We report the experience obtained from a prospective study on 30 patients with inoperable, locally far advanced, difficult to treat with RT, squamous cell, or metatypical carcinomas of the skin, recruited in the context of an IO/RT prospective study. Overall, the study protocol aims to build clinical experience on the addition of hypofractionated RT to standard IO in patients with locally advanced (with or without metastasis) epithelial head-neck, lung, pelvic, and skin tumors, who start anti-PD-1 ΙΟ as standard of care (patients with documented resistance to previous chemotherapy, patients unable to receive chemotherapy for any reason, or patients who are eligible to receive first line IO). RT was to be directed to the primary tumor and/or selected metastatic lesions using sub-radical (3 fractions of weekly 8Gy) or radical doses (6 or 8 Gy/week for 6 and 4 fractions, respectively) according to the discretion of physicians who would take into account the individual clinical status and aim of therapy. Radical RT doses were chosen when eradication of the ‘in-field’ disease could provide a chance for cure.

For LA-sqCSC, neoadjuvant IO with the cemiplimab anti-PD1 monoclonal antibody is a proposed therapeutic approach by the National Comprehensive Cancer Network (NCCN) 1.2024 guidelines [7] for very high-risk disease and in patients where curative surgery and RT are not feasible. IO can be administered in an attempt to reduce the tumor burden and, eventually, facilitate RT or even surgery. Given our 20-year excellent experience with treating large skin carcinomas with 6 consecutive fractions of 6-Gy electron irradiation, this regimen was included in the protocol specifically for patients with skin cancer.

The endpoint of the study was to build clinical experience on the feasibility and efficacy of IO/RT regimens for LA-sqCSC, and compare the overall response, locoregional progression-free (LPFS) and overall and disease-specific survival (OS) rates with those reported in clinical trials of IO alone, although such comparisons can be only indicative given eventual differences in the treated populations. The herein clinical complete responses (CRs) could not be directly compared to pathologic responses reported in published studies.

The study has been approved by the local Scientific and Research Ethics Committee (Approval number ES9 04-5-2022). The study was conducted according to the Declaration of Helsinki and the Guidelines for Good Clinical Practice. Moreover, approval for the administration of cemiplimab has been obtained for each patient separately, following application to the National Organization for the Provision of Health Services (EOΠYY). All patients provided written informed consent and approved the use of their laboratory and clinical data for research purposes.

Inclusion criteria were patients with very large inoperable squamous or metatypical skin carcinomas, difficult to treat with radical RT. Exclusion criteria were Performance Status (PS) > 2, major heart, pulmonary, liver, kidney, active infection, autoimmune disease, HIV infection, organ transplantation, ongoing immunosuppressive therapy, including corticosteroid treatment, and pregnancy.

The median age was 80.5 years and 11/30 patients had poor PS (2 of WHO scale) due to advanced age (not related to the disease). Patients suffered from very large tumors (median size of 7.5 cm), the majority of which displayed extensive ulceration and tissue necrosis (28/30). Patient and disease characteristics are reported in Table 1.

Diagnosis and staging of disease were based on biopsy followed by CT-scan, MRI, or PET-CT imaging. Full blood counts, glucose levels, biochemical liver and kidney function, and ECG were assessed before recruitment. Thyroid function (TSH, T3, and T4), C-reactive protein (CRP) and creatinine phosphokinase (CPK) levels were also assessed to obtain baseline values for monitoring immunotherapy-related adverse events (irAEs).

Response to cemiplimab and/or IO/RT was documented with direct clinical examination and photography for subsequent analysis, as well as CT/MRI or PET scans if necessary (in cases with bone erosion or nodal/metastatic disease) every 4 months till documentation of complete response (CR), and 6 months thereafter. Clinical assessment of response was performed every 3 weeks on the day of IO administration. We used the RECIST 1.1 criteria to record response [8], with a modification to serve the purpose of the current treatment algorithm. CR refers to elimination of all detectable disease. Partial response (PR) was defined as decrease in the sum of longest diameters (of all irradiated lesions) by more than 30%. Reduction of tumor dimensions by 10–29% was considered as minimal response (MR). Progressive disease (PgD) was documented as an increase of > 20% in the longest dimension. All other cases were recorded as stable disease (SD).

irAEs and RT-related toxicities were recorded by consultation, clinical examination, hematological evaluation, and standard biochemical tests before each cycle of cemiplimab. The serum levels of CPK, CRP, and thyroid function evaluation were recorded every three cycles. The NIH/NCI (National Institute of Health/National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 scale was used to score irAEs and acute radiation toxicity [9].

