Radiation Therapy for Brain Metastases

Project Summary Title and Description

Radiation Therapy for Brain Metastases
Objective. This evidence report synthesizes the available evidence on radiation therapy for brain metastases. Data sources. We searched PubMed®, Embase®, Web of Science, Scopus, CINAHL®, clinicaltrials.gov, and published guidelines in July 2020; assessed independently submitted data; consulted with experts; and contacted authors. Review methods. The protocol was informed by Key Informants. The systematic review was supported by a Technical Expert Panel and is registered in PROSPERO (CRD42020168260). Two reviewers independently screened citations; data were abstracted by one reviewer and checked by an experienced reviewer. We included randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to non-small cell lung cancer, breast cancer, or melanoma. Results. In total, 97 studies, reported in 190 publications, were identified, but the number of analyses was limited due to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied; 25 trials were terminated early, predominantly due to poor accrual. Most studies evaluated WBRT, alone or in combination with SRS, as initial treatment; 10 RCTs reported on post-surgical interventions. The combination treatment SRS plus WBRT compared to SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; confidence interval [CI], 0.69 to 1.73; 4 RCTs; low strength of evidence [SoE]) or death due to brain metastases (relative risk [RR], 0.93; CI, 0.48 to 1.81; 3 RCTs; low SoE). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; CI, 0.76 to 1.26; 5 RCTs; moderate SoE). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or post-surgical interventions. We did not find systematic differences across interventions in serious adverse events radiation necrosis, fatigue, or seizures (all low or moderate SoE). WBRT plus systemic therapy (RR, 1.44; CI, 1.03 to 2.00; 14 studies; moderate SoE) was associated with increased risks for vomiting compared to WBRT alone. Conclusion. Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.
Authors of Report
Methodology description
Systematic Review
Report can be found here: https://pubmed.ncbi.nlm.nih.gov/34152714/ and https://effectivehealthcare.ahrq.gov/products/radiation-therapy-brain-metastases/research Data was entered into this project prospectively
Funding Source
Agency for Healthcare Research and Quality and Patient-Centered Outcomes Research Institute

Key Questions

1. Key Question 1. What is the effectiveness of WBRT, alone or in combination with SRS or systemic therapies, as initial treatment in patients with brain metastases on patient-relevant outcomes, such as overall survival and quality of life?
2. Key Question 2. What is the effectiveness of SRS/fractionated stereotactic radiation as initial treatment in patients with brain metastases on patient-relevant outcomes, such as overall survival and quality of life?
3. Key Question 3. What is the effectiveness (or comparative effectiveness) of postoperative SRS compared to WBRT, observation, or preoperative SRS in patients with brain metastases on patient-relevant outcomes, such as overall survival and quality of life?
4. Key Question 4. What are the adverse effects (i.e., serious harms) of WBRT, SRS, and systemic therapies for patients with brain metastases (either alone or in combination)?

Associated Extraction Forms

Associated Studies (each link opens a new tab)

Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trialD. W. Andrews; C. B. Scott; P. W. Sperduto; A. E. Flanders; L. E. Gaspar; M. C. Schell; M. Werner-Wasik; W. Demas; J. Ryu; J. P. Bahary; L. Souhami; M. Rotman; M. P. Mehta; W. J. Curran2004
Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastasesD. Antonadou; M. Paraskevaidis; G. Sarris; N. Coliarakis; I. Economou; P. Karageorgis; N. Throuvalas2002
Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trialH. Aoyama; H. Shirato; M. Tago; K. Nakagawa; T. Toyoda; K. Hatano; M. Kenjyo; N. Oya; S. Hirota; H. Shioura; E. Kunieda; T. Inomata; K. Hayakawa; N. Katoh; G. Kobashi2006
Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119)L. Berk; B. Berkey; T. Rich; W. Hrushesky; D. Blask; M. Gallagher; M. Kudrimoti; R. C. McGarry; J. Suh; M. Mehta2007
Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trialP. D. Brown; S. Pugh; N. N. Laack; J. S. Wefel; D. Khuntia; C. Meyers; A. Choucair; S. Fox; J. H. Suh; D. Roberge; V. Kavadi; S. M. Bentzen; M. P. Mehta; D. Watkins-Bruner2013
Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical TrialP. D. Brown; K. Jaeckle; K. V. Ballman; E. Farace; J. H. Cerhan; S. K. Anderson; X. W. Carrero; F. G. Barker; R. Deming; S. H. Burri; C. Menard; C. Chung; V. W. Stieber; B. E. Pollock; E. Galanis; J. C. Buckner; A. L. Asher2016
Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trialP. D. Brown; K. V. Ballman; J. H. Cerhan; S. K. Anderson; X. W. Carrero; A. C. Whitton; J. Greenspoon; I. F. Parney; N. N. I. Laack; J. B. Ashman; J. P. Bahary; C. G. Hadjipanayis; J. J. Urbanic; F. G. Barker; E. Farace; D. Khuntia; C. Giannini; J. C. Buckner; E. Galanis; D. Roberge2017
Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001P. D. Brown; V. Gondi; S. Pugh; W. A. Tome; J. S. Wefel; T. S. Armstrong; J. A. Bovi; C. Robinson; A. Konski; D. Khuntia; D. Grosshans; T. L. S. Benzinger; D. Bruner; M. R. Gilbert; D. Roberge; V. Kundapur; K. Devisetty; S. Shah; K. Usuki; B. M. Anderson; B. Stea; H. Yoon; J. Li; N. N. Laack; T. J. Kruser; S. J. Chmura; W. Shi; S. Deshmukh; M. P. Mehta; L. A. Kachnic; N. R. G. Oncology for2020
Association of Neurosurgical Resection With Development of Pachymeningeal Seeding in Patients With Brain MetastasesD. N. Cagney; N. Lamba; S. Sinha; P. J. Catalano; W. L. Bi; B. M. Alexander; A. A. Aizer2019
Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancerK. I. Cao; N. Lebas; S. Gerber; C. Levy; R. Le Scodan; C. Bourgier; J. Y. Pierga; A. Gobillion; A. Savignoni; Y. M. Kirova2015
Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled studyP. Chabot; T. C. Hsia; J. S. Ryu; V. Gorbunova; C. Belda-Iniesta; D. Ball; E. Kio; M. Mehta; K. Papp; Q. Qin; J. Qian; K. D. Holen; V. Giranda; J. H. Suh2017
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trialE. L. Chang; J. S. Wefel; K. R. Hess; P. K. Allen; F. F. Lang; D. G. Kornguth; R. B. Arbuckle; J. M. Swint; A. S. Shiu; M. H. Maor; C. A. Meyers2009
Radiation therapy for brain metastases from lung carcinoma. Prospective randomized trial according to the level of lactate dehydrogenaseM. Chatani; Y. Matayoshi; N. Masaki; T. Inoue1994
Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell CarcinomaL. Chen; J. Douglass; L. Kleinberg; X. Ye; A. E. Marciscano; P. M. Forde; J. Brahmer; E. Lipson; W. Sharfman; H. Hammers; J. Naidoo; C. Bettegowda; M. Lim; K. J. Redmond2018
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 studyD. Chua; M. Krzakowski; C. Chouaid; M. G. Pallotta; J. I. Martinez; M. Gottfried; W. Curran; N. Throuvalas2010
A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excisionP. Davey; D. Hoegler; M. Ennis; J. Smith2008
The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastasesX. Deng; Z. Zheng; B. Lin; H. Su; H. Chen; S. Fei; Z. Fei; L. Zhao; X. Jin; C. Y. Xie2017
