Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases

NCT03297788 | Completed

• 1 other identifier: ENCEPHALON
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Patients suffering from small cell lung cancer (SCLC) are at high risk for developing brain metastases (BM). To prevent a clinical manifestation of preexisting microscopic brain dissemination, prophylactic cranial irradiation (PCI) is offered to both limited and extensive disease patients, if they respond to first line regime, thus being at risk or at chance to develop clinical brain metastases. However, up to 10-15% of patients present with BM at initial diagnosis. If MRI is used as a diagnostic tool for initial staging the number even increases up to 15-20%. Additionally, between 40 - 50% of patients develop BM until time of death and the risk of developing BM further increases with prolonged survival. Treatment options are usually limited to WBRT and palliative chemotherapy but the actual effect of therapeutic WBRT has mainly been studied in small retrospective and nonrandomized studies. WBRT has been established as the treatment standard in patients with cerebral metastases from SCLC, however, it has only modest efficacy. Results might be improved by additional dose escalation. A SRS to cerebral metastases may be indicated in patients with intracranial disease, and the current protocol is aimed at exploring the neurocognition and efficacy of SCLC in patients with brain metastases treated with SRS or WBRT. The present trial aims to exploratory investigate the treatment response to ´conventional whole brain radiotherapy´ (WBRT) and ´stereotactic radiotherapy´(SRS) in SCLC patients.

Conditions

SCLC; Brain Metastases

Keywords

SCLC; Brain Metastases; SRS (stereotactic radiosurgery); WBRT (whole brain radiotherapy)

Outcome Measures

Primary Outcomes (1)

• Neurocognition

  Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)

  3 month after treatment

Secondary Outcomes (10)

• Intracranial progression

  up to 12 month after treatment

• Intracranial progression

  up to 12 month after treatment

• Overall survival (OS)

  12 month OS

• Death due to brain metastases

  up to 12 month after treatment

• Locally progression-free survival

  up to 12 month after treatment

Study Arms (2)

Arm A: SRS

EXPERIMENTAL

Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases

Radiation: SRS

Arm B: WBRT

ACTIVE COMPARATOR

Patients receive whole brain radiotherapy (WBRT)

Radiation: WBRT

Interventions

SRS RADIATION

For SRS the dose prescription to the PTV will be as follows: * 20 Gy to the 70%-isodose (lesions \< 2 cm max. diameter) * 18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter) * 6 x 5 Gy to the conformally surrounding isodose (lesions \> 3 cm max. diameter)

Arm A: SRS

WBRT RADIATION

WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.

Arm B: WBRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• histologically confirmed small cell lung cancer (SCLC)
• Magentic resonance (MR)-imaging confirmed cerebral metastases (no resection, max. number of 10)
• age ≥ 18 years of Age
• For women with childbearing potential, (and men) adequate contraception.
• Ability of subject to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrolment in the trial)

You may not qualify if:

• refusal of the patients to take part in the study
• previous radiotherapy of the brain
• Patients who have not yet recovered from acute high-grade toxicities of prior therapies
• Known carcinoma \< 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy
• Pregnant or lactating women
• Participation in another competing clinical study or observation period of competing trials, respectively
• MRI contraindication (i.e. cardiac pacemaker, implanted defibrillator, certain cardiac valve replacements, certain metal implants)
• Karnofsky score (KPS) \<60
• Simultaneous cytotoxic chemotherapy
• Last application of chemotherapy/immunotherapy/targeted therapy \<1 week before cerebral radiotherapy

Sponsors & Collaborators

• Juergen Debus: lead
• Heidelberg University: collaborator

Study Sites (1)

University Hospital of Heidelberg, Department of Radiation Oncology

Heidelberg, 69120, Germany

Location

Related Publications (38)

• Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006 Jun 7;295(21):2483-91. doi: 10.1001/jama.295.21.2483.

  PMID: 16757720 BACKGROUND

• Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, Kristjansen PE, Johnson BE, Ueoka H, Wagner H, Aisner J. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84. doi: 10.1056/NEJM199908123410703.

  PMID: 10441603 BACKGROUND

• Bentzen SM, Constine LS, Deasy JO, Eisbruch A, Jackson A, Marks LB, Ten Haken RK, Yorke ED. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S3-9. doi: 10.1016/j.ijrobp.2009.09.040.

  PMID: 20171515 BACKGROUND

• Bergqvist M, Brattstrom D, Bennmarker H, Wagenius G, Riska H, Brodin O. Irradiation of brain metastases from lung cancer: a retrospective study. Lung Cancer. 1998 Apr;20(1):57-63. doi: 10.1016/s0169-5002(98)00015-4.

