M) with survival compared to untreated controls of 43, 45, and 77%, respectively. Furthermore, there are multiple histological similarities between the patient's original tumor, the cell line, and the transplantable tumor. These data indicate that OVCAR-3 may be of use for investigations as to the significance of androgens and estrogens and the mechanisms of cytotoxic drug resistance in ovarian cancer.

Topics: Cell Division; Cell Line; Cell Survival; Cisplatin; Culture Techniques; Cytosol; Doxorubicin; Estradiol; Estrenes; Female; Humans; Karyotyping; Melphalan; Metribolone; Ovarian Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid

Fourteen patients with advanced ovarian epithelial carcinoma were treated with a combination of chemotherapy and immunotherapy. The chemotherapy consisted of either melphalan or a combination of adriamycin, cytoxan, and cisplatin. The immunotherapy consisted of the injection of autologous radiation-attenuated tumor and Corynebacterium parvum. No significant toxicity occurred as a result of the immunotherapy, and there was no evidence of tumor growth at the sites of injection. The autologous tumor skin test showed prognostic value. Skin testing with C parvum was of less prognostic value than tumor. All other studies of immunologic status, including T- and B-cell enumeration and blastogenic responsiveness of the patients' lymphocytes to autologous tumor and mitogens, were of no prognostic value.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Vaccines; Cells, Cultured; Combined Modality Therapy; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Propionibacterium acnes; Skin Tests

Because of an encouraging response rate in a pilot study of adriamycin, BCNU, and cyclophosphamide (ABC), the Southeastern Cancer Study Group conducted a phase II study of ABC in patients with melphalan-resistant ovarian carcinoma. Of 36 evaluable patients, there were only 4 partial responses to therapy, for a partial response rate of 11%. Durations of response were 4 to 50 + weeks, and the overall median survival was 29 weeks. No complete responses were seen. Dose-limiting toxicity was granulocytopenia. We conclude that ABC is generally ineffective in management of alkylator-resistant ovarian adenocarcinoma.

Topics: Adenocarcinoma; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Resistance; Drug Therapy, Combination; Female; Humans; Melphalan; Ovarian Neoplasms

Topics: Amphotericin B; Animals; Cell Line; Cell Survival; Doxorubicin; Drug Synergism; Female; Humans; Leukemia L1210; Melphalan; Mice; Ovarian Neoplasms; Teratoma

The data on 41 patients with epithelial malignant tumors of the ovaries, who received sarcolysin at different stages of combined treatment, were analyzed. The following factors of therapeutic effect of sarcolysin were established: age of 41-50 years, presence of ascites, administration by two routes--intravenously and intracavitarily and a total dose in excess of 160 mg. Still another factor is contributed by the extent of surgical procedure carried out as primary treatment.

Topics: Adenocarcinoma; Adult; Cystadenocarcinoma; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

Topics: Acute Disease; Alkylating Agents; Female; Humans; Leukemia; Melphalan; Ovarian Neoplasms

Topics: Brenner Tumor; Castration; Female; Humans; Hysterectomy; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy Dosage; Reoperation

Between 1958 and 1973, 2412 women with epithelial ovarian carcinoma were treated at Radiumhemmet. Of these tumors, 14.5 per cent were of borderline malignancy. The 5-year relative survival rate was 34 per cent among the patients with true malignant tumor and 93 per cent in the borderline cases. Even in advanced stages (IIb-IV) the 5-year survival rate was 78 per cent in the borderline cases. Advanced stage and high age at diagnosis, true malignancy and tumors of serous, clear cell or anaplastic type were associated with poor prognosis. The 5-year relative survival rate of patients with epithelial ovarian carcinoma in an early stage improved during the period, from 67 to 81 per cent.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoma; Endometriosis; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Radiotherapy Dosage; Statistics as Topic; Time Factors

Ten patients with advanced ovarian carcinoma were treated with hexamethylmelamine and melphalan after failing first-line combination chemotherapy. In eight patients residual disease was evident only at second-look laparotomy. Surgical debulking was accomplished in four patients but only two patients had residual disease of less than 2 cm. Two of these four patients are alive without evidence of disease to 20 and 24 months. The remaining patients have expired (median survival 6 months). The combination of hexamethylmelamine and melphalan after surgical debulking at second-look operation may improve the salvage of patients with advanced ovarian carcinoma.

