thioguanine-anhydrous and Rectal-Neoplasms

In order to redefine the effectiveness of 5-fluorouracil (5-FU) as palliative therapy in patients with metastatic colorectal carcinoma, and to compare the effectiveness of 6-thioguanine (6-TG) with that of 5-FU, we studied 176 patients with metastatic colorectal carcinoma in a randomized prospective trial (SEG 79G1268 ). The pretreatment performance status of all patients was greater than 50% (ambulatory), and there was an equal distribution of patients with favorable pretreatment characteristics into each of the treatment regimens. Complete responses were only seen to 5-FU, but were obtained in only 3% of instances. The overall complete plus partial response rates were not different for 5-FU (8%) versus 6-TG (3%), or for patients who had shown prior progression on chemotherapy and who then received 6-TG in a nonrandomized fashion (7%). The time to tumor progression on each of the treatment programs was similar, 1.0 months. Survival was also similar in each regimen in the randomized study (6.3 months for 5-FU versus 7.9 months for 6-TG). However, survival was only 4.8 months for patients with previously drug-resistant tumors treated with 6-TG in the nonrandomized arm. In 16 patients failing 6-TG who then received 5-FU, there were no objective responses. Similarly, in patients failing 5-FU on this study who then received 6-TG, there were no responses in nine patients. Dose-limiting toxicity was observed in 40% to 51% of patients, and consisted of myelosuppression, vomiting, or diarrhea. It is concluded that 5-FU is a minimally effective agent in a very small number of patients with metastatic colorectal carcinoma. The drug 6-TG is equally ineffective in this setting. Alternative treatment programs to the systemic use of 5-FU should be considered in patients requiring palliative chemotherapy.

Topics: Adenocarcinoma; Bone Marrow; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Male; Middle Aged; Prospective Studies; Random Allocation; Rectal Neoplasms; Thioguanine; Vomiting

In a randomized multi-institutional trial of the Eastern Cooperative Oncology Group, 316 patients with advanced measurable colorectal adenocarcinoma were treated with a weekly schedule of 5-fluorouracil given orally and intravenously with oral-5-fluorouracil in combination with cyclophosphamide or 6-thioguanine, or with oral Methyl CCNU administered once every eight weeks. On failure or progression, 133 protocol patients crossed-over to a secondary therapy, while 116 other patients previously treated with 5-fluorouracil off protocol were randomized to treatment with Methyl CCNU or B-2'-deoxythioguanosine. Response rates among patients who had received no prior chemotherapy were 18% to oral 5-FU, 15% to intravenous 5-FU and to MeCCNU, 12% to 5-FU and 6-thioguanine and 5% to cyclophosphamide and 5-FU, with little activity (3% response rate) in crossover or previously treated patients. Treatment with 5-FU, particularly oral 5-FU was associated with the least drug-related toxicity. Hematologic toxicity was greatest with Methyl CCNU, but was no more frequent in previously treated than in untreated patients. A tendency toward cumulative bone marrow depression was noted. 5-FU was effective only in ambulatory patients, whereas responses among non-ambulatory patients were seen only in the group treated with Methyl-CCNU.

Topics: Adenocarcinoma; Antineoplastic Agents; Bone Marrow; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Deoxyguanosine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Neoplasm Metastasis; Rectal Neoplasms; Semustine; Thioguanine; Thionucleosides

Patients with a wide range of gastrointestinal cancers have been treated with nitrosoureas by the Eastern Cooperative Oncology Group. Methyl-CCNU, CCNU, and streptozotocin have been evaluated as single agents in the treatment of colorectal carcinoma. Methyl-CCNU has had an extensive trial in gastric carcinoma as a single agent and in combination with 5-fluorouracil (5-FU). It has also been used to treat pancreatic carcinoma and, in a few patients, carcinoma of the biliary tract. In gastric cancer it would appear that a synergistic effect on response rates has resulted from the combination of methyl-CCNU and 5-FU. The addition of cyclophosphamide to this combination as an induction agent detracted significantly.

Topics: Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Neoplasms; Humans; Lomustine; Nitrosourea Compounds; Rectal Neoplasms; Semustine; Stomach Neoplasms; Thioguanine

Cholestatic jaundice induced by hepatic intra-arterial 5-fluorodeoxyuridine (FUDR) demonstrated marked improvement in three patients following treatment with oral corticosteroids. Subsequent "prophylactic" use allowed continuation of chemotherapy and improved quality of life. Corticosteroid use in selected patients with FUDR-induced cholestatic jaundice may be beneficial.

Topics: Adrenal Cortex Hormones; Cholestasis; Colonic Neoplasms; Floxuridine; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Rectal Neoplasms; Thioguanine

Topics: Adult; Aged; Colonic Neoplasms; Drug Evaluation; Female; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Rectal Neoplasms; Thioguanine; Time Factors

Consecutive studies were undertaken in advanced colorectal adenocarcinoma, comparing two different schedules of the combination methyl-CCNU, 6-thioguanine, and 5-fluorouracil in 89 patients. The two schedules exhibited similar efficacies, with a combined complete and partial remission rate of 17%, a median response duration of 36+ weeks, and a median survival of 53+ weeks. Significant symptomatic benefit was seen in 52% of patients. Toxicity was predominantly hemopoietic and gastrointestinal, being acceptable overall, with only minor qualitative differences between the two protocols. These triple-drug regimens exhibit response rates and survival patterns comparable with those reported for other multidrug combinations and some single agents. It would appear that major improvements in the management of advanced-stage disease must await the availability of more efficacious agents used alone or in combination.

Topics: Adenocarcinoma; Adult; Aged; Colonic Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Nitrosourea Compounds; Rectal Neoplasms; Semustine; Thioguanine

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Cricetinae; Culture Techniques; Cyclohexanes; Cyclophosphamide; Disease Models, Animal; Drug Therapy, Combination; Fluorouracil; Humans; Mice; Nitrosourea Compounds; Rats; Rectal Neoplasms; Thioguanine