Skin cancer and hyperthermia and radiotherapy - SAHARA: study protocol for a multicenter, two-arm, open-label, randomized controlled phase II non-inferiority trial.

backgroundNon-melanoma skin cancer (NMSC) is common among Caucasians, particularly in elderly patients, with rising incidence due to aging populations. Primary risk factors include cumulative sun exposure, advanced age and immunosuppression. While surgery and radiation therapy (RT) are standard treatments, RT is often preferred for elderly patients with large tumors or comorbidities. Hypofractionated RT schedules are effective but can cause significant side effects. Enhancing radiosensitivity through water-filtered infrared-A (wIRA) hyperthermia may reduce required radiation doses and mitigate side effects.

methodsThis two-arm, prospective, open-label, randomized controlled phase 2 non-inferiority trial will compare local control outcomes between high-dose RT alone versus de-escalated RT, immediately following mild wIRA-hyperthermia in treating NMSC. The study aims to demonstrate noninferiority with a -10% margin and 80% power (alpha = 0.1, one-sided), enrolling 100 patients. The intervention group will receive wIRA-hyperthermia combined with RT (6 fractions of 5 Gy each over 3 weeks), while the control group will receive standard RT (12 fractions of 4 Gy each over 4 weeks). The primary endpoint is local control after two years, defined as 'no need for further intervention'. Secondary endpoints include acute and late toxicities and quality of life (QoL), assessed using the QLQ-ELD14 questionnaire. Inclusion criteria are histologically confirmed invasive NMSC, tumor stage ≥ T2, local recurrence allowed after non-RT treatment > 6 months ago, age ≥ 65 years, and ECOG performance status 0-2. Exclusion criteria are non-basal/squamous cell carcinoma histology, T1 tumors, node-positive status, post-resection cancers < 6 months, tumor thickness > 2 cm, critical area invasion, multiple lesions exceeding treatment capacity, recent or concurrent chemo- or immunotherapy, connective tissue disorders, proximity to previously irradiated areas, medical immunosuppression, and wIRA-incompatible conditions (e.g., tattoos, increased photosensitivity). DISCUSSION: This study aims to determine whether de-escalated RT following wIRA-hyperthermia can achieve comparable local control rates to standard RT in treating NMSC, potentially offering a treatment with fewer side effects and shorter durations. Success in this trial could lead to improved treatment protocols for elderly patients with NMSC, reducing side effects and enhancing QoL.

trial registrationThe trial has been registered prospectively on ClinicalTrials.gov under the identifier NCT06384053, as of April 25th, 2022.