Topics: Adenocarcinoma, Papillary; Aged; Altretamine; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Triazines

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

Following surgery for epithelial carcinoma of the ovary, FIGO stages IIc, III and IV, 110 patients received chemotherapy in one of four treatment regimens (Melphalan; Cyclophosphamide-Methotrexate-Fluoro uracil; Cyclophosphamide-Cisplatinum; Cyclophosphamide-Cisplatinum-Fluoro-uracil). Melphalan alone was as effective as combination chemotherapy and less toxic. The study confirms that the survival duration is inversely correlated to the stage of the disease and to the amount of residual disease following surgery. It also confirms the role of the "second look" surgery in the evaluation of the response to chemotherapy, and in the overall management of the disease.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma; Cisplatin; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Laparotomy; Melphalan; Methotrexate; Middle Aged; Neoplasm Staging; Ovarian Neoplasms

Topics: Aged; Female; Humans; Melphalan; Ovarian Neoplasms

Late side effects of chemotherapy were studied in 51 women who had received at least 300 mg of melphalan for ovarian cancer and had survived for at least three years. Hematologic, statistical, and cytogenetic methods were employed. Six cases of iatrogenic leukemia were found. They appeared to represent a hematologic entity that is fairly difficult to recognize. The risk of iatrogenic leukemia in women who survived for three years or more after melphalan treatment was calculated to be 950 times greater than the leukemia risk in the total female population. The cytogenetic changes were studied with three methods focused on sister chromatid exchange, chromosome aberrations, and DNA damage. The sister chromatid exchange frequency showed a marked increase, but it was corrected within a few months. Chromosome aberrations expressed by chromosome rearrangements were increased in the peripheral lymphocytes and may persist for several years. The frequency of DNA stand breaks was decreased indicating the presence of DNA cross-links. Any of these types of genetic alteration could be the initiating event in carcinogenesis.

Topics: Acute Disease; Adult; Aged; Bone Marrow; Female; Follow-Up Studies; Humans; Iatrogenic Disease; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Risk; Sister Chromatid Exchange; Smoking

Topics: Castration; Child; Cystadenocarcinoma; Female; Humans; Melphalan; Ovarian Neoplasms

Topics: Acute Disease; Aged; Alkylating Agents; Female; Humans; Leukemia; Melphalan; Ovarian Neoplasms; Prognosis

The present work uses an in vitro test model to measure the sensitivity of human ovarian cancer cells to Melphalan and Melphalan combined with Adriamycin. With this model we studied the possible correlation between the in vitro results and the response to these cytostatic drugs in vivo. Cancer cells from 20 patients with advanced ovarian cancer were tested. The in vitro effects of the drugs were measured as differences in incorporation of labeled 3H-thymidine in drug containing tubes and in control tubes. The effects of the drugs on the different cancer cells varied greatly from strong sensitivity to resistance. In vitro and in vivo results were compared one year after start of patient treatment. The overall agreement was 16/20, 80%. The in vitro method thus estimates a tumor cell characteristic which has a biological meaning also in in vivo conditions.

Topics: Adenocarcinoma; Carcinoma; Cells, Cultured; Doxorubicin; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endometriosis; Female; Humans; In Vitro Techniques; Melphalan; Ovarian Neoplasms; Retrospective Studies

Thirty-seven of 137 patients had a "second-look" laparotomy in the course of their management of carcinoma of the ovary. Patients were stratified according to three indications: (1) evaluation of disease with intent of stopping therapy, (2) assessment of signs of recurrent or persistent disease with a view to debulking tumor mass and changing chemotherapy, and (3) further tumor resection following cis-platinum combination therapy and determination of further chemotherapeutic agents. "Second-look" laparotomy may be performed after a shorter time interval when combination therapy is given because of the dose-limiting side effects of some of these agents and a more aggressive surgical approach in debulking tumors. At the time of laparotomy, cytologic testing is performed on the peritoneal fluid, and only areas suspicious for malignancy are biopsied. Thirteen percent of patients with no evidence of disease at "second-look" laparotomy developed recurrent disease. Twenty-nine percent of patients classified as clinically free of disease had malignancy present at the time of operation. Continued routine use of "second-look" laparotomy after appropriate chemotherapy is recommended.

Topics: Adenocarcinoma; Ascitic Fluid; Biopsy; Cisplatin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Laparotomy; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Recurrence; Time Factors

The human tumor stem cell assay (HTSCA) has been used to study the in vitro sensitivity rates of anticancer drugs used in the treatment of 115 patients with previously untreated and relapsing ovarian cancer. The data from these studies have identified patterns of cross resistance and residual sensitivity between these agents, and have allowed the prospective selection of single agents possessing in vitro activity for the treatment of 32 patients with relapsing disease. cis-Platinum and vinblastine were the most active agents in vitro against ovarian TCFUs from both previously untreated and relapsing patients. Prior therapy with even one drug was associated with the acquisition of resistance to several classes of compounds (e.g., melphalan resistance was almost always associated with in vitro adriamycin resistance, P less than 0.001). A clinical trial yielding similar data would have required nearly 450 evaluable ovarian cancer patients. In 11 of 32 patients in vitro testing predicted sensitivity to single agents: eight of these had partial remissions for a predictive accuracy of 73%. In 33 instances the HTSCA had 100% accuracy in predicting the lack of clinical response. Thus, the HTSCA for advanced ovarian cancer appears to have a similar predictive accuracy rate to the estrogen receptor assay for predicting the response to hormonal therapy for disseminated breast cancer.

