Michael Lowe, MD
Ragini Kudchadkar, MD
DOES COMPLETE lymph node dissection for sentinel node–positive melanoma still have a role in the management of this disease? That’s debatable. Although it does not improve overall survival over observation alone, complete lymphadenectomy may have other benefits, according to a dialogue at the 2017 Debates and Didactics in Hematology and Oncology Conference at Sea Island, Georgia, between Michael Lowe, MD, Assistant Professor of Surgery, and Ragini Kudchadkar, MD, Associate Professor of Hematology and Medical Oncology, both at Emory University, which sponsored the conference.
Point: No Overall Survival Benefit
ALTHOUGH COMPLETION lymph node dissection for patients with positive sentinel nodes has long been the standard of care in melanoma, Dr. Lowe argued against it. “I’m a surgeon, and I am arguing that this surgery is irrelevant,” he said. “It should no longer be considered the standard of care.” While Dr. Lowe does not believe that complete lymph node dissection is always irrelevant, he does believe that it is not the right procedure for all patients. He argues that recent data suggest that we can safely avoid the procedure in most patients with melanoma.
Routine use of completion lymph node dissection is not backed by level 1 evidence, and several clinical trials found no overall survival benefit, vs observation. In addition, completion lymph node dissection conveys a risk for lymphedema and wound complications, “and this should be part of the discussion with patients when lymphadenectomy is being considered,” added Dr. Lowe.
I am arguing that [completion lymph node dissection] is irrelevant. It should no longer be considered standard of care.— Michael Lowe, MD
Completion lymph node dissection became the standard of care largely based on the “incubator” hypothesis: Melanoma spreads from the primary tumor to the sentinel node, where metastatic clones are “incubated” to become the source of systemic metastasis. The argument for more surgery is based on the prediction that removal of both sentinel and nonsentinel lymph nodes will prevent the distant spread of cancer.
But just as likely, he said, is the alternative “marker” hypothesis: Primary melanoma has an equal chance of simultaneously spreading to the sentinel node and to distant sites. Under this scenario, completion lymph node dissection would have no therapeutic significance, he maintained.
Three Studies, No Overall Survival Benefit
THREE IMPORTANT studies published over the past 7 years have shown that completion lymph node dissection does not improve overall or melanoma-specific survival. Memorial Sloan Kettering Cancer researchers retrospectively evaluated outcomes of patients with positive sentinel nodes who did and did not undergo completion lymph node dissection.1 Both recurrence-free and disease-specific survival did not differ between the treatment groups.
“These retrospective data have provided the rationale to forgo completion lymph node dissection in highly selected patients— mostly older patients who are too ill to undergo more surgery or patients who do not want another operation not supported by level 1 evidence [proving] that it will actually benefit them,” Dr. Lowe said.
The more recent prospective phase III trial from Germany, DeCOG-SLT, validated those findings.2 DeCOG-SLT, which randomized 473 patients with positive sentinel nodes to undergo completion lymph node dissection or observation, showed no difference in overall survival at 3 years. Follow-up was short and it excluded patients with head and neck melanomas. Because of these limitations, some considered the study to be insufficient in settling the question of benefit with completion lymph node dissection.
However, stronger confirmation came from the larger MSLT-II study,3 recently published in The New England Journal of Medicine with results similar to DeCOG-SLT. Observation included examination and ultrasound of the nodal basin every 4 months for the first 2 years, every 6 months for years 3 to 5, and annually through year 10.
“The results were the same as in DeCOG-SLT. Patients lived just as long if they had observation for a positive sentinel node,” revealed Dr. Lowe. After a median follow-up of 43 months, melanoma-specific survival at 3 years was 86% in each arm, regional recurrence–free survival was 77% with observation and 92% with completion lymph node dissection (P < .001), and disease-free survival was 63% and 68% (P = .05), respectively. “The likelihood of seeing a statistically significant difference in melanoma-specific survival, at any time in the future, was determined to be essentially zero,” he added.
