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Standard surgery for melanoma with sentinel-node metastases does not extend survival
Immediate completion lymph node dissection conferred no survival benefit compared with nodal observation among patients with melanoma who had sentinel node metastases, according to results of the randomized phase 3 MSLT-II trial.
Dissection improved disease control and offered prognostic information, but the procedure appeared associated with higher rates of complications.
“This study ... has provided us with outstanding data [that demonstrate] active close observation of the lymph node basin in patients with a positive sentinel lymph node is a safe alternative to completion lymph node dissection,” researcher Jeffrey M. Farma, MD, FACS, co-director of the melanoma and skin cancer program at Fox Chase Cancer Center, told HemOnc Today. “[Results also show] node dissection can be reserved for select high-risk patients immediately, or when there is clinical or radiographic recurrence in the lymph node basin. This collaborative effort provides high-level data that will change practice patterns internationally for melanoma patients.”
Prior research showed sentinel lymph node biopsy is associated with longer melanoma-specific survival among patients with node-positive, intermediate-thickness melanomas, defined as those 1.2 mm to 3.5 mm. However, the benefit of completion lymph node dissection — which consists of removing and performing biopsies on all lymph nodes near the original tumor — for patients with sentinel node metastases had not been established, according to study background.
The MSLT-II trial included 1,939 patients with sentinel node metastases detected by standard pathological assessment or multimarker molecular assay.
Researchers — led by Mark B. Faries, MD, co-director of the melanoma program and head of surgical oncology at The Angeles Clinic and Research Institute, an affiliate of Cedars-Sinai — randomly assigned patients to immediate completion lymph node dissection or nodal observation via ultrasonography.
The intention-to-treat analysis included 1,934 patients (dissection, n = 967; observation, n = 967). The per-protocol analysis included 1,755 patients (dissection, n = 824; observation, n = 931).
Melanoma-specific survival served as the primary endpoint. Secondary endpoints included DFS and cumulative rate of nonsentinel node metastasis.
After median 43-month follow-up, per-protocol analysis showed no significant difference between the dissection and observation groups with regard to mean 3-year rate of melanoma specific survival (86 ± 1.3% vs. 86 ± 1.2%). Analyses adjusted for other prognostic factors continued to show no significant between-group differences (HR for death = 1.08; 95% CI, 0.88-1.34).
“The new findings likely will result in many fewer of these procedures being performed around the world,” Faries said in a press release. “The results also will likely affect the design of many current and future clinical trials of medical therapies in melanoma.”
Patients assigned dissection achieved a higher 3-year DFS rate (68 ± 1.7% vs. 63 ± 1.7%), driven primarily by a higher rate of disease control in regional nodes at 3 years (92 ± 1% vs. 77 ± 1.5%; P < .001). Adjusted analyses showed the rate of nodal recurrence among patients with sentinel node metastases detected by pathological assessment was 69% lower in the dissection group (HR = 0.31; 95% CI, 0.24-0.41).
Researchers reported no significant difference in distant metastasis-free survival between groups (adjusted HR = 1.1; 95% CI, 0.92-1.31).
“Immediate completion lymph node dissection reduced the rate of regional nodal recurrence by nearly 70%, leading to a small but significant decrease in the overall risk [for] recurrence,” Faries and colleagues wrote. “[Because] no significant difference between the groups was noted in the primary endpoint, differences with respect to the secondary endpoints must be interpreted with caution. A nonsignificant difference in distant metastasis–free survival was noted at late time points but, as of this writing, events at those time points have been few, and additional follow-up is necessary.”
Nonsentinel node metastasis — observed in 11.5% of patients assigned dissection — strongly and independently predicted recurrence (HR = 1.78; P = .005).
Researchers also reported a higher rate of lymphedema in the dissection group (24.1% vs. 6.3%; P < .001). Most lymphedema cases (64%) were mild, 33% were moderate and 3% were severe.
The lack of survival benefit observed for immediate completion lymph node dissection contrasts with results of the MSLT-I trial, which showed patients with nodal disease and intermediate-thickness melanomas achieved better outcomes with immediate surgery than delayed surgery.
“[MSLT-II results suggest] that any increase in survival with early surgery occurred among patients with disease that was limited to the sentinel node,” Faries and colleagues wrote. “Patients with nonsentinel node metastases may still undergo salvage treatment with completion lymph node dissection, but the timing of that intervention does not appear to be critical.”
Prior to use of sentinel node biopsy, standard treatment at early melanoma diagnosis included dissection of all regional lymph nodes. Now, all regional nodes are removed only if sentinel nodes are positive for cancer.
Immediate complete lymph node dissection will remain an option for some patients, but it no longer will be the only standard option, Faries said.
The implications are clear, according to Omid Hamid, MD, chief of research/immuno-oncology at The Angeles Clinic and Research Institute, co-director of the cutaneous malignancy program at Cedars-Sinai and a HemOnc Today Editorial Board member.
“This new approach spares patients significant negative side effects and clarifies the road forward in development of additional therapies,” Hamid, who was not involved with the study, said in a press release. “Dr. Faries and colleagues’ contribution to the field of surgical oncology cannot be overstated.” – by Mark Leiser
Disclosure: Amyx Foundation, Borstein Family Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, John Wayne Cancer Institute Auxiliary and the NCI funded this study. Faries reports fees for advisory board service to Amgen, Immune Design and Myriad Genetic Laboratories. Farma reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Vernon K. Sondak
The surgical management of the regional lymph nodes in melanoma has long been an area of controversy. Sentinel lymph node biopsy has been widely adopted as an alternative to elective lymph node dissection — radical lymphadenectomy for clinically normal lymph nodes without prior knowledge of the pathological status of the nodes — and nodal observation with radical lymphadenectomy at the time of biopsy-proven nodal recurrence, known as therapeutic lymphadenectomy.
