Further experience with isophosphamide.
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Biomedical subjects
Publications and source records attributed to G Falkson.
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Dibromodulcitol was administered orally on Days 1-10 every 3-4 weeks to 29 patients with metastatic breast carcinoma refractory to previous combination chemotherapy. Initial doses between 70 and 280 mg/m2/day were utilized. The dose was escalated as tolerated in subsequent cycles in individual patients. Hematosuppression was dose-limiting. At doses of greater than 200 mg/m2/day leukopenia (greater than 1000 cells/mm3) and thrombocytopenia (greater than 25,000 platelets/mm3) occurred in one of 28 cycles and two of 27 cycles respectively. In contrast, at doses of less than or equal to 200 mg/m2/day leukopenia and thrombocytopenia occurred in four of 18 cycles and five of 18 cycles respectively. Recovery of leukocytes (less than 4000 cells/mm3) and platelets (less than 100,000 platelets/mm3) by Day 29 after the start of therapy was also delayed at higher doses. Responses were observed in three of 29 evaluable patients and subjective improvement of osseous disease in one additional patient. A dose of 180 mg/m2/day X 10 Every 28 days is recommended in previously treated patients to avoid severe hematologic side effects.
Thirty women with histologically proven advanced ovarian or breast cancer were treated with cytembena. Of nine patients with ovarian cancer and 21 with breast cancer none had worthwhile objective remissions. Cytembena was given at a dose of 250 mg/m2/day for a course of 5 days repeated at weekly intervals. Improvement, particularly relief of pain from skeletal metastases, was observed in 16 of the patients; an additional seven patients had stable disease while treated with cytembena. Cytembena has no hemopoietic toxicity, but nausea and vomiting and an "autonomic storm" phenomenon are dose-limiting factors. Further studies incorporating this drug in combination regimens seem warranted.
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Advanced Hodgkin's disease was considered incurable until 1966. The development of combined chemotherapy has led to intensIVe treatment and to cures. Results obtained in 104 patients treated according to acute leukaemia group B protocols are discussed. Staging according to the Rye classification was used, as these patients were treated from 1966 to 1971. Methodology and dosage schemes are discussed. Reponse rates reached 88%, with extended survival. The modifications of therapeutic schedules which led to long-term, unmaintained remissions, are explained. The 5-year survival rate of patients with Hodgkin's disease in stages III and iv who responded, was 82,7%. The effect of histological subclassification on the prognosis is considered. The importance of accurate documentation is stressed, and also the use of laparotomy to prove the staging of the disease so as not to deny the patient the benefit of potential cure with chemotherapy.
One hundred twenty patients with inoperable metastatic malignant melanoma were randomly allocated to treatment with either a combination of BCNU 150 mg/m2 and vincristine 2 mg/m2 given every 30 days, or one of two regimens of DTIC: 300 mg/m2/day x 6 or 100 mg/m2/8 hours x 18 given every 30 days. Eight of the 51 (16%) patients who were originally treated with the BCNU and vincristine combination had 50% or more objective tumor regression, compared to 6 out of 25 (24%) patients treated with daily injections of DTIC, and 6 out of 21 (29%) patients treated with DTIC injections every 8 hours. The median duration of response to the BCNU and vincristine combination was 60 days, and the median duration of survival from initiation of treatment was 6.5 months in the responders and 3.3 months in the nonresponders. The median duration of response was 90 and 100 days for the daily and 8-hour regimens of DTIC respectively, andthe median duration of survival from commencement of treatment was 8.5 months for the responders and 3.5 months for the nonresponders. None of the 43 patients who failed to respond to the initial treatment program or whose disease progressed after initial improvement responded to the alternate treatment regimen.
