Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel.

PURPOSE: To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting. PATIENTS AND METHODS: Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m(2)/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m(2) by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. RESULTS: One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). CONCLUSION: The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.

Duke Scholars

Author Paul Kelly Marcom Medicine, Medical Oncology