Novel Agents in the
Treatment of Lung Cancer

New Approaches to First-Line Therapies

Brain Metastases

April F. Eichler, MD, MPH, Jay S. Loeffler, MD,
Tracy T. Batchelor, MD
Massachusetts General Hospital Cancer Center

Metastatic brain tumors are the most common intracranial neoplasm in adults. Although their exact incidence is unknown, the yearly incidence has been estimated to be as high as 200,000 in the United States alone.⁹⁴ Recent population-based data suggest that 8% to 10% of adults with cancer will develop symptomatic brain metastases during their lifetime.^95,96 The majority of brain metastases originate from 1 of 3 primary malignancies: lung (40-50%), breast (15-25%), and melanoma (5-20%). The frequency of metastatic brain tumors appears to be rising due to improved imaging modalities and earlier detection as well as longer survival after primary cancer diagnosis due to more effective treatment of systemic disease. The latter appears to be especially true for women with breast cancer.

The distribution of brain metastases generally parallels blood flow, with 80% occurring in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem.^97,98 In the era of magnetic resonance imaging, most patients have multiple brain metastases at diagnosis. Common clinical features include headache, neurological deficit, and seizures. Detailed neuropsychological testing demonstrates cognitive impairment in 65% of patients with brain metastases, usually across multiple domains.⁹⁹ Neurological deficits may be due to destruction or displacement of brain tissue by expanding tumor, tumor-associated edema leading to further disruption of surrounding white matter tracts, increased intracranial pressure, and/or vascular compromise.

Symptomatic Strategies

The management of brain metastases can be divided into symptomatic and therapeutic strategies. Symptomatic therapy often includes corticosteroids to reduce vasogenic brain edema and anticonvulsants to prevent recurrent seizures. In addition, there are increasing data to suggest that medications such as methylphenidate and donepezil can improve cognition, mood, and quality of life in patients with brain tumors.^100-102 In general, corticosteroids are prescribed only to patients who are symptomatic from their brain metastases. The lowest dose is recommended to control symptoms but avoid deleterious side effects. Bevacizumab and other agents that inhibit VEGF signaling may also prove beneficial in the control of vasogenic brain edema associated with metastases; prospective trials are ongoing to assess this possibility. Prophylactic administration of anticonvulsants to brain metastasis patients who have not experienced a prior seizure is not recommended.¹⁰³ However, brain metastasis patients undergoing craniotomy for resection of their tumor may benefit from anticonvulsants in the perioperative period. Brain metastasis patients who have experienced a prior seizure clearly benefit from the administration of anticonvulsants.

Therapeutic Strategies

Therapeutic approaches to brain metastases include surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Many patients are treated with a combination of these, and treatment decisions must take into account factors such as patient age, functional status, primary tumor type, extent of extracranial disease, prior therapies, and number of intracranial lesions. Figure 5 depicts a general framework for consideration in the management of patients with brain metastases.¹⁰⁴ WBRT alone remains the standard of care for the 80% of the brain metastasis population who present with > 1 brain metastasis, and results in a median survival of approximately 15-20 weeks. Approximately 1 in 5 patients with a brain metastasis present with a single brain lesion. In this patient population, it is recommended that either resection or biopsy be considered to definitively establish the diagnosis of the brain lesion. In one study, 11% of patients with cancer and a single brain lesion were found to have nonmetastatic brain lesions after histopathological review. Two out of three randomized, controlled trials have demonstrated that resection followed by WBRT confers a survival advantage over WBRT alone in the treatment of patients with single brain metastases.^105,106 Thus, resection is generally recommended for patients with a surgically accessible single brain metastasis. Another potential advantage of surgery is the reduction of mass effect and brain edema, which often results in symptomatic improvement and allows discontinuation of corticosteroids. Although there have been no prospective, controlled studies, smaller retrospective studies suggest that resection may also confer survival advantage for patients with 2-4 accessible brain metastases.

Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) is a less invasive treatment than surgery and allows targeting of brain metastases typically < 4 cm in longest dimension. SRS followed by WBRT afforded longer overall survival compared to WBRT alone for patients with a single brain metastasis in a randomized trial.¹⁰⁷ However, there was no survival advantage for patients with 2-3 brain metastases who received SRS. There have been no prospective, randomized studies of resection versus radiosurgery for patients with single brain metastases. Two randomized trials have demonstrated that patients who receive WBRT after resection or SRS had a lower likelihood of relapse in the brain compared to patients who did not receive WBRT, although there was no apparent survival advantage of WBRT in this setting.^108,109 A number of radiosensitizers have been combined with WBRT with the goal of enhancing the efficacy of radiation for patients with brain metastases. Unfortunately, recent randomized trials of 2 of these agents, motexafin-gadolinium and efaproxiral, did not prolong survival in the brain-metastasis population.^99,108

Chemotherapy

Chemotherapy for patients with brain metastases is receiving increasing attention as subsets of brain metastasis patients are surviving longer and symptomatic neurotoxicity from WBRT is recognized more frequently in these long-term survivors. Unfortunately, older studies of chemotherapy enrolled patients with brain metastases from multiple primary tumor types, making it very difficult to draw conclusions regarding the efficacy of any particular agent. More recent multicenter studies have restricted eligibility to subsets of brain metastasis patients, which should allow more definitive assessments of various cytotoxic and molecularly targeted agents.¹¹¹ However, at this point chemotherapy for brain metastases should be considered a topic for investigation.¹⁰⁴

(click table to view larger version)

< < PREVIOUS

NEXT > >