Role of Adjuvant Regional Nodal Irradiation in Resected Melanoma: A Secondary Analysis of SWOG S1404

Abstract

<h3>Purpose/Objective(s)</h3> Results from TROG 02.01 demonstrated that adjuvant radiotherapy (RT) in high-risk melanoma patients is associated with improved locoregional control (LRC). The aim of our study is to evaluate the role of adjuvant RT in standard risk (SR), high risk (HR) and ultra-high risk (UHR) melanoma patients in the immunotherapy era. S1404 randomized resected stage III and stage IV melanoma patients to standard of care adjuvant immunotherapy or pembrolizumab after surgery. <h3>Materials/Methods</h3> We retrospectively analyzed the data for 1239 patients enrolled in S1404. We stratified the patients according to SR (no high-risk features), HR (defined according to TROG 02.01 trial) and UHR (extracapsular extension with 5 or more positive nodes or 4 cm or greater nodal size). Recurrence free survival (RFS) and time to regional recurrence (TtRR) were primary outcomes; distant metastasis free survival (DMFS) was a secondary outcome. RFS was estimated using the Kaplan-Meier method and associations with the outcome were evaluated using Cox regression models. TtRR and DMFS were estimated with cumulative incidence curves and associations with the outcome were evaluated using cause-specific regression models. <h3>Results</h3> Of 1239 patients analyzed, 136 patients (11%) completed RT. The most common RT regimen used was 30 Gy/5 fractions (37%) followed by 48 Gy/20 fractions (31%). Fifty three percent of patients were HR per TROG02.01. More HR patients received RT compared to SR (16 % versus 6%; p-value <= 0.001). Among the patients who received RT 76/136 (56%) were advanced stage (Stage IIIC/ resected Stage IV) compared with those who did not 390/1103 (35%); p value <= 0.001. Similarly macroscopic lymph node involvement was significantly higher in RT group, 89/136 (65%) versus 457/1103 (41%); p value <=0.001. TtRR was significantly longer for patients who completed RT (all comers: 9% RR @ 4 year no RT vs 1% @ 4 year with RT; p value = 0.015). For high-risk patients, TtRR was longer for patients who received RT regardless of PD1 status (12% RR @ 4 year no RT vs 2% @ 4 year with RT; p value = 0.009). No significant difference in value of RT was seen based on anatomic nodal site, study arm or BRAF mutation status. Among patients treated with pembrolizumab, a trend toward RFS benefit was seen in patients treated with RT (HR = 1.54, 95% confidence interval 0.94-2.53; p=0.085). There was no significant difference in DMFS between those who completed RT versus not. <h3>Conclusion</h3> Our study validated the results of previous studies and suggests consideration of adjuvant RT in high-risk patients regardless of planned adjuvant immunotherapy for improved LRC. We recommend the use of adjuvant RT in patients with macroscopic nodal involvement with extracapsular extension or with heavy nodal burden even in the immunotherapy era.