Phase II study of 4'-deoxydoxorubicin (esorubicin) in advanced or metastatic adenocarcinoma of the stomach.

4'-deoxydoxorubicin (DxDx) was administered to 17 patients with locally advanced or metastatic gastric adenocarcinoma. Treatment cycles were repeated every 21 days. 15 eligible patients with a Karnofsky performance status of 50% or better (median: 70%) received at least one course of treatment; a median of 2 courses of DxDx was delivered (range 1 to 13). The median dose per treatment course was 26 mg/m2 (range 8.5 mg/m2 to 53 mg/m2). 69% of patients required dose reduction following the first course of therapy due to grade 3 or 4 myelosuppression, primarily neutropenia. The principal side effects included anemia, mild gastrointestinal toxicities, and alopecia; one patient experienced a 10% decrease in cardiac ejection fraction without clinical cardiac toxicity. Of the 15 patients assessable for response and toxicities, 1 patient had a partial response lasting 2.5 months. The median survival from the time of the first treatment was 3.3 months. We conclude that DxDx has only limited activity in the treatment of advanced gastric adenocarcinoma.

Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy.

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.

Reversal of cancer chemotherapeutic resistance by amphotericin B--A broad phase I-II pilot study.

In order to determine if it was possible to reverse clinically evident chemotherapeutic drug-resistance, 51 evaluable patients received chemotherapy (in doses and schedules on which they had previously demonstrated tumor progression) together with amphotericin B (AMB). AMB was given in 1-, 2-, or 4-day courses. There was 1 complete response (2%), and 5 partial responses (10%). Response rates tended to be higher in the 4-day treatment program (23%) than in the 1- or 2-day AMB treatment schedules (8%). Toxicity was that expected with chemotherapy (myelosuppression), or AMB alone (fever, chills, and reversible mild azotemia). We conclude that AMB is only infrequently able to reverse clinical drug-resistance, but that this might have palliative effects in a small number of patients in whom other standard chemotherapeutic drugs lack clinical effectiveness.

Preliminary analysis of a randomized comparison of 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer.

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.

High-dose continuous infusion folinic acid and bolus 5-fluorouracil in patients with advanced colorectal cancer: a phase II study.

Encouraging results have recently been reported for studies using folinic acid in combination with 5-fluorouracil (5-FU) in the treatment of patients with gastrointestinal (GI) malignancies. Thirty-six patients with advanced colorectal cancer with unequivocal evidence of progression while treated with fluoropyrimidines were treated with a six-day continuous infusion of 500 mg/m2/d of folinic acid initiated 24 hours before a five-day course of 5-FU administered as an intravenous (IV) bolus of 370 mg/m2/d. An initial dose of 250 mg/m2/d of 5-FU was used in patients previously treated with ionizing radiation and/or a nitrosourea. Three objective partial responses were observed. The overall median duration of survival was 8.1 months. Toxicity was acceptable and not in excess of that expected for 5-FU alone.

Effects of amphotericin B with combination chemotherapy on response rates and on survival in non-small cell carcinoma of the lung.

Thirty-seven patients with non-small cell carcinoma of the lung were randomized to receive doxorubicin, lomustine, hexamethylmelamine, and methotrexate (ACHM) or ACHM plus amphotericin B (AMB). The complete plus partial response rate was 39% for ACHM plus AMB, compared to 23% for ACHM alone. However, the median duration of complete or partial response was only 3.0 months with ACHM plus AMB, compared to 7.0 months with ACHM. Most importantly, median survival was only 4.0 months with ACHM plus AMB, compared to 8.0 months with ACHM (P = 0.08; two-tail test). Myelosuppression was enhanced by the addition of AMB. Although AMB has biological and antitumor activity in certain clinical circumstances, it does not appear to have a meaningful role in palliative therapy of patients with non-small cell bronchogenic carcinoma.

Continuous five-day infusion of PALA and 5FU: a pilot phase II trial.

In order to determine whether a simultaneous infusion of N-(phospho-n-acetyl)-L-aspartic acid (PALA) was able to increase the rate of antitumor response to 5-fluorouracil (5-FU), a pilot study was conducted. Of 10 evaluable patients with previously drug-untreated colorectal carcinoma, there were only two partial responses, lasting 2.3 and 1.6 months. No partial responses were observed in three evaluable patients with soft tissue sarcomas. The dose-limiting toxicity was dermatitis. The simultaneous infusion of PALA and 5-FU is not likely to produce a high number of antitumor responses of long duration in patients with colorectal carcinoma.

Comparisons of Cooperative Group evaluation criteria for multiple-drug therapy for breast cancer.

The variability of response rates and durations for multiple-drug therapy for advanced breast cancer may be due in part to the evaulation criteria of the investigators. To assess the impact on outcome, a single data set comprising the patients registered in Central Oncology Group protocol 7020B was analyzed by the evaluation criteria of the Central Oncology Group, the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Southeastern Cancer Study Group, as well as by a personally derived "flexible clinical interpretation of treatment benefit." The response rates and durations were quite similar by the criteria of all groups except those of the Southeastern Cancer Study Group, which gave lower rates and longer duration. These differences were consistent with the evaluation criteria for each group and confirmed the differences noted in their published reports. When "flexible" criteria were used, the differences deviated from those using strict group criteria. This might explain, in part, reports from single institutions of response rates that were higher than those achieved in cooperative group studies.

5-FU versus combination therapy with tubercidin, streptozotocin, and 5-FU in the treatment of pancreatic carcinomas: COG protocol 7230.

From May 1972 until May 1976, 105 patients were entered on Central Oncology Group protocol 7230 to compare the combination of streptozotocin, tubercidin, and 5-fluorouracil (5-FU) versus 5-FU alone in the treatment of adenocarcinoma and islet cell carcinoma of the pancreas. Twenty-nine were not evaluable. Thirty-six evaluable cases received 5-FU, and 40 received the combination, with no significant difference in time to progression or survival. Toxicity in the two regimens was somewhat different but was essentially similar in magnitude. Results indicate no benefit in the treatment of adenocarcinoma of the pancreas with the three-drug combination over 5-FU alone. All of the islet cell tumor patients benefited from the combination by response or arrest of progression of disease. Further study should be directed toward the use of this combination in the treatment of functioning and non-functioning islet cell tumors of the pancreas.

Yoshi 864 (1-propanol, 3,3'-iminodi-, dimethanesulfonate [ester], hydrochloride): a phase II study in solid tumors.

Two hundred and eight acceptable patients were treated with Yoshi 864 (2 mg/kg/day by iv push X 5 days repeated once every 6 weeks). Toxicity was minimal. There was an overall response rate of 11%. Cross resistance with other alkylating agents may not be present. Because of its lack of toxicity, Yoshi 864 should be further evaluated in chronic myelocytic leukemia, lymphomas, and carcinomas of the ovary and bladder where significant responses were seen. It should also be evaluated in combinations as a replacement for other alkylating agents which cause more nausea and vomiting.