Effect Of Primary Breast Cancer Extirpation In Stage Iv Patients

Metastatic breast cancer is considered by many to be an incurable disease and therefore the treatment of such patients, whether with systemic therapy (chemotherapy, hormonal therapy), or with surgery is considered palliative (1). However, it has been suggested by others that there may be role for curative surgery in the treatment of selected patients with metastatic breast cancer (2, 3). Khan et al. were one of the first to describe an aggressive local surgical approach to metastatic breast cancer as a possible way of improving overall survival. They retrospectively examined over 16,000 patients with stage IV breast cancer derived from the National Cancer Data Base between 1990-1993, finding that 43% received either no operation or a variety of other diagnostic or palliative procedures and 57% underwent either a partial or total mastectomy (3). This study revealed that those patients who had free surgical margins had an improved overall 3-year survival compared to those not surgically treated. Multivariate analysis also showed that the overall number of metastatic sites, the type of metastatic burden, and the extent of resection of the primary tumor as significant independent prognostic factors.

Others began to focus on the true impact of local surgery on overall survival of women who initially presented with metastatic breast cancer and an intact primary tumor. Babiera et al. retrospectively analyzed 224 patients with metastatic breast cancer, of which 82 (37%) underwent surgical removal of the primary and the remainder (63%) were treated without surgery (4). They found that the patients who underwent removal of the primary tumor had a significant improvement in metastatic progression-free survival compared to the group that did not undergo surgery. Additionally, this study contradicts the notion that surgical removal of the primary is associated with an enhancement of distant metastatic tumor growth, a concept supported by several previous studies (5-7).

Rapiti et al. compared 300 patients with metastatic breast cancer who presented with an intact primary tumor of which 58% had no surgical intervention of the primary and 42% had a complete surgical removal of the primary (8). They found that the 5-year survival for those undergoing surgery with negative surgical margins was 27%, 16% with positive surgical margins, 12% with an unknown margin status, and 12% for women who did not undergo any form of surgery for their primary tumor. Thus, surgery of the primary tumor (with negative surgical margins) in patients with metastatic breast cancer was significantly linked to a >50% reduction in breast cancer mortality compared to women who did not have surgical treatment.

It has long been suggested that tumor cells from various histologies are capable of producing immunosuppressive cytokines and able to escape recognition by the host immune system through a variety of cellular mechanisms (9-11). Indeed, several lines of evidence suggest that early and complete surgical resection of distant metastatic disease may provide a survival benefit for patients with melanoma. Danna et al. elegantly demonstrate that the surgical removal of the primary tumor in mice (BALB/c-derived transplantable tumor 4T1 mammary carcinoma) with metastatic disease resulted in rebounding of antibody and cellmediated responses and restoration of immunocompetence (12).

This approach, best described as "complete cytoreductive immuno-therapeutic surgery (CCIS)," which removes the bulk of tumor burden in most cases, is hypothesized to allow for an improved overall function of the host antitumor immune response (13). Morton et al. hypothesize that CCIS of metastatic disease may allow the host immune system to overcome tumor-induced immunosuppression, recently describing his results from the premature closure of the onamelatucel-L (Canvaxin) trial designed to assess the efficacy of this vaccine in both stage III and stage IV melanoma patients. Although both trials were closed to further accrual early due to an interim analysis that revealed no probable efficacy over placebo, some very interesting results were nonetheless found in stage IV patients. The design of the Canvaxin trial for stage IV patients required that all patients receive definitive surgical removal of all metastatic disease prior to entry into the trial. Although there was no advantage to receiving the Canvaxin vaccine over placebo, they found that a remarkably high 40% of all patients (in both arms) were alive at 5 years, suggesting that prolonged survival may be due not to the vaccine, but instead to complete surgical resection of metastatic disease (14). This provides a clear proof-of-principle that CCIS of metastatic disease may be a critical part of the overall strategy for improvement of long-term survival in selected patients with advanced cancer.

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