Cemiplimab anti-PD-1 IO was delivered at a dose of 350mg iv., every three weeks. IO was interrupted immediately after development of any grade 2 or higher irAE, excluding controllable thyroid dysfunction.

RT for local disease was given with 12–15-MeV electrons using a linear accelerator (ELEKTA, Precise). The electron energy was defined by measuring the maximum depth of tumors in CTs or MRIs and adding 1cm addition depth to be covered by the 90% isodose curve.

Laterally, the field margins were drawn 2 cm away from the clinical border, taking also into account anatomic constraints. Especially for tumors located on areas overlying brain tissue, special care was taken to avoid overdosage of the brain. As none of the tumors in this study displayed MRI findings of bone involvement, the 90% isodose curve was chosen to cover 0.5 cm beyond the bone surface. This allowed a sharp reduction of the dose to the superficial brain parenchyma, as at 1 cm deeper to the 90% isodose, dose distribution drops to 50% with 12 MeV and 65% with 15-MeV energy. Bolus material of appropriate thickness was used to cover certain thinner areas of the tumor.

Patients received a daily dose of 6 Gy for 6 consecutive daily fractions (physical dose 36 Gy). The estimated biologic dose to normal tissues equivalent to 2 Gy fractionation (EQD2) without time correction was 60 Gy, for α/β = 4Gy. Taking into account the 22-day overall treatment time (OTT) reduction (30 days OTT of a conventionally fractionated scheme delivering 60 Gy vs. 8-day OTT with the hypofractionated schedule), and considering a λ value of 0.2 Gy/day (accounting for normal tissues), the time-corrected biologic dose (EQD2) is estimated to 68Gy [10]. This regimen has been routinely applied in our department, and has been recommended in a meta-analysis showing good cosmetic results [11]. The Royal College of Radiologists suggests a 32.5–35 Gy regimen delivered in 4–5 daily fractions for tumors less than 4cm, or 45 Gy in 10 consecutive fractions, with the latter being also supported by the European Society for Radiotherapy and Oncology (ESTRO) for basal cell carcinoma [12, 13]. All the aforementioned regimens provide an EQD2 of approximately 64 Gy, without time correction. The efficacy of hypofractionated RT is similar to conventional [14, 15] and is certainly more convenient, especially for elderly patients, due to the drastic reduction of visits to the RT departments.

An algorithmic approach was developed based on complete and incomplete tumor responses to IO and the time-points when RT would be inserted. The treatment algorithm is schematically shown in Fig. 1. Response was recorded on every cycle, and, according to the response, patients underwent RT (non-complete responders) (while continuing cemiplimab) or continued cemiplimab alone (complete responders). For patients who underwent RT, IO continued for at least 4 cycles after achievement of CR. Complete responders after IO, or IO/RT were offered to continue IO for 18 months (till progression or appearance of irAEs). IO interruption due to irAEs was followed by RT in non-complete responders and by watchful waiting in patients who had reached CR. Patients who relapsed after RT were offered palliative systemic therapy, preferably with cetuximab, platinum, and/or antimetabolite combination.

Immuno-radiotherapy treatment algorithm

Supplemental Fig. 1s provides a consort flowchart of the study.

The primary endpoint of the study was to build clinical experience on the feasibility and efficacy of IO/RT regimens for LA-sqCSC, and compare the overall response, LPFS and overall and disease-specific survival (OS) rates with those reported in clinical trials of IO. LPFS and OS were defined as the time between start of IO and the first date of documentation of locoregional progressive disease or death from any cause or cancer. LPFS and OS curves were plotted with the Kaplan–Meier method, using the GraphPad Prism version 8.0 statistical package.