Journal of Neuro-Oncology

, 94:409 | Cite as

Gamma Knife radiosurgery after radiation therapy as an adjunctive treatment for glioblastoma

  • Nader Pouratian
  • R. Webster Crowley
  • Jonathan H. Sherman
  • Jay Jagannathan
  • Jason P. SheehanEmail author
Clinical Study - Patient Study


Despite a randomized trial showing no benefit of stereotactic radiosurgery (SRS) prior to radiation therapy (RT), the benefits of SRS after RT and at the time of progression require further characterization. We retrospectively reviewed 48 patients with histopathological diagnoses of glioblastoma (GBM) that were treated with SRS over a 16-year period (1991–2007). Twenty-two were treated as part of their initial treatment paradigm and 26 were treated at the time of progression. The primary endpoints studied were overall survival (OS), survival after SRS and time-to-progression (TTP). Patients treated at the time of progression had significantly longer OS than those treated on initial presentation (17.4 vs. 15.1 months, P = 0.003). On multivariate analysis, Radiation Therapy Oncology Group (RTOG) class III patients, those with more extensive resections, and those who were not on steroids at the time of SRS had significantly improved OS. SRS margin dose was a significant prognostic factor for TTP on multivariate analysis (HR = 0.78, 95% CI: 0.62–0.98). In the subgroup of patients treated with GKS as part of their initial treatment, an increasing number of weeks between surgical resection and GKS was a poor prognostic factor on multivariate analysis (HR = 1.11, 95% CI: 1.01–1.23). In patients who were treated with SRS at the time of progression, chemotherapy was associated with a longer TTP (P = 0.028). Our results suggest that SRS provides a survival advantage when delivered after RT. This benefit may be best appreciated in RTOG class III patients. Moreover, SRS may be a viable alternative to open surgery for aggressive management of GBM at the time of recurrence. Prospective studies of SRS for GBM should focus on these two groups of patients.


Gamma Knife Radiosurgery Glioblastoma 



Many of these patients were treated by Dr. Ladislau Steiner for their radiosurgery and by Dr. John Jane Sr. and Dr. Mark Shaffrey for their tumor resections.


