Phase II study of cystemustine in advanced renal cancer.
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Biomedical subjects
Publications and source records attributed to J Chauvergne.
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Sixty patients with advanced carcinoma of the cervix were treated with 3-week cycles of chemotherapy consisting of bleomycin (10 mg/m2, D1, 2, 3), mitomycin (10 mg/m2, D1), cisplatin (80 mg/m2, D3), etoposide (100 mg/m2, D1, 2, 3). Twenty-six patients had prior therapy. Toxicities noted were primarily nausea, vomiting, asthenia, fever and myelosuppression, especially in the pre-treated patients. One patient died of pulmonary toxicity. Of the 34 untreated patients, 25 objective responses (74%) were observed, with two complete responses (6%) and among the 26 pre-treated patients, ten objective responses (39%) with only one complete response. The mean duration of response was 3.8 months [2-14]. These data indicate that combination chemotherapy regimen is active against advanced and recurrent cervical cancer but caution is required for administration and continuation of treatment after four cycles. This method of chemotherapy has significant potential for primary treatment in patients with locally advanced disease.
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From 1975 to 1988, 144 patients naive of treatment, with non-metastatic soft tissue sarcoma were treated at Fondation Bergonié by surgery, followed by radiotherapy and without chemotherapy. An analysis of prognostic variables was done on this population to determine patients for whom an adjuvant chemotherapy would be relevant. Prognostic variables in overall survival (OS), metastasis-free survival (MFS), disease-free and local free recurrence survivals were analysed by univariate and multivariate analysis. In multivariate analysis using Cox's model, only tumour depth and tumour grade were significant with the MFS end point, while tumour depth, tumour grade and tumour site were significant when considering OS. A predictive stratification for patients is proposed: a favourable prognostic group with grade 1 tumour or superficial, grade 2 tumour (5-year OS: 97.8%; 5-year MFS: 100%); an intermediate prognostic group with deep, grade 2 tumour or superficial, grade 3 tumour (5-year OS: 58.8%; 5-year MFS: 48.1%); and finally a poor prognostic group with deep, grade 3 tumour (5-year OS: 31.7%; 5-year MFS: 34.1%). Patients in the intermediate and poor prognostic groups who present a high metastatic risk are to be considered for adjuvant chemotherapy trials.
From January 1985 to December 1987, 228 women with breast cancer smaller than 3 cm were treated by surgery +/- radiotherapy. All of them had axillary node involvement (N+) and/or lacked estrogen and progesterone steroid receptors (EPR-). They were randomized in an adjuvant chemotherapy trial comparing 9 intravenous CMF courses (cyclophosphamide, methotrexate, 5FU)--113 patients--to a polychemotherapy consisting of 3 courses of MTV (mitomycin C, thiotepa, vindesine) plus 3 courses of EVM (epirubicin, vincristine, methotrexate)--115 patients. Prognostic factors were well balanced between the two treatment groups. With a 59-month median follow-up, local breast relapses are more frequent in the CMF group, but regional and metastatic recurrences are the same in the two groups. Overall survival is identical. Toxicity is different: alopecia and neurotoxicity are more frequent in the MTV+EVM group, but general and digestive toxicities are equivalent. Haematologic toxicity is greater in the CMF group, requiring more frequent dosage reductions.
One hundred and thirteen patients with advanced squamous cell cancer of the head and neck were entered into a multicenter trial. Median age was 54 yr (range: 33-74 yr). Median Karnofsky index was 70 (60-100). Thirty-five patients had had prior induction chemotherapy. The first schedule was carboplatin 300 mg/m2, dl and fluoro-uracil 1000 mg/m2/d administered in continuous IV infusion for 96 h every 4 weeks (group 1). The second schedule was carboplatin 350 mg/m2, dl and fluoro-uracil administered at the same dose every 3 weeks (group II). Median number of cycles was 3 (range: 1-16). Seven patients were not eligible. The response rate was 26% (95% confidence limits: 18-34). Nine patients had a complete response. The median duration of response was 6 months (2-16+). The response rates in the 2 groups were not statistically different (21 and 31%) but disease progression was more frequent in group I (61%) than in group II patients (25%). Six early deaths occurred, without sign of drug toxicity. Grade 2 hematological toxicity between or before any cycle was more frequent in group II patients, in particular for leucopenia (13 vs 42%, P less than 0.05). One death was related to granulopenia. Grade 2 or 3 gastric toxicity was observed in 43 patients. No other major toxicity was observed. In our study, combination therapy with carboplatin and fluoro-uracil was found to be moderately active but myelotoxic.
