High-dose methotrexate and 5-fluorouracil in patients with advanced colorectal carcinoma. A randomized study of two pretreatment intervals.

Thirty-two patients with untreated advanced colorectal carcinoma received high-dose methotrexate pretreatment followed sequentially by 5-fluorouracil (5-FU). Patients were randomized to receive high-dose methotrexate pretreatment at one of two intervals (0 h or 3 h before 5-FU). There were 16 patients in each study arm. The median methotrexate dose was 1,000 mg/m2 (range, 600-1,200 mg/m2) and that of 5-FU was 1,000 mg/m2 (range, 800-1,200 mg/m2). Treatments were repeated every 21 days. Three patients achieved partial remission (1 in the 3-h interval arm and 2 in the 0-h interval arm). As the response rate using this regimen was noted to be 9% with a less than 5% chance of achieving a response rate higher than 20%, we terminated this study although the therapy resulted in mild-to-moderate but infrequent toxicity. We thus conclude that pretreatment with high-dose methotrexate given at short intervals followed by 5-FU has no significant activity against colorectal carcinoma.

Phase II study of adriamycin with sequential methotrexate and 5-fluorouracil (AMF) in gastric carcinoma.

The purpose of this study was to evaluate the response rate, methotrexate plasma levels, and toxicity of a three-drug regimen in patients with gastric carcinoma. A total of 37 patients with advanced measurable adenocarcinoma of the stomach were treated with Adriamycin, methotrexate, and 5-fluorouracil (AMF). Adriamycin and methotrexate were given as i.v. infusions on day 1; 24 h following methotrexate administration, patients received an i.v. infusion of 5-fluorouracil concomitantly with oral leukovorin factor (given over 48 h). Methotrexate levels were monitored regularly in all patients, and courses were repeated every 3 weeks. The median dose levels per course were 50 mg/m2 (range, 40-60 mg/m2) for Adriamycin, 1,000 mg/m2 (range, 650-1,250 mg/m2) for 5-fluorouracil, and 500 mg/m2 (range, 160-625 mg/m2) for methotrexate. Of 36 evaluable patients, 8 (22%) achieved an objective response, including 1 complete remission. Stable disease was noted in 11 patients and a minor tumor regression occurred in 1. The median survival duration of all patients was 6 months (range, 2-31+ months). AMF was well tolerated; toxicities were mild to moderate, most frequently involving nausea and vomiting, mucositis, and neutropenia with or without fever. There was no death directly attributable to chemotherapy. Although the AMF regimen used a well-documented preclinical concept of synergism between methotrexate and 5-fluorouracil, response and survival results suggest a modest activity of this combination in patients with gastric cancer. Better preclinical models are necessary for the development of effective combination chemotherapy.

Sequential methotrexate and 5-fluorouracil in the primary treatment of metastatic colorectal carcinoma.

Thirty-three patients with metastatic colorectal carcinoma were treated with sequential conventional dose methotrexate (60 mg/m2) followed within 1 hour by 5-fluorouracil (1000 mg/m2) every 3 weeks. Thirty of 33 patients were assessable for response. One patient (3%) achieved a partial remission (3.5 months). Three patients demonstrated minor tumor regressions. In an additional 17 patients, tumor stabilization was observed. The treatments were tolerated without any significant morbidity. A disappointingly low response rate was observed in our study as opposed to previous reports. Further clinical studies are necessary to establish the optimum dose levels and scheduling of sequential methotrexate and 5-fluorouracil.

High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults.

High-dose methylprednisolone (HDMP) was used to treat 18 episodes of severe (grades III and IV) acute graft-versus-host disease (GVHD) that developed after allogeneic bone marrow transplantation in 12 patients with acute leukemia and in 2 with aplastic anemia. Most of the patients showed rapid improvement in GVHD, with complete resolution of the skin and gut manifestations. However, the response of liver disease to the treatment was slow and incomplete. Complications seen were interstitial pneumonia and fungal and viral infections. Seven patients survived for more than two months following the treatment of acute GVHD. Five of these became long-term survivors with a median survival of 22+ months (range 11-38 months); all five long-term survivors developed chronic GVHD and are alive at the time of this report. It appears that HDMP is an effective treatment for severe acute GVHD. However, its true efficacy can only be ascertained in a randomized study comparing high-dose and conventional-dose methylprednisolone.