Systemic therapy for brain metastases
- Jan Drappatz, MD
Jan Drappatz, MD
- Associate Director
- Adult Neuro-Oncology Program
- Associate Professor
- Departments of Neurology and Medicine
- University of Pittsburgh
- Section Editor
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
- Deputy Editors
- April F Eichler, MD, MPH
April F Eichler, MD, MPH
- Senior Deputy Editor — Neurology and Sleep Medicine
- Assistant Professor of Neurology
- Harvard Medical School
- Diane MF Savarese, MD
Diane MF Savarese, MD
- Senior Deputy Editor — UpToDate
- Deputy Editor — Oncology and Palliative Care
- Clinical Instructor of Medicine
- Harvard Medical School
Metastases account for more than one-half of all intracranial tumors in adults. Brain metastases are being diagnosed more often, due to both improved detection of small metastases by magnetic resonance imaging (MRI) and a true increase in incidence resulting from improved systemic therapy of extracranial disease. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)
The primary approaches to the treatment of patients with brain metastases include whole brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery (SRS). There is only limited evidence documenting the superiority of these approaches compared to systemic chemotherapy in the treatment of patients with brain metastases.
The roles of various factors that determine responsiveness to systemic treatment will be reviewed here, along with the efficacy and risks of such treatment in the tumors that most commonly metastasize to the brain. The use of WBRT, SRS, and surgery in the management of brain metastases are discussed elsewhere, as is the treatment of leptomeningeal carcinomatosis. (See "Overview of the treatment of brain metastases" and "Treatment of leptomeningeal metastases (carcinomatous meningitis)".)
FACTORS AFFECTING RESPONSIVENESS
Blood brain barrier — The blood-brain barrier limits the passage of large molecules and hydrophilic drugs into normal brain. Whereas hydrophilic chemotherapy agents generally do not penetrate primary brain tumors because of this, several studies suggest that such drugs can reach brain metastases [1,2]. The observed contrast enhancement of metastases on computed tomography (CT) and magnetic resonance imaging (MRI) also suggests that the blood-brain barrier is at least partially disrupted in metastases  and also high-grade primary brain tumors that contrast enhance.
The responsiveness of some brain metastases to conventional chemotherapy also indicates that the blood-brain barrier is not always impermeable. However, there are only limited data on the potential enhanced delivery of chemotherapeutic agents via intraarterial infusion and blood brain barrier disruption in patients with brain metastases, and this approach cannot be recommended [4,5]. (See "Experimental treatment approaches for high-grade gliomas", section on 'Blood-brain barrier'.)
- Zhang RD, Price JE, Fujimaki T, et al. Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 1992; 141:1115.
- Stewart DJ. A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J Neurooncol 1994; 20:121.
- Davey P. Brain metastases: treatment options to improve outcomes. CNS Drugs 2002; 16:325.
- Fortin D, Gendron C, Boudrias M, Garant MP. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in the treatment of cerebral metastasis. Cancer 2007; 109:751.
- Fortin D, Desjardins A, Benko A, et al. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: the Sherbrooke experience. Cancer 2005; 103:2606.
- Donelli MG, Zucchetti M, D'Incalci M. Do anticancer agents reach the tumor target in the human brain? Cancer Chemother Pharmacol 1992; 30:251.
- Lesser GJ. Chemotherapy of cerebral metastases from solid tumors. Neurosurg Clin N Am 1996; 7:527.
- Postmus PE, Smit EF. Chemotherapy for brain metastases of lung cancer: a review. Ann Oncol 1999; 10:753.
- Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin 2003; 21:1.
- Moscetti L, Nelli F, Felici A, et al. Up-front chemotherapy and radiation treatment in newly diagnosed nonsmall cell lung cancer with brain metastases: survey by Outcome Research Network for Evaluation of Treatment Results in Oncology. Cancer 2007; 109:274.
- Lee JS, Murphy WK, Glisson BS, et al. Primary chemotherapy of brain metastasis in small-cell lung cancer. J Clin Oncol 1989; 7:916.
- Kristjansen PE, Soelberg Sørensen P, Skov Hansen M, Hansen HH. Prospective evaluation of the effect on initial brain metastases from small cell lung cancer of platinum-etoposide based induction chemotherapy followed by an alternating multidrug regimen. Ann Oncol 1993; 4:579.
- Twelves CJ, Souhami RL, Harper PG, et al. The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 1990; 61:147.
- Seute T, Leffers P, Wilmink JT, et al. Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy. J Clin Oncol 2006; 24:2079.
- Grossi F, Scolaro T, Tixi L, et al. The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer. Crit Rev Oncol Hematol 2001; 37:61.
- Kristensen CA, Kristjansen PE, Hansen HH. Systemic chemotherapy of brain metastases from small-cell lung cancer: a review. J Clin Oncol 1992; 10:1498.
- Postmus PE, Smit EF, Haaxma-Reiche H, et al. Teniposide for brain metastases of small-cell lung cancer: a phase II study. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1995; 13:660.
- Korfel A, Oehm C, von Pawel J, et al. Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. a multicentre phase II study. Eur J Cancer 2002; 38:1724.
- Groen HJ, Smit EF, Haaxma-Reiche H, Postmus PE. Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 1993; 29A:1696.
- Kaba SE, Kyritsis AP, Hess K, et al. TPDC-FuHu chemotherapy for the treatment of recurrent metastatic brain tumors. J Clin Oncol 1997; 15:1063.
- Chen G, Huynh M, Fehrenbacher L, et al. Phase II trial of irinotecan and carboplatin for extensive or relapsed small-cell lung cancer. J Clin Oncol 2009; 27:1401.
- Postmus PE, Haaxma-Reiche H, Smit EF, et al. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 2000; 18:3400.
- Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999; 85:1599.
- Fujita A, Fukuoka S, Takabatake H, et al. Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 2000; 59:291.
- Cortes J, Rodriguez J, Aramendia JM, et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 2003; 64:28.
- Wong ET, Berkenblit A. The role of topotecan in the treatment of brain metastases. Oncologist 2004; 9:68.
- Bailon O, Chouahnia K, Augier A, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 2012; 14:491.
- Ebert BL, Niemierko E, Shaffer K, Salgia R. Use of temozolomide with other cytotoxic chemotherapy in the treatment of patients with recurrent brain metastases from lung cancer. Oncologist 2003; 8:69.
- Dziadziuszko R, Ardizzoni A, Postmus PE, et al. Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965). Eur J Cancer 2003; 39:1271.
- 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.
- Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 2001; 12:249.
- Giorgio CG, Giuffrida D, Pappalardo A, et al. Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. Lung Cancer 2005; 50:247.
- Siena S, Crinò L, Danova M, et al. Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Ann Oncol 2010; 21:655.
- Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer 2010; 68:264.
- Wagenius G, Brodin O, Nyman J, et al. Radiotherapy vs. temozolomide in the treatment of patients with lung cancer and brain metastases: A randomized phase II study (abstract). J Clin Oncol 2006; 24:398s. (Abstract available online at: www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed on June 8, 2006).
- Lee DH, Han JY, Kim HT, et al. Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first : result of a randomized pilot study. Cancer 2008; 113:143.
- Chiu CH, Tsai CM, Chen YM, et al. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. Lung Cancer 2005; 47:129.
- Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 2004; 15:1042.
- Wu C, Li YL, Wang ZM, et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer 2007; 57:359.
- Kim JE, Lee DH, Choi Y, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 2009; 65:351.
- Zee YK, Chin TM, Wong AS. Fatal cystic change of brain metastasis after response to gefitinib in non-small-cell lung cancer. J Clin Oncol 2009; 27:e145.
- Porta R, Sánchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011; 37:624.
- Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res 2012; 18:938.
- Wu YL, Zhou C, Cheng Y, et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol 2013; 24:993.
- Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 2013; 31:895.
- Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys 2013; 85:1312.
- Gerber NK, Yamada Y, Rimner A, et al. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014; 89:322.
- Magnuson WJ, Yeung JT, Guillod PD, et al. Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases. Int J Radiat Oncol Biol Phys 2016; 95:673.
- Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012; 77:556.
- Iuchi T, Shingyoji M, Sakaida T, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 2013; 82:282.
- Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015; 33:1881.
- Solomon BJ, Cappuzzo F, Felip E, et al. Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. J Clin Oncol 2016; 34:2858.
- Gadgeel SM, Shaw AT, Govindan R, et al. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34:4079.
- De Braganca KC, Janjigian YY, Azzoli CG, et al. Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol 2010; 100:443.
- Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 2006; 24:106.
- Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003; 21:2529.
- Antonadou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002; 20:3644.
- Verger E, Gil M, Yaya R, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys 2005; 61:185.
- Chua D, Krzakowski M, Chouaid C, et al. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study. Clin Lung Cancer 2010; 11:176.
- Robins HI, O'Neill A, Mehta M, Grossman S. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT & SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320: in regard to Sperduto et al. Int J Radiat Oncol Biol Phys 2013; 86:809.
- Guerrieri M, Wong K, Ryan G, et al. A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Lung Cancer 2004; 46:107.
- Ushio Y, Arita N, Hayakawa T, et al. Chemotherapy of brain metastases from lung carcinoma: a controlled randomized study. Neurosurgery 1991; 28:201.
- Neuhaus T, Ko Y, Muller RP, et al. A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer. Br J Cancer 2009; 100:291.
- Robinet G, Thomas P, Breton JL, et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol 2001; 12:59.
- Azar JM, Schneider BP, Einhorn LH. Is the blood-brain barrier relevant in metastatic germ cell tumor? Int J Radiat Oncol Biol Phys 2007; 69:163.
- Sundermeyer ML, Meropol NJ, Rogatko A, et al. Changing patterns of bone and brain metastases in patients with colorectal cancer. Clin Colorectal Cancer 2005; 5:108.
- Pectasides D, Pectasides M, Economopoulos T. Brain metastases from epithelial ovarian cancer: a review of the literature. Oncologist 2006; 11:252.
- Pakneshan S, Safarpour D, Tavassoli F, Jabbari B. Brain metastasis from ovarian cancer: a systematic review. J Neurooncol 2014; 119:1.
- FACTORS AFFECTING RESPONSIVENESS
- Blood brain barrier
- SMALL CELL LUNG CANCER
- NON-SMALL CELL LUNG CANCER
- Cytotoxic chemotherapy
- Targeted agents
- - EGFR tyrosine kinase inhibitors
- - ALK tyrosine kinase inhibitors
- - Bevacizumab
- Chemotherapy plus RT
- - Temozolomide
- - Other agents
- BREAST CANCER
- GERM CELL TUMORS
- GESTATIONAL TROPHOBLASTIC DISEASE
- NON-HODGKINS LYMPHOMA
- OTHER TUMORS
- RISK OF CNS HEMORRHAGE WITH ANTIANGIOGENIC AGENTS
- SUMMARY AND RECOMMENDATIONS