Melanoma is a type of cancer that can spread to the brain, making the disease harder to treat and worsening both survival and quality of life.

In recent years, treatments have improved significantly thanks to advances in surgery, radiotherapy, immunotherapy, and targeted therapy. These new treatments have greatly increased survival rates for patients with metastatic melanoma.

This study focuses on stereotactic radiosurgery, a highly precise form of radiotherapy used to treat brain metastases. Researchers want to better understand how this treatment works when combined with immunotherapy or targeted therapy, and whether the timing and sequence of treatments can improve outcomes.

Between 2026 and 2028, patients treated at the IEO for melanoma brain metastases will be observed and their clinical data collected. The goal is to improve future treatment strategies and help doctors choose the best therapeutic approach for each patient.

The therapeutic landscape of metastatic melanoma has undergone a radical transformation in the last decade, largely due to the recent introduction of immune checkpoint inhibitors (IT) and targeted therapies (TTs), and advances in surgery and radiotherapy (RT), which have changed the outlook of patients with melanoma brain metastasis.

Radiation therapy has been and remains an important component of treatment for patients with melanoma brain metastases.

Particularly, stereotactic radiosurgery (SRS), highly precise RT technique, for single or a small number of metastases, has emerged as a crucial component in the management of melanoma brain metastases, with whole brain RT usually reserved for selected patients who have widespread intracranial metastatic disease. SRS relies on the delivery of concentrated, high doses of radiation to one or more metastatic brain lesions of otherwise radio-resistant tumors such as melanoma, providing effective local control (LC) of the disease while minimizing damage to surrounding healthy tissue. SRS can be employed both as an independent primary local therapy, allowing a swifter transition to systemic therapy compared to classic surgical resection and as a salvage procedure after ineffective systemic treatment when the number of MBMs remains below 5-10 and their size is below 3 cm.

A recent systematic review of RT alone for MBMs reported a median survival of 7.5 months (IQR-6.7-9.0-months) after SRS and 3.5 months (IQR-2.4-4.0-months) after whole brain RT.

Although these advances have successfully improved the outcomes of patients with metastatic melanoma, its management remains challenging and complex, requiring a multidisciplinary approach that integrates surgery, systemic therapy, and RT to optimize patient outcomes.

Ongoing investigations in this field are now focused on determining the best strategies to combine RT modalities with systemic therapies (IT and TT), emphasizing the potential for synergistic effects that enhance treatment efficacy. However, data on optimal sequencing and toxicity management, particularly in the context of radiosurgery, remain limited and require careful evaluation. The approach of combining RT with IT or TT has therefore become established in practice but this strategy has not been evaluated in randomized controlled trials. Clinical guidelines vary in the strength of their recommendations for combining different treatments. Studies differ in terms of patient selection, the extent of extracranial disease, the number of lesions treated, and the definitions of concurrent versus non-concurrent therapies. These differences make it challenging to draw definitive conclusions about the optimal treatment strategy for melanoma brain metastases.

In this prospective observational study, the investigators aim to analyse the impact of RT in a well selected population of patient receiving SRS at the European Institute of Oncology- IRCCS- Milan- as first local approach for MBMs, in combination with different type and timing of systemic treatment.

By analysing data from patients treated with CyberKnife from 2026 to 2028, the investigatorsseek to provide insights into the effectiveness of SRS according LC, overall survival (OS) and progression-free survival (PFS) in this patient population.

The investigators aim to investigate also potential prognostic factors including demographic, clinical, and therapeutic factors, with a focus on the influence of concurrent versus non-concurrent systemic therapies.

Through this prospective observational study, the investigators aim both to contribute to the growing body of evidence supporting the use of SRS as a viable treatment option for patients with MBMs and to identify factors that may enhance treatment efficacy and improve patient outcomes.

Inclusion Criteria:

• Age > 18
• Written informed consent for treatment and research purposes
• Melanoma Brain Metastases (MBM) diagnosed with brain MRI/CT
• MBM treatable with stereotactic radiotherapy
• Systemic therapy (immunotherapy, target therapy, or both) is allowed, as concurrent or non-concurrent treatment with stereotactic radiotherapy

Exclusion Criteria:

• Leptomeningeal neoplastic infiltration
• Previous whole-brain radiotherapy or surgical removal of brain metastases
• Patients with histological diagnosis of non-cutaneous melanoma (e.g. uveal melanoma)

Patients receiving stereotactic radiotherapy for melanoma brain metastases as first local approach.

Target therapy and immunotherapy in combination or not will be permitted.

Given the descriptive nature of the study, no formal sample size calculation was performed. The planned sample size was predefined according to historical data from the RT Division and reflects the expected number of eligible patients treated at our institution over the planned three-year study period. Based on these data, we anticipate enrolling approximately 50 patients.