Table 6. Standard Adjuvant Chemotherapy Regimens for Stage I, II, IIIA, and Operable IIICHER2/neuNon-Overexpressing Breast Cancer continued...
It is important to note that DFS, RFS, and OS have not been reported in this trial. pCR rates, while hypothesis-generating, do not substitute for these other efficacy endpoints. Nevertheless, the results suggest that dual inhibition of HER2 by a monoclonal antibody and a tyrosine kinase should be further explored for patients with early stage HER2-positive breast cancer. Confirmatory results from the similarly designed, ongoing, CALGB-40601 (NCT00770809) trial are pending. More definitive efficacy data will be provided by the phase III ALLTO trial that is randomly assigning women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.
At present, there is no established role for the use of bevacizumab as part of neoadjuvant chemotherapy for breast cancer. Bevacizumab is a monoclonal antibody that works against vascular endothelial growth factor A and has shown some degree of efficacy in the metastatic setting. Two randomized phase III clinical trials of chemotherapy with or without bevacizumab have reported results. [223,224]
One trial randomly assigned 1,206 patients with primary operable HER2-negative breast cancer to receive chemotherapy with or without bevacizumab. The addition of bevacizumab significantly increased the rate of pCR (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = .02).[Level of evidence: 1iiDiv] However, the addition of bevacizumab increased the rates of hypertension, cardiac toxicity, hand-foot syndrome, and mucositis.
Another study randomly assigned 1,948 patients with operable HER2-negative breast cancer to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel with or without concomitant bevacizumab. The addition of bevacizumab in this study also significantly increased the rate of pCR (14.9% without bevacizumab vs. 18.4% with bevacizumab, P = .003).[Level of evidence: 1iiDiv] Similarly to other clinical trials, the addition of bevacizumab increased toxicity, with higher rates of febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension, but it did not increase surgical complications.
Of note, OS and DFS outcomes were not reported in either clinical trial.[223,224] Based on these results, bevacizumab should not be used in the treatment of operable breast cancer. Caution should be used in interpreting pCR as a primary clinical outcome. However, further study of bevacizumab for the treatment of operable breast cancer may be warranted.
Adjuvant radiation and chemotherapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery was studied in a randomized trial. Patients received either chemotherapy first (n = 122), consisting of CMFP plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation, or breast radiation first (n = 122), followed by the same chemotherapy. With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).[Level of evidence: 1iiA] The 5-year crude rates of first recurrence by site in the radiation-first and chemotherapy-first groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07). Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those that had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, though the statistical power of these subgroup analyses was low. Potential explanations for the increase in distant recurrence noted in the radiation therapy-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages due to increased myelosuppression.