Topical therapies are limited by depth of absorption, which can present a barrier to using these treatments for thicker plaques and tumors. Combining IL and topical routes was critical in our study design. Having good clinical experience using IL 5-FU in nonmelanoma skin cancers, we hypothesized that IL 5-FU would achieve a cytotoxic response through the full depth of thicker lesions and erode the surface of these lesions to facilitate penetration of topical IMQ. We additionally hypothesized that the combination of mechanisms of action would lead to an additive or synergistic response (Figure 1). By first inducing apoptotic cell death via 5-FU, we hoped to spill malignant lymphocyte neoantigens. Coupling that antigen exposure with an enhanced TH1-biased immune response driven by IMQ should facilitate tumor clearance and immune education against malignant T cells.
In our case series, all 15 lesions in 9 patients completely cleared, and no recurrences were observed at 26-month follow-up. No patients encountered any major adverse events, and the procedure was well tolerated by all.
Study Limitations—Limitations of this small study certainly exist. It is impossible to prove that our mechanistic theory is accurate given our strictly clinical assessment tools. We speculate that if our results had been achieved with IL 5-FU alone, future investigation with a prospective study using multiple treatment arms including a control would be warranted. Kannangara et al36 reported the use of topical 5-FU for MF and the drug’s utility in either topical or IL routes for CTCL, which deserves further study. It is less likely that results were achieved exclusively by IMQ because of the rapid tissue breakdown observed in the acute hemorrhagic phase. This phenomenon is best explained by the sudden apoptosis caused by DNA intercalation from 5-FU. The follow-up period is not uniform because this was a rolling enrollment study. Follow-up will be ongoing, and we aim to assess all patients up to at least the 5-year point. A final limitation of this study is the purely clinical end point. In the future, pretreatment and posttreatment biopsies would be useful in assessing proof of histologic response, and high-throughput sequencing may be used to look for molecular clearance via liquid biopsy. Lastly, careful observation for possible abscopal effect using the Severity-Weighted Assessment Tool score would be interesting and potentially contributory to our understanding of the impact of topical immune therapy on cutaneous tumor surveillance.
Conclusion
Combination IL 5-FU and topical IMQ is a well-tolerated, effective, and durable therapy for recalcitrant thick plaques and tumors of CTCL. This treatment is convenient and cost-effective. The procedure is performed in less than 5 minutes in an outpatient dermatology clinic. All patients received full insurance coverage for both drug and procedure fees under Medicare and commercial carriers.