Explaining the Difference in Regional Recurrence–Free Survival
AS EXPECTED, there was a difference in regional recurrence–free survival, but it should be noted that 11.5% of patients had disease that was not sentinel node–positive (ie, nodal involvement beyond the sentinel node), he said. These patients might be expected to recur; therefore, if they are excluded from analysis, leaving only the subset of patients in whom intervention in the nodal basin could help, then the regional recurrence–free rates were essentially the the same, Dr. Lowe explained.
For patients whose disease recurred only in the nodal basin, the recurrence risk was 7.7% with observation and 1.3% with completion lymph node dissection—an absolute difference of 6.4%. “With completion lymph node dissection, we are intervening on 100 patients to potentially save 6 from regional-only recurrence,” he pointed out.
This large study enrolled 1,934 patients, including those with head and neck melanomas. It had slightly longer follow-up, addressing the shortcomings of previous trials, and should settle the issue, according to Dr. Lowe.
“Until we find a way to determine who will have a positive sentinel node before sentinel node biopsy, all candidates for sentinel node biopsy should undergo this [procedure], and only highly selected patients should have completion lymph node dissection for sentinel node–positive disease.”
Counterpoint: Prognostic Information of Value
DR. KUDCHADKAR agreed completion lymph node dissection should not be performed in anticipation of a survival benefit, but she argued the surgery provides important prognostic information. By knowing the status of the lymph nodes, clinicians have accurate information for staging and risk stratification, which will allow high-risk patients to be selected for increasingly effective adjuvant therapy.
“Nonsentinel nodes do matter. Studies show that about 11% of nonsentinel nodes are positive at the time of surgery, and without completion lymph node dissection, we won’t have that information,” she said. “There are differences in outcomes based on single vs multiple nodes. Patients want to know their chance for recurrence.”
Dr. Kudchadkar also indicated that complete lymphadenectomy does benefit some patients, including, in early studies, patients with tumors 1.0 to 2.0 mm, nonulcerated, or occurring on limbs, and those whose nodes are electively removed, rather than removed only when clinically detectable.4 Completion lymph node dissection may also improve the quality of life of patients with bulky adenopathy in the neck or groin, she added.
I would advocate for complete lymphadenectomy for accuracy of staging. Patients want to know their risk.— Ragini Kudchadkar, MD
The key studies that have failed to show a survival benefit from completion lymph node dissection have limitations, including, in two of them, short follow-up and limited numbers of patients with head and neck melanoma, who have a risk of recurrence risk. She also maintained the populations may have been selected for good outcomes. “Surgeons would not enroll patients in a trial that might assign them to observation if they think those patients need completion lymphadenectomy from the beginning,” Dr. Kudchadkar commented. In addition, adjuvant trials required a complete lymph node dissection, which may have influenced who was allowed to enroll of MSLT trials. Additionally, patients in the observation arms were followed much more closely than patients in actual practice, perhaps leading to better outcomes than would be seen in actual practice.
Dr. Kudchadkar concluded: “The bottom line is I would advocate for complete lymphadenectomy for accuracy of staging. It’s important to us in deciding who gets adjuvant therapy, but it’s also because patients want to know their risk. The number of involved nodes definitely gives us more information…. I think completion lymph node dissection will remain part of melanoma management.”
In a debate, Drs. Lowe and Kudchadkar presented two extremes of an argument. It should be noted that the decision for complete lymph node dissection should be an on-going discussion between the treating physician and the patient. A multitude of factors, including risk of the procedure, patient age, location of melanoma, follow up requirements, and risk of systemic and locoregional recurrence should all be discussed thoroughly with the patient in order to make the best decision on whether to pursue a completion lymph node dissection in an individual. ■
DISCLOSURE: Drs. Kudchadkar and Lowe have no conflicts of interest.
1. Kingham TP, Panageas KS, Ariyan CE, et al: Ann Surg Oncol 17:514-520, 2010.
2. Leiter U, Stadler R, Mauch C, et al: 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.
4. Balch CM, Soong S, Ross MI, et al: Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7:87-97, 2000.