Topics: Antineoplastic Agents; Bleomycin; Cisplatin; Colony-Forming Units Assay; Drug Resistance; Drug Therapy, Combination; Female; Humans; Melphalan; Neoplasms, Experimental; Ovarian Neoplasms; Recurrence; Vinblastine

Twenty-three patients with Stage III, Stage IV, or recurrent epithelial ovarian cancer were treated with a combination of melphalan and levamisole to determine a tolerable dosage schedule, possible adverse effects, and a general estimate of response rate and duration. In seven patients with measurable disease there were four complete responses (57%) with a median duration of 75 weeks. Two of the complete responders have had negative second-look laparotomies while the other two patients have had subsequent progression. Of 16 patients with nonmeasurable disease two have had negative second-look laparotomies and two remain progression free. Thus 8 of 23 patients (35%) had complete responses or remain progression free whereas 4 of 23 patients (17%) have had negative second-look laparotomies. No serious toxicity was encountered. Immunologic monitoring did not indicate significant immunologic reconstitution in these immunosuppressed patients.

Topics: B-Lymphocytes; Drug Therapy, Combination; Female; Humans; Levamisole; Lymphocyte Activation; Melphalan; Middle Aged; Ovarian Neoplasms; Phytohemagglutinins; Pilot Projects; Pokeweed Mitogens; T-Lymphocytes

In 1970, a prospective multidisciplinary protocol was initiated for Stages I through III obviously malignant ovarian epithelial carcinomas. The planned sequential therapy included 1) surgery, 2) radiotherapy (2000 rads to whole abdomen, 3000 rad boost to pelvis), 3) chemotherapy (ten cycles of Alkeran), and 4) a "second-look" surgical procedure. Ninety-six patients were enrolled in this program through 1976. Median follow-up of the survivors was greater than 44 months. Adjusted disease-free survival was 90 percent for Stage I, 64 percent for Stages IIB--IIC, and 16 percent for Stage III. Stage III patients with no palpable tumor at time of initiation of radiation therapy had a survival of 37 percent. No Stage III patient with palpable tumor at time of initiation of radiation therapy was cured. Eight percent of patients developed small bowel obstruction requiring surgical intervention. Three percent of all patients died of hematologic causes; of the 30-month-plus survivors, 5 percent (2 of 37) developed acute myelogenous leukemia. Cure and toxicity will be examined in detail and compared with the literature.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Female; Humans; Intestinal Obstruction; Melphalan; Mesonephroma; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Pilot Projects; Prospective Studies; Radiotherapy; Time Factors

Cell populations obtained from ovarian cancer specimens were seeded in primary culture and morphologically identified as cancer cells. Methotrexate, cytosine arabinoside, 5-fluorouracil, antinomycin D, melphalan, and adriamycin were added to the culture medium at different concentrations and for various periods of time. The results are discussed in relation to the pharmacokinetic availability of drugs in the plasma compartment of patients treated by different therapuetic regimens. Totally inactive drugs can be identified by comparing plasma levels with active concentrations while for drugs active in vitro at concentrations in the range of pharmacokinetic levels, the percentage of responders among patients might be explained by the intrinsic variability of cancer cells.

Topics: Antineoplastic Agents; Cell Survival; Cytarabine; Dactinomycin; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance; Female; Fluorouracil; Half-Life; Humans; In Vitro Techniques; Melphalan; Methotrexate; Ovarian Neoplasms

An unambiguous and sensitive method based on gas chromatography-chemical ionization-mass spectrometry has been developed to quantitate L-phenylalanine mustard and has been applied to measure levels in plasma of five patients receiving 0.15 to 0.25 mg/kg (10 to 17 mg) of the drug p.o. Peak plasma levels of 50 to 190 ng/ml were found to occur between 0.7 and 2.3 hr after ingestion. The time for the plasma level to fall to one-half of the peak value varied from 0.6 to 3 hr, and very low levels (less than 2 ng/ml) were present by 24 hr.

