Merrick I. Ross, MD
PROBABLY THE MOST IMPORTANT advance in the treatment of newly diagnosed primary melanoma has been the incorporation of sentinel lymph node biopsy as part of initial surgical management. The routine use of sentinel lymph node biopsy, often termed “sentinel lymphadenectomy,” in appropriately selected patients has provided valuable staging information as well as improved treatment outcomes in the node-positive cohort in terms of melanoma-specific survival, regional disease control, and surgical morbidity.
MSLT-I Trial and Retrospective Series
ALTHOUGH SUCH benefits were observed from many single institutional reports and collaborative multicentered efforts, confirmation was realized from the final results of the prospective randomized Multicenter Selective Lymphadenectomy Trial (MSLT)-I published in 2014.1 In this trial, patients with primary melanoma were randomized to receive either wide excision of the primary lesion and sentinel lymph node biopsy or wide excision alone.
By design, the patients with a positive sentinel lymph node underwent completion lymph node dissection as “standard of care.” These patients experienced a 20% improved melanoma-specific survival compared with patients who developed clinical failure in the observed intact regional nodal basin(s) after randomization to wide excision alone. These results provided proof of concept that patient outcomes can be improved by treating lymph node disease when microscopic compared with delaying treatment until nodal disease becomes clinically apparent. Since completion lymph node dissection was part of the surgical treatment, the routine practice of completion lymph node dissection was supported as the “standard of care.”
Theoretically, however, only patients with disease in additional nodes in the same basin (non–sentinel lymph nodes) can derive benefit from completion lymph node dissection, and in reality, less than 20% of these patients actually harbor such disease. Furthermore, several retrospective series demonstrated that patients who had non–sentinel lymph node metastases were found to have a particularly poor prognosis, above what would be predicted by the total number of nodes involved.
The combination of a small percentage of patients who could be impacted by completion lymph node dissection and the observation that these patients may have a poor prognosis despite aggressive surgical treatment led many to challenge the obligatory transition to completion lymph node dissection after a positive sentinel lymph node biopsy. Two prospective randomized trials were designed to address this equipoise and to determine what fractional benefit was afforded by the completion lymph node dissection above what was achieved by the removal of diseased sentinel lymph nodes.
Randomized Completion Lymph Node Dissection Trials
THE TWO TRIALS—DeCOG-SLT2 and MSLT-II3—were of similar design, randomizing sentinel lymph node–positive patients to undergo completion lymph node dissection or nodal basin observation augmented by ultrasonography. Reported at the 2015 ASCO Annual Meeting and published in May 2016, the DeCOG-SLT study was a particularly small trial (279 patients in each arm), with the majority being at relatively low risk of harboring disease in non– sentinel lymph node, as nearly 70% of the patients had less than 1 mm of sentinel lymph nodes tumor burden. No melanoma-specific survival difference was observed after a median follow-up of 3 years, despite a significant increase in the nodal basin recurrence rate in the patients randomized to nodal basin observation.
“It would be difficult to continue to endorse the practice of routinely recommending completion lymph node dissection, and therefore these trial results should be practice-changing.”— Merrick I. Ross, MD
The MSLT-II trial results, reported by Faries et al3 and reviewed in the September 25, 2017, issue of The ASCO Post—reflected a median follow-up of 37 months. The patient population was nearly four times the size of the DeCOG trial but still comprised mostly patients at low risk for non–sentinel lymph node involvement, with only 11% of patients who received completion lymph node dissection having additional positive nodes. Similar to the DeCOG-SLT results, no difference in melanoma-specific survival was observed in MSLT-II, despite increased nodal basin disease recurrence in the observation/ultrasound treatment group. It is relevant to note that more patients had recurrence in the nodal basin than would be predicted by the frequency of non–sentinel lymph node involvement, based on the pathologic evaluation of the completion lymph node dissection specimens, suggesting clinically relevant submicroscopic disease exists in nodes undetected by routine pathologic techniques.
