5-aza-2'-deoxycytidine in advanced or recurrent cancer of the uterine cervix.
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Biomedical subjects
Publications and source records attributed to J Renard.
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Phase II trials of flavone acetic acid have been performed in a total of 87 patients including 17 with advanced breast cancer, 23 with advanced colorectal cancer, 25 with advanced malignant melanoma and 22 with advanced head and neck cancer. Patients with colorectal cancer and melanoma had received no prior chemotherapy; in breast and head and neck cancer patients prior chemotherapy had been given with a median of 5 and 2 drugs respectively. The schedule used was a once-weekly regime, with a dose of 4.8 gms/m2 given as a 1 hour infusion, together with alkalinization (with i.v. sodium bicarbonate) given before and after FAA. Reassessment was performed after 6 weekly doses, although in 23 patients fewer than 6 doses were given, because of early disease progression in 15, and undue toxicity in 5. An additional 3 patients died within 72 hours of having received FAA and, although the precise cause of death in each case was not established, FAA toxicity could not be excluded. Treatment was generally manageable, the major manifestations of toxicity comprising uncomfortable warmth and flushes, nausea, diarrhoea, and visual complaints. Hypotension was also documented in 8 patients. No objective responses were seen in any of the patient sub-groups, although disease-stabilization was seen in 3 patients with breast cancer, 1 patient with advanced colorectal cancer, 2 patients with advanced melanoma and 4 patients with head and neck cancer. Further Phase II studies, using a higher dose of 8.6 gm/m2 over 6 hours once weekly, are currently in progress in Europe.(ABSTRACT TRUNCATED AT 250 WORDS)
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The efficacy of a low-dose regimen of human recombinant interferon-gamma was studied in 40 patients with metastatic or locally advanced renal cell carcinoma. Patients received 100 micrograms/m2/day as an infusion over 4 h. The intention was to find an active but tolerable regimen as a basis for future combination treatments with other cytokines or cytotoxic drugs. Activity of this low-dose schedule had been reported. In the absence of rapid progression, treatment was given for at least 3 months, and in case of stable disease it was continued for prolonged periods in order not to miss late remissions. Toxicity was generally mild, with fever and constitutional symptoms predominating. Therapeutic efficacy was low with only one partial remission. Three patients had stable disease over 6, 9, and 15 months. This low-dose schedule cannot be recommended for the treatment of renal cell cancer.
Spirogermanium was given as a 90 minute infusion to 47 eligible patients with refractory Hodgkin's (9 patients) or non-Hodgkin's lymphoma (38 patients). The schedule was 80 mg/m2 three times a week for the first two weeks and 100 mg/m2, 3 times a week, for the two subsequent weeks. In case of response or stable disease, the treatment was continued with biweekly infusions of 100 mg/m2 until tumor progression. In 64% of cases, three or more combinations had been previously administered; 66% of patients presented an extra-lymphatic spread of disease. Two patients with Hodgkin's disease showed a partial response of 11 and 23 weeks and two patients with non-Hodgkin's lymphoma achieved a complete response of 12 and 24 weeks. Overall, 14 patients showed a tumor progression within the first month of treatment. The main toxicity was neurological, with dizziness and lethargy during the infusion in 50% of cases. Hematologic toxicity was almost absent. Spirogermanium is ineffective in heavily pretreated patients with non-Hodgkin's lymphoma. The confirmed lack of activity in patients with refractory malignant lymphoma and the need of repeated and prolonged infusions definitely discourage the clinical use of the drug.
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Fifty-seven patients with advanced measurable or evaluable colorectal cancer not previously treated with chemotherapy and tumor manifestations from colorectal cancer were treated with tauromustine (TCNU), a new nitrosourea with a therapeutic index against murine tumors better to or equal to that of the established nitrosoureas. The dose was 130 mg/m2 orally q 5 weeks. There were one CR and seven PR, for an overall response rate of 14%. Responding sites included the liver (one CR and two PR), lung (four PR) and lymph nodes (two PR). The median duration of response was 33+ weeks (21+ to 34 weeks). The main dose limiting toxicity was myelosuppression which seemed to be cumulative. Subjectively, the drug was well tolerated although most patients experienced nausea and vomiting for some hours. It is concluded that TCNU is a well tolerated compound with limited, but definite antitumor activity against colorectal cancer and that further studies in this disease could be of interest.
Menogaril was administered to 40 patients with advanced breast cancer who had not received anthracycline drugs previously. The drug was given iv as a 2-hour infusion, repeated every 4 weeks, at doses of 200 mg/m2 and 160 mg/m2 in good-risk and poor-risk patients. The overall response rate was 22% in patients with no prior chemotherapy and 10% in patients previously exposed to chemotherapy. Leukopenia was generally moderate and predictable. Phlebitis and erythema along the vein injected occurred in 34% and 17% of the cases, respectively. Menogaril is an active drug used in the treatment of patients with advanced breast cancer who have not had prior systemic therapy.
