Randomized study for the treatment of adult advanced Hodgkin's disease: mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) versus lomustine, vinblastine, and prednisone.

Forty-seven patients with advanced Hodgkin's disease were entered in a prospective, randomized trial comparing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) with a regimen containing lomustine (CCNU), vinblastine, and prednisone (CCNU-VP). Both groups were comparable for the variables of age, stage, substage (symptoms), histology, prior radiation, and sites of involvement. Seventy-two percent of CCNU-VP-treated patients achieved a pathologically documented complete remission (CR) compared to 41% of the MOPP-treated group. Two additional patients treated with MOPP had remission documented only clinically but have been long-term, disease-free survivors. There was a greater frequency of CR in the patients who had received previous irradiation when compared to patients with no prior irradiation. After a median follow-up of greater than 89 months, there is no statistical difference between the two treatment groups in survival (45% for MOPP and 60% for CCNU-VP). Further, no statistical difference in survival for the two treatment groups was noted when compared by histology, stage, or symptoms. The CCNU-VP combination was better tolerated with significantly less nausea and emesis. The alternative drug regimen of CCNU-VP appears to be as effective as MOPP in producing CR and long-term survival in patients with advanced Hodgkin's disease.

Significance of relapse after adjuvant treatment with combination chemotherapy or 5-fluorouracil alone in high-risk breast cancer. A Western Cancer Study Group Project.

Beginning in 1974, patients undergoing mastectomy at high risk for recurrence (greater than or equal to 4 nodes positive; median, 9.4 positive; range, 4 to 28) were randomized after stratification for menopausal status and radiotherapy to receive either 5-fluorouracil (5-FU, 500 mg/sq m i.v. every week) or cyclophosphamide, 400 mg/sq m; methotrexate, 30 mg/sq m; and 5-FU, 500 mg/sq m (CMF; all given i.v. every 2 weeks) in a 12-month program. All 62 patients remain evaluable with median follow-up now exceeding 70 months (range, 60 to 80 months). CMF significantly prevented early disease recurrence (97% relapse free on CMF versus 75% on 5-FU at 12 months; p less than 0.05) and demonstrated survival advantage during the initial 40-month follow-up. This significance was subsequently lost, and the percentages of relapse free and overall survival after 70 months are: (formula, see text) The apparently paradoxical relationship between relapse and survival on the 5-FU arm was related to survival after recurrence. Survival after recurrence was significantly longer on the 5-FU compared to the CMF arm (median of greater than 38 versus 10 months, respectively; p less than 0.01). These results suggest (a) long-term survival in adjuvant trials cannot be accurately predicted by short-term differences in relapse frequency, (b) survival after relapse may be influenced by the antecedent adjuvant therapy received, and (c) disease relapse does not necessarily preclude long-term survival.

Adriamycin and methyl-CCNU combination therapy in hepatocellular carcinoma: clinical and pharmacokinetic aspects.

Twenty-one patients with unresectable hepatocellular carcinoma (hepatoma) were treated with adriamycin (15-45 mg/m2 q21 D) and methyl-CCNU (75-150 mg/m2 q 63 D) with dosage adjusted for hepatic dysfunction. Objective response frequency was 14% with all responses occurring in patients with normal pretreatment bilirubin levels. Median survival of all patients was 87 days. Initial bilirubin levels greater than 2 mg/dl predicted for decreased survival (median 30 days vs. 115 days, P less than 0.05). Only moderate hematologic toxicity was observed. Plasma profiles of Adriamycin and adriamycinol were determined during 11 courses of Adriamycin administration in seven of these patients. Despite moderately elevated transaminase levels (all cases) and bilirubin levels (three cases), plasma Adriamycin profiles in hepatoma patients were not elevated (terminal half-life of 30 hours) and were indistinguishable from that of non-hepatoma patients with normal liver functions. However, delayed appearance of peak levels and prolongation of terminal half-lives were routinely observed for adriamycinol, a major metabolite of Adriamycin. This resulted ina significant increase in the CXT (concentration X time) ratio of adriamycinol/Adriamycin in hepatoma patients compared with nonhepatoma patients (2.36 +/- 2.12 vs 0.76 +/- 0.31, (P less than 0.05). We conclude that the combination of relatively mild toxicity and normal Adriamycin disposition indicates unusual tolerance to Adriamycin therapy for patients with hepatoma and cirrhosis. As a result, severe dosage adjustments of Adriamycin may not be indicated for all such patients having only moderate hepatic dysfunction.

Factors influencing the interim interpretation of a breast cancer trial: danger of achieving the "expected" result.

Interim analyses of a metastatic breast cancer trial suggested a significant survival benefit for a five-drug combination chemotherapy compared to a single agent sequential treatment. Subsequent analyses failed to support this observation. Factors influencing the interim interpretation of this trial were investigated and found to include: delayed reporting of data in key cases, treatment effect limited to a patient subset, and problems related to achieving the "expected" result.

Randomized comparison of two combination chemotherapy regimens containing doxorubicin in patients with metastatic breast cancer: a Western Cancer Study Group trial.

Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide, methotrexate, 5-FU, prednisone, and doxorubicin. On one schedule, referred to as "combination" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive "fixed-rotation" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule.