This report details a Phase I dose-ranging experiment of the use of emetine in patients with a variety of malignant diseases. The data show that emetine can be given intravenously a t 4-day intervals with minimal toxicity. Severe muscle weakness, the most important dose-limiting toxic effect, began a t approximately a 15 mg/kg cumulative dose level and resulted in discontinuance of therapy i n two patients. Of 5 patients who received greater than 10.4 mg/kg, 2 stabilized previously rapidly progressive disease, one had marked reduction in a purulent bloody vaginal discharge, a n d 2 who had received the highest total dose had 50% or greater reduction i n lung tumor size. T h e present data suggest a reasonable regimen t o be 1.5 mg/kg I V weekly for a minimum total dose of 15 nig/kg. Emetine is not myelosuppressive and therefore may be useful i n the patient with poor marrow reserve. Alternatively, it can be used in combination with agents of different toxicities in hope of showing additive effects without additive toxicity.
METINE, AN ALKALOID OF Cephaelis ipe-
A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5-fluorouracil 96-hour continuous infusions with either bolus mitomycin-C or oral methyl-CCNU. Mitomycin-C and methyl-CCNU were administered every eight weeks. The 5 FU-mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl-CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was no significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU-mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU-METHYL-CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl-CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.
The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.
The Southwest Oncology Group (SWOG) in a randomized trial evaluated 5FU infusions in combination with either Mitomycin-C or Methyl-CCNU in patients with disseminated large bowel cancer. A response rate of 18% was noted on the 5FU-Mitomycin limb as compared to 16% on the Methyl-CCNU arm (p = .39). Median survival for all treated patients was 43 weeks on both arms. Myelosuppression was found to be more significant on the Mitomycin-C arm. Regression analysis demonstrated that performance status, sex, and primary site were significant pretreatment characteristics for predicting survival. The response rates associated with this burdensome method of 5FU administration in combination with either Mitomycin-C or Methyl-CCNU appear to offer little advantage over bolus 5FU alone.
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