Chemotherapy and Radiation Therapy for Breast Cancer: What Is the Optimal Sequence?

The optimal integration of systemic and local therapy in the treatment of early-stage breast cancer has been controversial. Unlike the treatment for many other cancers, chemotherapy and radiation therapy (RT) are typically not given concurrently in patients with breast cancer because of the widespread use of anthracycline-based chemotherapy regimens and the concern for excessive radiation toxicity with concurrent treatment. Hence it is necessary to decide how best to sequence systemic and radiation therapies. This question arises for both patients treated with lumpectomy and those treated with mastectomy. In patients treated with lumpectomy, there is a concern that delaying the initiation of RT until after chemotherapy might lead to higher rates of local (breast) recurrence (LR). Theoretically, delays in RT may allow progression of microscopic disease beyond that which can be treated with standard RT doses. This concern is heightened by the use of more prolonged chemotherapy regimens, such as the addition of the taxanes to doxorubicin and cyclophosphamide (AC). Several retrospective studies have found higher rates of LR in women for whom RT is delayed, but this finding has not been consistent across studies. A recent abstract by Pierce and co-investigators from Southwest Oncology Group and Eastern Cooperative Oncology Group reported a retrospective analysis of the 10-year results from four randomized trials involving chemotherapy and RT in patients treated with lumpectomy. The sequencing was determined by the treating oncologists. There were no differences seen in the rates of local, regional, or distant recurrence based on sequence. Although such data are somewhat reassuring, biases in treatment selection confound the interpretation and generalizability of these retrospective reviews. The only prospective randomized trial designed to study the sequencing of chemotherapy (doxorubicin, cyclophosphamide, methotrexate, fluorouracil, prednisone) and RT was performed by our group. It was first reported in 1996 and later updated in 2001. Because only 244 patients were randomly assigned, the trial was underpowered to detect small but potentially important differences in outcome. At 10 years, the updated report showed no statistically significant differences in overall patterns of first failure or event-free survival. As noted in the 5-year report, there were more LRs in the arm of patients who received chemotherapy first and more distant recurrences in the arm of patients who received RT first as sites of first failure; however, the distribution of sites of first failure between the two arms was no longer significant. In a regression model that examined interactions, there was a statistically significant interaction between treatment sequence and margin status. In this subset analysis by margin status, patients with close margins had a low LR rate in the RT-first arm, compared with a substantially higher rate when RT was delayed. Patients with positive margins had high rates of LR, independent of sequence, and patients with negative margins had low rates of LR with either sequence. This subset analysis requires confirmation by other studies. However, it suggests the hypothesis that close margins indicate the possibility of a greater residual tumor burden, a risk factor for LR that is compounded by any delay in initiating RT. Concerns about the delay in RT must be balanced against the beneficial effects of chemotherapy on local control when combined with RT either given concurrently or in sequence. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 randomized trial, 760 estrogen receptor–negative and node-negative patients were randomly assigned to methotrexate and fluorouracil (MF) or to no adjuvant chemotherapy. For patients treated with lumpectomy, RT was given concurrently with MF. At 8 years, the cumulative LR rate among women treated with lumpectomy and adjuvant MF chemotherapy was 2.6%, compared with 13.4% among women who received RT alone (P .001). Similarly, NSABP-19 compared MF JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 1 JANUARY 1 2005