mesna and Testicular-Neoplasms

Between 1985 and 1989, 36 consecutive male patients with advanced germ-cell tumors, who had failed to be cured with either the cisplatin, vinblastine, bleomycin (PVB) or the cisplatin, etoposide, bleomycin (PEB) combinations, entered either of two modified salvage therapy regimens consisting of cisplatin, etoposide, and ifosfamide (PEI) or cisplatin, vinblastine and ifosfamide (PVI). All patients had evidence of active disease. Ifosfamide was given at the dosage of 2.5 gr/m2 (with mesna protection) on days 1 and 2; etoposide and cisplatin were given at the dosage of 100 mg/m2 and 40 mg/m2, respectively, on days 3 to 5. In the PVI schedule, vinblastine 6 mg/m2 was given on day 3. Overall, 20 (56%, C.I. 39 to 72) patients entered complete response (CR) or achieved disease-free status (NED) with post-chemotherapy surgery. After a follow-up of 2 to 7 years, 15 patients (42%, C.I. 24 to 58) remain alive and free of disease. None of the 9 patients unresponsive to the first-line therapy and/or with extragonadal primaries entered CR or achieved the NED status, versus 20 (74%, C.I. 58 to 91) of the 27 patients with primary testicular tumors who were responsive to the first-line therapy (p less than 0.001). PEI was used in 20 of these 27 patients, with excellent results (90% CR and 70% continuously NED) independently of primary therapy, PVB or PEB. By contrast, only 2 of the 7 patients treated with PVI following PEB entered CR. Toxicity was not life-threatening. Nine (25%) patients suffered granulocytopenic fever and 3 (8%) required platelet transfusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Etoposide; Follow-Up Studies; Humans; Ifosfamide; Male; Mediastinal Neoplasms; Mesna; Middle Aged; Neoplasms, Germ Cell and Embryonal; Retroperitoneal Neoplasms; Testicular Neoplasms; Vinblastine

Malignant mesothelioma is a highly treatment-resistant neoplasm. This study represents an attempt to define an effective form of systemic therapy.. Twenty-six patients with unresectable diffuse malignant mesothelioma were enrolled in Southwest Oncology Group (SWOG) study 8731 and treated with ifosfamide, 2 g/m2 intravenously for 4 days, and mesna 2 g/m2 intravenously for 5 days, every 3 weeks. Patients were either previously untreated with chemotherapy or had at most one prior systemic treatment.. Two patients, or 8% (95% confidence interval, 1-25%), achieved partial response, with response durations of 4 and 6 months. One additional patient met criteria for tumor size reduction but not duration criteria. Thirteen (50%) patients had stable disease of 4 months' median duration (range, 1-13 months). The median survival of the entire group was 6.5 months. The dose-limiting toxicity was granulocytopenia (11 patients, < or = 250/microliters).. Ifosfamide/mesna has modest activity in malignant mesothelioma. It could be tested using alternate dosage schedules and in combination with other agents in treating this highly resistant neoplasm.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Ifosfamide; Male; Mesna; Mesothelioma; Middle Aged; Peritoneal Neoplasms; Pleural Neoplasms; Remission Induction; Survival Analysis; Testicular Neoplasms