  PMID: 9699188 BACKGROUND

• Bernhardt D, Adeberg S, Bozorgmehr F, Opfermann N, Hoerner-Rieber J, Repka MC, Kappes J, Thomas M, Bischoff H, Herth F, Heussel CP, Debus J, Steins M, Rieken S. Nine-year Experience: Prophylactic Cranial Irradiation in Extensive Disease Small-cell Lung Cancer. Clin Lung Cancer. 2017 Jul;18(4):e267-e271. doi: 10.1016/j.cllc.2016.11.012. Epub 2016 Dec 2.

  PMID: 28027850 BACKGROUND

• Bernhardt D, Adeberg S, Bozorgmehr F, Opfermann N, Hoerner-Rieber J, Konig L, Kappes J, Thomas M, Herth F, Heussel CP, Warth A, Debus J, Steins M, Rieken S. Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy. J Neurooncol. 2017 Aug;134(1):205-212. doi: 10.1007/s11060-017-2510-0. Epub 2017 May 30.

  PMID: 28560661 BACKGROUND

• Bernhardt D, Bozorgmehr F, Adeberg S, Opfermann N, von Eiff D, Rieber J, Kappes J, Foerster R, Konig L, Thomas M, Debus J, Steins M, Rieken S. Outcome in patients with small cell lung cancer re-irradiated for brain metastases after prior prophylactic cranial irradiation. Lung Cancer. 2016 Nov;101:76-81. doi: 10.1016/j.lungcan.2016.09.010. Epub 2016 Sep 14.

  PMID: 27794411 BACKGROUND

• van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007 Jun;16(3):219-42. doi: 10.1177/0962280206074463.

  PMID: 17621469 BACKGROUND

• Carmichael J, Crane JM, Bunn PA, Glatstein E, Ihde DC. Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys. 1988 Mar;14(3):455-9. doi: 10.1016/0360-3016(88)90260-x.

  PMID: 2830211 BACKGROUND

• Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009 Nov;10(11):1037-44. doi: 10.1016/S1470-2045(09)70263-3. Epub 2009 Oct 2.

  PMID: 19801201 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. Int J Radiat Oncol Biol Phys. 1985 Sep;11(9):1699-707. doi: 10.1016/0360-3016(85)90223-8.

  PMID: 4030437 BACKGROUND

• Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):745-51. doi: 10.1016/s0360-3016(96)00619-0.

  PMID: 9128946 BACKGROUND

• Giannone L, Johnson DH, Hande KR, Greco FA. Favorable prognosis of brain metastases in small cell lung cancer. Ann Intern Med. 1987 Mar;106(3):386-9. doi: 10.7326/0003-4819-106-3-386.

  PMID: 3028222 BACKGROUND

• Herfarth KK, Izwekowa O, Thilmann C, Pirzkall A, Delorme S, Hofmann U, Schadendorf D, Zierhut D, Wannenmacher M, Debus J. Linac-based radiosurgery of cerebral melanoma metastases. Analysis of 122 metastases treated in 64 patients. Strahlenther Onkol. 2003 Jun;179(6):366-71. doi: 10.1007/s00066-003-1050-z.

  PMID: 12789461 BACKGROUND

• Hochstenbag MM, Twijnstra A, Wilmink JT, Wouters EF, ten Velde GP. Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis. J Neurooncol. 2000 Jul;48(3):243-8. doi: 10.1023/a:1006427407281.

  PMID: 11100822 BACKGROUND

• Kochhar R, Frytak S, Shaw EG. Survival of patients with extensive small-cell lung cancer who have only brain metastases at initial diagnosis. Am J Clin Oncol. 1997 Apr;20(2):125-7. doi: 10.1097/00000421-199704000-00003.

  PMID: 9124183 BACKGROUND

• Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep. 1981 Sep-Oct;65(9-10):811-4.

  PMID: 6268295 BACKGROUND

• Lassen U, Kristjansen PE, Hansen HH. Brain metastases in small-cell lung cancer. Ann Oncol. 1995 Nov;6(9):941-4. doi: 10.1093/oxfordjournals.annonc.a059363. No abstract available.

  PMID: 8624299 BACKGROUND

• Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S10-9. doi: 10.1016/j.ijrobp.2009.07.1754.

  PMID: 20171502 BACKGROUND

• Newman SJ, Hansen HH. Proceedings: Frequency, diagnosis, and treatment of brain metastases in 247 consecutive patients with bronchogenic carcinoma. Cancer. 1974 Feb;33(2):492-6. doi: 10.1002/1097-0142(197402)33:23.0.co;2-o. No abstract available.

  PMID: 4812766 BACKGROUND

• Nugent JL, Bunn PA Jr, Matthews MJ, Ihde DC, Cohen MH, Gazdar A, Minna JD. CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer. 1979 Nov;44(5):1885-93. doi: 10.1002/1097-0142(197911)44:53.0.co;2-f. No abstract available.

