Recent Advances in the Management of Brain Metastases in Non-Sma

Introduction
For more than 50 years, the mainstay of treatment has been definitive WBRT, which has been shown to improve survival and local control as well as palliate neurologic symptoms.^4-6 Focal treatments such as resection or stereotactic radiosurgery with WBRT have been shown to benefit a subset of patients.^7-9 With advances in chemical modifiers such as radiosensitizing agents and chemotherapy regimens, newer management strategies incorporating the application of these modalities with traditional treatments are emerging. Goals of treatment have expanded to provide not only symptomatic relief, improve neurologic status, and prolong survival, but also to prevent neurocognitive impairment, which may be related to the tumor itself or treatment rendered.

WBRT Alone
The appropriate use of WBRT can provide rapid attenuation of many neurologic symptoms, improve quality of life, and be especially beneficial in patients with large, multiple, or diffuse metastases, in patients whose lesions impinge on eloquent areas, and in patients with medical comorbidities that preclude them from surgery. Because multiple (more than one) metastases are found in approximately 80% of patients with brain metastases, WBRT is the treatment of choice for the vast majority of patients.

WBRT with Focal Treatment
Focal treatment combined with WBRT has been shown to improve overall survival in patients with a single metastasis based on prospective randomized trials.^7-9 Improved surgical techniques and postoperative care have resulted in a decline in morbidity to less than 5%, making resection a safer option for patients with brain metastases. Surgery is indicated when tissue is needed to establish a diagnosis or to provide immediate palliation.

Focal Treatment Alone
With the increased efficacy of focal treatments, an approach using resection or stereotactic radiosurgery alone, with WBRT reserved for salvage, has been proposed, especially for younger patients with a good performance status and controlled extracranial disease. The rationale for this practice is to avoid neurocognitive impairment that may occur with WBRT. Opponents of this approach point out that even under ideal circumstances, microscopic disease may remain in the majority of patients receiving focal treatments and may rapidly emerge as symptomatic metastases. The aim of adjuvant WBRT is to eradicate any residual disease to enhance local control, both at the focal site and in the rest of the brain. Defining the best approach in regard to the timing and sequence of these modalities remains to be clarified.

Neurocognitive Function
As some patients with brain metastases are surviving longer, understanding neurocognitive function has become increasingly important. Neurocognitive dysfunction may be caused by radiotherapy, systemic treatment such as chemotherapy and hormonal agents, surgery, adjuvant medications, and the tumor itself. Treatments with pharmacologic agents and modifications to radiotherapy are currently being examined in clinical trials. Further data are needed to validate these approaches.

Systemic Agents
Along with advances in the delivery of radiotherapy, the addition of systemic agents such as radiosensitizers and chemotherapy to radiotherapy is another strategy to improve treatment. Recently developed radiosensitizers such as motexafin gadolinium (MGd) and efaproxiral (RSR-13) have demonstrated initially promising results. These compounds are thought to have a synergistic effect when used in conjunction with radiotherapy; however, the optimal combination, including timing and sequence, is currently being investigated.

Prophylactic Cranial Irradiation
The role of prophylactic cranial irradiation (PCI), which has been beneficial in reducing the risk of brain metastases in patients with small cell lung cancer who achieved complete response to initial therapy, is still inadequately defined in patients with NSCLC. The rationale behind this approach is to eradicate occult microscopic disease before it manifests clinically, especially in high-risk patients or in those with better response to treatment, without causing severe adverse effects from treatment.

Conclusion
Despite advances in treatment delivery, a dramatic improvement in outcome has not been shown in patients with brain metastases from NSCLC. Definitive WBRT remains the standard of care for the majority of patients, especially those with multiple lesions. Although focal treatments such as resection and radiosurgery have shown numerically similar survival compared with focal treatment plus WBRT, these trials were not adequately powered for the survival endpoint, local control improved substantially with the addition of WBRT, and neurocognitive function was worse in the radiosurgery-alone arm. Until there is evidence that the omission of WBRT results in an improved clinical outcome, immediate adjuvant WBRT should remain the standard of care in patients receiving local treatment.

Future directions in the management of brain metastases in patients with NSCLC include trials investigating quality-of-life measures such as neurocognitive function. Strategies to improve neurocognitive function, such as pharmacologic agents and modifications in the delivery of radiotherapy, are under investigation. Furthermore, the application of multimodal approaches involving systemic agents such as radiosensitizers and chemotherapy has demonstrated promising results and is the subject of ongoing research. Further data are awaited before routine administration of these approaches is recommended.