What Do I Do Now?

September 20, 2010
Don S. Dizon, MD, FACP

The treatment of locally advanced breast cancer that does not completely resolve following neoadjuvant chemotherapy is unclear.

For patients with locally advanced breast cancers (LABC) primary or neoadjuvant chemotherapy (NAC) has become accepted as standard treatment. Advantages of NAC include shrinking the primary tumor, often making an advanced cancer resectable, and the theoretical treatment of metastatic disease that one cannot see, prior to definitive local treatment (surgery /- radiation therapy). NAC can reduce the extent of surgery required for the management of local breast cancer from mastectomy to lump- or segmentectomy, without compromising major outcome measures, such as overall and disease free survival, and this has been borne out in multiple trials. Still, women who completely resolve their breast cancers with chemotherapy before surgery have an excellent prognosis and this "complete pathologic response" remains a strong indicator that a women will survive her breast cancer.

However, the proportion of women receiving neoadjuvant chemotherapy who have complete resolution of their disease is not very high, and unfortunately, the treatment of women whose cancers do not completely resolve following NAC is not clear. There are no studies that have addressed the issue of "residual disease" and recommendations of how best to manage women in this circumstance are not evidence-based. The lack of any proven benefit for further chemotherapy in women with residual disease often results in a recommendation of "no further chemotherapy", which can often be an uncomfortable one for providers to give and patients to accept.



In one of the first studies to address this issue, the group at MD Anderson Cancer Center randomized women with high-risk breast cancer treated with primary chemotherapy to standard dosed adjuvant chemotherapy versus high-dose chemotherapy with peripheral blood stem cell support. In this study, women with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients received eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC) followed by randomization to two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and all patients were planned to undergo chest wall radiotherapy. Seventy-eight patients registered and 30 (38.5%) enrolled after NAC. Using intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% for FAC/no additional treatment versus 48% for FAC/high-dose chemotherapy ( =.35). The estimated 3-year survival rate was 77% and 58%, respectively ( =.23). Clearly, better treatment strategies are required for this population beyond the use of further standard agents.

In order to address this issue, we at Brown in collaboration with the group at the University of New Mexico are performing BrUOG 213. In this study women who have persistent breast cancer despite an anthracycline and a taxane-based neoadjuvant combination are given two chemotherapy agents together, capecitabine and gemcitabine. We chose these two agents because (1) earlier studies showed they could be combined safely and (2) because both drugs have a mechanism of action that does not mimic the actions of doxorubicin or paclitaxel. In addition to these chemotherapy agents we are using bevacizumab, as we believe a biologic may be of more use for women in whom chemotherapy alone did not completely work. We believe it is an important trial that asks a very important question. For further information on it, hit this link.