A randomised trial to compare cognitive outcome after gamma knife radiosurgery versus whole brain radiation therapy in patients with multiple brain metastases: research protocol CAR-study B

Wietske C M Schimmel, Eline Verhaak, Patrick E J Hanssens, Karin Gehring, Margriet M Sitskoorn, Wietske C M Schimmel, Eline Verhaak, Patrick E J Hanssens, Karin Gehring, Margriet M Sitskoorn

Abstract

Background: Gamma Knife radiosurgery (GKRS) is increasingly applied in patients with multiple brain metastases and is expected to have less adverse effects in cognitive functioning than whole brain radiation therapy (WBRT). Effective treatment with the least negative cognitive side effects is increasingly becoming important, as more patients with brain metastases live longer due to more and better systemic treatment options. There are no published randomized trials yet directly comparing GKRS to WBRT in patients with multiple brain metastases that include objective neuropsychological testing.

Methods: CAR-Study B is a prospective randomised trial comparing cognitive outcome after GKRS or WBRT in adult patients with 11-20 newly diagnosed brain metastases on a contrast-enhanced MRI-scan, KPS ≥70 and life expectancy of at least 3 months. Randomisation by the method of minimization, is stratified by the cumulative tumour volume in the brain, systemic treatment, KPS, histology, baseline cognitive functioning and age. The primary endpoint is the between-group difference in the percentage of patients with significant memory decline at 3 months. Secondary endpoints include overall survival, local control, development of new brain metastases, cognitive functioning over time, quality of life, depression, anxiety and fatigue. Cognitive functioning is assessed by a standardised neuropsychological test battery. Assessments (cognitive testing, questionnaires and MRI-scans) are scheduled at baseline and at 3, 6, 9, 12 and 15 months after treatment.

Discussion: Knowledge gained from this trial may be used to inform individual patients with BM more precisely about the cognitive effects they can expect from treatment, and to assist both doctors and patients in making (shared) individual treatment decisions. This trial is currently recruiting. Target accrual: 23 patients at 3-months follow-up in both groups.

Trial registration: The Netherlands Trials Register number NTR5463. ClinicalTrials.gov registration number NCT02953717 , first received October 27, 2016, 8 patients were enrolled in this study on 31 July 2017.

Keywords: Brain metastases; Cognitive functioning; Gamma knife radiosurgery; Hopkins verbal learning test; Neuropsychological assessment; Quality of life; Stereotactic radiosurgery; Whole brain radiation therapy.

Conflict of interest statement

Ethics approval and consent to participate

CAR-Study B has been approved by the local medical ethics review committee (METC Brabant, The Netherlands). Each participant gives written informed consent before participating in the trial.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Trial Flow
Fig. 2
Fig. 2
Prior distributions for failure rates of both groups, with prior mean 0.42
Fig. 3
Fig. 3
Bayesian power study