AS A RESULT OF SURGEON BIAS, both trials can be criticized for not adequately addressing the impact of completion lymph node dissection on melanoma-specific survival in the at-risk patient population. But, on the other hand, the at-risk population may be the least likely to derive a melanoma-specific survival benefit from an aggressive surgical approach, since those patients with microscopic nodal disease that has spread beyond the sentinel lymph nodes appear to have an inherent unfavorable biology in terms of systemic dissemination. Supporting this notion is the multivariable prognostic factor analysis from MSLT-II demonstrating that the presence of non–sentinel lymph node involvement is an important independent predictor of survival. The MSLT-II trial also showed that patients who had completion lymph node dissection experienced increased morbidity.
Given the collective evidence, it would be difficult to continue to endorse the practice of routinely recommending completion lymph node dissection, and therefore these trial results should be practice-changing.
How Should Practices Change?
THE LACK OF SURVIVAL BENEFIT with completion lymph node dissection should not come as a surprise. Assuming the survival benefits achieved in the node-positive cohort in MSLT-I were a function of the removal of microscopic nodal disease that prevents nodal disease progression, and given that more than 80% of sentinel lymph node–positive patients have nodal disease limited to the sentinel lymph nodes, one could have predicted that most of the melanoma-specific survival benefits in the node-positive cohort in MSLT-I were the result of the sentinel lymph node biopsy itself, with little if any contribution from completion lymph node dissection. Once patients became eligible for completion lymph node dissection randomized trials, those in both treatment arms would have already equally derived the benefits of sentinel lymph node biopsy. Therefore, the sentinel lymph node biopsy can now be elevated to a therapeutic as well as staging procedure, and the term “sentinel lymphadenectomy” rather than sentinel lymph node biopsy is an appropriate designation.
Although the survival results of the MSLT-II trial were somewhat predictable, completing the trial was critical to have a prospective assessment of the primary endpoint as well as to provide information regarding other important endpoints such as regional disease control, prognosis, and surgical morbidity. Many surgeons had already altered their practices prior to the results of the MSLT-II trial, given the low probability of meeting the primary survival endpoint, and adopted a selective approach to completion lymph node dissection based on published predictors of non–sentinel lymph node involvement such as sentinel lymph node tumor burden, number of sentinel lymph nodes removed, and primary tumor thickness. Patients with non– sentinel lymph node disease can derive improved regional disease control with lower surgical morbidity. In addition, valuable prognostic information obtained by pathologic assessment of the completion lymph node dissection specimen can help oncologists make rational decisions about the role for adjuvant therapy. Accurate staging, and in turn accurate prognosis assessment, has become a critical issue in light of the new AJCC staging criteria of the 8th edition and the recently published results of the effectiveness of two adjuvant therapy regimens, which almost assuredly will receive U.S. Food and Drug Administration approval for the stage III patient population in the coming weeks. It is relevant to this discussion to note that in these trials, the sentinel node–positive patients did undergo completion dissection.
The majority of the treating melanoma community will likely fall in line, and completion lymph node dissection will no longer be recommended on a routine basis. Some may actually abandon the procedure completely. But the goals of durable regional disease control and enhanced staging information are still valid and laudable in the overall management of patients with melanoma and therefore a selective approach based on the predicted risk of non–sentinel lymph node involvement, the involved nodal basin, the risk of the planned dissection, patient age and underlying comorbidities, and the likelihood of patients receiving adjuvant systemic therapy seems rational.
Based on the recently published data, it would be appropriate and prudent to include active nodal basin observation/ultrasound surveillance as part of the evolving nationally based consensus melanoma treatment guidelines and in this way offer patients with a positive sentinel node more than one viable option and support surgeons who endorse a selective approach to completion dissection. ■
DISCLOSURE: Dr. Ross reported no conflicts of interest.
1. Morton DL, Thompson JF, Cochran AJ, et al: Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370:599-609, 2014.
2. Leiter U, Stadler R, Mauch C, et al: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): A multicentre, randomised, phase 3 trial. Lancet Oncol 17:757-767, 2016.
3. Faries MB, Thompson JF, Cochran AJ, et al: Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 376:2211-2222, 2017.