Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.

PURPOSE: In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients. PATIENTS AND METHODS: From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year. RESULTS: After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival. CONCLUSION: The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer.

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15-17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a > oe = 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/ estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/ estramustine are recommended.