The persistent anchor of lymph node removal in patients with melanoma

The management of regional lymph nodes in patients with clinically lymph node-negative (NN) cutaneous melanoma has changed over the past 15 years since the description and rapid international adoption of sentinel lymph node biopsy (SNB), first published in 1992 by Morton et al. Elective lymphadenectomy for NN melanoma came to be replaced by selective lymphadenectomy (SNB) with or without completion lymphadenectomy (CLND), which was reserved only for patients who harbored melanoma deposits in sentinel lymph node(s). There is general or universal agreement on the following: 1) Approximately 18% to 20% of patients with clinically NNmelanoma will have positive sentinel lymph nodes; 2) sentinel lymphadenectomy will identify 95% of lymph node-positive (NP) patients (false-negative rate, approximately 5%) with truncal and extremity melanoma; 3) only 10% to 20% of patients will have melanoma identified in nonsentinel lymph nodes removed at CLND by hematoxylin and eosin staining; and 4) no patient benefits from the excision of negative lymph nodes. Therefore, the majority of patients who undergo CLND will receive all of the morbidity with no added benefit. Because SNB can accurately stage the lymph nodes with limited morbidity, what is the role of excising additional lymph nodes in sentinel lymph node-positive patients? Potential benefits of removing additional positive lymph nodes earlier rather than later include enhanced regional control and the removal of regional metastases, which themselves may be the source of distant metastases, therefore improving long-term survival. The Multicenter Selective Lymphadenectomy Trial 1 (MSLT-I), an international, randomized controlled trial of selective lymphadenectomy versus observation, hoped to show that early lymph node intervention was better than delayed intervention in patients who had regional lymph node metastases. The primary endpoint of that trial was melanoma-specific survival, and the third interim analysis results indicated that there was no difference between the observation group and the SNB study group (86.6% and 87.1%, respectively). An additional planned subgroup analysis of NP patients who underwent SNB (n1⁄4 122) compared with patients who became NP in the observation group (n 1⁄4 78) revealed a 20% improvement in survival in the SNB group and a higher number of positive lymph nodes in the observational group that underwent therapeutic lymph node dissection [TLND]. Critics have noted that such subgroup analyses after randomization have limited validity and that SNB may be removing and identifying false-positive, limited-burden lymph node disease that is not clinically relevant; however, it is exactly these NP patients who we need to evaluate. Long-term follow-up of over 3300 patients with pathologically NP, American Joint Committee on Cancer (AJCC) stage III melanoma from the 2008 AJCC Melanoma Staging Database indicates that there has been a near flattening of the survival curves at 10 years, with a 25% to 70% 10-year survival rate, suggesting that long-term control or cure is possible with the removal of positive lymph nodes in a substantial percentage of patients. Intuitively, it has always made sense to remove clinically relevant, positive lymph nodes when the tumor burden is lowest. The number of positive lymph nodes is related inversely to survival, and several studies have reported an increase in the number of positive lymph nodes in patients who undergo delayed TLND or undergo CLND after a false-negative SNB. In this issue of Cancer, Pasquali et al report a nonsignificant 18% higher 5-year overall survival of their patients (total number1⁄4 190) who underwent CLND