A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma.

BACKGROUND: Inoperable hepatocellular carcinoma is an incurable malignancy with no accepted standard therapy. Chemotherapy has demonstrated occasional responses and the need is great for a new and effective agent. Therefore the authors conducted this Phase II trial of a novel thymidylate synthase inhibitor, nolatrexed dihydrochloride (designed using structure-based computer modeling), in patients with advanced hepatocellular carcinoma. METHODS: Forty-one patients with unresectable or metastatic hepatocellular carcinoma were treated with nolatrexed, which was administered as a 24-hour outpatient intravenous infusion for 5 days at a dose of 795 mg/m2/day as free base (1000 mg/m2/day as salt) during each 21-day cycle. Prophylactic treatment was given for emesis and rash. RESULTS: Twenty-eight patients received at least 2 courses of treatment and 26 patients were evaluable. Two patients (8%) achieved a partial response and 2 additional patients achieved a minor response that was significant enough to allow surgical resection with curative intent. Fourteen patients (54%) achieved stable disease. The overall median survival was 7 months (10 months among patients who completed 2 cycles) and 1 patient remained free of disease at last follow-up, 37 months after surgery. Toxicity was modest and generally was comprised of stomatitis, nausea, malaise, and rash. CONCLUSIONS: Nolatrexed appears to have modest biologic activity in hepatocellular carcinoma. Due to the lack of alternative treatments, further study of this drug or an oral equivalent may be warranted.

Oral piritrexim in advanced bladder cancer: an effective drug after progression on MVAC chemotherapy?

Four patients with advanced or metastatic bladder cancer progressing after MVAC chemotherapy were treated with oral piritrexim. Three of the four patients were evaluable for response, and all three had a partial response to treatment. Piritrexim may be an effective drug for bladder cancer after progression on MVAC chemotherapy.

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.

BACKGROUND: The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity. METHODS: A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed. RESULTS: Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. CONCLUSIONS: Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.