What trial determined that adjuvant immunotherapy is preferred over completion lymph node dissection (CLND) for a patient with melanoma and a positive sentinel lymph node biopsy (SLNB)?

MSLT-II Trial Established Observation Over Routine CLND for Positive SLNB Melanoma

The Multicenter Selective Lymphadenectomy Trial II (MSLT-II) is the landmark randomized controlled trial that determined completion lymph node dissection (CLND) does not improve melanoma-specific survival compared to observation with nodal ultrasound surveillance in patients with sentinel lymph node-positive melanoma. 1

Key Trial Design and Findings

MSLT-II was a multicenter phase III randomized controlled trial conducted from December 2004 to March 2014 that enrolled 1,934 patients (1,755 in per-protocol analysis) with positive sentinel lymph node biopsies. 1 Patients were randomized to either immediate CLND (n=824) versus observation with frequent nodal ultrasonography and therapeutic lymph node dissection only if clinically detected nodal recurrence occurred (n=931). 1

Primary Survival Outcomes

• No significant difference in melanoma-specific survival was found between CLND and observation groups (HR 1.08; 95% CI 0.88-1.34; P=0.42). 1
• No significant difference in distant metastasis-free survival was observed (adjusted HR 1.10; 95% CI 0.92-1.31; P=0.31). 1
• The 3-year disease-free survival rate was 68% in the CLND group versus 63% in the observation group (log-rank P=0.05), with the difference attributed to regional nodal disease control rather than survival benefit. 1

Morbidity Differences

• Lymphedema was reported by 24.1% of patients in the CLND group compared to only 6.3% in the observation group, representing a nearly 4-fold increase in this quality-of-life-impairing complication. 1

Supporting Evidence from DeCOG-SLT Trial

The German Dermatologic Oncology Cooperative Group trial (DeCOG-SLT) provided corroborating evidence, randomizing 483 patients with positive SLNB (majority with micrometastasis) to CLND versus observation from January 2006 to December 2014. 1 This trial also found no survival benefit: overall survival HR 1.02 (90% CI 0.68-1.52; P=0.95). 1

Current Guideline Recommendations

The 2018 ASCO-SSO clinical practice guideline update, based primarily on MSLT-II results, now supports observation as an acceptable alternative to immediate CLND for appropriately selected patients with positive sentinel lymph nodes. 1 This represents a paradigm shift from the 2012 guidelines that recommended CLND for all patients with positive SLNB while awaiting MSLT-II results. 1

Real-World Implementation with Adjuvant Immunotherapy

Recent real-world data demonstrates that adjuvant anti-PD-1 therapy without immediate CLND achieves similar relapse-free survival rates (24-month RFS of 67%) as the original clinical trials that mandated CLND. 2 In a retrospective analysis of 326 patients receiving adjuvant anti-PD-1 without prior CLND, outcomes were comparable to historical trial data. 2

Regional Recurrence Patterns

• Patients who relapsed on adjuvant anti-PD-1 without immediate CLND had higher rates of regional nodal basin relapse (46%) compared to those with immediate CLND (11%). 2
• However, 55% of patients who relapsed without prior CLND successfully underwent salvage surgery including therapeutic lymph node dissection, with 70% remaining disease-free after salvage treatment. 2

Clinical Decision-Making Algorithm

For patients with positive SLNB, observation with close surveillance is now the preferred approach for most patients, particularly those with:

• Low-volume micrometastatic disease (SLN tumor deposit ≤1 mm) 2
• Stage IIIA or IIIB disease 2
• Non-ulcerated primary melanoma 2
• Access to high-quality nodal ultrasound surveillance 1

CLND may still be considered for higher-risk patients with:

• SLN tumor deposit >1 mm 2
• Stage IIIC/D disease 2
• Ulcerated primary melanoma 2
• Limited access to reliable imaging surveillance 3

Important Caveats

The MSLT-II trial included only a small number of patients with higher-volume sentinel node tumor burden, which limits statistical confidence for treatment recommendations in this subpopulation. 1 For these higher-risk patients, the decision to omit CLND requires careful consideration of the predicted likelihood of additional positive nodes, consequences of regional recurrence, and impact on adjuvant therapy recommendations. 3

Patients choosing observation must have access to and adherence with frequent nodal ultrasound surveillance, as regional recurrence rates are higher without immediate CLND. 2, 4 The observation strategy relies on early detection and salvage surgery for regional recurrences. 2