Boost Irradiation Integrated to Whole Brain Radiotherapy in the Management of Brain MetastasesDobi, A.; Fodor, E.; z, A.; , Z.; ti, A.; Tiszlavicz, L.; Reisz, Z.; Barz, P.; Varga, Z.; ty, K.2020
Management of brain metastases with stereotactic radiosurgery alone versus whole brain irradiation alone versus bothM. M. El Gantery; H. M. Abd El Baky; H. A. El Hossieny; M. Mahmoud; O. Youssef2014
A Randomized Controlled Open-Label Pilot Study of Simvastatin Addition to Whole-Brain Radiation Therapy in Patients With Brain MetastasesM. El-Hamamsy; H. Elwakil; A. S. Saad; M. A. Shawki2016
Stereotactic radiosurgery and fractionated stereotactic radiotherapy: comparison of efficacy and toxicity in 260 patients with brain metastasesE. Fokas; M. Henzel; G. Surber; G. Kleinert; K. Hamm; R. Engenhart-Cabillic2012
Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trialC. Gamboa-Vignolle; T. Ferrari-Carballo; O. Arrieta; A. Mohar2012
Prognostic factors for stereotactic radiosurgery-treated patients with cerebral metastasis: implications on randomised control trial design and inter-institutional collaborationD. D. Gonda; T. E. Kim; S. J. Goetsch; T. Kawabe; S. Watanabe; J. F. Alksne; J. A. Hattangadi; M. Nitta; K. Ott; D. W. Hodgens; B. S. Carter; M. Yamamoto; C. C. Chen2014
A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancerB. H. Gronberg; T. Ciuleanu; O. Flotten; A. Knuuttila; E. Abel; S. W. Langer; K. Krejcy; A. M. Liepa; M. Munoz; M. Hahka-Kemppinen; S. Sundstrom2012
A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lungM. Guerrieri; K. Wong; G. Ryan; M. Millward; G. Quong; D. L. Ball2004
RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learntA. Gupta; C. Roberts; F. Tysoe; M. Goff; J. Nobes; J. Lester; E. Marshall; C. Corner; V. Wolstenholme; C. Kelly; A. Wise; L. Collins; S. Love; M. Woodward; A. Salisbury; M. R. Middleton2016
Temozolomide added to whole brain radiotherapy in patients with multiple brain metastases of non-small-cell lung cancer: a multicentric Austrian phase II studyM. R. Hassler; W. Pfeifer; T. H. Knocke-Abulesz; K. Geissler; G. Altorjai; K. Dieckmann; C. Marosi2013
Whole-brain helical tomotherapy with integrated boost for brain metastases in patients with malignant melanoma - final results of the BRAINRT trialH. Hauswald; D. Bernhardt; D. Krug; S. Katayama; G. Habl; J. L. Bermejo; J. Debus; F. Sterzing2019
Oral HYCAMTIN Plus Whole Brain Radiation Therapy In Treatment Of Brain Metastases Resulting From Non-Small Lung CancerGlaxoSmithKline2012
Randomized comparison of whole brain radiotherapy, 20 Gy in four daily fractions versus 40 Gy in 20 twice-daily fractions, for brain metastasesP. H. Graham; J. Bucci; L. Browne2010
A Study of Whole Brain Radiation Therapy and Capecitabine in Breast Cancer Participants With Newly Diagnosed Brain MetastasisRoche Hoffmann-La2011
Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III TrialA. M. Hong; G. B. Fogarty; K. Dolven-Jacobsen; B. H. Burmeister; S. N. Lo; L. E. Haydu; J. L. Vardy; A. K. Nowak; H. M. Dhillon; T. Ahmed; B. Shivalingam; G. V. Long; A. M. Menzies; G. Hruby; K. J. Drummond; C. Mandel; M. R. Middleton; C. H. Reisse; E. J. Paton; V. Steel; N. C. Williams; R. A. Scolyer; R. L. Morton; J. F. Thompson2019
Radiation sensitization with sodium nitrite in patients with brain metastases: a pilot randomized controlled trialS. M. Hosseini; S. Arvandi; S. Razmjoo; H. Shahbazian; F. Rahim; T. Rafie; M. Barahman; A. Bagheri2015
Study on lung cancer cells expressing VEGFR2 and the impact on the effect of RHES combined with radiotherapy in the treatment of brain metastasesX. D. Jiang; M. H. Ding; Y. Qiao; Y. Liu; L. Liu2014
EGFR TKIs plus WBRT demonstrated no survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastasesT. Jiang; C. Su; X. Li; C. Zhao; F. Zhou; S. Ren; C. Zhou; J. Zhang2016
