FLASH Radiotherapy for Skin Cancer

Study Overview
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Brief Summary
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This is a single center randomized selected Phase II study of FLASH radiotherapy (RT) versus standard of care (SOC) radiotherapy in patients with localized Cutaneous Squamous Cell Carcinoma (cSCC) or Basal Cell Carcinoma (BCC). In summary, the aims of the study are to describe and compare the toxicity and efficacy of high dose rate radiotherapy (FLASH therapy) to SOC conventional radiotherapy (according to the standard guidelines per lesion size) through a randomized Phase II selection study in patients presenting localized cSCC or BCC requiring a radiotherapy treatment.

Official Title
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Randomized Phase II Selection Trial of FLASH Versus Conventional Radiotherapy for Patients With Localized Cutaneous Squamous Cell Carcinoma or Basal Cell Carcinoma

Conditions
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Basal Cell Carcinoma, Cutaneous Squamous Cell Carcinoma

Intervention / Treatment
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* Device: FLASH RT
* Device: Conventional RT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed study Informed Consent Form Karnofsky Performance Status (KPS) ≥ 60 Age ≥ 60 years Patients with histologically proven cSCC or BCC Patients requiring radiotherapy treatment according to the dermato-oncology tumor board: patients who cannot undergo surgical procedure or patients who decline surgical resection, and/or anatomical locations where surgery can compromise function or cosmesis. T1-T2 N0 lesions with a small (T1; lesion ≤ 2cm in diameter) or large (T2; 2cm < lesion ≤ 4 cm) volume (TNM Classification of Malignant Tumours (TNM) Union for International Cancer Control (UICC), 8th Edition) Lesions should be at least 4 cm apart if treated with 2 different modalities (including surgical treatment of lesions). Lesions should not be located on the face, except on the forehead, above a line situated 1 cm above the eyebrows. Lesions located on the scalp can be treated. Exclusion Criteria: Previous radiotherapy in the treated area Concomitant auto-immune disease with skin lesions Concomitant use of radio-sensitizer drug Cognitive disorders not compatible with the signature of informed consent or that may compromise compliance with the requirements of the study Current, recent (within 10 days prior to start of study treatment), or planned participation in an experimental drug study (before end of treatment (EOT) visit) Concomitant use of systemic oncological treatment for a cancer other than the skin cancer(s)

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: FLASH RT<br> | Device: FLASH RT<br>* For T1 (small) lesions: 22 Gy single dose FLASH RT; For T2 (large) lesions: 5 x 6 Gy fractionated dose FLASH RT<br>* Other names: High dose rate radiotherapy;|
| Active Comparator: Arm B: Conventional RT<br> | Device: Conventional RT<br>* For T1 (small) lesions: 22 Gy single dose conventional RT; For T2 (large) lesions: 5 x 6 Gy fractionated dose conventional RT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of ≥ grade 3 skin toxicity adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | To evaluate the safety of FLASH radiotherapy measured by the collection of ≥ grade 3 skin toxicity AEs according to CTCAE version 5.0. The severity of a specific event is graded i.e. mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), or death (grade 5) using the CTCAE Grading Table. | up to 6 weeks after radiotherapy | 
| Hierarchically tested efficacy measured by local control rate | At day 1, 21, 28, 42, and months 3, 6, and 12 post-treatment, the investigator will measure (with a caliper) the largest diameter of selected lesions for irradiation. Tumor response of each irradiated lesion will be assessed by the investigator as follow: Complete Response: the irradiated lesion is no more visualized Partial Response: the irradiated largest lesion dimension decreased by 30% at least from baseline (day 1) Progressive Disease: the irradiated largest lesion dimension increased by 20% at least from baseline (day 1) Stable Disease: no Complete Response, no Partial Response, no Progressive Disease | From Day 1 up to 12 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of acute side effects observed in radiation field |  | up to 3 months after radiotherapy | 
| Frequency of late side effects observed in radiation field |  | from ≥ 3 months after radiotherapy until 12 months post-treatment start | 
| Evaluation of tumor response | Blinded Imaging Central Review (BICR) of photographs will evaluate tumor response by grading the size of the residual tumor in comparison to the size of the tumor on the day of irradiation (in percentage). 0% means no residual tumor and treatment success, 100% or more indicate a total lack of tumor response. A baseline photograph will be taken the day of the treatment (day 1) in a pre-therapeutic setting with skin delineation of the lesion. Then photos will be repeated at day 21 (+/-2d), day 28 (+/-2d), day 42 (+/-3d) after treatment, then at 3 (+/-7d), 6 (+/-14d), 12 (+/-14d) months after treatment, and at progression. | From Day 1 up to 12 months post-treatment | 
| Evaluation of in radiation field normal tissues reaction around the treated tumors | Blinded Imaging Central Review (BICR) of photographs will evaluate in radiation field normal tissues reaction around the treated tumors by grading radiation induced skin reactions, grade 1-5, using the CTCAE scale. A baseline photograph will be taken the day of the treatment (day 1) in a pre-therapeutic setting with skin delineation of the lesion. Then photos will be repeated at day 21 (+/-2d), day 28 (+/-2d), day 42 (+/-3d) after treatment, then at 3 (+/-7d), 6 (+/-14d), 12 (+/-14d) months after treatment, and at progression. | From Day 1 up to 12 months post-treatment | 
| Epidermis thickness measured by Optical coherence tomography (OCT) | Epidermis thickness in micrometer will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Epidermis roughness measured by OCT | Epidermis roughness in micrometer will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Plexus depth measured by OCT | Plexus depth in micrometer will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Vessel density measured by OCT | Vessel density, expressed as percent of the surface covered by the vessels in the examined area, will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Size of vessels measured by OCT | Mean size (in micrometer) of all vessels in the examined area will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Number of hairs counted by OCT | Number of hairs in the examined area will be counted by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 
| Size of hairs measured by OCT | Mean size (in micrometer) of all hairs in the examined area will be measured by OCT and compared between irradiated skin and normal non-irradiated skin | at baseline, at 4 weeks, at 6 months, and at 12 months post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLASH therapy, basal cell carcinoma, cutaneous squamous cell carcinoma, high dose rate radiotherapy