CLND as standard of care for patients with SLN-positive metastatic melanoma is supported by a wealth of compelling prospective data.
A positive sentinel lymph node (SLN) is the most important prognostic factor in patients with clinically localized melanoma.[1,2] Complete lymph node dissection (CLND; by definition, lymph node dissection of the sentinel node–positive basin) and nodal basin observation with delayed (therapeutic) lymphadenectomy reserved for patients who experience resectable nodal recurrence represent two competing management philosophies. These approaches are being prospectively compared in randomized trials in which melanoma patients with at least one positive SLN are randomized to either CLND or nodal observation: the large Multicenter Selective Lymphadenectomy Trials (MSLT-1 and MSLT-2)[2,3] and the much smaller German Dermatologic Cooperative Oncology Group (DeCOG)-SLT trial. Until mature results from these studies are available, the standard of care remains CLND, based upon prospective evidence of lesser morbidity and superior survival. Outside of a clinical trial, this standard-of-care approach to the SLN-positive basin should be abandoned only with the greatest of caution.
SLN biopsy was designed to restrict lymphadenectomy only to the 15% to 20% of patients with microscopic nodal involvement at the time of presentation, not to definitively treat microscopic tumor metastases. The rationale for an observational approach is to avoid the morbidity of lymphadenectomy (specifically to avoid the possibility of lymphedema) for two subsets of patients who never manifest isolated recurrence in the lymph node basin: those who have no melanoma remaining in the nodal basin and those who experience distant treatment failure at or before the time of nodal recurrence. The percentages of patients in these subsets remain to be defined, and no accepted criteria can predict which patients are most likely to develop isolated nodal recurrence, and hence eventually require lymphadenectomy. Importantly, when eventual nodal recurrence makes delayed lymphadenectomy necessary, the procedure is actually associated with considerably higher morbidity than would have occurred had CLND been done promptly after SLN biopsy. Prospective data from the pioneering MSLT-1 trial indicate that patients undergoing delayed lymphadenectomy after nodal basin recurrence have significantly increased risk of complications, especially lymphedema, compared with patients who undergo CLND. Moreover, postoperative lymphedema was more likely to be moderate or severe after delayed lymphadenectomy. In the MSLT-1 trial, patients with isolated nodal recurrence had more total lymph nodes involved by melanoma than patients randomized to SLN biopsy who had a positive biopsy (all of whom were to have CLND; an average of 3.2 lymph nodes involved with metastatic melanoma vs only 1.4 positive nodes, respectively; P < .0001), and were more likely to meet established criteria for adjuvant radiation, which further increases the risk of postoperative lymphedema. Additionally, patients who underwent delayed lymphadenectomy had significantly longer hospital stays compared with those undergoing CLND. Therefore, the benefit some patients may derive by avoidance of lymphadenectomy is counterbalanced by higher morbidity, including increased risk of moderate to severe lymphedema and longer hospital stays in the event that a delayed CLND is required following observation.
Increased morbidity is not the only risk patients who forego standard-of-care CLND may face. The MSLT-1 trial demonstrated that patients with a positive SLN undergoing CLND had far better melanoma-specific survival than those patients who manifested nodal recurrence either on the observation arm or after a false-negative SLN biopsy (10-year melanoma-specific survival rates: 62.1% vs 41.5% and 34.4%, respectively). These data strongly suggest that unresected, clinically occult regional nodal disease can adversely affect melanoma-specific survival. Importantly, the survival curves for these groups did not begin to diverge until year 2 or beyond after initial surgery, and continued to widen for the entire 10-year period, which means preliminary results from the relatively small DeCOG-SLT study-with its 3-year median follow-up-cannot be relied upon to justify changing the standard of care away from CLND. Furthermore, SLN-positive patients who defer lymphadenectomy until clinically detected nodal recurrence may present with unresectable disease, representing a missed opportunity for regional disease control. Unfortunately, uncontrolled regional disease can result in problems that even today’s more effective systemic melanoma treatments do not always mitigate. At present, optimum follow-up strategies for monitoring the SLN-positive nodal basin in patients who chose to forego CLND have not been defined. However, it is clear that nodal basin recurrence can occur years or even decades after initial surgery, so patients who choose nodal observation are committed to long-term follow-up of uncertain value.
CLND also offers additional staging and prognostic information that influence subsequent adjuvant systemic therapy options. For example, metastases in nonsentinel nodes upstage patients with non-ulcerated primaries from stage IIIA to IIIB or IIIC. Currently, lymphadenectomy is an eligibility requirement for cutting-edge adjuvant therapy trials such as Southwest Oncology Group (SWOG) 1404 (ClinicalTrials.gov identifier: NCT02506153), which randomizes stage III melanoma patients to an anti–programmed death 1 antibody or standard-of-care adjuvant therapy (high-dose interferon or high-dose ipilimumab). Offering our SLN-positive patients access to all standard and investigational adjuvant therapy options is yet another reason why standard-of-care CLND should not be abandoned lightly.
In summary, CLND as standard of care for patients with SLN-positive metastatic melanoma is supported by a wealth of compelling prospective data. Patients choosing nodal observation, but ultimately requiring delayed lymphadenectomy, risk unresectable regional recurrence and increased morbidity, a longer stay in the hospital, and potentially poorer survival. This is a high price for many patients to pay in order for an undefined fraction of others to avoid lymphadenectomy entirely (but not the need for decade-long follow-up of the nodal basin). Consequently, until we have better ways of defining those patients who have been cured by SLN biopsy alone (or the long-term results of current prospective trials indicate otherwise), nodal observation should be chosen by SLN-positive patients only after very careful consideration, and not routinely recommended by surgeons or oncologists as a proven alternative to avoiding CLND.
Financial Disclosure:Dr. Sarnaik serves on the scientific advisory board of B4CC, Inc; Dr. Zager serves on the scientific advisory board of Amgen, Inc, Castle Biosciences, Inc, and Delcath, Inc; Dr. Sondak serves on the scientific advisory board of Bristol-Myers Squibb, Inc, and Merck, Inc.
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