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Female; Gas Chromatography-Mass Spectrometry; Humans; Melphalan; Mesothelioma; Multiple Myeloma; Ovarian Neoplasms; Time Factors

Topics: Animals; Cells, Cultured; Cyclophosphamide; Cytological Techniques; Drug Evaluation, Preclinical; Female; Humans; Melphalan; Ovarian Neoplasms; Thiotepa

Topics: Female; Humans; Medroxyprogesterone; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Thiotepa

Topics: Bone Marrow; Cystadenoma; Female; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Ovarian Neoplasms; Radiotherapy

A 67-year-old woman suffered from an ovarian carcinoma with lymph nodes metastasis. During 3 years, she was treated with alkylating agents (Melphalan). At the end of therapy, no recurrence was observed. Two years later, she developed concomitantly pyoderma gangrenosum and acute myelomonocytic leukaemia. Death occurred rapidly. The association between pyoderma gangrenosum and acute leukaemia is discussed in the light of 16 cases previously reported in the literature. In this case, an induction of leukaemia by cytostatic drugs seems likely. The authors conclude that pyoderma gangrenosum may be considered as a cutaneous signs of acute leukaemia.

Topics: Aged; Cystadenocarcinoma; Female; Humans; Leukemia, Myeloid, Acute; Lymphatic Metastasis; Melphalan; Ovarian Neoplasms; Pyoderma

45 patients with ovarian cancer stage III and IV were treated with melphalan, which was injected intravenously over a time period of six hours. None of the patients had been treated previously with chemotherapeutic drugs. 30 of the patients suffered from ovarian cancer stage III, and 17 of this group went into remission which in three cases lasted longer than twelve months. Six of 15 patients suffering from stage IV ovarian cancer went into remission as well. In comparing monochemotherapy with polychemotherapy, which is applied intravenously as well over a much longer time interval we found approximately the same remission rate. Because of the lower toxicity in the treatment with melphalan and the short period of application, there is a significant advantage to using monochemotherapy rather than polychemotherapy for stage III and IV ovarian cancer.

Topics: Drug Evaluation; Female; Humans; Injections, Intravenous; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Time Factors

The effectiveness of chemoimmunotherapy was evaluated in 45 previously untreated stage III ovarian cancer patients. Response rate, progression-free interval, and survival were considerably better than in a similar group of 63 patients treated with a single alkylating agent alone.

Topics: Evaluation Studies as Topic; Female; Humans; Immunotherapy; Melphalan; Ovarian Neoplasms; Propionibacterium acnes; Remission, Spontaneous; Time Factors

Topics: Antineoplastic Agents; Dactinomycin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Time Factors; Vincristine

Cell suspensions from nine human ovarian primary cancers, their metastases and ascitic cells were treated in vitro with amethopterin and melphalan. Effects were measured by incorporation of H3-TdR or H3-UdR into the cells. There was significant heterogeneity of cytostatic effects on cells from the three sources in a given patient. Ascitic cells did nt represent a "mean" of the cancer cell clones. The implications of these findings should be considered if cytostatic in vitro prediction tests are used to guide cytostatic treatment of patients.

Topics: Ascitic Fluid; Cells, Cultured; Female; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Peritoneal Neoplasms

With a direct in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs, we performed 32 retrospective or prospective clinical studies in nine patients with myeloma and nine with ovarian cancer treated with standard agents that were tested in vitro. The results were clearly correlated (P is less than 0.00001). Unique patterns of sensitivity and resistance to the six drugs tested were observed for individual patients. In eight cases of myeloma and three of obarian carcinoma in vitro sensitivity corresponded with in vivo sensitivity whereas in one case of myeloma it did not. In vitro resistance correlated with clinical resistance in all five comparisons in myeloma and all 15 in ovarian cancer. We conclude that this assay shows sufficient promise to warrant larger-scale testing to determine its efficacy for selection of new agents and individualized cancer chemotherapy regimens.

Topics: Antineoplastic Agents; Bleomycin; Carmustine; Clone Cells; Doxorubicin; Drug Resistance; Female; Hematopoietic Stem Cells; Humans; Melphalan; Methotrexate; Multiple Myeloma; Ovarian Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Vinblastine

A case of proved delayed recurrence of a granulosa cell tumor 18 years after initial diagnosis is presented. L-Phenylalanine mustard was given after radiation was refused for the unresectable mass. A prolonged complete remission was produced. The present status of palliative therapy of recurrent granulosa cell tumor is discussed with a request for the reporting of experiences with more patients treated with chemotherapy.

Topics: Female; Granulosa Cell Tumor; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Palliative Care; Remission, Spontaneous; Time Factors

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

During the years 1966-1973 474 patients with ovarian carcinoma were treated with melphalan. Of these, 48 patients received at least 300 mg melphalan and survived at least 3 years; four cases of acute leukemia were found among these 48 patients. All cases belonged to a group of 12 cases receiving 800 mg melphalan or more.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms; Time Factors

Topics: Adult; Aged; Altretamine; Castration; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; United States

One hundred and eleven consecutive women with FIGO Stages III and IV ovarian adenocarcinoma were treated with melphalan as their initial chemotherapy. The response rate was 19.8% with 10.8% having a complete response. There was a statistically significant improvement in response in those women with no prior radiation therapy. Moreover, there was a statistically significant improvement in median survival in those patients achieving a complete response to melphalan as compared to those with a partial response, with no change or progression of their malignancy. A review of the results of maximal surgery and combination chemotherapy is presented as a plan of therapy to improve upon the results of melphalan chemotherapy in women with advanced ovarian carcinoma.