References

    1. Kaal EC, Niël CG, Vecht CJ. Therapeutic management of brain metastasis. The Lancet Neurology. 2005;4:289–298. doi: 10.1016/S1474-4422(05)70072-7.
    1. Lippitz B, Lindquist C, Paddick I, Peterson D, O’Neill K, Beaney R. Stereotactic radiosurgery in the treatment of brain metastases: the current evidence. Cancer Treatment Reviews Elsevier Ltd. 2014;40:48–59. doi: 10.1016/j.ctrv.2013.05.002.
    1. Khalsa SSS, Chinn M, Krucoff M, Sherman JH. The role of stereotactic radiosurgery for multiple brain metastases in stable systemic disease: a review of the literature. Acta Neurochir. 2013;155:1321–1328. doi: 10.1007/s00701-013-1701-5.
    1. Niranjan A, Lunsford LD, Emerick RL. Stereotactic radiosurgery for patients with metastatic brain tumors: development of a consensus radiosurgery guideline recommendation. Basel: Karger. 2012;25:123–38.
    1. Rahmathulla G, Toms SA, Weil RJ. The molecular biology of brain metastasis. J Oncol. 2012;2012:1–16. doi: 10.1155/2012/723541.
    1. Chang EL, Wefel JS, Maor MH, Hassenbusch SJ, Mahajan A, Lang FF, et al. A pilot study of neurocognitive function in patients with one to three new brain metastases initially treated with stereotactic radiosurgery alone. Neurosurgery. 2007;60:277–83–discussion283–4.
    1. Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, et al. Updates in the management of brain metastases. Neuro-Oncology. 2016;18:1043–1065. doi: 10.1093/neuonc/now127.
    1. Elaimy AL, Mackay AR, Lamoreaux WT, Fairbanks RK, Demakas JJ, Cooke BS, et al. Clinical outcomes of stereotactic radiosurgery in the treatment of patients with metastatic brain tumors. World neurosurgery. 2011;75:673–683. doi: 10.1016/j.wneu.2010.12.006.
    1. Ellis TL, Neal MT, Chan MD. The role of surgery, radiosurgery and whole brain radiation therapy in the Management of Patients with metastatic brain tumors. International Journal of Surgical Oncology. 2012;2012:1–10. doi: 10.1155/2012/952345.
    1. Perez-Larraya JG, Hildebrand J. In: Biller J, Ferro JM, editors. Handbook of clinical neurology. Amsterdam: Elsevier; 2014. p. 1143–57.
    1. Wefel JS, Parsons MW, Gondi V, Brown PD. Neurocognitive aspects of brain metastasis. Handb Clin Neurol. Amsterdam: Elsevier. 2018;149:155–65.
    1. Platta CS, Khuntia D, Mehta MP, Suh JH. Current treatment strategies for brain metastasis and complications from therapeutic techniques. Am J Clin Oncol. 2010;33:398–407. doi: 10.1097/COC.0b013e318194f744.
    1. Mehta MP. Survival and neurologic outcomes in a randomized trial of Motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21:2529–2536. doi: 10.1200/JCO.2003.12.122.
    1. Barani IJ, Larson DA, Berger MS. Future directions in treatment of brain metastases. Surg Neurol Int. 2013;4:S220–30.
    1. McTyre E, Scott J, Chinnaiyan P. Whole brain radiotherapy for brain metastasis. Surg Neurol Int Medknow Publications. 2013;4:S236–S244. doi: 10.4103/2152-7806.111301.
    1. Abe E, Aoyama H. The role of whole brain radiation therapy for the Management of Brain Metastases in the era of stereotactic radiosurgery. Curr Oncol Rep. 2011;14:79–84. doi: 10.1007/s11912-011-0201-0.
    1. Habets EJJ, Dirven L, Wiggenraad RG, Verbeek-de Kanter A, Lycklama À, Nijeholt GJ, Zwinkels H, et al. Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study. Neuro-oncology Oxford University Press. 2016;18:435–444. doi: 10.1093/neuonc/nov186.
    1. Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases. JAMA. 2016;316:401–409. doi: 10.1001/jama.2016.9839.
    1. Suh JH. Stereotactic radiosurgery for the management of brain metastases. N Engl J Med. 2010;362:1119–1127. doi: 10.1056/NEJMct0806951.
    1. Tsao MN. Brain metastases: advances over the decades. Ann Palliat Med. 2015;4:225–232.
    1. Cochran DC, Chan MD, Aklilu M, Lovato JF, Alphonse NK, Bourland JD, et al. The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with gamma knife surgery. J Neurosurg. 2012;116:978–983. doi: 10.3171/2012.2.JNS111353.
    1. 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.
    1. Baschnagel A, Wolters PL, Camphausen K. Neuropsychological testing and biomarkers in the management of brain metastases. Radiat Oncol. BioMed Central Ltd. 2008;3:1–12.
    1. Dietrich J, Monje M, Wefel J, Meyers C. Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist. 2008;13:1285–1295. doi: 10.1634/theoncologist.2008-0130.
    1. Soussain C, Ricard D, Fike JR, Mazeron J-J, Psimaras D, Delattre J-Y. CNS complications of radiotherapy and chemotherapy. Lancet. 2009;374:1639–1651. doi: 10.1016/S0140-6736(09)61299-X.
    1. Greene-Schloesser D, Moore E, Robbins ME. Molecular pathways: radiation-induced cognitive impairment. Clin Cancer Res American Association for Cancer Research. 2013;19:2294–2300. doi: 10.1158/1078-0432.CCR-11-2903.
    1. Tofilon PJ, Fike JR. The radioresponse of the central nervous system: a dynamic process. Radiat Res. 2000;153:357–370. doi: 10.1667/0033-7587(2000)153[0357:TROTCN];2.
    1. Suh JH. Hippocampal-avoidance whole-brain radiation therapy: a new standard for patients with brain metastases? Journal of clinical oncology. Proc Am Soc Clin Oncol. 2014;32:3789–3791. doi: 10.1200/JCO.2014.58.4367.
