Clinical trial NCT05545007: Preoperative vs Postoperative Hypofractionated Radiosurgery for Patients With Large Brain Metastases
Official title: Phase III Randomized Trial Comparing Preoperative Hypofractionated Radiosurgery (HSRS) to Postoperative Hypofractionated Radiosurgery (HSRS) for Patients With Large Brain Metastases (= 2.1cm) Suitable for Surgical Resection
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Brain Metastases, Adult
Keywords: pre-operative hypofractionated radiosurgery
surgical resection
large brain metastases
post-operative hypofractionated radiosurgery
Lead sponsor: Istituto Clinico Humanitas
Sponsor class: OTHER
Collaborators: name: Brainlab AG
First posted: 2022-09-19
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Rate of LMD (leptomeningeal disease) occurrence
timeFrame: 1 year
Secondary outcomes:
measure: Rate of local recurrence
timeFrame: 1 year
measure: Rate of brain distant progression
timeFrame: 1 year
measure: Overall Survival
timeFrame: 1 year
measure: Radiation Necrosis Evaluation
timeFrame: 1 year
measure: Rate of surgical Morbidity
timeFrame: 1 year
measure: Quality of Life and neurocognitive functions evaluation
timeFrame: 1 year
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: IRCCS Istituto Clinico Humanitas
state: Milano
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Florence
country: Italy
facility: AOUC Azienda Ospedaliero-Universitaria Careggi
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Naples
country: Italy
facility: Ospedale del Mare
city: Rome
country: Italy
facility: Policlinico Umberto I
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Rome
country: Italy
facility: AOU Sant'Andrea
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
Study officials:
References: