Radiotherapy versus imiquimod for complex lentigo maligna: A phase 3 randomized clinical trial

Lentigo Maligna (LM) represents a slow-growing melanocytic neoplasm in situ that typically develops on the sun-exposed skin of elderly individuals, often presenting as an irregularly pigmented macule. It was already known that surgical excision serves as the primary therapeutic strategy to prevent the progression of these lesions into invasive lentigo maligna melanoma, which carries a much higher risk of metastasis. However, the frequent occurrence of these patches on the face and neck often complicates surgical removal due to functional or aesthetic concerns, especially in patients with significant comorbidities. Non-surgical alternatives such as ionizing radiation or topical immune response modifiers like imiquimod have emerged as potential solutions for patients who are not candidates for invasive procedures. Despite their use in clinical practice, a definitive comparison regarding their long-term efficacy and impact on patient well-being remained elusive in the existing medical literature. This absence of evidence motivated a comprehensive phase 3 trial to evaluate the relative merits of these two distinct nonsurgical interventions in a controlled setting.

This multi-institutional phase 3 randomized clinical trial evaluated the comparative efficacy, safety, and patient-reported outcomes of radiotherapy versus topical imiquimod for the treatment of complex skin lesions. The researchers sought to establish a clear evidence base for treating complex Lentigo Maligna (LM) in patients for whom surgery was contraindicated, technically difficult, or undesirable. The primary objective involved measuring the rate of treatment failure over a twenty-four-month period to determine the long-term durability of these nonsurgical approaches. Secondary goals included assessing the initial clinical response at the six-month mark and monitoring for any development of invasive disease within the treated area. The study also prioritized the evaluation of health-related quality of life (HRQL) to ensure that these treatments did not adversely affect patient psychosocial health or daily functioning. By comparing these two modalities, the investigators aimed to provide clinicians with data-driven guidance for managing this challenging dermatological condition in elderly populations.

The investigators conducted a multi-institutional, phase 3 randomized trial between August 2015 and November 2021 to compare two distinct nonsurgical protocols for cutaneous malignancy. One hundred twenty-six patients were randomly assigned to receive either localized ionizing radiation or the topical application of the imidazoquinoline compound, imiquimod. The primary endpoint was defined as the occurrence of treatment failure within twenty-four months of the initial therapeutic intervention to assess long-term efficacy. Secondary outcomes were meticulously tracked, including the clinical response rate at six months and the incidence of progression to invasive malignancy during the follow-up period. Safety monitoring involved the documentation of acute skin toxicity, which was categorized using standardized clinical grading scales to ensure objective comparison between groups. The research team utilized validated questionnaires to assess health-related quality of life (HRQL) and emotional well-being at baseline and during subsequent follow-up visits.

The analysis revealed that both the radiotherapy and imiquimod groups achieved a high clinical response rate of ninety-five percent at the six-month assessment, indicating strong initial efficacy. At the twenty-four-month mark, the researchers recorded twelve treatment failures in the radiation cohort and six failures in the topical treatment group among the randomized participants. Statistical evaluation of these failure rates produced an odds ratio (OR) of 2.35 with a ninety-five percent confidence interval (CI) ranging from 0.82 to 6.75. The resulting p-value of 0.11 indicated that the difference in failure rates between the two interventions did not reach statistical significance in this cohort. Both treatment modalities were well-tolerated by the participants, with most experiencing only grade 1 or grade 2 acute skin toxicity during the active treatment phase. Long-term data showed no significant differences in skin symptoms or health-related quality of life (HRQL) between the two randomized arms at the end of the study.

The study concludes that both radiotherapy and topical imiquimod are efficient and well-tolerated options for the management of complex Lentigo Maligna (LM) in non-surgical candidates. Neither nonsurgical intervention appears to have a negative impact on the health-related quality of life (HRQL) of patients over a two-year period following treatment. These findings suggest that both modalities are viable alternatives when surgical resection is not feasible or preferred by the patient due to anatomical constraints. The authors noted that the trial was underpowered due to the early cessation of recruitment, which may affect the precision of the comparative failure rates reported. Improved emotional scores across both groups post-treatment highlight the psychological benefit of achieving local control of these cutaneous lesions and reducing the risk of progression. This research provides a foundation for incorporating these nonsurgical strategies into the clinical care pathways for elderly or surgically ineligible patients with melanocytic neoplasms.