Topics: Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Melphalan; Ovarian Neoplasms

Topics: Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Vasculitis

Fibrinogen/fibrin degradation products (FDP) in the serum of 50 patients with ovarian carcinoma was examined by Nyléhn's immunochemical method. FDP were rarely found in early but frequently in advanced stages of ovarian tumours. With successful treatment, FDP decreased; otherwise persistently high FDP concentrations were observed in the serum. The determination serum FDP might be a valuable aid in assessing the effect of treatment.

Topics: Adult; Aged; Carcinoma; Cyclophosphamide; Cystadenocarcinoma; Female; Fibrin Fibrinogen Degradation Products; Fluorescent Antibody Technique; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Topics: Acute Disease; Alkylating Agents; Altretamine; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Risk; Thiotepa; Time Factors; Uracil Mustard

Ovarian carcinomas are highly sensitive to chemotherapy. The alkylating agents were most extensively investigated. With these drugs remissions can be obtained in about 50% of the patients. Some early results seem to show a higher response rate and a longer duration of remission after combination chemotherapy. In ovarian carcinoma it has to be the aim of the chemotherapy to obtain a complete remission. The indications for chemotherapy are not yet well defined. Treatment is definitely indicated in stage IV (FIGO) or in recurrent disease after radiotherapy. This treatment has to be given as a long-term therapy over a long period of time. In stage III and II b disease a combined treatment plan has to be developed by the radio- and chemotherapist. At the present time no data are available which prove or disprove the value of an adjuvant chemotherapy in the early stages of ovarian carcinoma. Remembering the somewhat promising results of adjuvant chemotherapy in breast cancer, it is conceivable that prophylactic chemotherapy will prove to be indicated in early stages of ovarian carcinoma.

Topics: Altretamine; Antineoplastic Agents; Chlorambucil; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Hydroxyprogesterones; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mitomycins; Nitrosourea Compounds; Ovarian Neoplasms; Thiotepa; Vinblastine; Vincristine

Topics: Cyclophosphamide; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Melphalan; Ovarian Neoplasms

This paper presents an interim analysis of 279 patients with epithelial carcinoma of the ovary who were entered into a prospective study started in April, 1971. One hundred and three patients were available for analysis three years after diagnosis. Apart from the survival differences by stage and treatment method, this study has shown that the completeness of the initial pelvic operation, in Stages II and III, is of greater prognostic importance than the stage. The importance of the features of the pelvic disease which interfere with the removal of all pelvic organs led the authors to conclude that factors other than stage should be considered in prescribing postoperative treatment. To date, the disease-free survival trends in Stages IB, II, and asymptomatic Stage III show that physicians should place much greater emphasis on the initial operative features when they are seeking the most effective combination of irradiation and chemotherapy. Analysis of failures shows that upper abdominal irradiation is more effective than daily chlorambucil in preventing progression of disease to that area. However, early evidence indicates that chlorambucil added to pelvic irradiation improves the control of pelvic disease. Improved methods of treatment have not yet been identified for early Stage I (IA) and advanced presentations (symptomatic Stages III and IV).

Topics: Abdomen; Castration; Chlorambucil; Cyclophosphamide; Fallopian Tubes; Female; Humans; Hysterectomy; Melphalan; Middle Aged; Ovarian Neoplasms; Pelvis; Prognosis; Prospective Studies

A patient with a progesterone-producing granulosa cell carcinoma is the basis of this report. Seven years after initial surgical therapy pelvic masses were palpated. At laparotomy the recurrence of tumor was confirmed, and many nonresectable metastases were discovered on the surface of the liver and on the mesentery of the bowel. An exceedingly high plasma progesterone level of 6270 pg/ml was obtained in the postoperative period. During 12 months of single agent chemotherapy with melphalan, serial plasma progesterone assays declined to 310 pg/ml. Complete tumor regression was subsequently confirmed by laparoscopy. Evaluation of progesterone levels in patients with granulosa cell tumors is recommended to determine the incidence of this finding and to further assess its value in following response to therapy.

Topics: Aged; Female; Granulosa Cell Tumor; Hormones, Ectopic; Humans; Hysterectomy; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Progesterone

Topics: Adenocarcinoma; Female; Humans; Leukemia, Plasma Cell; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms

Topics: Acute Disease; Female; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms

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

One hundred and three patients with advanced ovarian cancer underwent a second-look operation following chemotherapy. Patients should have ten or more courses of chemotherapy before second-look operation. Those patients with no evidence of disease at second laparotomy should discontinue their chemotherapy. Patients who continued chemotherapy after the second-look operation did better than those who were treated with radiation after surgery. Only patients with clinical remission benefit from the second-look procedure. Advantages of second-look operations following chemotherapy are discussed.

