Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer.
An increasing portion of patients with cancer are manifesting brain metastases, with a prevalence of up to 40% and an incidence of approximately 170,000 new cases per year in the United States. The goal for management of brain metastasis is to achieve control of symptoms and recurrence, both at existing sites of metastasis (local control) and through the prevention of new lesions (distal or regional control). This control can then contribute, in combination with systemic treatments, to improved neurologic function, performance status, and potentially overall survival.
The evidence-based treatment of brain metastasis in any individual patient will often incorporate surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy over the course of the illness.1 Most importantly, treatments directed at brain metastases must be coordinated with treatments for systemic disease.
Here, we frame the key considerations for appropriately guiding therapeutic decisions for patients with brain metastases.
Patient Characteristics
Decision-making about brain metastases requires knowledge of expected overall survival in a patient with metastatic cancer. Will this patient live long enough that control of metastatic disease in the brain will contribute to an improvement in overall outcome?
In historical studies, improved survival in patients with brain metastases was associated with age ≤ 65 years, Karnofsky performance status (KPS) ≥ 70, controlled systemic disease, and isolated brain relapse. A recently proposed Diagnosis-Specific Graded Prognostic Assessment from the Radiation Therapy Oncology Group has further accounted for the histology of the primary malignancy, which can more accurately predict the range of a single patient’s expected survival (Fig. 1).2
Tumor Characteristics
Use of screening MRI in patients with cancer has yielded increased detection of small, asymptomatic brain metastases. These lesions are are often subcentimeter in size and are amenable to treatment by whole-brain irradiation or stereotactic radiosurgery (or both), on an outpatient basis. Traditionally radioresistant histologies such as melanoma, renal cell carcinoma, and sarcoma are associated with poor rates of local control when only whole-brain irradiation is administered.
Surgical resection is usually indicated in the local control of larger (> 3 cm in diameter) lesions causing mass effect, those resulting in significant surrounding edema, obstructive hydrocephalus, and especially for those in the posterior fossa. Clinical equipoise remains on the management of asymptomatic lesions between 1 cm and 3 cm, for which local control can be achieved by either surgery or stereotactic radiosurgery.
Surgical Resection
Two randomized controlled trials demonstrate survival benefit with surgical resection and whole-brain radiotherapy as compared with whole-brain radiotherapy alone for the management of a single brain metastasis in patients with good performance status. Level 2 evidence suggests that lesions larger than 3 cm or those resulting in mass effect may have improved outcomes with surgical resection rather than stereotactic radiosurgery. Taken together with the randomized controlled trial data for stereotactic radiosurgery of a single lesion (see below), there is strong evidence for a survival benefit from an initial strategy of focally directed therapy (surgery or stereotactic radiosurgery) for patients with a single brain metastasis and good performance status.
Available data are insufficient to guide management for patients with lower performance status (KPS < 70). This subgroup may have decreased overall survival secondary to systemic progression, and thus local control of asymptomatic brain lesions may not improve their overall outcome.
Stereotactic Radiosurgery
While resection is recommended for single brain metastases larger than 3 cm in locations amenable to surgery, stereotactic radiosurgery appears to offer an equivalent option for the management of a smaller single lesion in terms of local control and survival (Fig. 2).3 Level 1 evidence supports the use of stereotactic radiosurgery for single brain metastases (in addition to whole-brain radiotherapy) in patients with KPS ≥ 70 to obtain improved survival. Indeed, with regard to lesions < 3 cm, level 2 evidence suggests equivalence of surgical resection and stereotactic radiosurgery when used together with whole-brain radiotherapy in terms of recurrence and survival rates.
Stereotactic radiosurgery combined with whole-brain radiotherapy may be superior to whole-brain irradiation alone to preserve function in patients with two to four metastatic lesions. Which patients with multiple metastases may benefit from stereotactic radiosurgery is currently an area of active study; factors such as tumor histology or potential response to systemic targeted therapeutics may play an important role.
Adjuvant Whole-brain Radiation Therapy
No study has yet been reported with enough power to observe a difference in survival for patients receiving stereotactic radiosurgery alone compared to those undergoing stereotactic radiosurgery and whole-brain radiotherapy. However, there has been a significant difference noted in local and distant recurrence in patients for whom whole-brain radiotherapy is withheld. The timing of whole-brain irradiation has therefore been controversial. Patients with asymptomatic brain metastases and extensive systemic disease are able to initiate chemotherapy sooner if the intracranial disease is initially treated with stereotactic radiosurgery, and whole-brain radiotherapy is withheld until distal failure in the brain.
Given the lack of clear survival benefit and the well known detrimental effects on cognitive function with adjuvant whole-brain radiation therapy,4 an alternative treatment paradigm is close postoperative (or post–stereotactic radiosurgery) surveillance, with whole-brain radiotherapy reserved as salvage therapy at the time of brain recurrence. Ongoing randomized controlled trials will clarify whether withholding of upfront whole-brain radiotherapy affects intracranial recurrence, survival, and neurocognitive function, with the hope that evidence-based criteria can be developed to guide the sequenced application of these treatments.
Recommendations
The goal of brain metastasis management is to achieve local and regional control as a means of preserving performance status and neurologic function and potentially improving overall survival. Patients with a single brain metastasis (up to 30% of patients on initial presentation) have a proven survival benefit from focally directed therapy (stereotactic radiosurgery or surgery). Surgical resection and stereotactic radiosurgery appear to have therapeutic equivalence for asymptomatic supratentorial lesions less than 3 cm. These modalities are particularly important for the local control of traditionally radioresistant histologies such as melanoma, renal cell carcinoma, and sarcoma.
While whole-brain radiotherapy clearly affects intracranial recurrence rates when applied after resection or stereotactic radiosurgery, the effect on overall survival has been less easily demonstrable. Taken together with the potential detrimental effects of whole-brain radiotherapy on neurocognitive function, this has led to clinical trials to identify patient subgroups in which whole-brain irradiation may be reserved as salvage therapy. ■
Dr. Shankar is Senior Resident, Department of Neurosurgery, Massachusetts General Hospital. Dr. Cahill is Assistant Professor in Neurosurgery, Harvard Medical School, and Attending Neurosurgeon, Massachusetts General Hospital, Boston.
Disclosure: Drs. Shankar and Cahill reported no potential conflicts of interest.
References
1. Robinson PD, Kalkanis SN, Linskey ME, et al: Methodology used to develop the AANS/CNS management of brain metastases evidence-based clinical practice parameter guidelines. J Neurooncol 96:11-16, 2010.
2. Sperduto PW, Kased N, Roberge D, et al: Summary report on the graded prognostic assessment. J Clin Oncol 30:419-425, 2012.
3. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363(9422):1665-72, 2004.
4. Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 10:1037-1044, 2009.
