mesna and Breast-Neoplasms

Metastases from cystosarcoma phyllodes are rare, and treatment generally is ineffective. Four patients were treated with ifosfamide (alone in three and combined with doxorubicin in one). Two patients had complete remissions that lasted 26 and 61+ months. One other patient had a partial response that lasted 13 months. The complete responders were both treated as soon as metastases appeared, when they had only a small volume of disease. This appears to represent a significant improvement on other described regimens for this condition, and further trials of ifosfamide are warranted. Close follow-up of patients at high risk for metastases is suggested.

Topics: Adult; Breast Neoplasms; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Metastasis; Phyllodes Tumor

Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.. Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy.. Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration.. The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI.. clinicaltrials.gov NCT01205503.

Topics: Antineoplastic Agents; Breast Neoplasms; Cognition Disorders; Cross-Over Studies; Doxorubicin; Drug Interactions; Female; Humans; Interleukin-18; Lymphoma, Non-Hodgkin; Male; Mesna; Middle Aged; Oxidation-Reduction; Protective Agents; Receptors, Tumor Necrosis Factor; Solubility; Tumor Necrosis Factor-alpha

A prospective trial to evaluate the efficacy and toxicity of ifosfamide (IFX) and vinorelbine (VNB) in patients with prior anthracycline therapy for metastatic breast cancer (MBC) was conducted. At the same time, the scheduling of VNB in order to minimize toxicity of the combination was also evaluated.. Twenty-three patients with MBC who had already received initial chemotherapy with doxorubicin-containing regimens either as adjuvant or as first-line treatment in MBC were entered into the study. IFX 3 g/m(2) and mesna 3 g/m(2) were given in divided doses over 2 days. In 4 patients, VNB was given 25 g/m(2) on days 1 and 3 in 3-h infusion. In 8 patients, VNB was given on days 1 and 8 and in 5 patients VNB was given on days 1 and 15. Thirteen patients had received doxorubicin in adjuvant setting, while 10 patients received doxorubicin as first-line treatment in metastatic disease. Dominant disease sites were soft tissues in 7 patients, visceral in 12 patients, and bone in 4 patients. The median age was 47 years.. Overall objective response was seen in 12/23 patients (52.2%). Four patients achieved complete remission (CR), 8 patients achieved partial remission (PR). The median duration of response was 9 months in responding patients, and the median overall survival duration was 15 months. The major dose-limiting toxicities were neutropenia grade III and IV in 8/17 patients and asthenia grade III and IV in 4 patients.. IFX and VNB is an active combination. Neutropenia and asthenia were most significant when VNB was given on days 1 and 3. In the best-tolerated regimen, VNB was given on days 1 and 8.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Treatment Outcome; Vinblastine; Vinorelbine

Forty-six patients were included in a phase II study to evaluate the response rate and toxicity of a combination of ifosfamide and vinorelbine in metastatic breast cancer patients previously treated with one or more regimens of chemotherapy. Treatment consisted of ifosfamide 1.6 g/m(2) IV days 1-3 (with mesna) and vinorelbine 25 mg/m(2) IV days 1 and 8, every 3 weeks up to 6 cycles. The median age was 55 years (range 40-76), the World Health Organization (WHO) performance status was 0-1 in 93% of the patients and 2 in the remaining 7%. In all, 43% had received two or more previous lines of chemotherapy, and 91% had been treated with anthracyclines. Forty-four patients were evaluable for response, and all patients for toxicity. The overall response rate was 36.4% [95% confidence interval (CI) 22.4-52.2]. Stabilization was observed in 20.4% and progression in 43.2%. The median time to progression was 25 weeks (95% CI 14-36). Median relative dose intensity (=actual received dose intensity/planned dose intensity) was 0.99 for ifosfamide and 0. 80 for vinorelbine. The main toxicity was hematological, with 63% of the patients experiencing grade 3-4 neutropenia. With a moderate toxicity, this is an active regimen that may be taken into consideration in pretreated metastatic breast cancer patients when further chemotherapy is indicated.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Vinblastine; Vinorelbine