Topics: Dose-Response Relationship, Drug; Female; Humans; Melphalan; Ovarian Neoplasms; Time Factors

Lymphocyte-mediated cytotoxicity (cell-mediated immunity) to ovarian carcinoma cells and serum blocking factor were measured in 37 patients. Short-term cultures of tumor cells and a low ratio of effector to target cells were used throughout the study, minimizing nonspecific cytotoxicity. Sixteen patients were followed for long periods of time, and correlation with the course of the disease and with therapy could be obtained. Although the level of cell-mediated immunity did not always correspond to the clinical status of the patient, the presence of blocking factor was associated with clinical relapse in 14 of 16 patients. Chemotherapy with single alkylating agents or combinations of drugs caused no significant or permanent depression of cell-mediated immunity as measured in this way. In addition, blocking factor disappeared in 2 patients during remission. It appears that the chemotherapy for ovarian carcinoma may not be significantly immunosuppressive against established levels of cell-mediated immunity and may in certain instances have effects potentially beneficial to the host as evaluated by lymphocyte-mediated cytotoxicity and blocking factor studies.

Topics: Antibodies, Neoplasm; Antigen-Antibody Complex; Antigens, Neoplasm; Cytotoxicity Tests, Immunologic; Female; Follow-Up Studies; Humans; Immunity, Cellular; Melphalan; Ovarian Neoplasms; Recurrence; Remission, Spontaneous

We report the serum levels of carcinoembryonic antigen (CEA) in 109 patients with ovarian cancer. Histology, degree of differentiation, and clinical stage influenced the incidence of positive CEA. Although CEA was significantly raised in patients with a variety of tumours, the highest incidence (77 per cent) was found in those with serious cystadenocarcinoma. Nearly all (94 per cent) of the poorly differentiated tumours were associated with a positive CEA result. Serial CEA levels provided a useful guide to management during cytotoxic chemotherapy, rapidly falling levels indicating a favourable tumour response which was reflected clinically. However, only two-thirds of tumours were associated with detectable CEA levels in serum, day-to-day variations in individual serum levels occurred, and CEA levels tended to fall paradoxically during terminal illness. The significance of persistently low levels in the apparent absence of disease was uncertain.

Topics: Adenocarcinoma; Carcinoembryonic Antigen; Cystadenocarcinoma; Cystadenoma; Dysgerminoma; Endometriosis; Female; Follow-Up Studies; Granulosa Cell Tumor; Humans; Melphalan; Mesonephroma; Ovarian Neoplasms; Pregnancy

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

Most patients with epithelial cancer of the ovary are not cured by surgery, since their cancer has spread beyond the ovaries. The majority of these patients are not suitable for postoperative irradiation therapy, since the residual tumors are too large to be effectively treated with irradiation or they have metastasized to areas that cannot be effectively irradiated. Approximately 50% of the patients with advanced ovarian cancer who are treated postoperatively with melphalan will benefit from this chemotherapy. Approximately 40% of the patients who do not respond to chemotherapy with melphalan will benefit from treatment with a combination of actinomycin D, 5-fluorouracil, and cyclophosphamide. A second-look operation after 12 or more cycles of chemotherapy is often helpful in planning future treatment of patients, and it may be curative in a few patients if all the remaining tumor can be excised.

Topics: Altretamine; Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

In an attempt to improve the survival rates in women with advanced ovarian adenocarcinoma (abdominal spread), they were treated with sequential therapy. This consisted of operation followed by chemotherapy, second-look exploratory laparotomy, and finally whole-abdomen irradiation. Only those patients who had a complete clinical response to chemotherapy and subsequently underwent a second operation and irradiation were evaluated. Seventy-five per cent of the patients had recurrent cancer within the treated area after sequential therapy was completed. Morever, of four patients with no gross residual cancer after the second operation, three had cancer recurrences within the treated area. It is concluded that methods of treating advanced ovarian adenocarcinoma other than sequential therapy must be found.