Twenty-two patients with advanced testicular cancer received iproplatin at a dose of 180-240 mg/m2 every 4 weeks. All the patients progressed or recurred after chemotherapy including cisplatin. The most severe toxicity was thrombocytopenia with two toxic deaths after a first cycle of 240 and 180 mg/m2 respectively. Nausea and vomiting were almost universal but mild in intensity. One renal failure occurred 6 weeks after the first cycle while the tumor was progressing. No antitumor activity was observed in this heavily pretreated population of patients.
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Data of five phase II clinical trials on iproplatin and carboplatin, conducted by the ECTG, have been pooled in order to evaluate the extent of toxicities of these compounds. One hundred and seventy patients treated with iproplatin and 65 patients treated with carboplatin were evaluable. Most of them (81%) had been previously treated with chemotherapy. Doses ranged from 180 to 300 mg/m2 every 4 weeks for iproplatin, and from 350 to 450 mg/m2 every 5 weeks for carboplatin, according to the initial status of the patient. WHO criteria were used to grade toxic effects. Weekly blood counts were performed, and lowest observed counts were analysed by non-parametric methods. Censored data were analysed by actuarial methods. Thrombocytopenia was the dose-limiting toxicity and was dose related. Leucopenia was less severe. The risk of thrombocytopenia varied largely amongst patients, and could be predicted from the initial platelet count, the initial creatinine level and prior therapy with alkylating agents. The cumulative risk increased with the total dose, but with a decreasing hazard rate, and without additional delay to platelet recovery. Nausea, vomiting and diarrhoea were the most frequently observed non-haematological side-effects, and were more severe with iproplatin than with carboplatin. Peripheral neuropathy was observed in some cases, but could be due to prior treatments. Renal toxicity did not cause major problems. Our results confirm the findings of the phase I trials: thrombocytopenia is dose-limiting for both drugs, and renal side-effects are negligible. The risk model of thrombocytopenia, consistent with Egorin's model for carboplatin, could serve as a basis for dose adjustment. The feasibility of the scheme could be insufficient for prolonged treatment.
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Iproplatin (cis-dichloro-trans dihydroxy-bis-isopropyl-amine platinum [IV]; CHIP) was administered intravenously (IV) at monthly intervals at doses of 300 mg/m2 and 240 mg/m2 to ten previously untreated and 97 previously treated patients with advanced ovarian carcinoma. The overall response rate was 78% among patients with no prior chemotherapy, 42% among patients with prior chemotherapy not including cisplatin, and 22% among patients with prior chemotherapy including cisplatin. Overall response rates to iproplatin were 6.4% and 54% in patients with/without clinical evidence of tumor resistance to cisplatin. Thrombocytopenia was the dose-limiting toxicity, median time to nadir and to recovery being 2 and 4 weeks, respectively. Patients who had received prior chemotherapy regimens for greater than 1 year showed a 10% greater reduction in platelet count (mean platelet nadir +/- SD, 57.5 +/- 49.96 X 10(3)/microL) and a higher incidence of grade 3 to 4 thrombocytopenia after the first cycle than patients who had received prior chemotherapy regimens for less than 1 year (94.7 +/- 65.99 X 10(3)/microL) Moderate to severe vomiting and diarrhea occurred in 84% and 16% of patients pretreated with chemotherapy. Neuropathy (6%) was reported only in patients with prior cisplatin treatment. Mild and reversible renal toxicity was observed in 6% of cases. Iproplatin is an active drug in ovarian cancer; the results achieved in patients previously treated with cisplatin strongly suggest that the two drugs are cross-resistant.
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The Early Clinical Trials Cooperative Group of the EORTC conducted several phase II studies with a pyrimidine analogue of deoxycytidine, 5-aza-2'-deoxycytidine (DAC). The drug was given as three consecutive 1 h i.v. infusions of 75 mg/m2, separated by intervals of 7 h; courses were repeated every 5 weeks. A total of 101 eligible patients were studied: 42 with colo-rectal adenocarcinoma, 27 with squamous cell carcinoma of the head and neck, 18 with malignant melanoma and 14 with renal cell carcinoma. Drug-induced toxicities consisted of moderate myelosuppression, and nausea and vomiting. One single partial remission was seen in a patient with malignant melanoma. DAC given in this dose and schedule is devoid of antitumour activity in adult patients with these refractory types of carcinomas.