Thirty patients with advanced breast cancer, previously treated with anthracycline and 5 fluorouracil in bolus administration, were evaluated with a chemotherapy regimen generally used in head and neck cancer. Treatment schedule consisted of: cisplatin 100 mg/m2 on d 1 and 5 fluorouracil 1000 mg/m2 continuous infusion on d 2-3-4-5 every 21 d. With all measurable lesions and 27 evaluable patients, the response rate was 29% (95% confidence interval: 12-47%), with 5 complete responses (3 soft tissue - 2 lung) and 3 partial responses (1 lung - 2 liver). The median duration of response is 4.5 months (range 2-11 months). The 30 patients (93 courses) are evaluable for toxicity. Hematologic toxicity was mild: anemia 68% grade 0, neutropenia 68% grade 0 and thrombocytopenia 83% grade 0. Nausea and vomiting were severe 83% grade 3 + 4 at d 1. Others side effects were mild including 5/91 mucositis grade 2 + 3, peripheral neuropathy 1/31 grade 2 and 2/91 reversible rise in serum creatinine greater than 1.5 mg/dl.
From 1982 to 1987, a randomized phase III trial was performed in order to determine the long-term effect of induction chemotherapy before standard pelvic irradiation in stage IIb-N1, III squamous cell carcinomas of the cervix. Patients were randomized to either chemotherapy and radiotherapy (C + R group) vs radiotherapy alone (R group). Radiotherapy for all patients consisted of 50 Gy in the pelvis with a boost by external irradiation or by brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen was an association of methotrexate (10 mg/m2, D2-4), chlorambucil (4 mg/m2, D1-5), vincristine (0,7 mg/m2, D1), cisplatin (80 mg/m2, D5), given every 3 wks; at least 2 courses were to be given before assessing efficacy and 2 more courses were given to patients who responded. One hundred and fifty-one patients were fully evaluable, after a mean follow-up of 38 mths (range 2-7 years), 76 in the R arm and 75 in the C + R arm. The response rate (greater than 50%) to chemotherapy was 42.5%. After completion of treatment, the complete response rate was 86.8% in the R arm and 86.3% in the C + R arm. The 3 year disease-free survival was 58.7% in the C + R group and 54.5% in the R group, and the median survival was 39.5% and 47 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group (when chemotherapy had been active) than in the R group (p = 0.04). Although radiotherapy was not modified whether patients had initial chemotherapy or not, tolerance was not significantly different between the 2 groups. The data collected in this study indicate that: 1) efficacy of induction chemotherapy is the only available predictive test for long-term results, 2) tolerance to treatment is crucial for optimal chemotherapy delivery, 3) higher dose intensity of chemotherapy in cervical carcinoma is associated with a better tumor reduction, and probably a better survival.
A series of thirty consecutive epithelial ovarian cancer patients were reviewed after long-term follow-up (more than 5 y) since their second-look operation (SLO). All patients had advanced tumors (stages IIb-IV). Primary chemotherapy consisted of a cisplatin-associated regimen. For all patients adjuvant treatment had been planned after completion of the SLO. Mean follow-up after SLO was 68 months (47-103 months). Tumor status at SLO divided the patients in 2 subgroups: Group A = 13 patients (43%), with no evidence of histologically proved disease at time of operation (NED); Group B = 17 patients (57%), with macroscopic persistence of tumor. Survival was significantly better in the first group than in the second (77% at 5 yr vs less than 25%). Recurrence rate in the NED group was 7.7% (1 recurrence at 32 months). Eight of 17 patients with gross tumor at SLO underwent satisfactory resection. However, recurrence rate was high (75%) and survival rate was low (25% at 5 yrs). This result was not significantly better than that of patients with no optimal resection at SLO (9 patients, survival 22%). Second effort resection at SLO does not seem to be beneficial in these patients after partial failure of initial chemotherapy with cisplatin. The usefulness of systematic second look operations is discussed. Controlled randomized trials should be made to determine the exact role of SLO in ovarian cancer treatment.