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

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

The aim of the study was to investigate a dose-intensified, preoperative chemotherapy with 3 cycles (cy) of epirubicin 60 mg/m2, ifosfamide 5 g/m2 with mesna 5 g/m2, biweekly with G-CSF 5 micrograms/kg (filgrastim), in terms of toxicity, clinical and pathological remission rates and changes of immunohistochemical characteristics (ER, PR, c-erbB2, p53) during chemotherapy of inoperable patients (pt) with poor prognosis (locally advanced (LABC, 9 pt), inflammatory breast cancer (IBC, 12 pt) and M0.. Following preoperative chemotherapy (63 cy) and mastectomy patients received adjuvant 3 cy of epirubicin 60 mg/m2 and paclitaxel 175 mg/m2 (biweekly) with G-CSF (54 cy), and subsequently radiation of the thoracic wall and tamoxifen 20 mg/day.. Primary toxicity (T): grade 3 alopecia (21 pt), grade 3-4 leucopenia (7 cy), grade 1-2 leucopenia (26 cy), grade 1-2 anemia (61 cy), grade 1-2 neurocortical T (13 cy), grade 1-2 neurosensory T (7 cy), grade 1 cardiac toxicity (1 pt). ORR: 65% (CR: 0 pt, PR: 13 pt, NC: 8 pt). The grades of histological regression were: 0: 14 pt, 1: 6 pt, 2: 0 pt, 3: 1 pt. No significant correlation was observed between the clinical response and the histological regression (Fischer's exact test). The immunohistochemical expression of tumor characteristics did not change significantly during preoperative chemotherapy (Wilcoxon test). 81% of the pt were disease-free after a median follow-up of 20 months (7-26).. This therapy is safe, feasible and effective, both as primary and adjuvant chemotherapy in women with LABC and IBC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Epirubicin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Immunohistochemistry; Mastectomy; Mesna; Middle Aged; Neoplasm Staging; Paclitaxel; Pilot Projects; Protective Agents; Recombinant Proteins; Survival Analysis; Tamoxifen; Treatment Outcome

Ifosfamide and paclitaxel are antineoplastic agents with broad activity and with different mechanisms of action. A Phase I trial was conducted to determine the maximum tolerated dose and associated toxicities of these agents when used in combination.. Patients with refractory, incurable solid tumors were entered on a 5-step Phase I trial of ifosfamide, given in doses of 2-3 g/m2 intravenous (i.v.) bolus for 3 days with mesna support, and paclitaxel, given in doses of 135-190 g/m2 i.v. by continuous infusion over 24 hours. Paclitaxel was given after the first dose of ifosfamide on Day 1.. Twenty-three patients were treated, and the maximum tolerated dose was the highest planned dose level of the trial: ifosfamide, 3 g/m2/day i.v. for 3 days, and paclitaxel, 190 mg/m2 i.v. over 24 hours. Hematologic toxicity was not dose-limiting, and although neutropenia occurred, it was brief (median, 2-4 days) and resulted in hospitalization for neutropenia and fever in only 7 of 111 courses of therapy. For patients treated at the highest dose level, only 1 of 50 courses of therapy resulted in hospitalization for neutropenia and fever. Nonhematologic toxicity also was not severe and no significant neuropathy occurred. Although patients entered into the study were heavily pretreated, responses were observed, particularly in patients with breast or ovarian carcinoma.. Ifosfamide and paclitaxel can be administered safely in the doses used in this study and there are indications of significant antitumor effect. Further studies are necessary to explore the antineoplastic activity of this regimen, particularly for patients with breast and ovarian carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colonic Neoplasms; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasms; Neutropenia; Ovarian Neoplasms; Paclitaxel

The aim of this paper is to evaluate the activity of ifosfamide in previously treated patients with metastatic breast cancer. From June 1991 through November 1992, 29 patients with metastatic breast cancer were treated with single-agent ifosfamide, 2 g/m2 intravenously daily for 5 days, with mesna support. All patients had previously received chemotherapy; all but one had previously received cyclophosphamide. The ifosfamide-mesna regimen was the first-line metastatic regimen in 15 patients, the second-line metastatic regimen in 13 patients, and the third-line metastatic regimen in one patient. Two partial remissions (7%) were observed; both occurred in the first-line metastatic group. The partial remissions were noted in patients who had completed adjuvant cyclophosphamide therapy 60 and 91 months earlier. Both responses were seen in lung metastases. The response durations were 5 and 8 months on continued therapy. The main adverse effects were granulocytopenia, fatigue, nausea, vomiting, and stomatitis. At the dose used in this study, ifosfamide and mesna given without growth-factor support resulted in significant myelosuppression and produced only two partial remissions (7%) in 29 patients. Further study of ifosfamide as an isolated agent in previously treated patients is not warranted.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Breast Neoplasms; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Metastasis; Remission Induction

