Sequential methotrexate and 5-fluorouracil (FU) vs. FU alone in metastatic colorectal cancer. Results of a randomized multicenter trial. The Association of Medical Oncology (AIO) of the German Cancer Society.

Methotrexate (MTX) modulates 5-fluorouracil (FU) in several in vitro and in vivo experimental systems. Results of phase II studies have suggested improved response rates for the sequential application of MTX and FU in colorectal cancer. In a prospective randomized multicenter study we compared sequential MTX (300 mg/m2) and FU (900 mg/m2) using a seven-hour time interval and leucovorin rescue with FU (450 mg/m2/d for five days) in patients with previously untreated metastatic colorectal cancer. Of 172 patients randomized 159 were eligible for survival analysis and 153 for toxicity and response evaluation. Complete or partial response has been seen in 25.3% of patients receiving sequential MTX and FU and in 17.6% of those receiving FU alone (p = 0.11). There have been two long-term survivors, apparently cured by MTX/FU. Overall toxicity was more pronounced with FU alone, but sequential MTX/FU caused four toxic deaths. Median survival and survival rates at one and two years were not significantly different. It is concluded that this schedule of sequential MTX and FU is no more effective than a dose-intensive treatment with FU alone in metastatic colorectal cancer.

Phase III study of 5-FU and carmustine versus 5-FU, carmustine, and doxorubicin in advanced gastric cancer.

Seventy-seven patients with advanced gastric carcinoma were prospectively randomized to receive 5-FU and carmustine (FB) with or without doxorubicin (FAB). Thirty-five patients were evaluable for response. Neither the response rates (partial remission, 11% for FB and 24% for FAB) nor survival times (median, 4.0 months for FB and 5.5 months for FAB) were statistically different. The median survival of patients with partial remission (7.8 months) and those with no change (7.4 months) was significantly prolonged compared to patients with progressive disease (4.5 months). The side effects of both regimens after the first treatment cycle (except alopecia in FAB) were low. After the second cycle more pronounced myelosuppression in the FAB arm was observed.

Etoposide, adriamycin, and cisplatinum (EAP) combination chemotherapy for advanced gastric cancer. A phase II trial by the "Chemotherapiegruppe Gastrointestinaler Tumoren (CGT)".

In a multicenter trial, 49 patients with histologically proven advanced gastric cancer were treated with a combination chemotherapy consisting of etoposide 120 mg/m2 d 4, 5, 6 adriamycin 20 mg/m2 d 1, 7 and cisplatinum 40 mg/m2 d 2, 8. Therapy was repeated every 4 weeks, 45 patients were evaluable for response after 8 weeks of treatment. Eight patients achieved a partial remission (PR: 18%), 17 patients had no change (NC: 38%), and 20 patients showed tumor progression (P: 44%). Four patients with primarily inoperable tumor and without distant metastases who achieved a partial remission, underwent second look operation with curative intention. All 4 patients died within 12 months after second look operation due to tumor recurrence. Median survival time of all patients was 9 months. Toxicity was considerable. WHO grade 3/4 toxicity appeared in 20-30% of patients (nausea, vomiting, loss of appetite, leucopenia). After 3 cycles complete alopecia was present in 70% of patients. Severe infection, requiring treatment, occurred in 10 patients. Five patients discontinued therapy because of intolerable subjective toxicity. The observed response rate of 18% objective partial remissions is disappointing and does not give support to the communications reporting response rates over 50% with EAP and other regimens including cisplatinum. In conclusion, and considering the high subjective and objective toxicity of this regimen, it can not be recommended for standard use in patients with advanced gastric cancer.

5-Fluorouracil, 4-epidoxorubicin, and mitomycin C (FEM) combination chemotherapy for advanced gastric carcinoma. A phase-II trial by the "chemotherapiegruppe gastrointestinaler tumoren (CGT)".

In a phase-II-trial 40 patients with advanced gastric cancer were treated with 5-fluorouracil, 4-epidoxorubicin, mitomycin C (FEM) combination therapy. Twenty-five out of 30 patients with measurable disease were evaluable for response after 8 weeks of treatment. Seven patients achieved a partial remission (PR), suggesting a response rate of 28%. Ten patients had no change (NC) and 8 patients showed progression (P). The median time to progression for patients with PR was 7.2 months and for patients with NC 6.3 months. Median survival time for all patients was 5.3 months, for patients with PR and NC 9.9 months. WHO grade 3 toxicity appeared in 3% (WBC and nausea/vomiting) and 15% (alopecia) of patients. The data suggest that this regimen is not more active, but is better tolerated than the original FAM schedule. Therefore it seems suitable for out-patient treatment, for elderly patients and for those who cannot be treated by more aggressive drugs.