Immune Checkpoint Inhibitors in Field Cancerization and Keratinocyte Cancer Prevention

Abstract

Importance: Therapies for individual keratinocyte carcinomas (KCs) do not prevent the onset of new KCs in a field of sun damage, and therefore the KC burden remains unchanged.

Objective: To investigate the association of immune checkpoint inhibitors (ICIs) with changes in field cancerization evaluated by the number of actinic keratoses (AKs) and KCs at baseline compared with 12 months after starting ICI therapy.

Design, setting, and participants: This prospective cohort study was performed at the outpatient oncology clinic of a single tertiary public hospital in Brisbane, Australia, from April 1, 2022, to November 30, 2023. Consecutive immunocompetent adults starting therapy with an inhibitor for programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PDL-1) for any active cancer, with a planned treatment duration of at least 6 months, and who exhibited clinical AKs on their forearms were eligible. Those with immunosuppression, concurrent chemotherapy or radiotherapy, or recent topical fluorouracil use were excluded.

Exposures: Intravenous ICI therapy, either PD-1 or PDL-1 inhibitors with or without a cytotoxic T-lymphocyte-associated protein 4 inhibitor, with therapy duration determined by the treating oncologist.

Main outcomes and measures: Clinical AKs were counted and photographed before and 3, 6, and 12 months after starting ICI therapy. KC numbers were evaluated based on histopathology reports of all skin lesions excised 12 months before and after starting ICI therapy. Participants' medical history, primary cancer tumor response using Response Evaluation Criteria in Solid Tumors, and adverse events were recorded.

Results: A total of 23 participants were recruited, of whom 17 (73.9%) were male, with a mean (SD) age of 69.7 (9.6) years. No participants withdrew; however, 4 died during the study due to disease progression. The mean (SD) AK number significantly decreased from 47.2 (33.8) at baseline to 14.3 (12.0) at 12 months (P < .001). Younger patients (8 of 12 [66.7%] vs 4 of 12 [33.3%]; P = .007) and those with a history of blistering sunburn (12 of 12 [100%] vs 0; P = .005) were more likely to reduce their AK numbers by 65% or greater. KC total numbers decreased from 42 in the 12 months before starting ICI therapy to 17 in the 12 months after. The number of cutaneous squamous cell carcinomas decreased from 16 to 5 in the same period.

Conclusions and relevance: This pilot cohort study found that ICIs used for any cancer were associated with a significant reduction of AKs, suggesting potential as an immunopreventive strategy for high-risk individuals. Given the known effects of other chemopreventive agents on KCs, further investigation into ICIs managing field cancerization is required, especially considering toxicity and cost.

Figure 1.. Study Flow Diagram

AKs indicates actinic keratoses; ICI, immune checkpoint inhibitor.

Figure 2.. Number of Clinical Actinic Keratoses at Each Time Point After Starting Immune Checkpoint Inhibitor (ICI) Therapy

Circles represent individual patients; midlines, means; and whiskers, SDs. ^aP < .001, paired t test.

Figure 3.. Reduction in Actinic Keratoses Count After 12 Months of Immune Checkpoint Inhibitor Therapy

Baseline indicates before the first infusion of immune checkpoint inhibitors. Boxes at the bottom of panels were added to cover text.