In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients.. Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration.. Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels.. Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Breast Neoplasms; Cyclophosphamide; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Equipment Failure; Erythrocyte Transfusion; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hematuria; Home Infusion Therapy; Humans; Mesna; Middle Aged; Neoplasm Metastasis; Paclitaxel

The ifosfamide, mesna and epirubicin (IMEpi) combination is administered to 16 patients having advanced metastatic breast carcinoma as second-line chemotherapy. We observed complete response in 6%, partial response in 44% (total overall response rate of 50%), stable disease in 12% and progressive disease in the remaining 38% of the patients. The median remission duration in responders was calculated to be 9.6 months. IMEpi regimen had a tolerable toxicity profile including alopecia, nausea and vomiting, microscopic hematuria, leukopenia and neurotoxicity in which serious complications necessitating discontinuation of the chemotherapy were not encountered. It might be concluded that IMEpi chemotherapy combination is an effective alternative among schedules in the management of patients with stage IV breast carcinoma without serious side effects.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epirubicin; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Staging; Remission Induction; Salvage Therapy

Twenty patients with locally advanced or metastatic breast cancer were treated with four cycles of ifosfamide/mesna 5 g m-2 and epirubicin 60 mg m-2 every 14 days with granulocyte colony-stimulating factor (G-CSF, Filgrastim). Complete remission occurred in six out of the 20 patients (30%, 95% confidence interval 12-54%) and there were 12 partial responders (60%, 95% confidence interval 37-81%), thus giving an overall response rate of 90% (95% confidence interval 63-97%). Two patients had progressive disease. The median duration of response for those patients with metastatic disease was 7.3 (1.3-20.1+) months. The median survival time for these patients was 15 (5.3-27.9+) months. Of the four patients treated with locally advanced disease three achieved a complete clinical response and one a partial response. Three out of four of these patients subsequently underwent a mastectomy, and in one of these no viable tumour was seen. Our conclusion is that this regimen is excellent palliation for metastatic disease and possibly useful neoadjuvant treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Metastasis; Neutropenia

Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths. The combination of ifosfamide and carboplatin had little activity as the second-line treatment in our population of patients with heavily pretreated metastatic breast cancer. Oral mesna was effective for urothelial protection, permitting outpatient administration of ifosfamide.

Topics: Adenocarcinoma; Adult; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cystitis; Female; Humans; Ifosfamide; Mesna; Middle Aged; Remission Induction

Ifosfamide is an oxazaphosphorine analogue of cyclophosphamide with proven activity in breast cancer but substantial urotoxicity. The introduction of mesna as a uroprotective agent provided a stimulus for reexamination of ifosfamide for therapy of women with metastatic breast cancer. Twenty women with measurable (18 patients) or evaluable (2 patients) disease were entered into a phase II clinical trial of ifosfamide plus mesna as first-line chemotherapy. Ifosfamide was administered i.v. at a dose of 1,800 mg/m2 in 1 L D5W over 2 h on five consecutive days. Mesna was administered i.v. at a dose of 400 mg/m2 over 15 min immediately before and 1 h after ifosfamide, and then every 4 h for three more doses. The last three doses could be given either i.v. or orally. The planned cycle length was 28 days. Three patients (15%), all with measurable disease, achieved a partial response (95% confidence interval: 3 to 38%). Median time to progression was 137 days and median survival was 407 days. Toxicities included cumulative myelosuppression and substantial nausea and emesis. Four patients were removed from treatment because of toxicity alone and a fifth refused further therapy. We conclude that ifosfamide, plus mesna, as given in this protocol has definite but limited antitumor activity and poor tolerability.

Topics: Aged; Antineoplastic Agents, Alkylating; Breast Neoplasms; Cystitis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Metastasis; Remission Induction

28 patients with recurrent advanced breast cancer were treated with a salvage regimen consisting of vincristine, epirubicin and ifosfamide/mesna (VIE). All patients had poor prognostic characteristics defined as relapse within 12 months of chemotherapy or as relapse within a radiotherapy field. Chemotherapy was infused continuously through a central venous catheter using a portable pump. Ifosfamide (3 g/m2) mixed with mesna (3 g/m2) was infused for 7 days followed by epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2) over a further seven days and alternated for a total of 6 weeks. 9 of the 28 patients (32%) responded to VIE (six partial and three complete responses). This included 6 of the 18 patients (33%) who had previously received doxorubicin or mitoxantrone, 6 of the 17 patients (35%) who had an inoperable in-field relapse after radiotherapy for locally advanced cancer, and 5 of the 21 patients (24%) relapsing within 6 months of previous chemotherapy. Median duration of response and overall survival were 3.7 and 6.9 months, respectively. Myelotoxicity was mild. One patient had neutropenic sepsis, 3 patients ahd grade 3 nausea and vomiting and one patient developed paralytic ileus attributed to vincristine. Central venous catheter complications occurred in 12 of 33 catheters requiring removal in 6. Continuous infusional chemotherapy using vincristine, epirubicin and ifosfamide achieves a 32% overall response rate in treatment-resistant advanced breast cancer, and is associated with minimal toxicity and a short treatment period. VIE may be a suitable alternative to conventional chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epirubicin; Female; Hemoglobins; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Middle Aged; Neutropenia; Salvage Therapy; Time Factors; Vincristine

High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and thiotepa have been shown to influence the metabolism of each other. However, altering a dose regimen can have a profound effect on the pharmacokinetics of the compounds involved. The aim of this study was to investigate the effect of altering the fractionated administration schedule of the CTC regimen on cyclophosphamide and thiotepa pharmacokinetics. Plasma samples were collected from 124 patients who received a fractionated tiny CTC or CTC regimen of cyclophosphamide (1000 or 1500 mg m(-2) d(-1)), thiotepa (40 or 60 mg/m2 twice daily), and carboplatin (267 or 400 mg m(-2) day(-1)) for 4 days, and 16 patients who received an unfractionated mini CTC regimen of cyclophosphamide (3000 mg/m2 at day 1), carboplatin (400 mg/m2 at days 1 and 2), and thiotepa (250 mg/m2 at day 2). Plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined using high-performance liquid chromatography coupled with tandem mass spectrometric detection; plasma concentrations of thiotepa and tepa were determined using gas chromatography. Pharmacokinetics of cyclophosphamide and thiotepa were assessed using nonlinear mixed-effect modeling. The study showed that alteration of a fractionated high-dose regimen into a simplified unfractionated regimen resulted in saturation of thiotepa elimination, with a Vmax of 212 (+/-58) micromol/h and a Km of 13.7 (+/-5.9) microM. This resulted in an increased dose-corrected exposure to thiotepa (13%) and decreased dose-corrected exposure to its metabolite tepa (21%). Elimination of cyclophosphamide was not shown to be saturable. Dose-corrected exposures to cyclophosphamide and its active metabolite 4-hydroxycyclophosphamide were comparable in both regimens. Because the simplified unfractionated mini CTC regimen was more patient-friendly and because overall dose-corrected exposures to cyclophosphamide and thiotepa were not affected to a relevant extent, our data suggest that this unfractionated regimen can be used safely in future studies.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Breast Neoplasms; Chromatography, Gas; Chromatography, High Pressure Liquid; Cyclophosphamide; Expectorants; Female; Forecasting; Humans; Infusions, Intravenous; Male; Mesna; Models, Statistical; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Testicular Neoplasms; Thiotepa

Topics: Antineoplastic Agents, Alkylating; Breast Neoplasms; Combined Modality Therapy; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Recurrence, Local; Phyllodes Tumor; Protective Agents; Remission Induction

A 68-year-old female who had undergone treatment several years previously for breast cancer presented with diplopia and unilateral proptosis and exposure keratopathy related to biopsy-proven rhabdomyosarcoma of the sinus and orbit. Further evaluation revealed multiple metastatic lesions felt to have originated from the primary sinus and orbital tumor. Histopathologic examination showed primitive-appearing rhabdomyosarcoma with some features suggestive of the alveolar subtype. Orbital or sinus rhabdomyosarcoma is seen almost exclusively in the pediatric population, but may very rarely occur in adults. There are several genetic mutations that appear to play a role in both rhabdomyosarcoma and certain breast tumors. There is also increasing evidence that even low doses of radiation may contribute to the future development of cancer, particularly in susceptible individuals. In our patient with atypical demographics for rhabdomyosarcoma, the previous neoplasm and treatment thereof may have predisposed to the development of this rare tumor.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Maxillary Sinus Neoplasms; Mesna; Orbital Neoplasms; Rhabdomyosarcoma