Topics: Adenocarcinoma; Chlorambucil; Cyclophosphamide; Dactinomycin; Female; Fluorouracil; Laparotomy; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms

Preliminary results of three prospective controlled ongoing Gynecologic Oncology Group studies in ovarian carcinoma are discussed. The first study involves "Postoperative Treatment of Women With Resectable Ovarian Cancer With Radiotherapy, Melphalan, or No Further Treatment" (77 evaluable patients). Although there is a trend favoring chemotherapy, the differences as yet are not statistically significant. The second protocol evaluates "Postoperative Treatment of Women With Stage III Ovarian Cancer by Radiotherapy or Melphalan, Either Alone or in Both Sequences" (141 evaluable patients). The progression-free interval is shorter with either therapeutic modality alone and longer with the two combinations of radiation and chemotherapy. The third protocol deals with "Treatment of Women With Disseminated or Recurrent Advanced Ovarian Cancer With Melphalan Alone, in Combination With 5-FU, in Combination with 5-FU and Dactinomycin, or in Combination with Cytoxan, 5-FU, and Dactinomycin" (200 evaluable patients). In terms of progression-free interval, the study favors combination chemotherapy.

Topics: Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

One hundred and sixteen human tumours were transplanted to thymectomized, irradiated, antilymphocyte serum-treated mice. In 12 cases the recipient mice died rapidly, presumably from infection. With the remaining 104 tumours, three-quarters grew to a varying extent, retaining the characteristic histological features of the primary tumours. Implant nodules varied widely in composition, from solid tumour and stroma to dense fibrous tissue without recognizable tumour cells. There was no relation between degree of malignancy and ability to grow, and also some benign tumours grew.In 44 cases, mice were treated with the drug or drugs most likely to be used in the patients and the effects on the implants were assessed histologically. Two tumours were largely destroyed and one showed marked metaphase arrest. Three other tumours showed lesser changes that were attributable to the drug but were of equivocal significance.There appeared to be differences in drug sensitivity between structurally different clones of the same tumour, and some tumours treated with two alkylating agents were damaged by one and not the other, suggesting that this model may have substantial discriminatory power. Assays such as this should not be used to guide treatment of the patient without prior validation. The practical and ethical difficulties of validation by clinical trial may be insurmountable, and an alternative approach to validation is proposed which does not raise these difficulties.

Topics: Animals; Chlorambucil; Cyclophosphamide; Dactinomycin; Disease Models, Animal; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Immunosuppression Therapy; Male; Melphalan; Methotrexate; Mice; Mice, Inbred CBA; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Thiotepa; Thymectomy; Transplantation, Heterologous; Triaziquone; Urinary Bladder Neoplasms; Vinblastine; Vincristine

Topics: Antibody Formation; Antineoplastic Agents; Body Weight; Cyclophosphamide; Cystadenocarcinoma; Endometriosis; Erythrocyte Count; Female; Humans; Leukocyte Count; Melphalan; Mesonephroma; Middle Aged; Ovarian Neoplasms; Time Factors

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Leukemia, Experimental; Leukocyte Count; Lymphoid Tissue; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Ovarian Neoplasms; Rats; Sarcoma 180; Sarcoma 37; Sarcoma, Experimental; Spleen; Splenic Neoplasms; Thymus Gland; Thymus Neoplasms; Time Factors; Triazines

Topics: Adenocarcinoma, Mucinous; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Drug Combinations; Female; Fluorouracil; Humans; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Animals; Antineoplastic Agents; Cell Line; Chromosome Aberrations; Drug Resistance; Female; Melphalan; Mercaptopurine; Mitosis; Ovarian Neoplasms; Rats; Thiotepa

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Ascites; Chlorambucil; Cobalt Isotopes; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Endometriosis; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Radiotherapy, High-Energy; Thiotepa; Vinblastine; Vincristine

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antineoplastic Agents; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

Topics: Culture Techniques; DNA, Neoplasm; Female; Fluorouracil; Humans; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Parathion; Thiotepa; Thymidine; Tritium

Topics: Antineoplastic Agents; Cyclophosphamide; Female; Humans; Melphalan; Ovarian Neoplasms; Palliative Care; Postoperative Care; Pyrimidines; Thiotepa

Topics: Adolescent; Aged; Bone Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Thrombocytopenia; Tonsillar Neoplasms; Uterine Neoplasms

Topics: Animals; Cell Line; Chromosome Aberrations; Culture Techniques; Female; Melphalan; Neoplasms, Experimental; Ovarian Neoplasms; Radiation Effects; Rats; Thiotepa

Topics: Alkylating Agents; Anesthetics, Local; Cyclophosphamide; Female; Humans; In Vitro Techniques; Melphalan; Ovarian Neoplasms; Sulfhydryl Compounds; Thiotepa

Topics: Ambulatory Care; Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Drug Combinations; Estrogens; Female; Hospitalization; Humans; Melphalan; Methotrexate; Ovarian Neoplasms; Prognosis; Remission, Spontaneous; Thiotepa; Triaziquone

Topics: Animals; Cell Division; Chromosome Aberrations; Drug Resistance; Female; Genetic Variation; Melphalan; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Polyploidy; Rats

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Female; Fluorouracil; Humans; Mechlorethamine; Melphalan; Ovarian Neoplasms; Thiotepa; Vinblastine

