The evolving clinical management of sentinel node-positive melanoma: The impact of MSLT-II on clinical practice

Since the development and adoption of lymphatic mapping and sentinel lymph node (SLN) biopsy for patients with clinically node-negative primary cutaneous melanoma in the 1990s, completion lymph node dissection (CLND) has been recommended for patients with a tumor-involved SLN.^1-3 The results of the Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) provide evidence to refine treatment recommendations for melanoma patients with a positive SLN.⁴

Structure and goals

MSLT-II opened in 2004 as a phase III, multicenter, randomized controlled trial (RCT) of patients with at least one positive SLN (identified either by histopathology or as part of an additional component of the trial, by reverse-transcriptase polymerase chain reaction [RT-PCR])—randomizing patients to SLN biopsy (SLNB) with CLND versus SLNB with close observation of the mapped nodal basin(s), including nodal basin ultrasonography surveillance. The primary endpoint of the trial was melanoma-specific survival (MSS). Planned secondary endpoints included same basin nodal recurrence rate, disease-free survival (DFS), distant metastasis-free survival, and overall survival.

Two pathways were available for patient entry into the study. At some centers, patients undergoing wide excision and SLNB could be screened and preenrolled, followed by randomization if the patient had a positive SLN once SLN pathology was known. Patients with a known positive SLN also could be enrolled directly (see Figure 1). From 2004 to 2014, a total of 1,939 patients were randomized 1:1 to each arm and 1,755 patients ultimately were treated per protocol (824 with CLND and 931 with nodal observation and ultrasound).

After 43 months median follow-up, investigators reported no difference in three-year MSS between arms (86 percent for both, p = 0.42) with or without risk adjustment or exclusion of the 12 percent of patients with a histopathology-negative/RT-PCR-positive SLN. Three-year DFS was worse for patients in the observation arm (63 percent) versus CLND arm (68 percent), p = 0.05, reflective of a higher three-year same basin nodal relapse rate in the observation arm (23 percent versus 6 percent). Reported morbidity included lymphedema rates of 6 percent and 24 percent following observation or CLND, respectively. Among patients in the CLND arm, 15 percent, 8 percent, and 1 percent had mild, moderate, or severe lymphedema, respectively.

Limitations and opportunities

The rate of non-sentinel lymph node (NSLN) metastasis in the patients who underwent CLND in MSLT-II was 11.5 percent, reflective of the patient population enrolled, mainly patients with low burden disease in a single SLN, and at the lower end of the spectrum for NSLN involvement (9–23 percent).^5-7 In MSLT-II, >80 percent of patients had only one positive SLN, and the largest SLN metastasis diameter measured ≤1 mm in two-thirds of patients, potentially limiting statistical confidence and clinical application for patients with a higher SLN disease burden. Among patients screened and preenrolled, of those eligible, only 62 percent (377/608) with histopathologically positive SLNs and 56 percent (226/407) with histopathologically negative/RT-PCR-positive SLNs were randomized, indicating potential selection bias.

Incorporating the MSLT-II findings into clinical practice supports that for patients with clinically occult disease in a SLN, CLND is no longer required. However, for the small subset of patients for whom information from CLND would alter adjuvant treatment recommendations, CLND may play a role. Although MSLT-II included a minority of patients with significant SLN tumor burden, potentially questioning the applicability of the findings in high-risk patients, exploratory analyses reported in MSLT-II did not indicate a survival benefit from CLND for any subsets defined by SLN tumor burden.

The same basin nodal failure rate following CLND suggests opportunities for surgical standardization and quality improvement regarding technical aspects of CLND. To date, international efforts in this regard include procedural descriptions and suggested minimum node count per anatomic basin (15 for axillary LND and 8 for superficial inguinal LND in MSLT-II).^4,5,8,9 Compliance, however, appears suboptimal.¹⁰ Data on the number of nodes removed in the CLND arm of MSLT-II has not been published. The American College of Surgeons Operative Standards Manual provides surgical standards for oncologic surgery, and volume two includes melanoma surgery.

Areas for future investigation

The Food and Drug Administration’s approval of two new classes of drugs, targeted and immune checkpoint inhibitor agents, has dramatically changed the management of patients with advanced and unresectable melanoma and, more recently, adjuvant therapy options for patients with stage III disease following CLND. To date, clinical trials studying adjuvant therapy for stage III melanoma required CLND as an eligibility criterion. The impact, if any, of omission of CLND for SLN-positive patients who subsequently receive contemporary adjuvant therapy at present is unknown. The prognostic value of precise nodal staging including NSLN status, highlighted in MSLT-II in which a positive NSLN conferred a 1.78-fold increased risk of melanoma-related death, has been well-described, and can contribute to the decision to offer patients adjuvant therapy.^4,6 Methods to estimate NSLN status have been proposed, but consensus on an optimal algorithm is lacking.^2,11 Efforts are under way to develop molecular prognostic and predictive signatures for both the primary melanoma and nodal metastasis that may supplant and/or complement conventional histopathological biomarkers and further refine surgical staging and treatment in the near future.¹² From a pragmatic standpoint, no data are available at present to compare the cost of observation with imaging versus CLND nor on patient-reported outcomes (PROs). While MSLT-II and other studies report greater morbidity with SLNB and CLND compared with SLNB alone, prospective PROs data from another RCT suggest that quality of life and functional status from three months postoperatively onward is no different between patients treated with SLNB or SLNB and CLND.¹³

Although retrospective data suggest follow-up of a decade may be needed to see treatment-based survival differences among patients with SLN-positive melanoma,¹⁴ a recent update at the 2018 American Society of Clinical Oncology meeting of the previously published German Dermatologic Cooperative Oncology Group randomized clinical trial that compared CLND with nodal observation in patients with SLN metastasis <2 mm did not show divergence of overall survival with longer follow-up.¹⁵

Conclusions

Balancing the goals of minimized risk of relapse with reduced morbidity suggests SLNB may be both diagnostic and therapeutic for melanoma patients with clinically occult, SLN-positive disease and that surveillance with nodal basin ultrasound is an appropriate management strategy for many patients in lieu of routine CLND. Although some patients may not be optimal candidates for observation, the MSLT-II data do not clearly identify such a subset. Referral to a surgical oncologist with expertise in melanoma, preferably in a multidisciplinary care setting, may be extremely valuable to allow a careful informed discussion between patient and surgeon with consideration of patient comorbidities, tumor histopathology, likelihood of NSLN involvement, accessibility of imaging follow-up, consequences of regional relapse, potential morbidity, indications, risks and benefits of adjuvant therapy, and patient preferences.

References

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