Intraoperative brachytherapy for resected brain metastases

Abstract

Brain metastases are the most common intracranial malignancies in adults. Surgical resection is the preferred treatment approach when a pathological diagnosis is required, for symptomatic patients who are refractory to steroids, and to decompress lesions causing mass effect. Radiotherapy is administered to improve local control rates after surgical resection. After a brief review of the literature describing the treatment of brain metastases using whole-brain radiotherapy, postoperative stereotactic radiosurgery, preoperative radiosurgery, and brachytherapy, we compare patient-related, technical, practical, and radiobiological considerations of each technique. Finally, we focus our discussion on intraoperative brachytherapy, with an emphasis on the technical aspects, benefits, efficacy, and outcomes of studies utilizing permanent Cs-131 implants.

Introduction

Brain metastases, the most common intracranial neoplasms in adults (1), develop in approximately 30% of all cancer patients, and is the cause of death in up to 50% of these individuals (2). They are commonly located at the gray–white matter interface where the blood vessel caliber decreases, and their dissemination corresponds with blood flow: 80% of patients develop multiple intracranial metastases, with 80% occurring in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem (3). Incidence rates are expected to rise with the emergence of increasingly effective systemic agents that, while conferring improved systemic control translating to increased survival, possess limited ability to bypass the blood–brain barrier (4). As only 10% of patients become symptomatic from brain metastases, incidence rates are also increasing with improved surveillance (2). Primary lung cancers account for over 50% of intracranial metastases, with breast cancers, melanoma, and colon cancers, respectively, accounting for approximately 20%, 10%, and 5% of all brain metastasis primaries (2). Epidemiologically, these primaries are also among the most common malignancies in the United States. Conversely, small cell lung cancers, melanoma, germ cell tumors, and choriocarcinomas demonstrate proportionally high neurotropism rates.

Symptomatic management options include corticosteroids and supportive care (5). Chemotherapeutic agents historically demonstrated little efficacy in treating brain metastases owing to the inability to enter the central nervous system. However, the utility of targeted agents and immunotherapy in the context of multidisciplinary treatment strategies is currently an area of active investigation. Commonly utilized treatment options include whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and surgical resection.

WBRT was the initial standard therapy and continues to play a pivotal role in treating brain metastases, particularly in the setting of multiple lesions, and in the presence of recurrent metastases or leptomeningeal disease. The first Radiation Therapy Oncology Group (RTOG) randomized trials established WBRT as an effective modality for patients with favorable performance status and/or well-controlled primary disease. However, these initial studies reported overall survival (OS) rates of only a few months (6). Patchell et al. improved on these outcomes in a randomized trial comparing WBRT to surgical resection followed by WBRT among patients with a single brain metastasis. They demonstrated that surgery followed by WBRT improved OS to 40 weeks, compared to 15 weeks with WBRT alone (7). Patchell and colleagues subsequently randomized 95 patients who underwent surgical resection of a single metastasis to observation or postoperative WBRT and reported no significant difference in OS among the cohorts. However, tumor recurrence was reduced from 46% in the observation group to 10% in the WBRT group, as well as a reduction in new brain metastases and death due to neurological causes in the WBRT group, thus establishing postoperative WBRT as the standard of care for brain metastases (8).

SRS is a minimally invasive option for patients in lieu of, or in combination with surgery; however, there is a dearth of appropriately powered randomized control trials comparing surgical resection and SRS alone for brain metastases. RTOG 9508 demonstrated that an SRS boost improves local control (LC) after WBRT with no difference in survival among patients with one to three brain metastases (9). Conversely, several randomized trials evaluating SRS alone vs. SRS with WBRT demonstrated that the latter may improve local and distant tumor control, but OS rates remained the same as using SRS alone [10], [11], [12]. Patients undergoing WBRT were also more likely to exhibit neurological decline [13], [14]. These findings, alongside studies showing SRS, may be an appropriate option for patients with multiple brain metastases (15), which promotes its increasing utilization over WBRT.

Surgical resection is offered to patients who require pathological confirmation, have a large (greater than 2 cm) metastasis, or are acutely experiencing mass effect or neurological symptoms refractory to steroids (16). Conversely, patients with a poor performance status, a large number of brain metastases, or a high risk of surgery-related morbidity (e.g., if the metastasis is adjacent to eloquent brain structures) may be deemed unresectable (16). Patients may also elect for SRS in lieu of surgical resection. Surgical resection without any adjuvant intracranial treatment has 1- to 2-year LC rates of 47–59%, and thus, adjuvant radiotherapy is typically given in an effort to maximize LC [8], [12], [17]. Given concerns of neurocognitive decline after WBRT, the paradigm is shifting to postoperative SRS [17], [18], [19]. The relative benefits and disadvantages of giving SRS preoperatively are also under investigation, with a retrospective multi-institutional study comparing preoperative SRS to postoperative WBRT showing no differences in OS and local recurrence at 2 years (20). The only prospective trial evaluating preoperative SRS demonstrated an 85.6% 1-year LC rate without radionecrosis (21), and one trial (NCT02514915) is currently accruing.

Another appealing option to improve postoperative LC rates and obviate the need for adjuvant radiation and commute for postoperative radiation treatments entails intracavitary brachytherapy. This review discusses the rationale, technique, outcomes, evidence, and future directions regarding the use of intracavitary brachytherapy as an adjunct treatment to surgical treatment. We discuss various types of brachytherapy and radioactive isotopes available for this procedure, as well as the benefits of the most novel radioisotope, Cesium-131 (Cs-131), which offers a great promise as the radioisotope of choice in the future.