Phase III study of combined chemohormonal therapy in metastatic prostate cancer (ECOG 3882): an Eastern Cooperative Oncology Group study. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Randomized trial of combination chemotherapy in hormone-resistant metastatic prostate carcinoma. Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure. Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity.
This study, a phase III multicenter randomized trial opened by ECOG in April 1983 and closed in June 1986 was designed to evaluate whether a combination of doxorubicin and an intravenous formulation of diethylstilbestrol diphosphate (DES) was superior to doxorubicin alone in men with hormone refractory prostate cancer. All patients received doxorubicin at a dose of 50 mg/m2 iv every 3 wk either alone or with 1 g DES iv daily for 5 d followed by 1 g iv twice weekly for four cycles (12 wk). The 51 evaluable patients with visceral metastases displayed a significantly increased response rate (27% vs 63%) on the combined therapy arm (p = 0.04). However, the 111 evaluable patients with osseous disease exhibited no difference in response rate between either arm with a p-value of >0.99. Similarly, clinical response rates revealed no difference between the two arms. Cases of cardiac toxicity graded as severe, life threatening, or lethal in the combined therapy arm were 10 times more frequent in the combined-therapy arm than in the doxorubicin-alone group (6.75% compared to 0.7%). This difference was statistically significant (p = 0.0041). All of the cases of superficial and deep venous thrombosis occurred on the combined-therapy arm. There were no other significant differences in the numbers of grade 3 or 4 toxic events. The most common toxicity was hematologic. Failure-free survival duration did reach statistical significance in the combined-therapy group (p = 0.012), although the actual durations were short (2.6-3.2 mo). There was no difference in overall survival between the two groups. A randomized trial was conducted in patients with small-cell lung cancer (SCLC) to determine if survival can be improved by a weekly chemotherapy regimen combining various drugs.
                Two hundred twenty-three patients were randomized to receive either six courses of a multiple-drug combination (MDC) regimen (Adriamycin [ADR; doxorubicin; Farmitalia Carlo Erba, Milan, Italy] 25 mg/m2 intravenously [i.v.] on day 1; etoposide [VP16] 120 mg/m2 i.v. on day 1; cyclophosphamide [CPA] 500 mg/m2 i.v. on day 1; cisplatin 60 mg/m2 i.v. on day 8; vindesine [VDS] 3 mg/m2 i.v. on day 8; vincristine [VCR] 2 mg i.v. on day 15; methotrexate [MTX] 100 mg/m2 i.v. on day 15), or a standard chemotherapy (SC) regimen (ADR 50 mg/m2 i.v. on day 1; CPA 1 g/m2 i.v. on day 1; VP16 80 mg/m2 i.v. on days 1 to 3).
                In 98 MDC-treated and 101 SC-treated assessable patients, we observed 69% and 62% objective responses rates, respectively. There was no significant difference in survival, with median durations and 2-year overall survival rates of 49 and 43 weeks and 8.5% and 7.9%, respectively. There was a significant increase in response rate in favor of MDC patients with limited disease (84% v 62%). Toxicity was tolerable, although SC was more hematotoxic, with 76% (v 59%) experiencing leukopenia and 17% (v 7%) experiencing thrombocytopenia (grades III and IV). If the cumulative doses received were nearly equal to the scheduled cumulative doses in both arms, the total relative dose-intensity (RDI) was significantly higher in the SC arm. The difference was due to increased treatment delays in the MDC arm.
                Weekly MDC failed to improve survival rates in patients with SCLC. We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).
                High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.
                Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar.
                The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use. Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial.
                Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol.
                403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths.
                Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study. A prospective randomized study was conducted in 51 patients with stage D hormone-resistant prostatic carcinoma, comparing a combination of doxorubicin and lomustine (DC) with cyclophosphamide and 5-FU (CF). Patients were assessed objectively (employing National Prostate Cancer Project criteria) and subjectively (using a numerical scoring scheme). Each regimen was well tolerated with acceptable levels of myelosuppression. The objective partial response rate was 57% for DC and 8% for CF. Objective stabilization occurred, respectively, in 14% and 44% of the patients. Similarly, DC demonstrated a significantly superior subjective response rate (partial plus complete) of 82%, compared to 48% for CF. Patients with poor initial performance status or liver involvement had significantly lower response rates and reduced survival. Overall, there was no significant difference in survival between the two arms, reflecting the similarity between DC and CF in total objective response rate (partial response plus stable disease). DC provided superior palliation and was well tolerated by an essentially geriatric population. One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure. We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen.
Compared to single-agent doxorubicin, the combination chemotherapy regimens evaluated, given in conventional doses, produced only marginal increases in response rates, at the expense of increased toxic effects and with no improvements in overall survival.