Treatment of Brain Metastases in Lung Cancer: Strategies to Avoid/Reduce Late Complications of Whole Brain Radiation Therapy
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Brain metastases occur in 20-40 % of lung cancer patients. The use of whole brain radiation therapy (WBRT) has been shown to ameliorate many neurological symptoms, facilitate corticosteroid reduction, enhance quality of life (QOL), and prolong survival. The acute and early delayed side effects of WBRT are generally mild and inconsequential, whereas late complications often are progressive, irreversible, and may have a profound effect on neurocognitive function and QOL. Nevertheless, WBRT remains the cornerstone for treatment of multiple brain metastases due to its efficacy and the paucity of other treatment options. In avoidance of WBRT and its potential toxicity, patients of good performance status and ≤3 metastases may be treated reasonably with focal therapy alone (surgery or radiosurgery) without a compromise in survival. In patients with multiple brain metastases and those undergoing prophylactic cranial irradiation (PCI), established methods to mitigate the late complications of WBRT include total dose observation, dose per fraction restrictions, and avoidance of concomitant chemotherapy. Current areas of active research that hold great potential for benefit include hippocampal-sparing radiotherapy and the use of neuroprotective agents.
KeywordsWhole brain radiation therapy Brain metastases Neurocognitive impairment Quality of life Neuroprotection Hippocampus
Conflict of Interest
Mark G. Shaw declares that he has no conflict of interest.
David L. Ball has board membership with Boehringer-Ingelheim, Pfizer, and Lilly Oncology and received payment for the development of educational presentations from Lilly Oncology and Pfizer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as:• Of importance ••Of major importance
- 1.U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Available at http://www.cdc.gov/cancer/lung/statistics/. Accessed July 2013.
- 14.Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M, Hirota S, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68(5):1388–95. doi: 10.1016/j.ijrobp.2007.03.048.PubMedCrossRefGoogle Scholar
- 16.Gondi V, Paulus R, Bruner DW, Meyers CA, Gore EM, Wolfson A, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of radiation therapy oncology group randomized trials 0212 and 0214. Int J Radiat oncol biol Phys. 2013;86(4):656–64. doi: 10.1016/j.ijrobp.2013.02.033.PubMedCrossRefGoogle Scholar
- 20.•Tallet AV, Azria D, Barlesi F, Spano JP, Carpentier AF, Goncalves A, et al. Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol. 2012;7:77. doi: 10.1186/1748-717X-7-77. This concise paper is a review of current literature on radiation-induced neurocognitive impairment with an exploration of different assessment techniques. The paper also explores the differences between therapeutic and prophylactic cranial irradiation. PubMedCrossRefGoogle Scholar
- 21.Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys. 2001;51(3):711–7.PubMedCrossRefGoogle Scholar
- 22.Gregor A, Cull A, Stephens RJ, Kirkpatrick JA, Yarnold JR, Girling DJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997;33(11):1752–8.PubMedCrossRefGoogle Scholar
- 23.Komaki R, Meyers CA, Shin DM, Garden AS, Byrne K, Nickens JA, et al. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys. 1995;33(1):179–82. doi: 10.1016/0360-3016(95)00026-U.PubMedCrossRefGoogle Scholar
- 26.Newcomer JW, Craft S, Hershey T, Askins K, Bardgett ME. Glucocorticoid-induced impairment in declarative memory performance in adult humans. J Neurosci: Off J Soc Neurosci. 1994;14(4):2047–53.Google Scholar
- 29.•Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY. CNS complications of radiotherapy and chemotherapy. Lancet. 2009;374(9701):1639–51. doi: 10.1016/S0140-6736(09)61299-X. This paper describes in great detail the treatment induced neurological complications of radiotherapy, chemotherapy, and combined treatment and the pathophysiological basis of these injuries. PubMedCrossRefGoogle Scholar
- 31.••Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73. doi: 10.3389/fonc.2012.00073. This review provides excellent coverage of the theories of radiation-induced brain injury and the pathophysiological mechanisms behind injury. Potential targets for ameliorating injury are discussed. PubMedCrossRefGoogle Scholar
- 33.Sun A, Bae K, Gore EM, Movsas B, Wong SJ, Meyers CA, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol. 2011;29(3):279–86. doi: 10.1200/JCO.2010.29.6053.PubMedCrossRefGoogle Scholar
- 34.Le Pechoux C, Laplanche A, Faivre-Finn C, Ciuleanu T, Wanders R, Lerouge D, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol. 2011;22(5):1154–63. doi: 10.1093/annonc/mdq576.PubMedCrossRefGoogle Scholar
- 35.Wolfson AH, Bae K, Komaki R, Meyers C, Movsas B, Le Pechoux C, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;81(1):77–84. doi: 10.1016/j.ijrobp.2010.05.013.PubMedCrossRefGoogle Scholar
- 45.Gondi V, Tome WA, Marsh J, Struck A, Ghia A, Turian JV, et al. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol. 2010;95(3):327–31. doi: 10.1016/j.radonc.2010.02.030.PubMedCrossRefGoogle Scholar
- 46.•Mehta MP. Radiation Therapy Oncology Group: RTOG 0933 Protocol. Available at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0933 Accessed July 2013. This article, the RTOG 0933 protocol, describes the rationale behind hippocampal sparing radiation and provides an excellent stepwise guide on how to contour and plan for hippocampal sparing radiotherapy.