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

To evaluate the activity of two cycles of high-dose ifosfamide, carboplatin, and etoposide (ICE) with autologous hematopoietic progenitor cell support (aHPCS) in patients with poor-prognosis, chemotherapeutically sensitive germ cell cancer.. Twenty patients with germ cell tumor who had persistent disease or relapse from standard-risk or high-risk presentation were entered on this pilot study. The entry criteria included relapsed gonadal and extragonadal germ cell cancer unlikely to be cured by standard salvage therapy but without proven refractoriness to chemotherapy. Treatment consisted of two cycles of ICE chemotherapy with mesna uroprotection and aHPCS. On the first cycle, ifosfamide (IFX), 2 gm/m2; carboplatin, 400 mg/m2; and etoposide, 20 mg/kg, were administered on days -6, -5, and -4. On the second cycle, the doses and schedule of carboplatin and etoposide were identical, and patients with normal renal function received additional IFX, 2 g/m2 on day -3 and 1 g/ m2 on day -2. Mesna, 600 mg/m2 every 6 hours, was given until 24 hours following the final dose of IFX on each cycle, and autologous bone marrow and/or peripheral stem-cells were infused on day 0.. All twenty patients are assessable for toxicity and current disease status. Two patients received only one cycle of therapy, one because of the development of active hepatitis C following cycle 1, and one because of renal insufficiency. No patient died as a result of protocol therapy, and no patient developed debilitating peripheral neuropathy, symptomatic hearing loss, or severe renal insufficiency requiring dialysis. The median time to recovery of > or = 500 neutrophils/microL and platelets > or = 50,000/microL was day +11 and day +15, respectively. The median maximum creatinine was 1.6 mg/dL on each treatment cycle, and there was no other significant organ toxicity. With a median follow-up of 45 months, nine patients are alive and disease-free following protocol chemotherapy. One patient with embryonal cancer developed progressive pulmonary metastases 3 months after completing high-dose therapy, underwent complete resection of lung metastases, and remains disease-free at 63+ months. Eight patients are continuously disease free at 23+ to 70+ months after protocol therapy. Eleven patients died of progressive disease between 4 and 23 months following completion of treatment.. These results compare favorably to other studies in similarly selected patients undergoing salvage therapy with one or two cycles of chemotherapy containing high-dose carboplatin and etoposide with or without cyclophosphamide (CTX) or IFX. The excellent safety and tolerability profile of this regimen and its encouraging activity in poor-prognosis patients make it worthy of further study as part of initial therapy in randomized protocols for high-risk disease and early in the treatment of relapsed germ cell cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Etoposide; Female; Follow-Up Studies; Germinoma; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Mediastinal Neoplasms; Mesna; Middle Aged; Ovarian Neoplasms; Pilot Projects; Retroperitoneal Neoplasms; Testicular Neoplasms

Ifosfamide is clinically used in combination chemotherapy regimens for the treatment of patients with high-grade lymphomas, sarcomas and metastatic germ cell tumours. In order to reduce the oxazophosphorine-related urothelial toxicity, sodium mercaptoethane sulphonate (mesna) is used in different schedules following the administration of ifosfamide. The proposed mechanism of mesna activity is the binding of toxic oxazaphosphorine metabolites such as acrolein in the urine of the patients. Since an influence of mesna on ifosfamide anti-tumour activity is controversial, the current study has used xenografts from two human testicular cancer cell lines heterotransplanted into nude mice to study the anti-tumour activity of ifosfamide in combination with different dosages and schedules of mesna. In both human testicular cancer cell lines, H 12.1 and 2102 EP, ifosfamide demonstrated anti-tumour activity as a single agent. No reduction in ifosfamide activity was observed with the application of mesna at a dose range from 50% to 200% of the ifosfamide dose. Furthermore, the application of mesna before and 3 h after ifosfamide, a schedule used in many clinical protocols because of the short half life of mesna, not only maintained high ifosfamide anti-tumour activity but also seemed to be associated with the lower systemic and urothelial toxicity of ifosfamide therapy compared with ifosfamide given alone. In conclusion, the experimental in vivo system using human heterotransplanted testicular cancer cell lines confirms the significant anti-tumour activity of ifosfamide in malignant germ cell tumours and demonstrates that mesna does not impair ifosfamide anti-tumour activity in this model. These results are most likely transferable to the use of mesna in patients with metastatic testicular cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Screening Assays, Antitumor; Humans; Ifosfamide; Male; Mesna; Mice; Mice, Nude; Neoplasm Transplantation; Testicular Neoplasms; Tumor Cells, Cultured

Fifty patients with histologically confirmed advanced malignancies were treated with ifosfamide and mesna plus other cytostatics. The other cytostatic drugs added to the treatment regimen were cisplatin (36 pts), etoposide (31 pts) and doxorubicin (20 pts). Among previously untreated patients objective response was documented in 12 of 19 pts with ovarian cancer, 9 of 14 with small cell cancer of the lung and in all 3 pts with Ewing's sarcoma. Among patients with disease refractory to prior cytostatic treatment, objective response was documented in 8 of 9 with testicular cancer, 1 of 3 with high grade lymphoma and 0 of 2 with osteosarcoma. Side-effects due to the combination of ifosfamide plus mesna and other cytostatics were acceptable. No life-threatening or lethal toxicities occurred. Most commonly encountered toxicities were leukopenia (64%), nausea and vomiting (84%), alopecia (63%), CNS toxicity (30%) and renal toxicity (12%).

