As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.