Topics: Animals; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Leukopenia; Lung Neoplasms; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Rats; Sarcoma 180; Sarcoma, Experimental; Thiotepa; Triazines

Topics: Adenocarcinoma; Ascitic Fluid; Busulfan; Chromosomes; Female; Humans; Karyotyping; Lymphatic Metastasis; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Pleural Neoplasms

Topics: Adenine; Carbon Isotopes; Culture Techniques; Female; Hemangiosarcoma; Humans; Lysine; Melphalan; Mesenchymoma; Neoplasm Proteins; Ovarian Neoplasms; Pancreatic Neoplasms; RNA, Neoplasm; Stomach Neoplasms; Uridine

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Female; Fluorouracil; In Vitro Techniques; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasms, Experimental; Ovarian Neoplasms; Rats; Thiotepa

Topics: Abdominal Neoplasms; Adenocarcinoma, Papillary; Aged; Alkylating Agents; Ascitic Fluid; Chromosomes; Female; Humans; Hydroxyprogesterones; Karyotyping; Melphalan; Methods; Neoplasm Metastasis; Neoplastic Cells, Circulating; Ovarian Neoplasms

Topics: Adult; Cyclophosphamide; Cystadenoma; Dysgerminoma; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Teratoma; Thecoma; Thiotepa

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: Adenocarcinoma; Adenocarcinoma, Papillary; Cystadenoma; Female; Granulosa Cell Tumor; Humans; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma; Cystadenocarcinoma; Cystadenoma; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

Topics: Choriocarcinoma; Cyclophosphamide; Dysgerminoma; Female; Humans; Male; Melphalan; Methotrexate; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Pregnancy; Teratoma; Testicular Neoplasms; Vincristine

Topics: Adenocarcinoma; Chromium Isotopes; Cobalt Isotopes; Cystadenoma; Dysgerminoma; Female; Gold Isotopes; Granulosa Cell Tumor; Humans; Melphalan; Ovarian Neoplasms; Phosphorus Isotopes; Sertoli-Leydig Cell Tumor; Teratoma; Time Factors

Topics: Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Female; Humans; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Thiotepa

Topics: Alkylating Agents; Ascites; Cyclophosphamide; Female; Humans; Melphalan; Ovarian Neoplasms; Prognosis; Thiotepa

Topics: Adolescent; Adult; Choriocarcinoma; Dysgerminoma; Female; Humans; Male; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Pregnancy; Teratoma; Testicular Neoplasms; Vincristine

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Palliative Care

Topics: Female; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Multiple Myeloma; Neoplasms; Osteosarcoma; Ovarian Neoplasms; Research; Sarcoma; Sarcoma, Ewing; Testicular Neoplasms; Thymoma

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: Choriocarcinoma; Dysgerminoma; Female; Humans; Male; Melphalan; Neoplasms; Ovarian Neoplasms; Pregnancy; Teratoma; Testicular Neoplasms

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: Abdomen; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Cyclophosphamide; Female; Geriatrics; Hodgkin Disease; Humans; Hypothermia; Hypothermia, Induced; Leiomyosarcoma; Mechlorethamine; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Pelvis; Rectal Neoplasms; Retroperitoneal Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms

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: Alkylating Agents; Antineoplastic Agents; Biomedical Research; Blood Platelets; Bone Marrow; Erythrocyte Count; Female; Humans; Leukocyte Count; Melphalan; Ovarian Neoplasms; Pharmacology; Tetracycline; Toxicology; Uterine Cervical Neoplasms

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Carbohydrate Metabolism; Carcinoma; Carcinoma, Ehrlich Tumor; Female; Glucose; Humans; Melphalan; Metabolism; Ovarian Neoplasms; Oxidative Phosphorylation; Peptides; Pharmacology; Phosphorylation; Research; Sarcoma; Sarcoma, Experimental; Toxicology

Topics: Animals; Autoradiography; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Chloramphenicol; Culture Media; DNA; DNA, Neoplasm; Female; Humans; Melphalan; Ovarian Neoplasms; Pharmacology; Phenylalanine; Proteins; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Experimental

Topics: Carcinoma; Female; Humans; Melphalan; Ovarian Neoplasms

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: Drug Therapy; Dysgerminoma; Female; Humans; Male; Melphalan; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Seminoma; Testicular Neoplasms

Topics: Female; Humans; Melphalan; Ovarian Neoplasms

Topics: Antineoplastic Agents; Cytostatic Agents; Female; Humans; Melphalan; Ovarian Neoplasms

Topics: Antineoplastic Agents; Female; Humans; Melphalan; Ovarian Neoplasms; Thiotepa

Topics: Dysgerminoma; Female; Humans; Male; Melphalan; Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Phenylalanine; Seminoma; Testicular Neoplasms; Testis