Skin Cancer Precursor Study Finds Imiquimod Plus Freezing Outlasts Light Therapy

Actinic keratoses are among the most common reasons people visit a dermatologist, and for good reason. These rough, scaly patches on chronically sun-exposed skin are not merely a cosmetic nuisance; they are visible markers of a process dermatologists call cutaneous field cancerization, in which wide areas of skin damaged by years of ultraviolet exposure harbor cells on the pathway toward squamous cell carcinoma. Because the damage is regional rather than confined to single lesions, treating one spot at a time rarely solves the problem. Field treatments aim to reset the entire affected zone, whether that zone covers the scalp, the forehead, or the cheeks. Yet a persistent frustration has shadowed every available therapy: none of them appears to cure the field permanently, and lesions reliably creep back over time. What has been missing, until now, is a careful, quantitative picture of how quickly that relapse actually happens after each of the main combination treatments.

A new retrospective study from Greek researchers, published in the Archives of Dermatological Research, tackles precisely that question by measuring relapse kinetics, the speed and pattern with which actinic keratoses return after treatment. The team, led by Despina Exadaktylou and Ioannis D. Bassukas with colleagues in Athens and Ioannina, compared three real-world regimens used on the head: cryosurgery alone, cryosurgery followed by daylight photodynamic therapy, and cryosurgery followed by four weeks of topical imiquimod, an immune-response modifier applied as a cream. Their central finding is striking. The combination of mild freezing followed by a month of imiquimod produced a therapeutic effect lasting on average about fourteen months, significantly longer than either cryosurgery alone or cryosurgery paired with daylight photodynamic therapy, both of which delivered roughly eight to eight and a half months of benefit before relapse set in.

The study owes its unusual design to an unexpected legacy of the COVID-19 pandemic. During lockdowns, routine dermatology follow-ups across Greece and much of Europe were postponed, sometimes for many months or even years. For patients treated for field cancerization before the pandemic, that disruption meant the interval between treatment and the first post-treatment skin examination stretched far beyond the usual clinical schedule. Rather than discarding these irregular records, the researchers recognized them as a natural experiment: a dataset in which follow-up times varied enormously, from as little as twenty-eight days to as long as 1,379 days after the cryosurgery session that began each treatment cycle. That variation, normally a nuisance in clinical research, allowed them to trace how disease burden evolved across a much wider window of time than a conventional fixed-schedule study could capture.

The analysis included 116 treatment cycles involving head-located field cancerization regions in 30 patients, 27 of them men, with a median age of 81 years. The treated areas comprised 83 scalp regions, 26 forehead regions, and 7 cheek regions. Forty cycles were treated with cryosurgery monotherapy, 27 with the combination of cryosurgery and daylight photodynamic therapy, and 49 with cryosurgery plus imiquimod. To quantify disease burden, the team used a modified version of the Actinic Keratosis Area and Severity Index, known as AKASI, restricted to the treated head subregions. By scoring the same anatomical area before treatment and again at the first follow-up visit, they could calculate a change-from-baseline that reflected how much the treatment had actually improved the field, and how much of that improvement had eroded by the time the patient returned.

The statistical machinery behind the study combined nonparametric comparisons with survival analysis, a technique more familiar from oncology trials tracking time to tumor recurrence. Wilcoxon and Kruskal-Wallis tests assessed differences in continuous measures such as AKASI scores, while Kaplan-Meier curves and Cox proportional hazards methods modeled the time until relapse, defined through the first post-treatment evaluation for each therapy cycle. Significance was set at a two-tailed probability level below 0.05. This survival-style framing is what makes the study’s headline numbers meaningful: instead of simply asking whether patients improved, the researchers asked how long the improvement endured, treating the disappearance of the therapeutic effect as an event that could be timed and compared across the three treatment arms.

