What Is the Role of Adjuvant Radiotherapy in Head and Neck Melanoma in the Era of Systemic Therapy?

Stage III melanoma encompasses a heterogenous group of patients with significant differences in loco-regional recurrence risk, prognosis, and survival. Stage IIIA melanoma patients present with minimal metastatic burden identified by sentinel lymph node biopsy (SLNB) and have favorable outcomes compared to stage IIIB patients with clinical regional disease. Locoregional (LR) failure rates ranging from 30% to 50% have been reported when high-risk (HR) clinicopathologic features are present. Prior to the approval of systemic therapy (ST) in stage III melanoma, studies recommended adjuvant radiation therapy (RT) for patients with extra-nodal extension (ENE), lymph nodes larger than 3 cm, involvement of multiple lymph nodes, recurrent disease, or any patient having undergone a therapeutic neck dissection.1 Adjuvant RT for HR cutaneous melanoma was shown to improve loco-regional recurrence (LRR), however, it failed to improve recurrence-free survival (RFS) and overall survival (OS). Majority of the studies which investigated the benefit of RT on local and regional control in stage III melanoma were conducted prior to the era of an effective adjuvant systemic immune checkpoint inhibitor (ICI) and targeted therapy (TT). The role of adjuvant radiotherapy in the era of modern systemic therapies is unclear. Loco-regional failure rates up to 30% to 50% at 10 years have been reported in patients with stage III melanoma especially in patients with high-risk features with positive margins, bulky nodal disease, extra-nodal extension, and multiple nodal involvement. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend definitive RT for unresectable local or regional melanoma and the consideration of adjuvant RT for patients with high-risk features for local (desmoplastic, positive margins) or regional recurrence (ENE, >2 cervical Lymph nodes).2 Systemic therapies including immunotherapy have been approved in the adjuvant setting for stage III melanoma and aim to replace the traditional therapeutic lymphadenectomy in stage IIIA disease. MSLT II trial, however, emphasized the importance of therapeutic lymphadenectomy on regional control in stage IIIB melanoma. Follow-up data from phase III trials of adjuvant ICI demonstrated no significant improvement in LRR with treatment, suggesting adjuvant ICI alone may be insufficient to prevent regional failure in certain high-risk patients. Adjuvant anti-PD-1 based therapy has demonstrated an improvement in RFS with a more favorable toxicity profile compared to anti-CTLA-4 and is now considered standard of care for patients with high-risk resected melanoma. Despite the improvements in outcome, isolated nodal basin recurrence was worse after adjuvant ST compared to ND (6% vs 1%, respectively).3 The literature lacks strong evidence on the added value of concurrent adjuvant RT and adjuvant ST. Salama et al.4 prospectively investigated the feasibility of concurrent Ipilimumab and RT in the adjuvant, neoadjuvant or definitive therapy for unresectable stage III melanoma. Twenty-four patients were enrolled: 13 in the adjuvant group (cohort 1) and 11 in the neoadjuvant/definitive group (cohort 2). Five patients (39%) in cohort 1 and 7 patients (64%) in cohort 2 had advanced stage IIIC disease. The combination of ipilimumab and RT had an adverse events profile comparable with that seen with either modality alone; 15% and 18% had grade 3 to 4 adverse events in cohort 1 and 2, respectively. Median follow-up was 25 months. There were 10 relapses or progressions during the study period, none within the radiation field. In cohort 1, the 6- and 12-month RFS was 85% and 69%, respectively. The 6- and 12-month PFS for cohort 2 was 73% and was unchanged at 24 months. Three of 11 patients in cohort 2 were ultimately able to undergo resection following neoadjuvant ST and RT. Each of these patients had either a pathological complete response or marked evidence of antitumor activity and remained disease-free at 2 years. Straker et al.5 retrospectively analyzed the 3-year recurrence and survival outcomes in patients with stage IIIB melanoma treated with neoadjuvant and/or adjuvant systemic therapy, with or without RT. The mean total radiation dose was 48.0 gray and median number of 20 fractions. Out of 98 patients, 76 patients (77.6%) were treated with systemic therapy alone and 22 patients (22.4%) received systemic therapy and adjuvant radiotherapy. Patients who received RT were more likely to have a higher risk of disease than those who received ST alone. Majority of the patients were treated with ICI. The 3-year cumulative incidence for regional recurrence was lower for patients who received ST/RT (3 patients, 13.9%) compared to ST alone group (18 patients, 25.2%); however, this difference was not statistically significant (P = .36). Out of 62 patients receiving adjuvant therapy: 45 patients (72.6%) received ST alone compared with 17 patients (27.4%) who received ST/RT. No significant difference in the 3-year cumulative incidence of regional recurrence was observed in the ST group (10 patients, 23.7%) and the ST/RT group (3 patients, 18.1%) (P = .79). Similar results were seen for in-transit and distant recurrence (54.5% and 38.5% for the ST and ST/RT groups, respectively, P = .25). Three-year Melanoma-specific survival was similar in both the treatment cohorts (76.6% and 90.9% for the ST and ST/RT groups, respectively, P = .2). Despite the nearly 50% reduction in the incidence of regional recurrences seen in this study with the addition of RT, this difference was statistically nonsignificant. This may be attributed to the use of effective modern therapies. However, the difference in disease severity between the two cohorts and small study groups may have confounded the results, leading to an underappreciation of the true impact of RT on regional recurrences. Interestingly, no patient who received neoadjuvant ST with RT developed a LNB recurrence, suggesting there may be additional value for the combination of neoadjuvant ST with RT. In the era of effective adjuvant systemic therapies, the use of ICI alone in the adjuvant setting may be insufficient to effectively reduce regional failure. Adjuvant RT may still have a significant value in improving regional control in stage III melanoma. Future studies should focus on whether select patient populations benefit from combination therapy. This recommendation is based on level 3 evidence (nonrandomized controlled cohort/follow-up study, Cohort study or control arm of the randomized trial).