Neel Maria Helvind

Background: Adjuvant anti‐PD‐1 therapy improves recurrence‐free survival in resected stage III melanoma, but its impact on survival remains uncertain. Objective: To evaluate the association of adjuvant anti‐PD‐1 therapy with overall survival (OS) and melanoma‐specific mortality (MSM) in patients with stage III melanoma. Methods: Five‐year OS and MSM were compared between stage III melanoma patients diagnosed before (pre‐cohort: June 2016–May 2018, n = 450) and after (post‐cohort: January 2019–December 2020, n = 552) implementation of adjuvant anti‐PD‐1 in Denmark. Post‐cohort patients receiving adjuvant anti‐PD‐1 were propensity score‐matched to pre‐cohort patients. Results: Median follow‐up exceeded 5 years in both cohorts. At the population level, no difference in 5‐year OS or MSM was demonstrated between the total cohorts. In the post‐cohort, 297 patients (53.8%) received adjuvant anti‐PD‐1. After matching ( n = 279 per group), adjuvant anti‐PD‐1 was associated with higher 5‐year OS (80.3% vs. 71.7%; HR 0.67, 95% CI 0.47–0.95; p = 0.022). 5‐year MSM estimates were inconclusive (16.6% vs. 20.8%, HR 0.77, 95% CI 0.52–1.14; p = 0.24). Among matched patients with occult nodal disease, results were also inconclusive (OS HR 0.70, 95% CI 0.46–1.06). Sensitivity power analyses indicated that only large effects were detectable given the available events. Conclusions: We were unable to demonstrate an improved survival at the population level after adjuvant anti‐PD‐1 introduction, but matched analysis showed higher OS in treated patients. However, uncertainty in disease‐specific outcomes and limited power preclude firm conclusions. Mature trial data are essential for defining the role of adjuvant therapy alongside emerging neoadjuvant strategies. Until then, carefully individualized adjuvant treatment decisions are of particular importance.

Importance: To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed.Objective: To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates.Design: Retrospective cohort study of prospectively collected nationwide population-based registry data.Setting: Nationwide, population-based cohort study.Participants: The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021.Exposures: First diagnosis of stage IA to IV cutaneous melanoma.Main Outcomes: Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival.Results: We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models.Conclusions and Relevance: This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with po