Preoperative vs Postoperative Hypofractionated Radiosurgery for Patients With Large Brain Metastases

NCT ID: NCT05545007

Last Updated: 2025-04-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 146 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-31
• Study Completion Date: 2027-01-31

Brief Summary

This is a phase III randomized trial with the aim to compare preoperative HSRS to postoperative HSRS in patients with large at least one BMs from solid tumors suitable for surgical resection.

Detailed Description

The occurrence of BMs is a huge and challenging issue affecting about 20-40% of patients with solid primary tumors. Among these, about 25% of patients harbored large BMs, defined as ≥ 2.1 cm. Single dose SRS, using the dose guidelines suggested by the Radiation Therapy Oncology Group (RTOG) 90-05 study, obtains an unsatisfactory local control (LC) rate ranging from 45-49%. In this subset of patients other treatment pathways have been investigated. In the 1990s, Patchell and colleagues determined that patients with good functional status, and solitary intracranial metastases should undergo surgical resection. Unfortunately, surgery alone is able to control tumor in only 50% of patients, and an adjuvant radiation therapy (RT) is required. For several years, adjuvant whole brain radiation therapy (WBRT) has been considered the standard of cure, but a high risk of impairment in neurological functions was recorded, without an actual benefit on survival. Different RT approaches have been inquired with the aim to reduce neurological toxicity preserving the same brain tumor control. Recent randomized trials showed that single dose SRS on the tumor bed might be a valid, and less toxic alternative to WBRT, although an increased risk of radio necrosis (RN) was noticed when large surgical cavities are treated. In the last years hypofractionated stereotactic radiosurgery (HSRS) has gained interest. Its goal is to reduce the risk of RN compared to single dose SRS, while providing similar, or perhaps, improved LC, probably in relation to the need of reducing the dose prescribed in cases of larger lesions using SRS.

However, there has been increasing evidence that patients treated with postoperative SRS have an increased rates of leptomeningeal disease (LMD) occurrence than what was observed when postoperative WBRT was used as the standard. Several retrospective studies have demonstrated a LMD rates up to 31% in the postoperative SRS setting.

The proposed mechanism of this increased risk is iatrogenic tumor dissemination into the cerebrospinal fluid (CSF) at the time of surgical resection, which was not as apparent when the entire intracranial CSF space was treated with routine postoperative WBRT, but has become more apparent with increasing use of postoperative SRS only. It is important to note that a standardized definition of radiographic LMD does not exist and ascertainment bias as to what constitutes radiographic LMD (vs local or distant meningeal failure as an example) is an unresolved issue.

Due to the perceived drawbacks of postoperative SRS, namely the need for cavity margin expansion due to target delineation uncertainty, the variable postoperative clinical course and potential delay in administering postoperative SRS, and the theoretical risk of tumor spillage into CSF at the time of surgery, investigators began to study the use of preoperative SRS as an alternative paradigm to maximize local control of the resection cavity and minimize neurocognitive detriment associated with WBRT. Preoperative SRS has several potential advantages compared to postoperative SRS consisting in :

• a better target delineation to an intact lesion
• the reduction of normal brain irradiated considering the useless of additional margins
• the potential prevention of any cells spilled during resection
• a greater oxygenation ratio of the intact region
• a sterilization effect
• the resection of the majority of irradiated tissues Based on this background we designed this phase III randomized trial comparing preoperative HSRS to postoperative HSRS in patients with large at least one BMs from solid tumors suitable for surgical resection.

Conditions

Brain Metastases, Adult

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HSRS pre-operative

Patients undergo HSRS (hypofractionated Radiosurgery) on day 1, consisting in 27 Gray (gy) administered in 3 daily fractions.

Within 1 weeks, patients undergo surgical resection.

Group Type: EXPERIMENTAL

Hypofractionated Radiosurgery (HSRS)

Intervention Type: RADIATION

HSRS converges multiple radiation beams to deliver a single, large dose of radiation to a discrete tumor target with high precision, thereby minimizing radiation dose to the surrounding normal tissue.

Brain metastases surgical resection

Intervention Type: PROCEDURE

Complete surgical resection of brain lesions with adeguate margins.

