Clinical Outcomes and Risk Stratification of Early-Stage Melanoma Micrometastases From an International Multicenter Study: Implications for the Management of American Joint Committee on Cancer IIIA Disease

Abstract

PURPOSE Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. METHODS Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. RESULTS Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension. CONCLUSION Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.

Risk Stratification of Sentinel Node Metastasis Disease Burden and Phenotype in Stage III Melanoma Patients

“…group is no different from that of the SNBgroup. 4,26 Our data would indicate that the additional information afforded by the SNB for pT4b melanomas is limited, with no low-risk nodal micrometastatic disease in the SNB? group and no difference in DSS between the SNB-and SNB?…”

“…1 Recently, a multinational consortium identified a subgroup of putatively low-risk AJCC IIIA patients with a greatly increased risk of recurrence and/or death, based on disease burden in the SN, measured as the maximum tumor deposit size (MTDS). 4 At the other end of this spectrum, the indications for offering adjuvant systemic therapy to patients with intermediate-to high-risk AJCC stage III, namely IIIB-IIID, melanoma have largely been standardized internationally. 5,6 Accordingly, all patients with pT2b-pT4b melanomas and a positive SNB are now considered for adjuvant systemic therapy without consideration of the burden of disease in the metastatic nodes, which could potentially have a bearing on conversations with patients regarding the benefits from treatment and the risks from toxicity and overtreatment.…”

ASO Author Reflections: Risk Stratification of Sentinel Node Metastases in Stage III Melanoma Patients in the Era of Adjuvant Systemic Therapy

“…This work by Hussain et al 3 is an extension of the research recently undertaken by an international consortium, which stratified the risk recurrence and death in a pT1b-pT2a SNB-positive (American Joint Committee on Cancer [AJCC] IIIA) cohort of patients. 4 In that study, maximum tumor deposit size (MTDS) was found to be the optimal phenotypical biomarker for this ostensibly low-risk group. The latest analysis of the current authors found that MTDS also was an important stratifying phenotypical biomarker for SNB-positive pT2b-pT4a primary melanomas, and that value was constant at 0.7 mm.…”

Dissecting the Need for Adjuvant Therapy in Patients With Early-Stage Melanoma With Micrometastases

“…The article from Moncrieff et al 1 addresses the critical question of selecting patients with a higher risk of relapse among those diagnosed with stage IIIA melanoma who present with a micrometastasis in the lymph nodes (tumor deposit in lymph nodes measuring < 1 mm). From a surgical perspective, the MSLT-II study established the current standard of care for patients with stage III melanoma in favor of sentinel lymph node dissection, followed by sonographic observation for 5 years.…”