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Five-day infusional fluorodeoxyuridine with oral leucovorin and escalating doses of interferon alpha-2b: a phase I
E E Vokes1, S M O'Brien, N J Vogelzang
1Department of Medicine, University of Chicago, IL 60637.
Abstract:
In a previous phase I study we identified the maximally tolerated dose (MTD) of a continuous intravenous infusion of fluorodeoxyuridine (FUdR) to be 0.3 mg/kg daily for 5 days when combined with oral leucovorin (LV) given at 100 mg q4h. In an attempt to modulate FUdR further, we added escalating doses of interferon alpha-2b (IFN) to FUdR/LV in a phase I cohort study. A total of 36 patients with refractory solid tumor were treated at two dose levels of FUdR and five dose levels of IFN. Although the initial patient cohort was treated with a dose of FUdR lower than that previously identified as the MTD [FUdR at 0.2 mg/kg daily with LV at 100 mg q4h and IFN at 2 million units (MU)/m2 daily], three of six patients developed grade 3 mucositis, indicating that the toxicity of FUdR/LV was increased in the presence of low doses of IFN. After decreasing the FUdR dose to 0.1 mg/kg daily, we could increase the dose of IFN from 2 to 30 MU/m2 daily in five additional cohorts of patients. With increasing IFN doses, no increase in mucositis or dermatitis was observed, indicating no further potentiation of FUdR/LV toxicity with higher IFN doses. However, known toxicities of IFN, including transient myelosuppression and hepatic transaminase elevation, were observed more frequently at IFN doses of 15 and 30 MU/m2 daily, where they became dose-limiting. We conclude that IFN modulates FUdR/LV at low doses, resulting in increased FUdR toxicity. When the dose of IFN is increased, this FUdR/LV toxicity does not appear to be potentiated further and IFN-related toxicities become dose-limiting.
Insights
Interferon alpha-2b (IFN) increases fluorodeoxyuridine (FUdR) toxicity at low doses when combined with leucovorin (LV). Higher IFN doses do not worsen FUdR/LV toxicity, but IFN-related side effects become dose-limiting.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Previous studies established the maximally tolerated dose (MTD) of fluorodeoxyuridine (FUdR) with leucovorin (LV).
- Investigating the combination of FUdR/LV with escalating doses of interferon alpha-2b (IFN) in patients with refractory solid tumors.
Purpose of the Study:
- To evaluate the safety and tolerability of combining FUdR/LV with increasing doses of IFN.
- To determine if IFN modulates the toxicity of the FUdR/LV regimen.
Main Methods:
- Phase I cohort study involving 36 patients with refractory solid tumors.
- Treatment involved continuous intravenous infusion of FUdR with oral LV and escalating doses of IFN.
- Dose escalation of FUdR and IFN was performed, monitoring for toxicities like mucositis and dermatitis.
Main Results:
- Low doses of IFN (2 MU/m2) combined with FUdR/LV increased the incidence of grade 3 mucositis.
- Increasing IFN doses up to 30 MU/m2 did not further potentiate FUdR/LV toxicity.
- Dose-limiting toxicities at higher IFN doses included myelosuppression and elevated hepatic transaminases.
Conclusions:
- Interferon alpha-2b modulates FUdR/LV toxicity at lower doses, increasing FUdR-related side effects.
- At higher doses, IFN-related toxicities become the dose-limiting factors, not further potentiation of FUdR/LV toxicity.