HSRS post-operative

Patients undergo surgical resection on day 1. Within 4-6 weeks, patients undergo HSRS (hypofractionated Radiosurgery), consisting in 27 Gray (gy) administered in 3 daily fractions.

Group Type: ACTIVE_COMPARATOR

Hypofractionated Radiosurgery (HSRS)

Intervention Type: RADIATION

HSRS converges multiple radiation beams to deliver a single, large dose of radiation to a discrete tumor target with high precision, thereby minimizing radiation dose to the surrounding normal tissue.

Brain metastases surgical resection

Intervention Type: PROCEDURE

Complete surgical resection of brain lesions with adeguate margins.

Interventions

Hypofractionated Radiosurgery (HSRS)

HSRS converges multiple radiation beams to deliver a single, large dose of radiation to a discrete tumor target with high precision, thereby minimizing radiation dose to the surrounding normal tissue.

Intervention Type: RADIATION

Brain metastases surgical resection

Complete surgical resection of brain lesions with adeguate margins.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Age >18 years
• Histological or cytological or radiological confirmation of solid tumor malignancy
• Clinical indication for surgical resection of one brain metastasis
• Karnosky performance status (KPS) ≥70
• Controlled or responsive extra cranial metastatic lesions
• Limited brain metastases (1-4 BMs)
• Single metastatic lesion ≥ 2.1 cm in maximum diameter (4 cm3)
• Lesions ≤2 cm conditioning mass effect or neurological deficits or massive edema unresponsive to steroids
• Written informed consent form

Exclusion Criteria

• Prior WBRT
• KPS < 70
• Diagnosis of small cell lung cancer (SCLC), germinal cell tumour or Lymphoproliferative disease
• Pregnant women
• Prior open neurosurgery for malignancy
• More than 4 brain metastases
• Patients with incompatibility to perform MRI

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brainlab AG

INDUSTRY

Sponsor Role: collaborator

Istituto Clinico Humanitas

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

ASST Spedali Civili di Brescia

Brescia, Brescia, Italy

Site Status: RECRUITING

AOUC Azienda Ospedaliero-Universitaria Careggi

Florence, Florence, Italy

Site Status: RECRUITING

IRCCS Istituto Clinico Humanitas

Rozzano, Milano, Italy

Site Status: RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Milan, Italy

Site Status: RECRUITING

Ospedale del Mare

Naples, naples, Italy

Site Status: RECRUITING

Policlinico Umberto I

Rome, Rome, Italy

Site Status: NOT_YET_RECRUITING

Fondazione Policlinico Universitario Agostino Gemelli

Rome, Rome, Italy

Site Status: NOT_YET_RECRUITING

AOU Sant'Andrea

Rome, Rome, Italy

Site Status: RECRUITING

Azienda Ospedaliera Santa Maria di Terni

Terni, Terni, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Pierina Navarria, MD

Role: CONTACT

pierina.navarria@cancercenter.humanitas.it

+39 028224 7458

Federico Pessina, MD

Role: CONTACT

federico.pessina@hunimed.eu

+39 028224 4617

Facility Contacts

Michela Buglione di Monale, MD, radiation oncologist

Role: primary

michela.buglione@unibs.it

Isacco Desideri, MD, radiation oncologist

Role: primary

isacco.desideri@unifi.it

Pierina Navarria, MD

Role: primary

pierina.navarria@humanitas.it

0282247458

Laura Fariselli, MD, radiation oncologist

Role: primary

laura.fariselli@istituto-besta.it

Francesca Maria Giugliano, MD, radiation oncologist

Role: primary

francescamaria.giugliano@aslnapoli1centro.it

Giuseppe Minniti, MD, radiation oncologist

Role: primary

minnitig@upmc.edu

Silvia Chiesa, MD, radiation oncologist

Role: primary

silvia.chiesa@policlinicogemelli.it

Anna Maria Ascolese, MD, radiation oncologist

Role: primary

aascolese@ospedalesantandrea.it

Paola Anselmo, MD, radiation oncologist

Role: primary

p.anselmo@aospterni.it

Other Identifiers

3270

Identifier Type: -

Identifier Source: org_study_id