The role of sentinel lymph node biopsy and options for treatment after initial surgery are areas that are of particular interest to patients who are newly diagnosed with melanoma.
Melanoma remains the deadliest form of skin cancer. Its rapidly increasing incidence over the last several decades, together with our aging population, will result in dramatic increases in the number of newly diagnosed patients.
Significant advances in the assessment and treatment of patients with melanoma over the last several years, however, now allow more individualized treatment, which is both more effective and less toxic than earlier alternatives.
Two areas that are of particular interest to patients who are newly diagnosed with melanoma are the role of sentinel lymph node biopsy in their care, and options for treatment after that initial surgery. Both areas have seen rapid advancement in the modern era and have been evaluated in clinical trials, data from which recently have been reported (Table 1).
Regional Lymph Node Management
In most cases in which melanoma metastasizes, the site of initial metastasis is the regional nodal basin. This clinical finding was noted more than a century ago and led to proposals for immediate removal of all regional lymph nodes at the time of initial treatment for every melanoma diagnosis. This “elective lymph node dissection,” however, was accompanied by a significant risk of morbidity, and in most cases, all of the lymph nodes removed in the operation were normal (Figure 1A). Randomized trials evaluating elective node dissection did not show an unequivocal survival benefit, though trends toward benefit were fairly consistent, with significant survival improvements in several subgroup analyses.
While the elective-node debate raged on, Morton and colleagues altered the treatment landscape through the development of lymphatic mapping and sentinel lymph node biopsy.1 This enabled regional staging, which was actually more accurate than the older, larger operation and spared most patients the morbidity of complete dissection. (Figure 1B). With a negative sentinel node, patients could have their regional nodes safely observed. At the time, those with sentinel node metastases went on to completion dissection. The old debate was completely reframed as a result.
The technique was subjected to evaluation in large, multicenter clinical trials. The long-term results of one of these trials, the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were reported in 2014 and clarified the utility of the procedure.1 First, MSLT-I confirmed that the pathologic status of the sentinel node was the most important prognostic variable. In fact, the staging accuracy of sentinel node biopsy was markedly better than that of elective lymph node dissection, because pathologists could concentrate their examination on a small number of nodes, making evaluations such as immunohistochemistry possible. This prognostic validation followed numerous prior retrospective series and other prospective clinical trial data.
MSLT-I also confirmed that the procedure was generally well tolerated with much less toxicity than compete dissection. Even for those patients who underwent full dissection, MSLT-I showed that proceeding with that surgery for clinically occult disease (detected by sentinel node biopsy) had a lower risk for the most feared complication, lymphedema, than those who underwent dissection for a clinically detected recurrence. Finally, for patients with intermediate thickness melanomas, early removal of nodal metastases was associated with a marked reduction in the risk of dying of melanoma compared with later removal at the time of clinical recurrence.
Based on these and other data, the procedure is now a accepted as part of standard melanoma management for patients with intermediate-thickness and thick melanomas. Uncertainty remains regarding which patients with thin melanoma should be considered for the procedure, due to their low risk of metastasis for those patients.
The most recent guidelines from the American Society of Clinical Oncology, the Society of Surgical Oncology, and the National Comprehensive Cancer Network suggest that for patients with melanomas with tumor thickness from 0.8 to 1 mm, the procedure should be considered as an option.2
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Treatment of a Positive Sentinel Lymph Node: MSLT-II
Lymphatic mapping and sentinel lymph node biopsy were initially developed as a method for determining which patients should have a complete regional node dissection. However, as experience with the procedure grew, it became apparent that most patients with sentinel node metastases had all of their regional disease removed at the time of the minimally invasive nodal biopsy. As a result, most patients undergoing completion lymph node dissection had only normal lymph nodes found. Those patients who did have nonsentinel node metastases also had a relatively unfavorable prognosis, similar to the prognosis of patients with clinically-apparent regional disease. This led to the question of whether immediate completion lymph node dissection was necessary for patients with positive sentinel nodes, or whether such patients could be safely followed with intervention only if they developed regional recurrences.
This question has now been prospectively evaluated in 2 randomized clinical trials, the results of which were recently reported. The 2 trials were the DeCOG-SLT from the German Dermatologic Cooperative Oncology Group (n=483 randomized) and MSLT-II (n=1939 randomized).3,4
Both trials showed that the additional regional surgery decreased the risk of recurrence in the nodal basin but did not reduce recurrences at distant sites or improve overall survival. There was significant staging or prognostic information gained from the completion dissection, which was independent of other variables (hazard ratio [HR], 1.78; P=.005). Both trials included nodal ultrasound to facilitate evaluation of regional nodes in follow up. These findings have been rapidly translated to guideline recommendations for management of patients with sentinel node melanoma metastases.2
At present, completion dissection remains an option for patients based on its ability to provide prognostic information and decreased risk of regional nodal recurrence, but careful observation is now an acceptable standard choice as well (Table 2). Unlike MSLT-I, MSLT-II did not demonstrate a suggestion of survival benefit in any particular subgroups. The trial was not powered to adequately address subgroups; therefore, some uncertainty remains regarding whether any specific patient cohorts would be better managed with immediate dissection. However, none of the groups that had been hypothesized to be more likely to benefit exhibited even trends toward improved outcomes.