The results tell a nuanced story. Immediately after treatment, only the two combination modalities produced a statistically significant improvement in the field: the reductions in AKASI scores were significant for cryosurgery plus daylight photodynamic therapy and for cryosurgery plus imiquimod, while cryosurgery alone did not reach significance for initial field improvement. More importantly, that early advantage faded as follow-up time lengthened, a pattern the authors describe as the initial improvement vanishing with increasing time to first evaluation. In other words, the visible benefit of field treatment is real but transient, and the longer one waits before examining the skin, the less distinguishable the treated field becomes from its pretreatment state. This modality-independent erosion of benefit underscores why time-to-relapse, rather than short-term clearance rates, should be the metric that guides treatment planning.

When the duration of the therapeutic effect was compared directly, the differences between regimens became clear. Cryosurgery monotherapy yielded a mean effect duration of 8.34 months, with a 95 percent confidence interval spanning 5.21 to 11.48 months. Cryosurgery combined with daylight photodynamic therapy performed almost identically, at 8.53 months with a confidence interval of 4.16 to 12.90 months. Cryosurgery followed by four weeks of imiquimod, by contrast, extended the mean effect duration to 14.15 months, with a confidence interval of 9.94 to 18.37 months. Both combination regimens were significantly superior to cryosurgery alone, but the imiquimod combination was also significantly superior to the photodynamic therapy combination, with the Kaplan-Meier analysis yielding p values of 0.007 and 0.032 for the respective comparisons. For elderly patients, many of whom face repeated treatment cycles over decades, an extra five to six months of clearance per cycle is a clinically meaningful gain.

The biological logic behind this result is consistent with what is known about how these therapies work. Cryosurgery physically destroys visible lesions but does little to address the microscopic field of mutated cells surrounding them. Daylight photodynamic therapy uses a topical prodrug, methyl aminolevulinate, which is converted into a photosensitizer inside abnormal cells; exposure to daylight then triggers reactive oxygen species that kill those cells, with the advantage of being nearly painless compared with conventional artificial-light photodynamic therapy. Imiquimod takes a different route entirely: it activates toll-like receptor 7 on immune cells, unleashing a localized innate and adaptive immune response that targets genetically damaged keratinocytes over the weeks the cream is applied. The longer relapse time observed with the immunocryosurgery approach suggests that recruiting the patient’s own immune system to patrol the treated field provides a more durable suppression of residual disease than a single photodynamic insult, even when both are anchored by the same cryosurgery session.

The authors are candid about the limitations of their work. The study is retrospective, relies on chart review, involves a small number of patients and treatment cycles, and draws all of its data from a single clinical setting. The wildly variable follow-up times, while analytically exploitable, also mean that the relapse estimates depend on the assumption that a single post-treatment evaluation can represent the state of the field at that moment. The patient population, overwhelmingly elderly men with scalp disease, may not generalize to other groups. Still, the study was conducted under institutional ethical approval and in accordance with the Helsinki Declaration, and the authors report no funding and no competing interests. As a first quantitative map of relapse kinetics after field treatment with adjuvant cryosurgery, it offers something the field has lacked: a timeline. If confirmed in larger, prospective studies, the message for clinicians managing cutaneous field cancerization could be simple and consequential, namely that when the goal is to keep sun-damaged skin clear for as long as possible, a month of immune activation after freezing may be worth more than a day in the sun.

Subject of Research: Relapse kinetics of actinic keratoses after field treatments combining cryosurgery with daylight photodynamic therapy or topical imiquimod

Article Title: Relapse kinetics of actinic keratoses after field treatments with adjuvant cryosurgery: a retrospective study of cases with variable follow-up times

Article References: Exadaktylou, D., Chroni, P., Stefaniotou, S., Spyridonos, P., Gaitanis, G., & Bassukas, I. D. (2026). Relapse kinetics of actinic keratoses after field treatments with adjuvant cryosurgery: a retrospective study of cases with variable follow-up times. Archives of Dermatological Research, 318(1), Article 443. https://doi.org/10.1007/s00403-026-04931-x

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04931-x

Keywords: actinic keratosis, cutaneous field cancerization, cryosurgery, imiquimod, daylight photodynamic therapy, relapse kinetics, AKASI score, Kaplan-Meier analysis, skin cancer prevention, retrospective study, COVID-19 pandemic, dermatology