June 07, 2017
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Standard surgery for melanoma with sentinel-node metastases does not extend survival

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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.

Jeffrey M. Farma
Mark B. Faries

“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).

Omid Hamid

“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.