  PMID: 227582 BACKGROUND

• Postmus PE. Brain Metastases From Small Cell Lung Cancer: Chemotherapy, Radiotherapy, or Both? Semin Radiat Oncol. 1995 Jan;5(1):69-73. doi: 10.1054/SRAO00500069.

  PMID: 10717129 BACKGROUND

• Quan AL, Videtic GM, Suh JH. Brain metastases in small cell lung cancer. Oncology (Williston Park). 2004 Jul;18(8):961-72; discussion 974, 979-80, 987.

  PMID: 15328892 BACKGROUND

• Scharp M, Hauswald H, Bischof M, Debus J, Combs SE. Re-irradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis. Radiat Oncol. 2014 Jan 3;9:4. doi: 10.1186/1748-717X-9-4.

  PMID: 24387239 BACKGROUND

• Schwartz LH, Seymour L, Litiere S, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, Hayes W, Hodi FS, Hoekstra OS, Huang EP, Lin N, Liu Y, Therasse P, Wolchok JD, de Vries E. RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 2016 Jul;62:138-45. doi: 10.1016/j.ejca.2016.03.082. Epub 2016 May 26.

  PMID: 27237360 BACKGROUND

• Schwer AL, Gaspar LE. Update in the treatment of brain metastases from lung cancer. Clin Lung Cancer. 2006 Nov;8(3):180-6. doi: 10.3816/CLC.2006.n.045.

  PMID: 17239293 BACKGROUND

• Shibamoto Y, Baba F, Oda K, Hayashi S, Kokubo M, Ishihara S, Itoh Y, Ogino H, Koizumi M. Incidence of brain atrophy and decline in mini-mental state examination score after whole-brain radiotherapy in patients with brain metastases: a prospective study. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1168-73. doi: 10.1016/j.ijrobp.2008.02.054. Epub 2008 May 19.

  PMID: 18495375 BACKGROUND

• Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S; EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. doi: 10.1056/NEJMoa071780.

  PMID: 17699816 BACKGROUND

• Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A. 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 Jan 1;31(1):65-72. doi: 10.1200/JCO.2011.41.0639. Epub 2012 Dec 3.

  PMID: 23213105 BACKGROUND

• Son CH, Jimenez R, Niemierko A, Loeffler JS, Oh KS, Shih HA. Outcomes after whole brain reirradiation in patients with brain metastases. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):e167-72. doi: 10.1016/j.ijrobp.2011.03.020. Epub 2011 May 27.

  PMID: 21620583 BACKGROUND

• Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.

  PMID: 19942357 BACKGROUND

• Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012 Feb 1;30(4):419-25. doi: 10.1200/JCO.2011.38.0527. Epub 2011 Dec 27.

  PMID: 22203767 BACKGROUND

• Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H, Nishio M, Kaneda H, Takayama K, Ishimoto O, Takeda K, Yoshioka H, Tachihara M, Sakai H, Goto K, Yamamoto N. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 May;18(5):663-671. doi: 10.1016/S1470-2045(17)30230-9. Epub 2017 Mar 23.

  PMID: 28343976 BACKGROUND

• Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, Xu W, Sahgal A. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr 18;2012(4):CD003869. doi: 10.1002/14651858.CD003869.pub3.

  PMID: 22513917 BACKGROUND

• Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK, Wenz F. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1311-8. doi: 10.1016/j.ijrobp.2008.03.009. Epub 2008 Apr 28.

  PMID: 18448270 BACKGROUND

• Wong WW, Schild SE, Sawyer TE, Shaw EG. Analysis of outcome in patients reirradiated for brain metastases. Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):585-90. doi: 10.1016/0360-3016(95)02156-6.

  PMID: 8621282 BACKGROUND

• Bernhardt D, Hommertgen A, Schmitt D, El Shafie R, Paul A, Konig L, Mair-Walther J, Krisam J, Klose C, Welzel T, Horner-Rieber J, Kappes J, Thomas M, Heussel CP, Steins M, Kieser M, Debus J, Rieken S. Whole brain radiation therapy alone versus radiosurgery for patients with 1-10 brain metastases from small cell lung cancer (ENCEPHALON Trial): study protocol for a randomized controlled trial. Trials. 2018 Jul 16;19(1):388. doi: 10.1186/s13063-018-2745-x.

  PMID: 30012190 DERIVED

MeSH Terms

Conditions

Brain Neoplasms; Snyder Robinson syndrome

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Stefan Rieken, PD.Dr.

  chief senior physician in the department of Radiation Oncology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of the Department Radiation Oncology

Study Record Dates

• First Submitted: September 19, 2017
• First Posted: September 29, 2017
• Study Start: December 1, 2017
• Primary Completion: October 1, 2023
• Study Completion: December 1, 2023
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)