Journal of Neuro-Oncology

, Volume 87, Issue 3, pp 299–307 | Cite as

Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial

  • Alexander Muacevic
  • Berndt Wowra
  • Axel Siefert
  • Joerg-Christian Tonn
  • Hans-Jakob Steiger
  • Friedrich W. KrethEmail author
Clinical-Patient Studies


Background Is Gamma Knife surgery alone as effective as surgery plus whole brain irradiation (WBRT) for patients with a single, small-sized brain metastasis? Methods Patients aged between 18 and 80 years harboring a single, resectable metastasis ≤3 cm in diameter, a Karnofsky performance score (KPS) ≥70, and a stable systemic disease were randomly assigned to microsurgery plus WBRT or Gamma Knife surgery alone. The primary end point was length of survival, secondary end points were recurrence of tumor in the brain, health related quality of life, and treatment related toxicity. Results Due to poor patient accrual, the study was stopped prematurely. The final analysis was based on 33 patients in the surgery and 31 patients in the radiosurgery group. Treatment results did not differ in terms of survival (P = 0.8), neurological death rates (P = 0.3), and freedom from local recurrence (P = 0.06). Patients of the radiosurgery group experienced more often distant recurrences (P = 0.04); after adjustment for the effects of salvage radiosurgery this difference was lost (P = 0.4). Radiosurgery was associated with a shorter hospital stay, less frequent and shorter timed steroid application (P ≤ 0.001), and lower frequency of grade 1/2 toxicities (according to the RTOG/EORTC CNS toxicity criteria, P ≤ 0.01). Improved scores for role functioning and quality of life were seen 6 weeks after radiosurgery (P < 0.05); this difference was lost 6 months after treatment. Conclusions In patients harboring a single, small-sized metastasis, Gamma Knife surgery alone is less invasive; local tumor control seems to be as high as after surgery plus WBRT. Distant tumor control, however, is significantly less frequently achieved (after radiosurgery alone). The role of radiosurgical salvage therapy (alternatively to WBRT) for distant tumor control deserves further prospective evaluation.


Brain metastases Gamma Knife surgery Prospective randomized study Radiosurgery Radiotherapy Surgery 



This study was granted by Elekta Research Foundation.


