Treatment of Brain Metastases from Ovarian and Endometrial Carcinomas Using Stereotactic Radiosurgery

Introduction

Ovarian and endometrial carcinomas together create a substantial cancer burden, combining for nearly 10% of all cancers in women in the United States ( ). Despite this figure, the incidence of brain metastases from these primary cancers is quite small: 0.3–2.2% for ovarian cancer and 0.4–1.2% for endometrial cancer ( ). However, as is the case with many primary malignancies, the incidence of brain metastases seems to be on the rise due to earlier diagnosis, improved systemic treatments, and prolonged survivals ( ). For example, about three quarters of patients with endometrial cancer are diagnosed at an early stage and experience a 5-year survival rate around 90% after primary therapy ( ). With the widespread use of platinum based therapies for ovarian carcinoma, longer term survival can be achieved in 30% of patients despite the fact that most women (~75%) are initially diagnosed with advanced stage disease ( ). Because of the low rates of central nervous system spread, ovarian and endometrial carcinomas have been described as “neurophobic” ( ). Both tend to recur or spread in a loco-regional fashion through direct extension to adjacent organs or via lymphatic dissemination. Less often these cancers spread hematogenously, and when they do, they tend to spread to the chest (lungs and pleural cavities) and the liver ( ). Unlike in melanoma, where brain metastases are often the first site of visceral spread, patients with endometrial and ovarian cancer develop brain metastases late in their course when they have widely disseminated and advanced stage disease. This results in meaningful challenges when deciding on how best to treat brain metastases.

The traditional reflexive approach for the treatment of brain metastases has long been the administration of fractionated whole brain radiation therapy (WBRT). The use of WBRT, for treatment of even a solitary metastasis, has been based on a number of antiquated notions: the absence of treatment alternatives, the widespread availability of delivery devices, the inability of chemotherapeutics to traverse the blood–brain-barrier, the capacity to rapidly begin treatment in the absence of detailed planning, and the presumed benefit of treating potential “micrometastatic disease” not detected on imaging. Despite tremendous improvements in systemic cancer therapies, there have been no meaningful changes in the safety and efficacy of WBRT despite numerous attempts at different fractionation schedules and radiation sensitizers ( ). More than ever, with ever increasing long-term survival from cancers, concerns have begun to mount regarding the delayed toxicities of WBRT. WBRT leads to progressive, irreversible white matter changes, or leukoencephalopathy in long-term survivors of brain metastases ( ). Similar changes in the white matter seem to correspond to neurocognitive dysfunction in diseases like vascular dementia and alcoholism ( ). In a survey of patients who underwent treatment for brain metastases, patients who had WBRT reported significant difficulties with short- and long-term memory, concentration problems, as well as mood disorders ( ). Indeed, in the first ever randomized clinical trial of brain metastases treatment using neurocognitive function as a primary outcome, demonstrated that when therapy included WBRT there was a significantly risk of decline in learning and memory function in as little as 4 months after treatment. In light of these types of findings, the utilization of WBRT ought to be carefully scrutinized in the setting of alternative therapies.

Stereotactic radiosurgery (SRS) has evolved as a safe and efficacious treatment alternative for brain metastases and there is a nearly three decade long experience detailed in the literature. SRS has several advantages over WBRT, including: it is typically performed in a single session, systemic therapies need not be stopped or delayed in the event of an SRS procedure, SRS administers a more radiobiologically effective tumoricidal dose, SRS is not inherently limited by potential toxic dose to normal tissue due to its conformality, and most importantly SRS is a targeted and individualized treatment approach. There is a growing emphasis that the study of brain metastases patients should be tailored to specific histologies or even molecular subtypes rather than the pooling of data from all tumor types. Avoidance of a “one-size-fits-all” approach can eliminate numerous confounding variables. For instance, receptor subtype has a meaningful prognostic significance for breast cancer patients, for some portending survival of greater than 2 years after initial diagnosis of brain metastases ( ). In contrast, for melanoma only performance status and the number of brain metastases seems prognostic ( ). In an often cited landmark randomized clinical trial comparing WBRT plus SRS to SRS alone for patients with brain metastases, 86% of patients were lung cancer patients ( ). The purpose of this report is to review the limited available data regarding the use of SRS for the treatment of brain metastases from ovarian and endometrial carcinoma.