End Results of Salvage Therapy After Failure of Breast-Conservation Surgery

Drs. Lannin and Haffty's comprehensive and thoughtful review of breast cancer recurrence following breast-conserving therapy details the risk factors for local recurrence, factors predictive of outcome at the time of a breast recurrence, and prognosis after recurrence. The complex interaction between local and distant recurrence is also explored; the authors argue that locally recurrent disease is both a marker of a more aggressive primary cancer, as well as a potential source for seeding distant sites. Strategies for managing local recurrences are also discussed. We are in agreement with this excellent review and will take this opportunity to expand on a few points. The strongest predictors of local recurrence following breast-conserving surgery are patient age, surgical margin, and the use of systemic therapy. The latter association has been convincingly demonstrated with both chemotherapy and hormonal therapy, and may potentially influence our thoughts on the adequacy of the surgical margin. The National Surgical Adjuvant Breast and Bowel Project B-06 trial[1] showed a reduced risk of local recurrence in women with positive nodes who received adjuvant systemic therapy (melphalan [Alkeran] and fluorouracil(Drug information on fluorouracil) [5-FU]) in addition to radiation therapy (8.8% rate of local recurrence at 20 years vs 14.3% for the entire cohort). The reduction in local recurrence with the addition of systemic therapy applies at least as much to the adjuvant use of tamoxifen(Drug information on tamoxifen) and, more recently, to aromatase inhibitors. Randomized trials of tamoxifen vs placebo in patients treated with breastconserving therapy have demonstrated a substantial reduction in local recurrence with tamoxifen when combined with radiation therapy.[2,3] In the Arimidex, Tamoxifen Alone and in Combination (ATAC) trial,[4] the local recurrence rate was at least as low in patients treated with anastrozole(Drug information on anastrozole) (Arimidex) as with tamoxifen. In the National Cancer Institute of Canada trial,[5] which studied the utility of an aromatase inhibitor following 5 years of tamoxifen, the addition of letrozole(Drug information on letrozole) (Femara) further reduced the risk of local recurrence. Whether the timing of the use of tamoxifen in relation to radiation therapy influences the risk of local recurrence remains unknown. A recent abstract by Pierce et al[6] found no difference in the risk of local recurrence when radiation was given concurrently or sequentially with radiation therapy. There is also evidence that the risk of local recurrence is potentially influenced by the timing of adjuvant chemotherapy. While several studies have shown an increased risk of local recurrence when radiation therapy is delayed, this effect seems to be most prominent in women with close margins. In the updated results of a randomized trial comparing chemotherapy followed by radiation therapy with immediate adjuvant irradiation followed by chemotherapy,[7] there were no statistically significant differences in the overall pattern of first failures, with a median follow-up of 11.3 years. In the group with close margins, however, the risk of local recurrence was 4% when radiation was delivered promptly after surgery, compared with 32% in the group that received delayed radiation. Overcoming Adverse Risk Factors
Some research has suggested that the addition of systemic therapy might overcome adverse risk factors for recurrent disease. Park et al[8] reported a retrospective look at the risk of local recurrence in 533 patients. On multivariate analysis, only margin status and the use of systemic therapy predicted for local recurrence. The risk of recurrence at 8 years was 7% in women with close (< 1 mm) or negative margins, and this increased to 13% with focally positive margins. However, the risk in women with focally positive margins fell to 7% with the addition of systemic therapy. Assersohn[9] also reported on a high-risk group of women with positive margins (defined as at the margin or within 1 mm). Local recurrence was 3% (2/70). Similarly, in a prospective trial of concurrent CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate, 5-FU) and reduced-dose radiation therapy (3,960 cGy to the whole breast, 1,600 cGy lumpectomy site boost),[10] crude rates of local recurrence were 4%, 6%, and 4% in patients with negative, close, and positive margins, respectively. Clearly, the more modern focus on anthracycline- based regimens makes concurrent integration with radiation therapy more problematic, resulting in the widespread use of a sequential approach. Galper et al[11] reported on one of the largest series of women with recurrences in the breast following conservative surgery. In this study, 341 patients were followed for a median of 85 months after a local recurrence. The disease-free survival rate at 5 years was 65%, which is consistent with the prognosis reported in multiple trials summarized by Lannin and Haffty. On multivariate analysis, factors influencing the risk of distant recurrence, second nonbreast malignancies, or death included invasive histology of the recurrent disease, time to recurrence of less than 1 year, and age > 60 at diagnosis. As Lannin and Haffty also emphasize, surgery less extensive than a mastectomy is associated with a higher risk of subsequent recurrence. Galper et al found that no local therapy at the time of recurrence (vs mastectomy) and a second local excision (when compared with mastectomy) were associated with a higher risk of distant spread.[11] Although there are small preliminary studies examining the role of partial breast irradiation following local recurrence in order to avoid mastectomy,[ 12,13] the data are far too premature for this strategy to become standard treatment. We agree that at the present time, the clear standard for treating breast recurrence following conservative surgery and radiation therapy is mastectomy. Despite the established increased risk of distant metastasis in patients with a local recurrence after breastconserving breastconserving therapy, we agree that there is little evidence firmly supporting the role of systemic therapy in such patients. Further study is required to more fully elucidate the role of systemic therapy in this situation.