  1. 1.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC et al (2004) 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 trial. Lancet 22:1665–1672CrossRefGoogle Scholar
  2. 2.
    DeAngelis LM, Mandell LR, Thaler HT, Kimmel DW, Galicich JH, Fuks Z et al (1989) The role of postoperative radiotherapy after resection of single brain metastasis. Neurosurgery 24:798–804PubMedCrossRefGoogle Scholar
  3. 3.
    Lang FF, Sawaya R (1998) Surgical treatment of metastatic brain tumors. Semin Surg Oncol 14:53–63PubMedCrossRefGoogle Scholar
  4. 4.
    Karnofsky DA, Burchenal JH (1949) The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM (ed) Evaluation of chemotherapeutic agents. Columbia University Press, New York, pp 191–205Google Scholar
  5. 5.
    Noordijk EM, Vecht CJ, Haaxma-Reiche H, Padberg GW, Voormolen JH, Hoekstra FH et al (1994) The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:711–717PubMedGoogle Scholar
  6. 6.
    Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ et al (1990) A randomized trial of surgery in the treatment of single metastasis to the brain. N Engl J Med 322:494–500PubMedCrossRefGoogle Scholar
  7. 7.
    Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH et al (1993) Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33:583–590PubMedCrossRefGoogle Scholar
  8. 8.
    Adler JR, Cox RS, Kaplan I, Martin DP (1992) Stereotactic radiosurgical treatment of brain metastasis. J Neurosurg 76:444–469PubMedGoogle Scholar
  9. 9.
    Alexander E 3rd, Moriarty TM, Davis RB, Wen PY, Fine HA, Black PM et al (1995) Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87:34–40PubMedCrossRefGoogle Scholar
  10. 10.
    Auchter RM, Lamond JP, Alexander E, Buatti JM, Chappell R, Friedman WA et al (1996) A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 35:27–35PubMedGoogle Scholar
  11. 11.
    Borgelt G, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW et al. (1980) The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6:1–9PubMedGoogle Scholar
  12. 12.
    Diener-West M, Dobbins TW, Phillips TL, Nelson DF (1989) Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys 16:669–673PubMedGoogle Scholar
  13. 13.
    Flickinger JC, Kondziolka D, Lundsford LD, Coffey RJ, Goodman ML, Shaw EG (1994) A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:797–802PubMedGoogle Scholar
  14. 14.
    Flickinger JC, Kondziolka D (1996) Radiosurgery instead of resection for solitary brain metastasis: the gold standard redefined. Int J Radiat Oncol Biol Phys 35:185PubMedCrossRefGoogle Scholar
  15. 15.
    Gaspar L, Scott C, Rotman M, Aspell S, Phillips T, Wasserman T et al (1997) Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751PubMedGoogle Scholar
  16. 16.
    Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC (1999) Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427–434PubMedGoogle Scholar
  17. 17.
    Mehta MP, Rozental JM, Levin AB, Mackie TR, Kubsad SS, Gehring MA et al (1992) Defining the role of radiosurgery in the management of brain metastasis. Int J Radiat Oncol Biol Phys 24:619–625PubMedGoogle Scholar
  18. 18.
    Muacevic A, Kreth FW, Horstmann GA, Schmid-Elsaesser R, Wowra B, Steiger HJ, Reulen HJ (1999) Surgery and radiotherapy compared with Gamma Knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 91:35–43PubMedGoogle Scholar
  19. 19.
    Pirzkall A, Debus J, Lohr F, Fuss M, Rhein B, Engenhart-Cabillic R, Wannenmacher M (1998) Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 16:3563–3569PubMedGoogle Scholar
  20. 20.
    Sanghavi SN, Miranpuri SS, Chappell R, Buatti JM, Sneed PK, Suh JH et al (2001) Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 51:426–434PubMedGoogle Scholar
  21. 21.
    Sneed PK, Suh JH, Goetsch SJ, Sanghavi SN, Chappell R, Buatti JM et al (2002) A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519–526PubMedGoogle Scholar
  22. 22.
    Sturm V, Kober B, Hover KH, Schlegel W, Boesecke R, Pastyr O (1987) Stereotactic percutaneous single dose irradiation of brain metastasis with a linear accelerator. Int J Radiat Oncol Biol Phys 13:279–282PubMedGoogle Scholar
  23. 23.
    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376PubMedCrossRefGoogle Scholar
  24. 24.
    Fayers P, Aaronson N, Bjordal K, Curran D, Groenvald M (1999) EORTC QLQ-C30 scoring manual, 2nd edn. Quality of Life Unit, EORTC Data Center, BrusselsGoogle Scholar
  25. 25.
    Osoba D, Aaronson NK, Muller M, Sneeuw K, Hsu MA, Yung WK et al (1997) Effect of neurological dysfunction on health-related quality of life in patients with high-grade glioma. J Neurooncol 34:263–278PubMedCrossRefGoogle Scholar
  26. 26.
    Osoba D, Aaronson NK, Muller M, Sneeuw K, Hsu MA, Yung WK et al (1996) The development and psychometric validation of a brain cancer quality-of-life questionnaire for use in combination with general cancer-specific questionnaires. Qual Life Res 5:139–150PubMedCrossRefGoogle Scholar
  27. 27.
    King MT (1996) The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res 5:555–567PubMedCrossRefGoogle Scholar
  28. 28.
    Osoba D, Rodrigues G, Myles J, Zee B, Pater J (1998) Interpreting the significance of changes in health-related quality-of-life-scores. J Clin Oncol 16:139–144PubMedGoogle Scholar
  29. 29.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:475–481CrossRefGoogle Scholar
  30. 30.
    Cox DR, Oakes D (1984) Analysis of survival data. Chapman and Hall, New YorkGoogle Scholar
  31. 31.
    Bindal AK, Bindal RK, Hess KR, Shiu A, Hassenbusch SJ, Shi WM et al (1996) Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 84:748–754PubMedCrossRefGoogle Scholar
  32. 32.
    Aoyama H, Shirato H, Tago M, Nakagawa K et al (2006) Stereotactic radisurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases. JAMA 295:2483–2491PubMedCrossRefGoogle Scholar
  33. 33.
    Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ et al (1998) Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 280:1485–1489PubMedCrossRefGoogle Scholar
  34. 34.
    Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B et al (1996) A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with single brain metastasis. Cancer 78:1470–1476PubMedCrossRefGoogle Scholar
  35. 35.
    Smalley SR, Laws ER Jr, O’Fallon JR, Shaw EG, Schray MF (1992) Resection for solitary brain metastasis. Role of adjuvant radiation and prognostic variables in 229 patients. J Neurosurg 77:531–540PubMedGoogle Scholar
  36. 36.
    Chougule PB, Burton-Williams M, Saris S, Zheng Z, Ponte B, Noren L et al (2000) Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 48:114 (Abstract)Google Scholar
  37. 37.
    Fuller BG, Kaplan ID, Adler J, Cox RS, Bagshaw MA (1992) Stereotactic radiosurgery for brain metastasis: the importance of adjuvant whole brain irradiation. Int J Radiat Oncol Biol Phys 23:413–418PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Alexander Muacevic
    • 1
    • 2
  • Berndt Wowra
    • 2
  • Axel Siefert
    • 3
  • Joerg-Christian Tonn
    • 1
  • Hans-Jakob Steiger
    • 4
  • Friedrich W. Kreth
    • 1
    Email author
  1. 1.Department of NeurosurgeryLudwig-Maximilians-University, Klinikum GroßhadernMunichGermany
  2. 2.Cyberknife Center MunichMunichGermany
  3. 3.Department of Radiation OncologyLudwig-Maximilians-University, Klinikum GroßhadernMunichGermany
  4. 4.Department of NeurosurgeryUniversity DuesseldorfDuesseldorfGermany

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