As originally conceived, sentinel lymph node biopsy was intended to obtain pathological staging of the regional nodal basin, with observation of the sentinel node–negative basin but completion lymphadenectomy whenever positive sentinel nodes are encountered.
This approach of sentinel lymph node biopsy followed by completion lymphadenectomy has been shown in a prospective randomized trial — the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) — to be associated with improved melanoma-specific survival for sentinel node–positive patients compared with patients randomly assigned to nodal observation but who subsequently developed nodal recurrence and underwent therapeutic lymphadenectomy.
Often, however, pathological analysis of the completion lymphadenectomy specimen performed after a positive sentinel lymph node biopsy fails to reveal any additional tumor-containing lymph nodes, prompting many to wonder whether completion lymphadenectomy was necessary in all patients with a positive sentinel lymph node biopsy.
Now we have the results of two prospective randomized clinical trials that tested this question: a relatively small study conducted in Germany referred to as the DeCOG-SLT trial, and the second Multicenter Selective Lymphadenectomy Trial, known as MSLT-II.
These two clinical trials involved 2,407 sentinel node-positive patients randomly assigned to either completion lymphadenectomy or nodal observation with serial ultrasonography and physical examination of the affected regional nodal basin.
As expected, few patients randomly assigned to completion lymphadenectomy had further melanoma detected in the lymph node dissection specimen (18% in DeCOG-SLT and 11.5% in MSLT-II). Median follow-up in both trials was relatively short (35 months in DeCOG-SLT and 43 months in MSLT-II), but the results of both trials are very similar. Neither trial showed any sign that completion lymphadenectomy is associated with improvement in melanoma-specific survival compared with nodal observation and therapeutic lymphadenectomy only for those patients who develop isolated nodal basin recurrence.
In an editorial accompanying the MSLT-II publication, renowned melanoma surgeon Daniel Coit, MD, stated: “If this aggregate of data is insufficient to extinguish the enthusiasm for immediate completion lymph-node dissection, then it is unclear what more is required.” So, is completion lymph node dissection outdated thinking with no role in modern practice, or does it remain an important aspect of the personalized care for patients with melanoma?
Let’s first answer Coit’s rhetorical question regarding what additional data would still inform decision-making regarding completion lymph node dissection. First and foremost is additional follow-up data over a longer period of time. In MSLT-I, the survival advantage associated with immediate lymphadenectomy in node-positive patients didn’t even begin to emerge for 2 years after surgery — and that was with the tumor-containing sentinel nodes left in the patient! It stands to reason that, once the tumor-containing sentinel nodes are removed, any benefit of removing nonsentinel nodes by completion lymphadenectomy would not become apparent for many months or even years. Additional data on the applicability of the trials results across all cohorts of sentinel node–positive patients also would be important before completely abandoning completion lymphadenectomy.
Another way to think about role of completion lymphadenectomy in contemporary melanoma management is to ask about the primary goals of nodal surgery. If the goal of surgery is to perform the fewest lymphadenectomies on patients, then sentinel lymph node biopsy followed by nodal observation in all cases would make sense. But if the goal is to minimize morbidity due to nodal disease and its treatment, there may be subsets of sentinel node–positive patients who have a very high risk for early nodal recurrence and, hence, might be better served by immediate lymphadenectomy rather than risk uncontrolled recurrence or at least a higher morbidity salvage surgery. Moreover, if the goal is to minimize overall morbidity and mortality due to melanoma, then the recognized prognostic information obtained by knowing the status of nonsentinel nodes combined with the more selective application of adjuvant systemic — and regional — therapy might represent the best strategy for at least some subsets of sentinel-node positive patients.
Finally, if the goal is to deliver patient-centered care that allows the patient to actively participate in treatment decision-making whenever two therapeutic strategies have similar anticipated survival rates, then it must be acknowledged that — for appropriately informed and selected patients — a proactive approach that includes completion lymph node dissection offers peace of mind, better staging information, excellent regional disease control and acceptable morbidity in the large majority of patients.
Completion lymph node dissection is not obsolete, at least not yet, and the best management of the sentinel node–positive patient will continue to involve a balanced discussion with patients about the risks and benefits of this procedure — now informed by two randomized trials and a high degree of confidence that there is no early impact of completion lymph node dissection on melanoma-specific mortality.
The likelihood is that many — perhaps even most — patients will be well served by a strategy that includes a thoroughly performed sentinel lymph node biopsy and careful nodal observation with subsequent therapeutic lymph node dissection in small percentage of patients who experience isolated nodal basin recurrence. Patients who undergo nodal observation after a positive sentinel lymph node biopsy also are appropriate for future adjuvant therapy trials — they have been uniformly excluded to date — and, indeed, nodal basin recurrence might represent an early endpoint for assessing therapeutic efficacy, much like pathological complete response has become in neoadjuvant therapy. The ideal strategy for management of the individual sentinel node-positive patient is still a goal we can only aspire to achieve, not a matter defined even by “practice-changing” clinical trials.
References:
Coit D. N Engl J Med. 2017;doi:10.1056/NEJMe1704290.
Faries MB, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1613210.
Leiter U, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)00141-8.
Morton DL, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1310460.