    1. Gondi V, Hermann BP, Mehta MP, Tomé WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Radiation Oncology Biology. 2012;83:e487–e493. doi: 10.1016/j.ijrobp.2011.10.021.
    1. Linskey ME, Andrews DW, Asher AL, Burri SH, Kondziolka D, Robinson PD, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neuro-Oncol. 2009;96:45–68. doi: 10.1007/s11060-009-0073-4.
    1. Douglas J, Goodkin R. A simple treatment planning strategy for patients with multiple metastases treated with Gamma Knife surgery. J Neurosurg. 2006;105(Suppl):2–4.
    1. Park S-H, Hwang S-K, Kang D-H, Lee S-H, Park J, Hwang J-H, et al. Gamma knife radiosurgery for multiple brain metastases from lung cancer. 2008;16:626–9.
    1. Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Watanabe S, et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors. J Neurosurg. 2014;121(Suppl):16–25.
    1. Ojerholm E, Lee JYK, Kolker J, Lustig R, Dorsey JF, Alonso-Basanta M. Gamma Knife radiosurgery to four or more brain metastases in patients without prior intracranial radiation or surgery. Cancer Med. 2014;3:565–571. doi: 10.1002/cam4.206.
    1. Kim C-H, Im Y-S, Nam D-H, Park K, Kim JH, Lee J-I. Gamma knife radiosurgery for ten or more brain metastases. J Korean Neurosurg Soc. 2008;44:358–363. doi: 10.3340/jkns.2008.44.6.358.
    1. Hunter GK, Suh JH, Reuther AM, Vogelbaum MA, Barnett GH, Angelov L, et al. Treatment of five or more brain metastases with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys Elsevier Inc. 2012;83:1394–1398. doi: 10.1016/j.ijrobp.2011.10.026.
    1. Suh JH, Chao ST, Angelov L, Vogelbaum MA, Barnett GH. Role of stereotactic radiosurgery for multiple (> 4) brain metastases. J Radiosurg SBRT. 2011;1:31–40.
    1. Nabors LB, Portnow J, Ammirati M, Brem H, Brown P, Butowski N, et al. Central nervous system cancers, version 2.2014. Featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2014;12:1517–1523. doi: 10.6004/jnccn.2014.0151.
    1. Soliman H, Das S, Larson DA, Sahgal A. Stereotactic radiosurgery (SRS) in the modern management of patients with brain metastases. Oncotarget. 2016;7:12318–12330.
    1. Wefel JS, Vardy J, Ahles T, Schagen SB. International cognition and cancer task force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol Elsevier. 2011;12:703–708. doi: 10.1016/S1470-2045(10)70294-1.
    1. Rades D, Dziggel L, Segedin B, Oblak I, Nagy V, Marita A, et al. A new survival score for patients with brain metastases from non-small cell lung cancer. Strahlenther Onkol. 2013;189:777–781. doi: 10.1007/s00066-013-0362-x.
    1. Witgert ME, Meyers CA. Neurocognitive and quality of life measures in patients with metastatic brain disease. Neurosurg Clin N Am. 2011;22:79–85. doi: 10.1016/j.nec.2010.08.010.
    1. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol. 2006;24:1305–1309. doi: 10.1200/JCO.2005.04.6086.
    1. Maassen GH, Bossema E, Brand N. Reliable change and practice effects: outcomes of various indices compared. J Clin Exp Neuropsychol. 3rd ed. Taylor & Francis Group; 2009;31:339–352.
    1. 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;10:1037–1044. doi: 10.1016/S1470-2045(09)70263-3.
    1. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16:e270–e278. doi: 10.1016/S1470-2045(15)70057-4.
    1. Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimization for allocation to clinical trials: a review. Control Clin Trials. 2002;23:662–74.
    1. O’Callaghan CA. OxMaR: open source free software for online minimization and randomization for clinical trials. Añel JA, editor. PLoS One. 2014;9:e110761–e110710.
    1. McPherson GC, Campbell MK, Elbourne DR. Use of randomisation in clinical trials: a survey of UK practice. Trials BioMed Central. 2011;13:198–8.
    1. ALEA online randomisation software. . Accessed 14 Feb 2018.
    1. Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. Biometrics. 1994;50:337–349. doi: 10.2307/2533377.
    1. Saville BR, Connor JT, Ayers GD, Alvarez J. The utility of Bayesian predictive probabilities for interim monitoring of clinical trials. Clin Trials SAGE Publications. 2014;11:485–493. doi: 10.1177/1740774514531352.
    1. Lezak MD. Neuropsychological assessment. USA: Oxford University Press; 2004.
    1. Dirven L, Armstrong TS, Taphoorn MJB. Health-related quality of life and other clinical outcome assessments in brain tumor patients: challenges in the design, conduct and interpretation of clinical trials. Neurooncol Pract. 2015;2:2–5.
    1. Smets EM, Garssen B, Bonke B, De Haes JC. The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39:315–325. doi: 10.1016/0022-3999(94)00125-O.
    1. Weitzner MA, Meyers CA, Gelke CK, Byrne KS, Cella DF, Levin VA. The functional assessment of cancer therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors. Cancer. 1995;75:1151–1161. doi: 10.1002/1097-0142(19950301)75:5<1151::AID-CNCR2820750515>;2-Q.
    1. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the hospital anxiety and depression scale. An updated literature review J Psychosom Res. 2002;52:69–77. doi: 10.1016/S0022-3999(01)00296-3.

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