Background
Phase III randomized controlled trial (ANZNTG 01.02/TROG 02.01) evaluating adjuvant RT vs. observation after complete lymph node dissection (CLND) in patients with high-risk melanoma with lymph node metastases. 250 patients from Australia/New Zealand. High-risk features: ≥1 parotid node, ≥2 cervical/axillary nodes, ≥3 inguinal nodes, extranodal extension, or node ≥3 cm. RT: 48 Gy in 20 fractions (2.4 Gy/fx) over 4 weeks.
Interventions and follow up
Arm A: Adjuvant RT — 48 Gy in 20 fractions to regional lymph node basin after CLND
Arm B: Observation after CLND
Primary endpoint: Lymph node field relapse
mFollow up: Median 73 month
Arm B: Observation after CLND
Primary endpoint: Lymph node field relapse
mFollow up: Median 73 month
Results
LN Field Relapse: RT 20% vs. observation 34%, HR 0.56, 95% CI 0.32–0.98, P=.023
OS: No significant difference (HR 1.09, P=.78)
Distant Metastases: No significant difference
Grade ≥3 toxicity: RT arm: lymphedema higher (20% vs 7%)
OS: No significant difference (HR 1.09, P=.78)
Distant Metastases: No significant difference
Grade ≥3 toxicity: RT arm: lymphedema higher (20% vs 7%)
Adverse events
Main adverse events: Adjuvant RT (48 Gy/20 fx): lymphedema grade ≥3 in 20% vs. 7% (observation). Radiation dermatitis (grade 1–2 common). No significant increase in grade ≥3 fibrosis or nerve damage. Toxicity profile acceptable for high-risk patients.
Conclusions
Adjuvant RT to the lymph node field after CLND significantly reduces lymph node field relapse in high-risk melanoma (HR 0.56, P=.023). However, no improvement in OS was demonstrated. The tradeoff is a modestly higher lymphedema risk with RT.
Key Limitations
Key Limitations: Designed before BRAF/MEK inhibitors and immune checkpoint inhibitors (ipilimumab, pembrolizumab) were available — the therapeutic landscape has changed dramatically; OS benefit may have been diluted by subsequent systemic therapies; trial was underpowered for OS as primary endpoint; modern adjuvant immunotherapy may make RT less critical in this setting.
Clinical Context
This is the only Phase III RCT of adjuvant RT for high-risk melanoma nodes. LC benefit is real but OS benefit is absent, and modern adjuvant immunotherapy (pembrolizumab, nivolumab, dabrafenib-trametinib) achieves superior systemic control. Current practice: adjuvant RT is used selectively for very-high-risk nodal features (gross extranodal extension, multiple nodes) in centers using combined modality approaches. Adjuvant RT + immunotherapy combination is under investigation.
References