The authors present a series of 10 pure dysgerminoma of the ovary treated between 1976 and 1984; mean age = 19.5 years, range 15-46 years. All patients had initial surgery: 8 annexectomies for 5 stages Ia and 3 stages IIIc nodal disease, 1 hysterectomy with bilateral adnexectomy for a 46 year old stade Ib patient and 1 case of salvage surgery for a progressive disease after a single adnexectomy. Two patients had no adjuvant therapy after initial adnexectomy (stage Ia tumors less than 10 cm in diameter). Four patients received a prophylactic subdiaphragmatic radiation therapy (3 stages Ia tumors larger than 10 cm, 1 stage Ib disease). Three patients received an irradiation for a subdiaphragmatic bulky disease and a prophylactic supradiaphragmatic irradiation (stage IIIc nodal disease). Two patients received chemotherapy, one for recurrence, the other for progressive disease. The authors discuss the therapeutic indications of pure dysgerminoma of the ovary, especially the conservative management of young patients wishing to preserve an hormonal and obstetric future and the value of radiologic and serologic follow-up. Recent data in the literature underline the efficacy of new combinations of cytotoxic agents and their role as an adjuvant of surgery in early as well as in advanced stages.
Fifty patients with advanced breast cancer (21 undergoing first and second stage palliative treatment: group 1, and 29 undergoing stage three or more: group 2), were included in a phase II trial with administration of a combination relay chemotherapy consisting of cisplatin (100 mg/m2/day) and fluorouracil (1,000 mg/m2/day), in continuous perfusion during 4 days, in cycles of five days repeated every three weeks (mean duration: 12 weeks). Toxicity was frequent and severe (a total of 17 treatments discontinued, and five deaths, 3 in group 1, 2 in group 2). The main manifestations of intolerance were threefold: haematological and leucopenia, in almost half of the patients, including 2 severe with 1 case of infectious complication and 4 thrombopenias requiring discontinuation of the treatment, including 2 with a severe haemorrhagic syndrome; cardiovascular, with three deaths due to heart failure; renal, most of the time laboratory tests disorders with 1 clinical syndrome. An objective response of more than fifty p. cent was obtained in five patients in group 1 (29.4%) and 3 patients in group 2 (11.1%); it lasted an average of 6.5 months and varied according to the locations: nodes (43%), liver (40%), pleuro-pulmonary (22%). Responses were obtained (13%) for lesions which resisted to previous chemotherapy. Five patients (14%) presented a functional improvement. The survival (mean = 4.8 months) was correlated, in group 1, to initial life conditions (p = 0.01) and was longer in group 1 for menopausal patients who had well tolerated the treatment (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
From 1972 to 1976, 95 patients with clinical stages I-IIIA Hodgkin's disease were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) before and after extended field radiotherapy. The CVPP schedule gave: (1) a constant drug dosage for each patient independent of body surface or weight; and (2) a total drug dosage dependent on haematological tolerance, since the treatment was given for 21 days or until the leukocyte count dropped to 2 x 10(9) l-1. The drug dosage per unit body surface (or 'dose density') significantly correlates with the drop in leukocyte count (P less than 0.001) and the tumour regression at the end of the induction course (P = 0.020). Disease-free survival is significantly related to dose density (P = 0.050) but not to dose intensity calculated on the duration of treatment (P = 0.240). However, after exclusion of three marginal recurrences due to border-line radiotherapy, the dose intensity significantly correlates with the disease-free survival (P = 0.031) and with the duration of complete remission (r = 0.870).
Chemotherapy of epidermoid bronchial cancer maintains, despite numerous therapeutic trails, a minimal efficacy and is shown to have no important effect on the duration of survival. Conversely, the immediate results obtained by chemotherapy for small cell carcinoma are remarkable particularly for the localised forms; there are numerous active drugs which can be usefully combined with radiotherapy to increase the level of complete remission and to attempt to influence the eventual outcome which remains unfavourable. However, this chemotherapy should benefit from the multiple research programmes which are currently underway to reinforce the effects of chemotherapy (new combinations of effective cytotoxic drugs, and the potential for changing biological responses) and to improve the techniques of application (for example, continuous infusions and chronomodulation). The intensification of chemotherapy (with or without the use of marrow transplants) seems to constitute, by the reduction of tumour mass that is induced, a factor determining the improvement in long-term results but is still limited only to small cell carcinomas.
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From 1982 to 1985, 279 patients with locally advanced breast cancer have been treated with induction chemotherapy, adjusted loco-regional treatment (surgery and/or radiotherapy) and adjuvant chemotherapy with or without immunostimulation. Overall and relapse free survivals are better for tumors with estrogen and progesterone receptors (EPR). For these patients, we may hope that tumoral reduction with hormonotherapy would get the same overall and relapse-free survivals as induction chemotherapy.