Topics: Adult; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Fatal Outcome; Female; Humans; Ifosfamide; Mesna; Phyllodes Tumor; Tomography, X-Ray Computed

Topics: Breast Neoplasms; Central Nervous System Diseases; Computer-Aided Design; Controlled Clinical Trials as Topic; Drug Design; Drug Interactions; Female; Humans; Mesna; Paclitaxel

We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 85 patients with high-risk stage II/III breast cancer. There were 71 patients with more than nine tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7.5 g m(-2)) and epirubicin (120 mg m(-2)) was given, and PBSC were harvested during G-CSF-supported leucocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose, 12,000 mg m(-2)), carboplatin (900 mg m(-2)) and epirubicin (180 mg m(-2)). Patients were autografted with a median number of 3.7 x 10(6) CD34+ cells kg(-1) (range, 1.9-26.5 x 10(6)) resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-one patients relapsed between 3 and 30 months following the last cycle of high-dose therapy (median, 11 months). The probability of disease-free and overall survival at 4 years were 60% and 83%, respectively. According to a multivariate analysis, patients with stage II disease had a significantly better probability of disease-free survival (74%) in comparison to patients with stage III disease (36%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (70%) compared to patients with receptor-negative ones (40%). Bone marrow samples collected from 52 patients after high-dose therapy were examined to evaluate the prognostic relevance of isolated tumour cells. The proportion of patients presenting with tumour cell-positive samples did not change in comparison to that observed before high-dose therapy (65% vs 71%), but a decrease in the incidence and concentration of tumour cells was observed over time after high-dose therapy. This finding was true for patients with relapse and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone rec

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Epirubicin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Estrogen; Recombinant Proteins; Tamoxifen; Treatment Outcome

Local control rate for inflammatory breast cancer (IBC) is < 50% with standard chemotherapy-radiotherapy regimen. Nineteen women (age range 40-65, median 50 years) with IBC (18 patients) or with a primary tumour of > 10 cm (one patient) received a novel treatment comprising hyperfractionated radiotherapy (HFRT) sandwiched between two cycles of infusional chemotherapy using vincristine, ifosfamide and epirubicin (VIE). The primary endpoint was local control. VIE was continuously infused for six weeks via a Hickman's line using a Deltec CADD-1 ambulatory pump. Ifosfamide (3 gm/m2) mixed with equi-dose mesna was infused for seven days and alternated every week with an infusion of epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2). HFRT consisted of 1.5 Gy twice daily for 34 frct (51 Gy) followed by a boost of 15 Gy in 10 frct. The total treatment time was less than 22 weeks. Median follow-up was 37 months. Local control rate was 58%. Three patients failed to respond initially and five relapsed in the breast at a median time of 36.8 months. Median overall and disease-free survival was 18 and 25.3 months respectively. Toxicity from VIE was minimal (WHO gd 3 emesis--two patients, gd 3 mucositis--one patient, neutropenic sepsis--three patients). Radiotherapy caused moist desquamation in 17/19 patients. Twenty-four central lines were complicated by seven line infections, three thromboses, and one extravasation. The local control rate of 58% with VIE + HFRT appears similar to reported chemoradiotherapy regimen, although the treatment time of 22 weeks is much shorter than other regimens which take up to 12 months. Toxicity is acceptable. Hickman-related complications need to be reduced. The study is ongoing.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Dose Fractionation, Radiation; Drug Administration Schedule; Epirubicin; Female; Humans; Ifosfamide; Infusion Pumps; Mesna; Neoplasm Staging; Survival Rate; Treatment Outcome; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Marrow Diseases; Breast Neoplasms; Carmustine; Cyclophosphamide; Defective Viruses; DNA, Complementary; DNA, Recombinant; Drug Resistance, Neoplasm; Ethics, Medical; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Interleukin-3; Interleukin-6; Mesna; Middle Aged; Paclitaxel; Pilot Projects; Recombinant Fusion Proteins; Retroviridae; Safety; Thiotepa

