Adjuvant treatment of in-transit melanoma: Addressing the knowledge gap left by clinical trials.
Authors: de Meza Melissa Melanie , Blokx Willeke , Bonenkamp Han J. , Blank Christian U. , Aarts Maureen J.B. , Van Den Berkmortel Franchette , Boers-Sonderen Marye J. , de Groot Jan Willem , Haanen John B. A. G. , Hospers Geke , Kapiteijn Ellen , van Not Olivier Jules , Piersma Djura , Van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , van den Eertwegh Alfonsus Johannes Maria , Suijkerbuijk Karijn , Wouters Michel W.J.M. 
Published: June 2022

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Background: Few clinical trials address the efficacy of adjuvant systemic treatment in patients with ITM. This study describes the efficacy of adjuvant systemic therapy of ITM patients beyond the clinical trial setting. Methods: All stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between 01-07-2018 and 31-12-2020 were included. Patients were divided into three groups: patients with ITM only, with ITM and nodal disease, and patients with nodal disease only. Differences in recurrence patterns were analysed. An exploratory analysis was performed for stage III patients who underwent surgical resection without adjuvant treatment. Recurrence-free survival (RFS) and overall survival (OS) at 12-months were assessed. Results: A total of 1037 stage III melanoma patients received adjuvant anti-PD-1 therapy, and 260 underwent surgical resection only. Of the adjuvant-treated patients, 16.9% had ITM only, 15.5% had ITM with nodal disease, and 66.8% had nodal disease only. Of the surgical resection only patients 20.4% had ITM only, 12.3% had ITM with nodal disease and 67.3% had nodal disease only. In the adjuvant-treated patients, 12-months RFS was comparable between patients with ITM only and patients with nodal disease only (71.1% vs. 72.2% respectively, p = 0.95), but significantly lower for patients with ITM and nodal disease (57.1%; ITM with nodal disease vs. ITM-only p = 0.01, and ITM with nodal disease vs. nodal disease only p < 0.01). Locoregional metastases occurred as first recurrence site in 72.7% of ITM-only patients, 42.9% of ITM and nodal disease patients and 38.9% of patients with nodal disease only, while distant recurrences occurred in 18.2% of patients with ITM only, in 36.7% of patients with ITM and nodal disease, and in 42.3% of patients with nodal disease only (p = 0.01). OS at 12-months was significantly higher for ITM-only patients compared to patients with ITM and nodal disease (97.7% vs. 90.6%, p < 0.01), and was better compared to patients with nodal disease only (97.7% vs. 94.4%, p = 0.05). OS at 12-months was comparable for patients with ITM and nodal disease and patients with nodal disease only (p = 0.19). In general, surgery-only ITM patients were older and had a worse performance score. 12-months RFS appeared worse compared to adjuvant-treated ITM patients (36.6% vs. 68.3%). In this group of surgery-only ITM patients OS at 12-months also appeared worse compared to adjuvant-treated ITM patients (89.7% vs. 95.5%). Conclusions: RFS rates in ITM-only patients are similar to non-ITM patients, while RFS in patients with ITM and nodal disease is shorter. Adjuvant-treated patients with ITM without nodal disease less often experience distant recurrences and have a superior OS compared to other adjuvant stage III patients. Our results suggest that other treatment strategies for ITM patients with nodal disease should be considered.