A clinical trial of the oral form of VP 16-213 (NSC-141540), a semisynthetic podophyllotoxin, was undertaken. In 20 patients, treatment was started at 200 mg/day p.o. for 5 days; courses were repeated after a rest period of 16 days. Five patients were treated at the same dose, repeated with only 9-day rest periods. Subsequently, 65 patients were given 300-400 mg/day for 5 days, with rest periods of 9 days between courses. The side effects encountered included anorexia, nausea and vomiting, stomatitis, diarrhea, leukopenia, thrombocytopenia, alopecia, and pruritus. Substernal discomfort with or without palpitations was reported by 18 patients; no explanation for this symptom could be found. No complete remissions (CR) were observed. Parital remissions (PR) and improvement (IMP) were seen as follows: small cell carcinoma, lung (10 patients)--2 PR, 3 IMP; adenocarcinoma, lung (4 patients)--1 PR; alveolar cell carcinoma, lung (1 patient)--1 IMP; mesothelioma (4 patients)--1 IMP; ovarian cancer (12 patients)--3 PR, 3 IMP; breast cancer (20 patients)--4 IMP; colon cancer (8 patients)--2 IMP; bladder cancer (4 patients)--2 IMP; histiocytic lymphoma (7 patients)--2 PR, 3 IMP; chronic myeloid leukemia (1 patient)--1 IMP.
Only a limited percentage of patients with metastatic malignant melanoma respond to single-agent chemotherapy. Vincristine, procarbazine, imidazole carboxamide dimethyl triazeno (DTIC) and bis-chloroethyl-nitrosourea (BCNU) have been used as single agents by various investigators. A response rate of +/- 20% was seen with vincristine (1-3) and BCNU (3, 4), and a response rate of 20-30% has been observed with DTIC (3, 5-8) and procarbazine (3, 9, 10). Newer agents such as triazeno imidazole carboxamide mustard (TIC mustard) (11), chloroethyl cyclohexyl nitrosourea (CCNU) (12), and chloroethyl methylcyclohexyl nitrosourea (methyl-CCNU) (13) have not so far proved superior. During the last years various drug combinations have been tried in an effort to improve the results of treatment in patients with metastatic malignant melanoma. In 1959 Moon reported objective response in 9 out of 20 patients who received a minimum of two courses of a combination of BCNU and vincristine (14). In a randomized trial performed by Acute Leukemia Group B (15), only 24% responded to this combination as compared to 32% and 29% for two different DTIC schedules. There were 120 patients who entered onto this protocol. A combination of DTIC plus cyclophosphamide plus vincristine was reported to give a 25% response (16). Workers at the Mayo Clinic reported objective response in 4 out of 18 patients treated with a combination of DTIC plus vincristine as compared to 1 out of 19 using CCNU (12). Costanza and co-workers (Eastern Co-Operative Oncology Group study) reported that 12 out of 61 patients responded to treatment with DTIC plus BCNU as compared to 9 out of 51 on DTIC alone (17); while Cohen (18) and co-workers reported that 10 out of 16 patients treated with the triple combination of vincristine plus BCNU plus DTIC showed significant response and concluded that this combined approach in the treatment of disseminated malignant melanoma warranted further study. Preliminary analysis of an Eastern Co-Operative Oncology Group protocol showed no statistical advantage of DTIC plus methyl-CCNU over each drug on its own (19). The present study was undertaken to investigate the possible advantage of combining DTIC plus vincristine plus BCNU plus procarbazine in courses of treatment. All of these agents are of some value on their own and all four have possible different mechanisms of action.
A study was designed to evaluate the effectiveness of prednisone therapy in poor-risk patients with multiple myeloma. Patients were treated with melphalan alone or in combination with prednisone at doses of either 0.6 mg/kg or 0.3 mg/kg. The group of patients receiving melphalan and prednisone 0.6 mg/kg had significantly improved responses in hemoglobin, lowering of the M-protein concentration, and reduction of azotemia. Significant benefits attributable to prednisone were not demonstrated in the group receiving 0.3 mg/kg. Good responses have been shown to produce improved survival. The combination of melphalan and prednisone is effective in producing good responses, but the dose of steroids is important. A dose of prednisone of 0.6 mg/kg in gradually decreasing doses has been found to be effective in production of good responses, especially in the uremic patient.
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