Patients with metastatic breast cancer will receive 4-5 cycles of induction chemotherapy on one of the ongoing Medicine Branch protocols. Patients achieving at least a partial response, and who do not have evidence of bone marrow involvement and who do not have metastatic bone disease, will undergo PBSC and bone marrow harvest when hematologic recovery has occurred. Patients who have not achieved a PR, but who are responding to therapy, may be treated with additional cycles of therapy in an attempt to achieve a PR. Such patients will be eligible for transplant if a PR is obtained. 70% of the bone marrow and PBSC will be cryopreserved. The CD34+ subpopulation from the remaining 30% of the bone marrow and PBSC harvest will be obtained using an anti-CD34+ antibody and immunoabsorption column. The bone marrow and peripheral blood CD34 cells will be transduced with a retroviral vector expressing the human MDR-1 cDNA. Patients with positive bone scans or histologic evidence of bone marrow involvement will be excluded from the gene transfer component of the protocol. The MDR-1 transduced CD34 cells will be reinfused along with the non-transduced bone marrow and PBSC into patients following high dose ICE chemotherapy. Serial peripheral blood and bone marrow samples will be obtained to study hematopoietic reconstitution with MDR-1 transduced cells. Patients with residual or progressive disease after ABMT will be treated with taxol or vinblastine. In these relapsed patients, peripheral blood and bone marrow samples will be obtained to study whether chemotherapy amplifies the proportion of hematopoietic cells containing the MDR-1 provirus. We will monitor the nadir blood counts of each patient receiving salvage chemotherapy for evidence of myeloprotection and correlate this data with changes in the mean proviral copy number. Sites of relapsed tumor will be biopsied to test for the presence of the MDR-1 provirus.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Clinical Protocols; Drug Resistance; Etoposide; Genetic Vectors; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Ifosfamide; Informed Consent; Interleukin-3; Interleukin-6; Mesna; Middle Aged; Neoplasm Metastasis; Paclitaxel; Pancytopenia; Recombinant Fusion Proteins; Recombinant Proteins; Retroviridae; Stem Cell Factor; Transplantation, Autologous; Vinblastine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Doxorubicin; ErbB Receptors; Female; Gene Expression; Genes, p53; Humans; Ifosfamide; Mesna; Mutation; Prognosis; Retrospective Studies; Tumor Suppressor Protein p53

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Doxorubicin; ErbB Receptors; Female; Humans; Ifosfamide; Mesna; Neoplasm Recurrence, Local

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Hematopoiesis; Humans; Ifosfamide; Liver Neoplasms; Mesna; Methotrexate; Middle Aged; Risk Factors; Survival Analysis

Four courses of ifosfamide with mesna given by intravenous infusions were combined with bolus doxorubicin in a phase II trial to treat patients with breast cancer. Ifosfamide can deplete intracellular glutathione levels and because doxorubicin resistance may be associated with elevated levels of intracellular glutathione these drugs were combined in an attempt to overcome clinical cytotoxic drug resistance. There were 31 women with poor prognosis advanced breast cancer in the study. Forty-five percent were younger than 40 years old, 68% had visceral dominant disease, 59% had more than two disease sites, and each of the five women tested had increased expression of primary tumor epidermal growth factor receptor. The objective response rate was 71% with manageable toxicity (95% confidence interval, 54% to 85%). The response rate in 22 patients not given prior chemotherapy was 72% and in 9 patients with cancers resistant to previous mitoxantrone monotherapy it was 67%. The high antitumor activity of this combination suggests further exploration of its use in breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Doxorubicin; Drug Evaluation; ErbB Receptors; Female; Humans; Ifosfamide; Mesna; Middle Aged; Survival Rate

In an ongoing phase II trial conducted in advanced breast cancer, we tested a therapy schedule consisting of continuous, 24-h infusion of 5 g/m2 ifosfamide (IFO) in 3 1 dextrose saline with mesna (MSN), repeated every 3 weeks until disease progression. Since September 1988, 16 heavily pretreated patients with advanced disease (11 with visceral lesions) considered refractory to standard chemotherapy (regimens always including cyclophosphamide) have been included. Objective partial remissions were observed in two cases (one in liver and one in soft-tissue and pleural lesions), and disease stabilization for at least 3 months occurred in four cases. No treatment-related death was recorded and tolerance was judged to be excellent (six cases) or acceptable in all instances. The haematological toxicity consisted mainly of transient leucopenia (nadirs evaluated by WHO scale as grade 3 in 43% and grade 4 in 29%), sometimes associated with thrombocytopenia (grade 3 in 7% and grade 4 in 7%). Other side effects included nausea and/or vomiting (grade 3-4 in 33%); worsening of preexisting alopecia (five cases); haemorrhagic cystitis (one case); mild, transient somnolence (two cases); and moderate fluid retention (two cases). We concluded that infusion of 5 g/m2 IFO over 24 h with MSN rescue might represent an acceptable second- or third-line salvage regimen. Close monitoring of haematological and renal function parameters is recommended. A larger number of patients will be treated in a continuation of this study to evaluate the true response rate within narrower confidence limits.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged

