Continuing and new roles for surgery in the management of patients with stage IV melanoma.

Abstract

Until a few years ago, it was generally agreed that the best treatment option for melanoma patients with distant metastases (stage IV disease) was complete surgical resection, whenever possible. Those with more widespread disease or who were deemed unfit for surgery were referred to medical oncologists, but they had little to offer in the way of effective systemic therapy, and often simply recommended palliative end-of-life care. In the second decade of the 21st century, however, we have witnessed a dramatic change in the management of metastatic melanoma, with the introduction of two novel therapeutic drug classes – targeted small molecule inhibitors of the oncogenic BRAF V600 mutation or a downstream signaling target (MEK), and immune checkpoint inhibitors consisting of monoclonal antibodies against CTLA-4 and PD-1. Accordingly, clinical decision making for patients with stage IV melanoma has become increasingly complex, and multiple clinical trials are in progress to determine the best strategies to combine or sequence systemic treatment and surgery. Some believe that a complete paradigm shift in the approach to patients with metastatic melanoma has occurred, with surgeons no longer playing any useful role. A more enlightened view is that we have entered an era of truly integrated and carefully coordinated multidisciplinary care of these patients. The reality is that surgery remains an excellent treatment option for patients with just one or a small number of distant metastases. Complete surgical resection offers a rapid, cost-effective means of rendering them clinically disease free and should be the first-line treatment in appropriately screened patients. This strategy is supported by the results of several clinical trials. Good survival outcomes were achieved in the CanvaxinTM stage IV trial, which compared patients who received adjuvant treatment with Bacillus Calmette–Guérin (BCG) and an allogenic melanoma vaccine after complete resection of metastatic disease to patients who received only BCG with placebo after resection [1]. While the study did not show any benefit in the vaccine-treated arm, 5-year overall survival (OS) rates following complete surgical resection were approximately 40% in both groups, substantially higher than would have been expected if the patients had been treated with the systemic therapies that were available at the time. The Southwestern Oncology Group’s prospective multicenter trial of patients with surgically resectable metastatic melanoma also found that prolonged OS can be achieved by complete resection. While median relapse-free survival (RFS) was short (5 months), median OS was 21 months and 4-year survival was 31% [2]. In the first Multicenter Lymphadenectomy Trial, retrospective analysis of patients who developed distant metastases found that inclusion of surgery as part of the treatment plan conferred a survival advantage, even in patients who developed high-risk visceral metastases. If surgery was performed, the median survival was 15.8 months, with a 4-year survival of 20.8%, compared with 6.9 months and 7.0%, respectively, in patients who received systemic medical therapy alone (p < 0.0001; HR: 0.406) [3].