Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors.

BACKGROUND: The long intracellular half-life of gemcitabine's active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), suggested that small increases in peak intracellular dFdCTP levels would have a profound effect on its intracellular area under the curve (AUC). Previous studies had shown that a dose rate of 10 mg/m2/min that achieved plasma gemcitabine concentrations of 15-20 mumol/l maximized the intracellular rate of accumulation of dFdCTP. This phase I study was therefore designed to evaluate the clinical feasibility of this pharmacologically-based strategy; assessing the toxic effects and anticancer activity of high weekly doses of gemcitabine administered at a fixed dose rate of 10 mg/m2/min. PATIENTS AND METHODS: Thirty one patients with solid tumor malignancies received 103 courses of gemcitabine. Twenty nine patients had received prior treatment. Weekly doses were escalated from 1200 mg/m2 administered intravenously over 120 minutes to 2800 mg/m2 over 280 minutes for three weeks every four weeks. RESULTS: The first-course MTD was 2250 mg/m2. The dose-limiting toxicity was myelosuppression with thrombocytopenia and granulocytopenia quantitatively more important than anemia. However, cumulative myelosuppression was documented suggesting that a lower MTD of 1800 mg/m2 was more appropriate with a recommended phase II starting dose of 1500 mg/m2. There was no neurologic toxicity. Nonhematologic toxicity was minimal and included fatigue, nausea, and skin rash, but was not dose dependent. Three objective responses were documented. CONCLUSIONS: Escalated doses of gemcitabine designed to maximize intracellular dFdCTP levels can be safely administered using a fixed dose rate. The encouraging anticancer effects documented in patients with refractory malignancies suggests that short gemcitabine infusions based on well-established cellular pharmacologic principles may improve the therapeutic index of this agent. Comparison with standard 30-minute bolus dosing will be evaluated in subsequent randomized phase II trials.

Thymidylate synthase inhibitors.

Folate analogues that inhibit thymidylate synthase (TS) selectively were developed based on TS and folate molecular structures and properties. The structure-activity relationship, preclinical and clinical development, and issues of potential importance in the future success of these TS inhibitors are reviewed herein. Properties of these new compounds depend mainly on the use of the reduced folate carrier (RFC) proteins for cellular entry and on intracellular polyglutamation, which augments TS inhibitory function and cellular retention. CB3717 [Zeneca (formerly ICI Pharmaceuticals), Macclesfield, United Kingdom], the first selective TS inhibitor developed, demonstrated antineoplastic activity in Phase I trials, but its development was abandoned due to nephrotoxicity. ZD1694 (Tomudex; Zeneca), a water-soluble, nonnephrotoxic quinazoline, demonstrated activity in colorectal, breast, and pancreatic cancer. Phase III trials of Tomudex in advanced colorectal cancer were completed recently. LY231514 (Eli Lilly Research Labs, Indianapolis, IN) uses the RFC and polyglutamation to exert its selective TS inhibitory action. Phase I trials of this compound have been completed. ZD9331 (Zeneca), currently in preclinical studies, was designed to obviate the use of the RFC for cellular entry. 1843U89 (Glaxo-Wellcome, Research Triangle Park, NC), currently in Phase I trial, does not require the RFC; polyglutamation of this potent TS inhibitor leads to its higher cellular retention without augmenting its TS inhibitory activity. Currently in clinical trials, AG337 (p.o. and i.v. forms) and AG331 (both by Agouron, La Jolla, CA) are lipophilic potent TS inhibitors with action independent of the RFC and polyglutamation. Multiple mechanisms through which cells may overcome TS inhibition have been described. Combining TS inhibitors with other agents that affect TS, interfere with TS gene and mRNA regulation, or inhibit salvage mechanisms of thymidylate depletion may potentially enable greater clinical utility of this class of compounds.

Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy.

PURPOSE: To determine the significance of the International Prognostic Index (IPI) score in adults with testicular lymphoma treated with doxorubicin-based regimens. PATIENTS AND METHODS: Untreated adults with testicular lymphoma who presented between 1969 and 1993 were studied. Those with Ann Arbor stages III and IV were included if they had a testicular mass at presentation. RESULTS: We identified 22 patients, 21 with intermediate-grade and one with high-grade lymphoma. All 10 patients with an IPI score < or = 1 had Ann Arbor stage I disease, whereas the 12 with an IPI score more than 1 had Ann Arbor stage II to IV disease. Complete remission (CR) was achieved in 73% of patients. At 153 months, 22% of all complete responders and 40% and 0% of those with IPI scores < or = 1 and more than 1, respectively, remained in CR (P = .01). With a median follow-up time of 113 months for survivors, the failure-free survival (FFS) rate at 153 months was 16% for all patients or 32% and 0% for those with IPI scores < or = 1 and more than 1, respectively (P = .02). The CNS or contralateral testis were involved in all patients who failed to respond to primary therapy and in 50% of those who relapsed from CR. CONCLUSION: The prognosis of patients with testicular lymphoma appears poor despite doxorubicin-based chemotherapy. On the basis of failures in the CNS and contralateral testis, we recommend prophylactic intrathecal chemotherapy and scrotal radiotherapy for all patients. Those with an IPI score < or = 1 can be treated with conventional doxorubicin-based regimens, but those with an IPI score more than 1 should be considered for investigational systemic therapy.