How best to manage radioresistant brain metastases (BM) tumor histology's such as renal cell cancer, melanoma and sarcoma remains problematic.  A number of retrospective studies purportedly show no benefit to overall survival, local control rate (BM treated with stereotactic radiosurgery (SRS)), or distant brain failure with the addition of whole-brain irradiation (WBI) to SRS.^1-4  Not evaluated is a comparison between WBI alone vs. SRS with or without WBI.  The premise for adjuvant SRS in these selected tumor histologies is based on the concept that radioresistant tumors show an improved response to large dose/fraction radiotherapy.  Adjuvant WBI followed with SRS at time of relapse may be an equi-efficacious treatment. A randomized trial is needed to provide evidence for these hypotheses.  The RTOG 9508 study that included approximately 5% of patients with melanoma did not demonstrate benefit when comparing WBI to WBI + SRS in patients with 1-3 BM. ECOG performed a small trial (n=36 patients) of radioresistant BM (melanoma, sarcoma, renal cell) treated with SRS and without WBI. All patients had a single BM and only 19% of patients had active systemic disease (i.e., the majority of patients were RTOG RPA class 1). Local control was seen in 60% (as compared to 85% in patients with radiosensitive tumor histologies in the RTOG 9508 trial), distant brain failure was 39% (twice that seen in the RTOG 9508 trial when WBI was administered), and brain cancer as a cause of death was 38% (twice that observed in RTOG 9508).³  These studies question the often-quoted position that radioresistant tumor histologies warrant differing treatments and suggest the need for prospective randomized trials.

How Are Antiepileptic Drugs Best Used With Brain Metastases?

The use of antiepileptic drugs (AED) in patients with BM should be reserved for patients with seizures (seen in 15%-25% of patients at presentation, 10%-20% after diagnosis and 25%-45% overall), and for seizure prophylaxis immediately following surgical resection.^5-7 Based on the recommendations of an American Academy of Neurology guidelines regarding AED use in patients with brain tumors, AED prophylaxis does not prevent first seizures, AED may manifest novel and increased risks in patients with cancer, and the practice of AED prophylaxis in patients with primary and metastatic brain tumors should be abandoned.⁷ If AED are indicated, emerging data recommends the use of non-enzyme inducing AED to minimize drug interactions that may confound the treatment of patients with cancer.

Several generalizations can be made regarding chemotherapy of BM based on the limited literature. Response to chemotherapy reflects inherent chemosensitivity of the primary tumor with best responses seen with small cell lung cancer (SCLC), intermediate responses seen with non-small cell lung cancer (NSCLC), and low response rates with melanoma.^8-12  In addition, response is determined by prior exposure to chemotherapy, as front-line chemotherapy has higher response rates than second- or third-line chemotherapy. Response to chemotherapy as compared to WBI or SRT is inferior and less durable in patients with SCLC, NSCLC, and melanoma.^8-12  The use of chemotherapy for the treatment of BM is most often limited to patients having failed radiotherapy (often both whole-brain and stereotactic), with multiple lesions, and in selected instances, for example solitary BM surgically resected and treated with intracavitary chemotherapy. The majority of chemotherapy trials for BM have utilized either single agent, e.g., temozolomide, or a histology-specific, multi-agent chemotherapy. A less common chemotherapy approach has been the placement of carmustine wafers in the bed of a resected tumor and most often solitary metastasis as mentioned above. More recently, targeted therapies, for example tyrosine kinase inhibitors such as erlotinib, have been used in patients with NSCLC and BM with modest success.^8,9  In patients with asymptomatic BM, primary chemotherapy and deferred WBI is reasonable; however, careful assessment of intracranial response is required. Often, the intracranial response is discordant with and less than the systemic response. In the later instance in which no response to primary chemotherapy is seen, WBI would be administered. As the majority of patients with BM are treated with WBI, the question of whether concurrent chemotherapy adds benefit remains important but unclear. The major utility of systemic chemotherapy in the treatment of BM is found when administered to patients' refractory to radiotherapy and to who no other treatment options remain.^8-12  In this limited context, chemotherapy may offer limited benefit though whether an advantage is seen with single vs. multi-agent chemotherapy is uncertain. The utility of targeted therapy, and in particular small molecule inhibitors, continues to evolve in oncology and hopefully will offer new therapies for patients with BM.¹³

References

1.                  Chang JE, Robins HI, Mehta MP. Therapeutic advances in the treatment of brain metastases. Clin Adv Hematol Oncol. 2007;5(1):54-64.

2.                  Hara W, Tran P, Li G,et al. Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma. Neurosurgery. 2009;64(2 Suppl):A26-32.

3.                  Manon R, O'Neill A, Knisely J, et al. Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E 6397). J Clin Oncol. 2005;23(34):8870-8876.

4.                  Suh JH, Chao ST, Vogelbaum MA. Management of brain metastases. Curr Neurol Neurosci Rep. 2009;9(3):223-230.

5.                  Posner J. Management of brain metastases. Revue Neurologique (Paris). 1992;148(6-7):477-487.

6.                  Posner JB. Brain metastases: 1995. A brief review. J Neuro-Oncol. 1996;27(3):287-293.

7.                  Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(10):1886-1893.

8.                  Langer CJ, Mehta M. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005;23(25):6207-6219.

9.                  Norden AD, Wen PY, Kesari S. Brain metastases. Curr Opin Neurol. 2005;18(6):279-292.

10.              Abrey LE, Olson JD, Raizer JJ, et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol. 2001;53:259-265.

11.              Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brainmetastases. Ann Oncol. 2001;12:249-254.

12.              Antondou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide concurrent radiotherapy in patients with brain metastases. J Clin Oncol.  2002;20:3644-3650.

13.              Lin NU, Carey LA, Liu M, et al. Phase II trial of lapatinib for brain metastases in patients with epidermal growth factor receptor-2 positive breast cancer. J Clin Oncol. 2008;12:1993-1999.