The object of the study was to evaluate the effectiveness of ifosfamide/etoposide and mesna therapy in advanced breast cancer. A total of 44 patients with breast cancer were included in the trial. Eligibility criteria included measurable, refractory disease; prior anthracycline therapy (or its contraindication); a life expectancy of at least 3 months; and adequate hepatic, renal, CNS and bone marrow function. All patients were less than or equal to 70 years of age and had a Karnofsky performance status of greater than or equal to 50%. There were 36 evaluable cases. Sites of metastatic disease included bone (19), skin (18), liver (9), lung (14), lymph node (19), and miscellaneous (7). Treatment consisted of 1,500 mg/m2 ifosfamide given i.v. on days 1-5, 120 mg/m2 etoposide given i.v. on days 1-3, and 400 mg i.v. mesna given with and at 4 and 8 h after ifosfamide. Cycles were repeated every 28 days. Initial doses were reduced by 25% or 50% in patients who had previously undergone both chemotherapy and radiotherapy. A median of 4 cycles (range, 2-8) were given. The myelotoxicity was marked: WHO grades 3/4 leukopenia (n = 37), grades 3/4 thrombocytopenia (n = 12), and grades 2/3 anemia (n = 13). Due to myelotoxicity, dose reduction or prolongation of treatment-free intervals was necessary in 28 cases. Alopecia was seen in 35 patients and CNS toxicity, in 8. Partial remission (PR) was obtained in five cases and complete remission (CR), in three. Sites of response included the lung (5), skin (4), lymph node (5), and peritoneum (1). The duration of response was 4 (n = 2) and 8 (n = 1) months for CR and 2 (n = 2), 6 (n = 2), and 10 (n = 1) months for PR. We conclude that the ifosfamide/etoposide and mesna regimen is effective, but its myelotoxicity is treatment-limiting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Etoposide; Female; Humans; Ifosfamide; Mesna; Middle Aged

Thirty-two patients with metastatic breast cancer had previously been treated with chemotherapy (including anthracyclines). They were included in a trial to receive 6 g/m3 ifosfamide, mixed with 6 g/m2 mesna in 1000 ml saline infusion, infused over 4 h. Therapy was repeated every 21 days; the dose was reduced by 50%. Twenty-eight patients could be evaluated. An average of 4.2 cycles (range 2-8) was applied. One patient (4%) showed complete remission. Ten patients (36%) had a partial response. Ten patients (36%) experienced SD and the remaining patients (25%) PD. We conclude that high-dose ifosfamide shows activity in this group of pretreated patients and merits further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged

Thirty-five patients with a median age of 55 years (range, 28 to 68 years) and a median Karnofsky status of 80% (range, 40% to 100%) were treated with ifosfamide (1.5 g/m2 plus mesna), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) intravenously (IV) days 1 and 8 at intervals of 4 weeks. Thirty-four patients had received previous chemotherapy, including anthracyclines in 28 patients. All patients were evaluable for response. A partial remission was achieved in six patients (17%), stable disease in 13 patients (37%), and 16 patients (46%) were unresponsive. Median time to progression was 7 months (range, 4 to 13 months) for partial responders, and 4 months for patients with stable disease. Median survival was 9 months for all patients, 13 months for partial responders, 16 months for no change, and 3 months for progressive disease. Toxicity was tolerable, with myelotoxicity being a dose-limiting factor, mainly in heavily pretreated patients. No treatment-related death occurred. In conclusion, this combination is effective and well tolerated. Ifosfamide is suggested for further evaluation in advanced breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Ifosfamide; Menopause; Mesna; Methotrexate; Middle Aged; Neoplasm Metastasis; Remission Induction; Time Factors

Twenty-six cycles of high-dose ifosfamide + mesna (HD-IFO + M) were applied to seven female patients with advanced breast cancer refractory to prior treatment, using three different durations of continuous infusion (4, 24, and 48 h) every 3 weeks. To evaluate the most tolerable time schedule, the duration of the infusions was changed periodically in each patient. Toxicity was low in general, but continuous infusion of HD-IFO + M over 24 h appeared to be the best tolerated. One partial response lasting 27 weeks was achieved and four patients achieved stable disease lasting from 9 to 12 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged