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Randomized Clinical Trial of Diethylstilbestrol versus Tamoxifen in Postmenopausal Women with Advanced Breast Cancer

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of bilateral oophorectomy with that of tamoxifen at a dose of 10 mg twice daily in premenopausal women with metastatic breast cancer, and to examine the efficacy of each as a crossover treatment. Initial treatment responses were seen in ten of 27 patients (37%) treated with oophorectomy and seven of 26 patients (27%) treated with tamoxifen. The difference was not statistically significant. Crossover responses were seen in five of 15 patients (33%) treated with oophorectomy, including three responses in ten prior tamoxifen nonresponders; and two of 18 patients (11%) treated with tamoxifen. Time to progression distributions were not significantly different during initial treatment, and no significant differences in survival were noted. Thus, there was no overall disadvantage to the use of tamoxifen as opposed to oophorectomy as initial hormonal therapy, and a failure to respond to tamoxifen did not preclude a response to subsequent oophorectomy. Exploratory data analysis within subsets indicated consistent differential treatment effects in the visceral dominant patients. Of the 16 such patients treated with oophorectomy, eight (50%) experienced objective responses but there were no responses in the 14 patients treated with tamoxifen. In the nine visceral dominant crossover patients who had not responded to initial tamoxifen, three (33%) subsequently responded to oophorectomy. Time to progression distributions within the visceral dominant subset appeared to be better for the patients treated initially with oophorectomy. However, one must be very cautious in drawing conclusions from exploratory subset analyses, especially with the small sample size. Further studies would be required to test any hypothesis of differential organ site responsiveness.

Phase II study of recombinant leukocyte A interferon (rIFN-αA) in disseminated malignant melanoma

Thirty‐one patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN‐αA), 50 × 106 units/m2 three times weekly for a planned treatment duration of 3 months. Seven objective regressions (23%), which ranged in duration from 3 to 11.2+ months, were observed. Forty‐two percent of 12 patients who were fully active (Eastern Cooperative Oncology Group [ECOG] performance score, 0) responded compared to 11% of 19 patients with impairment of performance status (ECOG, 1–3). Prior chemotherapy did not influence response rate. For all patients the median time to progression and of survival was 2 months and 6 months, respectively. Four patients had partial regressions in soft tissue (3, 4.6 months), pulmonary (7 months), and prostatic lesions (3 months). The latter was biopsy‐proven and assessed by serial computerized tomography (CT) scans. Three had complete regressions of soft tissue disease (2 patients, 6.4 and 10+ months each), and liver involvement (11.2+ months). The major toxicities were moderate to severe fatigue (87%), anorexia (58%), and confusion (23%). Performance score deteriorated in 84% of patients during the time they were receiving rIFN‐αA. Among the 13 patients whose tumors did not progress for at least 12 weeks, 7 required dose reductions or termination of treatment due to toxicities. Hematologic and hepatic toxicity was transient and of little clinical significance. The study indicates that rIFN‐αA has some antitumor activity accompanied by difficult side effects in patients with disseminated malignant melanoma.

Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma.

Thirty patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 12 X 10(6) U/m2, three times weekly for a planned treatment duration of three months. This dose was selected in view of our prior phase II data indicating that 50 X 10(6) U/m2 three times weekly produced excessive toxicity. In this current trial we observed three objective partial regressions (20%) among the 15 better-risk patients (performance score 0, 1, and no prior chemotherapy) with times to disease progression of 1.9, 9.6, and 12.9+ months. There were also three regressions (one complete and two partial) among the 15 poor-risk patients (performance score 2, 3, or prior chemotherapy) with progression times of 3, 3.2, and 9.6+ months. For all patients, the median survival time was 4.2 months. One half of the patients were observed to have progressive disease within one month of commencing treatment. Responding metastatic lesions were limited to soft tissue, although one patient also had a partial response of a lung nodule. The most substantial toxicities were moderate-to-severe myalgias (27%), nausea (33%), anorexia (47%), and fatigue (50%). Among the 22 patients with weight loss, the median was 2.3 kg (range, 0.6 to 8.4 kg). Hematologic and hepatic toxicity was transient and of little clinical significance. Our study indicates that rIFN-alpha A in the dose and schedule that we used is clinically tolerable and has antitumor activity in malignant melanoma. The response rate was similar to results observed in our previous study of a higher dose regimen.

Randomized clinical trial of megestrol acetate versus tamoxifen in paramenopausal or castrated women with advanced breast cancer

Fifty-five women with progressive metastatic breast cancer who were paramenopausal (1 to less than 5 years since last menstrual period) or castrated were randomized to receive either megestrol acetate (150 mg/m2 daily in three divided doses) or tamoxifen (10 mg twice daily). The regression rate (complete plus partial) was higher for tamoxifen (26%) than for megestrol acetate (14%), but not significantly so. Analysis of time to treatment failure showed no significant difference (medians: megestrol acetate, 65 days; tamoxifen, 58 days). There was survival advantage associated with megestrol acetate (P = 0.02 after adjustment for stratification factors) that is difficult to interpret given the results of analysis of regression and time to treatment failure for the two agents.

Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of tamoxifen (TAM) alone with that of TAM plus aminoglutethimide (AG) and hydrocortisone (HC). Patients failing TAM could receive AG and HC. Objective responses to therapy were seen in 21 of 49 TAM patients (43%) and 25 of 51 TAM, AG and HC patients (49%). Time to disease progression and survival distributions were not significantly different between the treatment arms. Toxicity was greater for patients treated with TAM, AG, and HC and the trial was discontinued early for this reason. Twenty-four patients received AG and HC after TAM therapy and three (12%) achieved a response. We conclude that the combination of TAM, AG, and HC is not recommended over TAM alone because toxicity appears to outweigh any potential therapeutic advantage.

A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A Southwest Oncology Group Study

Forty-one eligible patients with metastatic or recurrent carcinoma of the uterine cervix received 149 courses of carboplatin. The drug was administered at a starting dosage of 400 mg/m2 IV every 28 days. The overall response rate was 15% (two complete responses, four partial responses; 95% confidence interval 6-29%) and response durations were 2.0, 2.0, 2.5 +, 2.5+, 5.25 +, and 6.75 months. The major toxic effects included nausea and vomiting in 48% of courses, anemia in 47%, leukopenia in 38%, and thrombocytopenia in 22%. The activity of carboplatin against advanced cervical cancer is modest and similar to the activity of cisplatin alone. However, the toxicity profile of carboplatin is substantially better than that of cisplatin and warrants exploration of this agent against cervix cancer in more aggressive regimens or in combination with other agents.

A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5-fluorouracil, prednisone in patients with advanced breast cancer.

We assessed the efficacy of a regimen consisting of four cycles of cyclophosphamide, Adriamycin (Adria Laboratories, Inc, Columbus, Ohio), cisplatin (CAP) followed by maintenance with cyclophosphamide, 5-fluorouracil, prednisone (CFP) compared with CFP alone in a randomized trial of 86 patients with advanced breast cancer. The objective regression rates were 46% (CFP) and 49% (CAP with CFP) which included complete regression rates of 7% (CFP) and 4% (CAP with CFP). The median time to progression was nine months for CFP and six months for CAP with CFP. Median survival in the CFP group was 18 months v 11 months in the CAP recipients. Due to the therapeutic trend in favor of patients receiving CFP, we terminated the study before achieving our initially projected accrual. We observed over a twofold excess of substantial nausea and vomiting among patients receiving the platinum-based regimen. In our view, the CAP followed by the CFP regimen is a more toxic program that offers no clinically meaningful improvement over CFP to patients with advanced breast cancer.

Considerations for monitoring and evaluating treatment effects in clinical trials

The efficacies of various treatments commonly are evaluated and compared using prospective clinical trials. For ethical reasons, data from these trials are analyzed on an interim basis. The statistical test procedures used in these evaluations must be carefully selected and appropriately applied.

Randomized trial to evaluate the addition of tamoxifen to cyclophosphamide, 5-fluorouracil, prednisone adjuvant therapy in premenopausal women with node-positive breast cancer.

A randomized clinical trial was performed to determine if the addition of hormonal therapy with tamoxifen to a combination chemotherapy regimen was superior to the chemotherapy alone for adjuvant treatment of premenopausal women after mastectomy for node‐positive breast cancer. The chemotherapy regimen utilized consisted of cyclophosphamide (C), 5‐fluorouracil (F), and prednisone (P), and the doses employed were: C, 150 mg/m2 IV days 1 to 5; F, 300 mg/m2 IV days 1 to 5; and P, 10 mg orally three times daily on days 1 to 7. A total of ten courses of therapy, given every 6 weeks, was planned. Tamoxifen (T) was given at a dose of 10 mg twice daily and was stopped 6 weeks after the last course of CFP. Four hundred patients are fully eligible and evaluable. With a median observation time of 5.3 years, the proportion of recurrences on each arm were: CFP, 95 of 202 (47%); CFPT, 77 of 198 (39%). The relapse‐free survival distribution for CFPT was superior to that for CFP, at a borderline level of significance (two‐sided P = 0.06). When significant prognostic factors were considered in covariate analysis, CFPT was not significantly better than CFP (P = 0.43). This marked change in level was due to imbalance in several factors not considered in stratification. Currently, 31% of CFP and 25% of CFPT patients have died, and although there is a slight separation of the survival curves in favor of CFPT, the difference is not significant (P = 0.21). Analysis within receptor subsets also showed no significant advantage for the addition of tamoxifen. This study does not establish a significant advantage for the concurrent administration of tamoxifen with the CFP regimen. It does, however, clearly demonstrate the importance of examination of clinically important prognostic factors, even those not utilized in stratification, and consideration of these factors in covariate analysis if imbalances are present.