- 47.Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348–54. doi: 10.1016/j.ijrobp.2012.11.031.PubMedCrossRefGoogle Scholar
- 51.•Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: current concepts and approaches. J Oncol. 2010;2010:198208. doi: 10.1155/2010/198208. This paper describes the mechanisms of CNS toxicity and explores the role of hippocampal sparing, limbic circuit sparing, and neural stem cell sparing radiotherapy. PubMedCrossRefGoogle Scholar
- 52.•Barani IJ, Larson DA, Berger MS. Future directions in treatment of brain metastases. Surg Neurol Int. 2013;4 Suppl 4:S220–30. doi: 10.4103/2152-7806.111299. An excellent review of recent studies investigating the role of WBRT and SRS with a focus on multiple brain metastases and projections for future treatment regimes. PubMedGoogle Scholar
- 53.Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–91. doi: 10.1001/jama.295.21.2483.PubMedCrossRefGoogle Scholar
- 54.••Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–44. doi: 10.1016/S1470-2045(09)70263-3. The only phase III RCT of SRS versus SRS with WBRT with a primary endpoint of neurocognitive function. The study was closed early according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function. PubMedCrossRefGoogle Scholar
- 55.••Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–41. doi: 10.1200/JCO.2010.30.1655. This paper reports the EORTC phase III RCT of WBRT versus observation after local therapy for 1-3 brain metastases. This large 359 patient trial provides a definitive statement on the impact of WBRT after local therapy. PubMedCrossRefGoogle Scholar
- 57.Mahmood U, Kwok Y, Regine WF, Patchell RA. Whole-brain irradiation for patients with brain metastases: still the standard of care. Lancet Oncol. 2010;11(3):221–2. doi: 10.1016/S1470-2045(09)70389-4. author reply 3.
- 59.••Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013;31(1):65–72. doi: 10.1200/JCO.2011.41.0639. This paper reports the QOL outcomes from . It is the first such analysis and reveals a generally lower, albeit mild and transitory, change in QOL after WBRT. PubMedCrossRefGoogle Scholar
- 61.Brown WR, Blair RM, Moody DM, Thore CR, Ahmed S, Robbins ME, et al. Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J Neurol Sci. 2007;257(1–2):67–71. doi: 10.1016/j.jns.2007.01.014.PubMedCrossRefGoogle Scholar
- 64.Brown PD, Shook S, Laack NN, Wefel JS, Choucair A, Suh JH, et al. Memantine for the Prevention of Cognitive Dysfunction in Patients Receiving Whole-brain Radiation Therapy (WBRT): First Report of RTOG 0614, a Placebo-controlled, Double-blind, Randomized Trial. Int J Radiat Oncol Biol Phys. 2012;84(3):S1–2.CrossRefGoogle Scholar
- 65.Shaw EG, Rosdhal R, D'Agostino Jr RB, Lovato J, Naughton MJ, Robbins ME, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24(9):1415–20. doi: 10.1200/JCO.2005.03.3001.CrossRefGoogle Scholar
- 66.Rapp SR, Case D, Peiffer A, Naughton MJ, Stieber VW, Bayer GK et al. Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors. 2013 ASCO Annual Meeting. Oral Abstract Session, Central Nervous System Tumours. J Clin Oncol 31, 2013 (suppl; abstr 2006).Google Scholar
- 70.•Khasraw M, Ashley D, Wheeler G, Berk M. Using lithium as a neuroprotective agent in patients with cancer. BMC Med. 2012;10:131. doi: 10.1186/1741-7015-10-131. This summary article describes the role of lithium for neurocognitive dysfunction and its potential role in radiation neuroprotection. PubMedCrossRefGoogle Scholar
- 74.Barwon Health, Deakin University, Peter MacCallum Cancer Centre; Australia. A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer (TULIP). Available at http://clinicaltrials.gov/ct2/show/NCT01486459 NLM identifier: NCT01486459. Accessed July, 2013.
- 79.•Robbins ME, Zhao W, Garcia-Espinosa MA, Diz DI. Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets. 2010;11(11):1413–22. This comprehensive paper describes the role of RAS in the brain and the potential role of RAS blockers in amelioration of radiation-induced brain injury. PubMedCrossRefGoogle Scholar
- 81.Robbins ME, Payne V, Tommasi E, Diz DI, Hsu FC, Brown WR, et al. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2009;73(2):499–505. doi: 10.1016/j.ijrobp.2008.09.058.PubMedCrossRefGoogle Scholar
- 83.Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, et al. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res. 2012;178(1):46–56.PubMedCrossRefGoogle Scholar
- 86.Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME. The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys. 2009;75(3):870–7. doi: 10.1016/j.ijrobp.2009.06.059.PubMedCrossRefGoogle Scholar
- 87.Schnegg CI, Greene-Schloesser D, Kooshki M, Payne VS, Hsu FC, Robbins ME. The PPARdelta agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radic Biol Med. 2013;61C:1–9. doi: 10.1016/j.freeradbiomed.2013.03.002.PubMedCrossRefGoogle Scholar
- 88.Zhao W, Payne V, Tommasi E, Diz DI, Hsu FC, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2007;67(1):6–9. doi: 10.1016/j.ijrobp.2006.09.036.PubMedCrossRefGoogle Scholar
- 89.Wake Forest University. Pioglitazone Hydrochloride in preventing radiation-induced cognitive dysfunction in treating patients with brain tumors. Available from: http://clinicaltrials.gov/ct2/show/NCT01151670 NLM identifier: NCT0115670. Accessed July, 2013.
- 98.Wong-Goodrich SJ, Pfau ML, Flores CT, Fraser JA, Williams CL, Jones LW. Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation. Cancer Res. 2010;70(22):9329–38. doi: 10.1158/0008-5472.CAN-10-1854.PubMedCrossRefGoogle Scholar