Substituting Liposomal for Free Vincristine in CHOP Could Permit Higher Therapeutic Doses

HOUSTON-Vincristine is efficacious for the treatment of aggressive B-cell non-Hodgkin's lymphoma (NHL), but can have significant neurotoxicity at therapeutic levels. Liposomal vincristine has a longer half-life and preferentially greater accumulation in tumor cells and lymph nodes than free vincristine, allowing the use of higher doses. In an early phase II trial of liposomal vincristine for the treatment of relapsed NHL, response rates of 10% for indolent lymphoma and 47% for aggressive lymphoma were observed in 51 patients.[1] Less than 22% of patients (11 of 51) reported neurotoxicity after a median injected dose of 3.8 mg (range, 2.6 to 4.8 mg) and a median of four injections (range, 1 to 12 injections), and all patients with neurotoxicity had previously reported neuropathy from prior treatment with paclitaxel(Drug information on paclitaxel) or platinum drugs. Vincristine is a component of the cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin), vincristine (Oncovin), and prednisone(Drug information on prednisone) (CHOP) chemotherapy regimen. In elderly patients with diffuse large-B-cell lymphoma, complete response rates of 63% have been reported for CHOP alone and 76% for CHOP plus rituximab(Drug information on rituximab) (Rituxan).[2] Reduced Neurotoxicity Liposomal vincristine has reduced neurotoxicity relative to free vincristine. Substituting liposomal vincristine for free vincristine as a component of the CHOP regimen may lead to higher response rates with reduced toxicity.[3] Maria Rodriguez, MD, and colleagues at The University of Texas M.D. Anderson Cancer Center in Houston, tested this hypothesis among 73 patients with previously untreated aggressive NHL (ASH abstract 338).[3] Approximately half of the patients presented with poor prognostic factors, including 36 patients who were older than 60 years of age and 30 patients who had International Prognostic Factor Index scores of 2 or higher. All patients in the study received standard-dose CHOP (cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², prednisone 100 mg, but substituting liposomal vincristine 2.0 mg/ m² for free vincristine) for 5 days, plus six to eight courses of rituximab (375 mg/m²) every 21 days. Among the 66 patients who have completed treatment, the response rate was 100%; 62 patients had a complete response; 3 patients had an unconfirmed complete response (negative scan by positron emission tomography); and 1 patient had a partial response. After a median follow-up of 12 months, all patients were alive and only five patients had relapsed, of whom four were over 60 years old. Neuropathy with liposomal vincristine was mild (grade 0 to 2), and only 5 of 69 evaluable patients (7%) required dose adjustments because of neuropathy. Based on these results, the investigators concluded that CHOP with liposomal vincristine combined with rituximab is efficacious and well tolerated, particularly in elderly patients. The researchers urged the initiation of a randomized trial comparing this treatment regimen with standard CHOP plus rituximab to further evaluate this innovative modification.