Implications of MSLT-II for the Use of Sentinel Node Biopsy
Does the lack of survival benefit for completion lymph node dissection demonstrated in MSLT-II and DeCOG-SLT diminish the rationale for sentinel node biopsy? In fact, the result is probably the opposite. This is because it appears that most of the benefits in terms of staging and survival seen in MSLT-I were derived from the sentinel node portion of the intervention, rather than the larger complete dissection.
Although completion dissection provides significant staging information, the most important prognostic discrimination is provided by the sentinel node. Although regional disease-free survival is improved by completion dissection, most patients with regional metastases have all of their nodal disease removed with the sentinel node. So more often than not, regional control can be obtained with the minimally invasive, low morbidity lymphatic mapping procedure. Omitting sentinel node biopsy would result in increased clinical nodal recurrences and, therefore, increased need for complete dissections.
In addition, the combined results of MSLT-I and MSLT-II indicate that any survival benefit derived from early nodal intervention occurs in patients whose disease is limited to the sentinel node. Overall, it would seem the impetus for sentinel node biopsy is increased as a result of MSLT-II and DeCOG.
Adjuvant Medical Therapy
At the European Society of Medical Oncology (ESMO) meeting in September 2017, the landscape of adjuvant medical therapy for melanoma was changed forever. Until that time, choices for systemic treatment after surgical resection of metastatic disease were limited. Available agents included interferon-α; pegylated interferon-α, and ipilimumab, the anti-CTLA-4 checkpoint inhibitor.
All of these therapies were attended by the risk of significant toxicity. Interferon-α had been shown to improve recurrence-free survival, but its effects on overall survival were still debated—and modest at best. Ipilimumab (Yervoy) had shown both recurrence-free survival and overall survival improvements, but only, to date, in a population that generally did not have access to the drug in the metastatic setting. Because checkpoint inhibition can lead to long-term durable responses (or perhaps cures) in the metastatic setting, the overall survival benefit of this potentially toxic agent was not entirely clear.
Two trials presented at the ESMO meeting and subsequently published have altered this situation. One involved adjuvant therapy using a combination of inhibitors of BRAF and MEK in patients whose melanomas harbored a V600E or V600K mutation, which is present in approximately half of melanomas. This trial demonstrated a significant improvement in recurrence-free survival.5 Overall survival was also better in the treatment arm of the trial compared to the control arm (HR, 0.57; P=.0006). In that study, patients did generally have access to the same or similar drugs if they needed them in the metastatic setting, suggesting early treatment is more effective than later treatment at the time of recurrence.
The other study examined the use of nivolumab (Opdivo), an inhibitor of the programmed death-1 (PD-1) checkpoint.6 This study showed significantly improved recurrence-free survival compared with the control arm of ipilimumab, which, as we have seen, also has activity. This improvement over an active control therapy adds to the therapeutic impression for adjuvant anti-PD-1 therapy.
The toxicity that accompanied these adjuvant therapies also appears much more acceptable than that of our earlier options. Combined BRAF and MEK inhibition is associated with fever and muscle and/or joint pain as common adverse effects. Some toxicities, such as an increase in squamous carcinomas of the skin, seen with BRAF inhibition alone were not as frequent with the combination regimen.
Overall, only about 1 in 4 patients had to stop treatment due to side effects. For anti-PD-1 therapy, toxicities in general were autoimmune, as is the case overall for checkpoint inhibition. These adverse events for nivolumab, though, appear much less worrisome than those associated with ipilimumab, particularly in the adjuvant setting. Only about 8% of patients receiving nivolumab stopped treatment due to adverse effects.
While mortality from melanoma remains too high, significant progress has been made in recent years not only in improving outcomes, but also in decreasing the morbidity associated with treatment.
Using currently available techniques, patient prognosis now can be more precisely assessed, therapy can be individualized to risk, and patients can expect better long-term survival than was possible even a few years ago. Additional research will likely improve those results in the coming years.
The era of a nihilistic approach to melanoma is definitively over, having been replaced by a new era of personalized, less morbid, and more effective therapy. It should only get better going forward.
Dr Faries is co-director of the Melanoma Program and head of Surgical Oncology at The Angeles Clinic and Research Institute, an affiliate of Cedars-Sinai, in Los Angeles, CA.
Disclosure: Dr Faries is on the Novartis Advisory Board, Castle Biosciences Advisory Board, and is a consultant for Delcath Systems.
1. Morton DL, Thompson JF, Cochran AJ, et al; MSLT Group. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
2. Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. Ann Surg Oncol. 2018;25(2):356-377.
3. Leiter U, Stadler R, Mauch C, et al; German Dermatologic Cooperative Oncology Group. 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. 2016;17(6):757-767.
4. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222.
5. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823.
6. Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835.