Weighing a Dose-Dense Option for Adjuvant Chemotherapy and Trastuzumab in Early-Stage Breast Cancer

Abstract

The seminal trials of adjuvant trastuzumab all tested the hypothesis that adding trastuzumab to chemotherapy would improve outcomes compared with chemotherapy alone among women with HER-2–overexpressing breast cancer. Despite the profound similarity in the basic trial designs and the remarkable consistency of the trial results, the studies had many notable differences in the treatment program, including the eligibility criteria with regard to clinical characteristics and cardiac function, the concurrent or sequential use of chemotherapy and trastuzumab, the type and number of cycles of chemotherapy, and the duration of both chemotherapy and trastuzumab treatments. Thus, the optimal chemotherapy/trastuzumab regimen for early stage breast cancer remains undefined. Of the nearly 10,000 women who participated in the adjuvant trastuzumab trials, the vast majority received anthracycline-based regimens. Anthracyclines are a mainstay of treatment for early stage breast cancer, and retrospective analyses have suggested that the patients most likely to benefit from anthracycline treatment are those withHER-2–positivebreastcancers.Bothanthracycline-basedchemotherapy and trastuzumab are associated with increased rates of congestive heart failure (CHF), raising concerns about combining these strategies in the treatment of HER-2–positive disease, and leading to the avoidance of simultaneous use of anthracyclines with trastuzumab in the adjuvant trials. The patients who did not receive anthracyclines in the adjuvant trastuzumab trials included only the small number of patients who received nonanthracycline regimens, such as cyclophosphamide, methotrexate, and fluorouracil (CMF), before enrolling in the Herceptin Adjuvant Trial (HERA) trial, and those enrolled in the “TCH” (docetaxel/carboplatin/trastuzumab) arm of the Breast Cancer International Research Group (BCIRG) 006 study. That arm differed from the AC3T trastuzumab arms of the BCIRG trial with respect to the timing of trastuzumab vis-a-vis chemotherapy, the number of chemotherapy cycles, the duration of concurrent trastuzumab and chemotherapy, and the type of chemotherapy (cyclophosphamide versus carboplatin, and anthracycline versus not). Indeed, the approaches to the timing of trastuzumab and chemotherapy are important differences among the adjuvant trials. The duration of concurrent therapy ranged from none (HERA and North Central Cancer Treatment Group [NCCTG] N9831 sequential arm) to 9 weeks (Finland Herceptin [FinHer]) to 12 weeks (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31/NCCTG N9831 concurrent arms and BCIRG AC 3 T arm) to 18 weeks (BCIRG 006 TCH arm). Trastuzumab was initiated at the start of chemotherapy (FinHER and BCIRG 006 TCH arm), midway through chemotherapy (NSABP B-31/NCCTG N9831 and BCIRG 006 AC3 T arm), or after all chemotherapy was concluded (HERA and NCCTG N9831 sequential arm). Amid all these vagaries, how is one to know the best regimen? The major considerations in selecting the best regimen are treatment efficacy and treatment safety, particularly cardiac safety, which is the toxicity of greatest concern when adding trastuzumab to adjuvant chemotherapy. Unpublished preliminary data from the NCCTG N9831 trial suggest that concurrent use of chemotherapy and trastuzumab are superior to sequential therapy, a finding that has led to widespread use of concurrent treatment programs in North American practice. Unpublished preliminary data from the BCIRG trial suggest comparable efficacy between TCH and AC3 TH, though the study was not powered to establish the equivalence of the two trastuzumab-based approaches. Aside from these analyses, it is not possible to draw inferences regarding the most efficacious chemotherapy/trastuzumab regimen. Given the importance of cardiac toxicity, it is worth examining the methodologies used in the trials to assess cardiac safety. The landmark trials differed with respect to required cardiac function at baseline ( 50% before treatment in the BCIRG, NSABP and NCCTG trials; 55% after chemotherapy in the HERA trial) and differed in cardiac surveillance and definitions of cardiac toxicity. In the limited available follow-up, the incidence of symptomatic heart failure among trastuzumab-treated patients has ranged from 0.5 to 4.1%. Predictors of CHF include older patient age, preexisting hypertension, borderline-normal baseline left ventricular ejection fraction, and cumulative anthracycline exposure. A higher percentage of patients develop asymptomatic declines in ejection fraction of unclear long-term significance. Preliminary data suggest that the nonanthracycline TCH regimen may have a lower absolute risk by 1% to 2% than seen with AC 3 TH. However, the differences in the design and patient selection in the extant clinical trials make it difficult to determine which treatment strategy would be associated with the lowest risk of (CHF) for an individual patient. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 8 MARCH 1