Patients suffering from malignancies in advanced stages often develop brain metastases, which limit both the life span and the quality of life.

Combining surgery and radiotherapy for resectable brain metastases is standard of care but there is a lot of controversy on which kind of radiotherapy is best suitable. Recently, first volumetric in-silico analyses point to theoretical advantages of neoadjuvant stereotactic radiotherapy of brain metastases. Special about this trial is the direct comparison between the three currently discussed radiotherapy options for resectable brain metastases: Neoadjuvant stereotactic radiotherapy, intraoperative radiotherapy and adjuvant stereotactic radiotherapy.

This trial approach allows for detailed comparison of resected tissue samples, cerebrospinal fluid and blood of all patient groups. So, the investigators will investigate biomaterial of recently irradiated (neoadjuvant and intraoperative arms) and non-irradiated (adjuvant arm) tissue. All this prompts the main issues of the explorative randomized controlled phase 2 RADCAV trial: Is there a difference between neoadjuvant stereotactic radiotherapy vs. intraoperative radiotherapy vs. adjuvant stereotactic radiotherapy regarding the factors immune profiling, dosimetry, efficacy and toxicity. It can be hypothesized that the resected tissue differs between recently irradiated and non-irradiated brain metastases, for example regarding different histopathologic and molecular pathologic markers including immune environment, markers for cell death and markers for tumor invasion. Are there histopathologic and molecular pathologic markers of tumor cell response and prognosis so the investigators can better understand the effects of irradiation on metastatic brain tissue? And are there relevant differences in dosimetry that put patients at different risks for efficacy and toxicity?

Inclusion Criteria:

• Histologically confirmed solid malignancy

  • Metastatic brain disease (1-10 brain metastases), with at least one brain metastasis in a non-eloquent location (i.e. motor or speech) planned for resection
  • Maximum size of the brain metastasis <5cm
  • Eligibility of patients for both stereotactic radiotherapy and resection
  • Time interval from resection to adjuvant stereotactic radiosurgery of 2-6 weeks
  • Time interval from neoadjuvant stereotactic radiosurgery to resection of 1-7 days
  • Possibility to postpone resection for neoadjuvant stereotactic radiosurgery, if applicable
  • Karnofsky performance scores >= 70 or Eastern Cooperative Oncology Group (ECOG) >= 2 at enrollment
  • Age ≥ 18 years of age
  • For women with childbearing potential, (and men) adequate contraception.
  • Ability of subject to understand character and individual consequences of the clinical trial
  • Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

Necessity of immediate surgical resection due to life threatening symptoms

• brain metastasis directly located (≤10mm) next to the optic system or brain stem
• Refusal of the patients to take part in the study
• Small-cell lung cancer (SCLC) or hematologic malignancy as primary malignant illness
• Leptomeningeal disease suspected RadCav Trial Protocol Version 1.1, 01.07.2022 18
• Previous radiotherapy of the brain
• Contraindication for contrast-enhanced MRI
• Pregnant or lactating women
• Participation in another competing clinical study or observation period of competing trials, respectively