Evolution of Hypofractionated Stereotactic Irradiation for Radio-Resistant Brain Metastases From D1-3-5 to D1-2-3

Brain metastases (BM), originating from various primary tumors, are associated with decreased progression-free survival, overall survival, and neurological function. Stereotactic radiotherapy offers a precise and targeted approach to treat BM while minimizing cognitive side effects. Studies have shown comparable local control rates to surgery and conventional radiotherapy, but radioresistant cancers exhibit lower response rates whatever the technique of radiotherapy. The radiobiological implications of treatment duration in brain stereotactic irradiation remain understudied, resulting in a lack of available data. However, there is potential for a shorter irradiation duration to enhance tumor control without an accompanying increase in treatment-related toxicity. This study aims to demonstrate a benefit in terms of local control of a shorter spread of hypofractionated stereotactic radiotherapy at D1, D2, D3 vs D1, D3, D5, in the treatment of radioresistant brain metastases.

This prospective, multi-center, randomized, double-arm clinical trial aims to recruit patients with 1 to 5 unoperated brain metastases originating from radioresistant primary sites. Patients will be randomly assigned to either the D1,3,5 radiotherapy arm or the D1,2,3 radiotherapy arm and will be followed for 2 years. Stereotactic brain irradiation will be administered at a dose of 33 Gy delivered in 3 fractions at the isocenter.

The primary endpoint of the study is the assessment of local control at 6 months per brain metastasis. Secondary endpoints include evaluating cerebral control, overall survival, radionecrosis rate, quality of life, neurological function, and treatment-related toxicity.

A more condensed treatment approach may exploit the radiobiological properties of tumors, potentially increasing their sensitivity to radiation while minimizing the opportunity for tumor repopulation. Moreover, reducing treatment duration also has the potential to improve the patient's quality of life by minimizing fatigue towards the end of the irradiation course.

• Local control of brain metastases at 12, 18 and 24 months [Time frame: at 12, 18 and 24 months]
• Cerebral control at 12, 18 and 24 months [Time frame: at 12, 18 and 24 months]
• Overall survival [Time frame: From the date of randomization until the date of death from any cause, loss to follow-up, or 24 months, whichever occurs first]
• Progression-free survival [Time frame: According to local practices until the date of first documented progression or the date of death from any cause or until 24 months, whichever occurs first]
• Patient Quality of life [Time frame: Before radiotherapy, then at 3, 6, 12, 18 and 24 months from randomization]
• Patient Quality of life [Time frame: Before radiotherapy, then at 3, 6, 12, 18 and 24 months from randomization]
• Risk of leptomeningeal dissemination [Time frame: according to local practices until death from any cause or lost to follow-up or until 24 months, whichever came first]
• Radionecrosis-free survival [Time frame: according to local practices until death from any cause or lost to follow-up or until 24 months, whichever came first]
• Patient Safety [Time frame: From the date of randomization until the date of death from any cause, loss to follow-up, or 24 months, whichever occurs first]
• Patient Safety according to Patient Reported Outcome [Time frame: From the date of randomization until the date of death from any cause, loss to follow-up, or 24 months, whichever occurs first]
• Cognitive decline assessment [Time frame: At baseline (before radiotherapy), then at 3, 6 and 12 months from randomization]
• Cognitive decline assessment [Time frame: at baseline (before radiotherapy), then at 3, 6 and 12 months from randomization]