An extension of the validation cohort of the Dutch Early-Stage Melanoma (D-ESMEL) study for stage-specific analyses

There is a high need for accurate prognostic models among stage II melanoma to determine who may benefit from (neo)adjuvant systemic therapy. The Dutch Early- Stage Melanoma (D-ESMEL) study was designed to identify new prognostic features in a population-based sample of stage I/II melanoma patients in addition to American Joint Committee of Cancer (AJCC) staging. The validation cohort of the D-ESMEL study employs a nested case-control design. Initially, controls were randomly sampled to develop prognostic that included both known and new prognostic factors to assess the additive value of new prognostic factors. As a consequence, most controls had a very thin melanoma (<1.0 mm) while most cases had a thicker melanoma (>2.0 mm). This resulted in insufficient variability and high weights for stage II controls when applying weighted analyses in absolute risk prediction models. Therefore, randomly sampled controls were re-matched on AJCC stage (stage IA, IB, IIA, IIB, IIC), and new stage-matched controls were collected for cases who could not be rematched. The original D-ESMEL validation cohort included 5,815 stage I/II melanoma patients, of whom 154 developed distant metastasis (cases). 98/154 Cases were stage II and only 24 stage II controls were included, while the stage-matched design now includes 153 stage-matched case-control sets of which 97 stage II cases and 97 stage II controls derived from a population-based cohort of 5,785 stage I/II patients. The updated design increased the biological variability among stage II controls, balanced weights in weighted analyses and thereby facilitating reliable subgroup analyses in this clinically important subgroup.