Effects of surgery with salvage stereotactic radiosurgery versus surgery with whole-brain radiation therapy in patients with one to four brain metastases (JCOG0504): A Phase III, noninferiority, randomized controlled trialT. Kayama; S. Sato; K. Sakurada; J. Mizusawa; R. Nishikawa; Y. Narita; M. Sumi; Y. Miyakita; T. Kumabe; Y. Sonoda; Y. Arakawa; S. Miyamoto; T. Beppu; K. Sugiyama; H. Nakamura; M. Nagane; Y. Nakasu; N. Hashimoto; M. Terasaki; A. Matsumura; E. Ishikawa; T. Wakabayashi; Y. Iwadate; S. Ohue; H. Kobayashi; M. Kinoshita; K. Asano; A. Mukasa; K. Tanaka; A. Asai; H. Nakamura; T. Abe; Y. Muragaki; K. Iwasaki; T. Aoki; T. Watanabe; H. Sasaki; S. Izumoto; M. Mizoguchi; T. Matsuo; H. Takeshima; M. Hayashi; H. Jokura; T. Mizowaki; E. Shimizu; H. Shirato; M. Tago; H. Katayama; H. Fukuda; S. Shibui2018
Stereotactic radiotherapy of the tumor bed compared to whole brain radiotherapy after surgery of single brain metastasis: Results from a randomized trialL. Kepka; D. Tyc-Szczepaniak; K. Bujko; M. Olszyna-Serementa; W. Michalski; A. Sprawka; B. Trabska-Kluch; K. Komosinska; E. Wasilewska-Tesluk; B. Czeremszynska2016
Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancerD. Y. Kim; K. W. Lee; T. Yun; D. W. Kim; T. Y. Kim; D. S. Heo; Y. J. Bang; N. K. Kim2005
A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118)J. P. Knisely; B. Berkey; A. Chakravarti; A. W. Yung; W. J. Curran; H. I. Robins; B. Movsas; D. G. Brachman; R. H. Henderson; M. P. Mehta2008
Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic RadiosurgeryM. D. Johnson; V. Avkshtol; A. M. Baschnagel; K. Meyer; H. Ye; I. S. Grills; P. Y. Chen; A. Maitz; R. E. Olson; D. R. Pieper; D. J. Krauss2016
Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trialJ. P. Kirkpatrick; Z. Wang; J. H. Sampson; F. McSherry; J. E. Herndon; K. J. Allen; E. Duffy; J. K. Hoang; Z. Chang; D. S. Yoo; C. R. Kelsey; F. F. Yin2015
Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 studyM. Kocher; R. Soffietti; U. Abacioglu; S. Villa; F. Fauchon; B. G. Baumert; L. Fariselli; T. Tzuk-Shina; R. D. Kortmann; C. Carrie; M. Ben Hassel; M. Kouri; E. Valeinis; D. van den Berge; S. Collette; L. Collette; R. P. Mueller2011
Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastasesD. Kondziolka; A. Patel; L. D. Lunsford; A. Kassam; J. C. Flickinger1999
Immunotherapy is associated with improved survival and decreased neurologic death after SRS for brain metastases from lung and melanoma primariesLanier, C. M.; Hughes, R.; Ahmed, T.; LeCompte, M.; Masters, A. H.; Petty, W. J.; Ruiz, J.; Triozzi, P.; Su, J.; O'Neill, S.; Watabe, K.; Cramer, C. K.; Laxton, A. W.; Tatter, S. B.; Wang, G.; Whitlow, C.; Chan, M. D.2019
Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastasesS. M. Lee; C. R. Lewanski; N. Counsell; C. Ottensmeier; A. Bates; N. Patel; C. Wadsworth; Y. Ngai; A. Hackshaw; C. Faivre-Finn2014
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 studyD. H. Lee; J. Y. Han; H. T. Kim; S. J. Yoon; H. R. Pyo; K. H. Cho; S. H. Shin; H. Yoo; S. H. Lee; J. S. Lee2008
A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancerS. H. Lim; J. Y. Lee; M. Y. Lee; H. S. Kim; J. Lee; J. M. Sun; J. S. Ahn; S. W. Um; H. Kim; B. S. Kim; S. T. Kim; D. L. Na; J. Y. Sun; S. H. Jung; K. Park; O. J. Kwon; J. I. Lee; M. J. Ahn2015
Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastasesH. P. Liu; K. B. Zheng; J. W. Wang2017
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Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trialA. Mahajan; S. Ahmed; M. F. McAleer; J. S. Weinberg; J. Li; P. Brown; S. Settle; S. S. Prabhu; F. F. Lang; N. Levine; S. McGovern; E. Sulman; I. E. McCutcheon; S. Azeem; D. Cahill; C. Tatsui; A. B. Heimberger; S. Ferguson; A. Ghia; F. Demonte; S. Raza; N. Guha-Thakurta; J. Yang; R. Sawaya; K. R. Hess; G. Rao2017
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