Topics: Adolescent; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Etoposide; Female; Humans; Ifosfamide; Leukopenia; Lung Neoplasms; Male; Mesna; Middle Aged; Nausea; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Vomiting

Topics: Antineoplastic Combined Chemotherapy Protocols; Cystitis; Hemorrhage; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms

Twenty-one patients with refractory germ cell tumors were treated with a chemotherapy regimen containing etoposide (VP-16) (V) 75 mg/m2/day (days 1 to 5), ifosfamide (I) 3 g/m2/day (days 1 and 2) with a 3.6 g/m2 continuous infusion of mesna (days 1 and 2), and high-dose cisplatin (hP) 40 mg/m2/day (days 1 to 5). The regimen is referred to as VIhP. Nineteen patients were evaluable for response. Five patients (26%) achieved a complete remission (CR) with chemotherapy alone, and three patients (16%) were in CR after resection of a residual nonactive tumoral mass (e.g., necrosis and/or fibrosis and/or mature teratoma). Thus, a CR rate of 42% was achieved with the entire treatment. One additional patient achieved a CR after resection of active, bulky disease. Among the responders, five patients (26%) are still alive and disease-free at 6, 7, 9, 10, and 18 months after the initiation of the chemotherapy. However, toxicity was heavy in this protocol. Severe myelosuppression was observed with 10 patients developing aplasia and six patients documented sepsis. Reversible Grade 1-2 renal toxicity occurred in 14 patients, and Grade 2-3 peripheral neurotoxicity occurred in six patients. No hemorrhagic cystitis was encountered. We conclude that a VIhP regimen seems to play an active role in refractory germ cell tumors although the presence of high-dose cisplatin in this regimen does not appear to improve the response rate compared to that of a conventional dose. Toxicity, which seems to be enhanced, is currently under detailed study. However, the contribution of VIhP as a first-line treatment in poor prognosis, advanced germ cell tumors warrants further study.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Cisplatin; Etoposide; Evaluation Studies as Topic; Humans; Ifosfamide; Kidney Diseases; Leukopenia; Male; Mesna; Mesonephroma; Nausea; Sepsis; Teratoma; Testicular Neoplasms

Topics: Adult; Aged; Carcinoma, Bronchogenic; Female; Hematuria; Humans; Ifosfamide; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Mercaptoethanol; Mesna; Middle Aged; Neoplasms; Ovarian Neoplasms; Testicular Neoplasms

In a clinical phase II study 151 patients with refractory malignant diseases were treated with ifosfamide (60 mg/kg/day i.v. days 1-5, q 21-28 days). Altogether, 490 courses of treatment were given, 92 with conventional prophylactic measures (continuous infusion of 3-4 litre physiological saline plus alkalinization of the urine) and 398 with mesna prophylaxis (12 mg/kg i.v., 0, 4 and 8 h after administration of ifosfamide). The overall response rate (min. 25% tumor reduction) was 67/151 (44%) including four complete remissions in a fairly unfavourable patient group with testicular teratoma (39/87), soft tissue sarcoma (10/16), malignant melanoma (2/7), osteogenic sarcoma (3/6), Ewing's sarcoma (2/6), lymphoma and acute leukemia (5/7) or other histologies (6/22). The response rate in patients pretreated by cyclophosphamide containing regimen was 7/19 (36%) including one complete remission and one partial remission. Mesna was highly effective in reducing the frequency of hemorrhagic cystitis from 25/92 (27%) to 16/398 (4%) ifosfamide courses. The antitumor activity of ifosfamide in testicular cancer was not reduced by mesna. In conclusion, ifosfamide with the potent uroprotector mesna appears to compare favourably with the most active agents in the treatment of malignant diseases.

Topics: Cyclophosphamide; Drug Evaluation; Drug Interactions; Female; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasms; Testicular Neoplasms; Urinary Tract

In an open multicenter phase III trial, prophylaxis of the urinary tract with sodium 2-mercaptoethanesulfonate (Mesnum) was carried out in 242 patients treated with oxazaphosphorines for various malignant tumors. Under the protection of Mesnum 29 patients were treated with cyclophosphamide (Endoxan), 195 with ifosfamide (Holoxan) and 8 with trofosfamide (Ixoten). Other cytostatics were also used (polychemotherapy) in 92 cases. On administration of Mesnum, 7 macrohematurias reappeared, only 3 of them however with correct application, and 22 microhematurias, 12 of them with correct application. Cylindrurias were re-established in 3 patients. In Mesnum we have a compound which can control the urotoxicity ("uroprotector") of oxazaphosphorines which limits their therapeutic use.

Topics: Adolescent; Adult; Aged; Bronchial Neoplasms; Child; Cyclophosphamide; Female; Gastrointestinal Diseases; Hematuria; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Ovarian Neoplasms; Phosphoramide Mustards; Testicular Neoplasms