  1. 1.
    CBTRUS (2008) Statistical report: primary brain tumors in the United States, 2000–2004. Central brain tumor registry of the United States. Accessed via Accessed 01 Nov 2008
  2. 2.
    Chang JE, Khuntia D, Robins HI et al (2007) Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol 5:894–902, 907–915Google Scholar
  3. 3.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi: 10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
  4. 4.
    Brem H, Piantadosi S, Burger PC et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The polymer-brain tumor treatment group. Lancet 345:1008–1012. doi: 10.1016/S0140-6736(95)90755-6 PubMedCrossRefGoogle Scholar
  5. 5.
    Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncology 5:79–88. doi: 10.1215/15228517-5-2-79 Google Scholar
  6. 6.
    Walker MD, Strike TA, Sheline GE (1979) An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725–1731PubMedGoogle Scholar
  7. 7.
    Silbergeld DL, Chicoine MR (1997) Isolation and characterization of human malignant glioma cells from histologically normal brain. J Neurosurg 86:525–531PubMedCrossRefGoogle Scholar
  8. 8.
    Wallner KE, Galicich JH, Krol G et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409PubMedGoogle Scholar
  9. 9.
    Hochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911PubMedGoogle Scholar
  10. 10.
    Sneed PK, Gutin PH, Larson DA et al (1994) Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. Int J Radiat Oncol Biol Phys 29:719–727PubMedGoogle Scholar
  11. 11.
    Kondziolka D, Flickinger JC, Bissonette DJ et al (1997) Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 41:776–783. doi: 10.1097/00006123-199710000-00004 (discussion 783–785)PubMedCrossRefGoogle Scholar
  12. 12.
    Shrieve DC, Alexander E 3rd, Black PM et al (1999) Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90:72–77PubMedCrossRefGoogle Scholar
  13. 13.
    Mahajan A, McCutcheon IE, Suki D et al (2005) Case-control study of stereotactic radiosurgery for recurrent glioblastoma multiforme. J Neurosurg 103:210–217PubMedCrossRefGoogle Scholar
  14. 14.
    Nwokedi EC, DiBiase SJ, Jabbour S et al (2002) Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 50:41–46. doi: 10.1097/00006123-200201000-00009 (discussion 46–47)PubMedCrossRefGoogle Scholar
  15. 15.
    Combs SE, Widmer V, Thilmann C et al (2005) Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer 104:2168–2173. doi: 10.1002/cncr.21429 PubMedCrossRefGoogle Scholar
  16. 16.
    Souhami L, Seiferheld W, Brachman D et al (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853–860. doi: 10.1016/j.ijrobp.2004.04.011 PubMedGoogle Scholar
  17. 17.
    Tsao MN, Mehta MP, Whelan TJ et al (2005) The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 63:47–55. doi: 10.1016/j.ijrobp.2005.05.024 PubMedGoogle Scholar
  18. 18.
    Scott CB, Scarantino C, Urtasun R et al (1998) Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40:51–55. doi: 10.1016/S0360-3016(97)00485-9 PubMedCrossRefGoogle Scholar
  19. 19.
    Curran WJ Jr, Scott CB, Horton J et al (1993) Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704–710. doi: 10.1093/jnci/85.9.704 PubMedCrossRefGoogle Scholar
  20. 20.
    Mirimanoff RO, Gorlia T, Mason W et al (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569. doi: 10.1200/JCO.2005.04.5963 PubMedCrossRefGoogle Scholar
  21. 21.
    Gorlia T, van den Bent MJ, Hegi ME et al (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981–22981/CE.3. Lancet Oncol 9:29–38. doi: 10.1016/S1470-2045(07)70384-4 PubMedCrossRefGoogle Scholar
  22. 22.
    Sarkaria JN, Mehta MP, Loeffler JS et al (1995) Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 32:931–941. doi: 10.1016/0360-3016(94)00621-Q PubMedCrossRefGoogle Scholar
  23. 23.
    Hohwieler Schloss M, Freidberg SR, Heatley GJ et al (1989) Glucocorticoid dependency as a prognostic factor in radiotherapy for cerebral gliomas. Acta Oncol 28:51–55. doi: 10.3109/02841868909111181 PubMedCrossRefGoogle Scholar
  24. 24.
    Kondziolka D, Somaza S, Martinez AJ et al (1997) Radioprotective effects of the 21-aminosteroid U-74389G for stereotactic radiosurgery. Neurosurgery 41:203–208. doi: 10.1097/00006123-199707000-00032 PubMedCrossRefGoogle Scholar
  25. 25.
    Kondziolka D, Mori Y, Martinez AJ et al (1999) Beneficial effects of the radioprotectant 21-aminosteroid U-74389G in a radiosurgery rat malignant glioma model. Int J Radiat Oncol Biol Phys 44:179–184. doi: 10.1016/S0360-3016(98)00552-5 PubMedCrossRefGoogle Scholar
  26. 26.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  27. 27.
    Hau P, Baumgart U, Pfeifer K et al (2003) Salvage therapy in patients with glioblastoma: is there any benefit? Cancer 98:2678–2686. doi: 10.1002/cncr.11845 PubMedCrossRefGoogle Scholar
  28. 28.
    Stummer W, Reulen HJ, Meinel T et al (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–576 (discussion 564–576)PubMedCrossRefGoogle Scholar
  29. 29.
    Keles GE, Lamborn KR, Chang SM et al (2004) Volume of residual disease as a predictor of outcome in adult patients with recurrent supratentorial glioblastomas multiforme who are undergoing chemotherapy. J Neurosurg 100:41–46PubMedCrossRefGoogle Scholar
  30. 30.
    Hsieh PC, Chandler JP, Bhangoo S et al (2005) Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57:684–692. doi: 10.1227/01.NEU.0000175550.96901.A3 (discussion 684–692)PubMedCrossRefGoogle Scholar
  31. 31.
    Hall WA, Djalilian HR, Sperduto PW et al (1995) Stereotactic radiosurgery for recurrent malignant gliomas. J Clin Oncol 13:1642–1648PubMedGoogle Scholar
  32. 32.
    Loeffler JS, Alexander E 3rd, Shea WM et al (1992) Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 10:1379–1385PubMedGoogle Scholar
  33. 33.
    Shaw E, Scott C, Souhami L et al (2000) Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291–298. doi: 10.1016/S0360-3016(99)00507-6 PubMedCrossRefGoogle Scholar
  34. 34.
    Florell RC, Macdonald DR, Irish WD et al (1992) Selection bias, survival, and brachytherapy for glioma. J Neurosurg 76:179–183PubMedCrossRefGoogle Scholar
  35. 35.
    Curran WJ Jr, Scott CB, Weinstein AS et al (1993) Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02. J Clin Oncol 11:857–862PubMedGoogle Scholar
  36. 36.
    Irish WD, Macdonald DR, Cairncross JG (1997) Measuring bias in uncontrolled brain tumor trials—to randomize or not to randomize? Can J Neurol Sci 24:307–312PubMedGoogle Scholar
  37. 37.
    Lustig RA, Scott CB, Curran WJ (2004) Does stereotactic eligibility for the treatment of glioblastoma cause selection bias in randomized studies? Am J Clin Oncol 27:516–521. doi: 10.1097/01.coc.0000135641.82026.c4 PubMedCrossRefGoogle Scholar
  38. 38.
    Gomez-Rio M, Rodriguez-Fernandez A, Ramos-Font C et al (2008) Diagnostic accuracy of 201Thallium-SPECT and 18F-FDG-PET in the clinical assessment of glioma recurrence. Eur J Nucl Med Mol Imaging 35:966–975. doi: 10.1007/s00259-007-0661-5 PubMedCrossRefGoogle Scholar
  39. 39.
    Hu LS, Baxter LC, Smith KA et al (2009) Relative cerebral blood volume values to differentiate high-grade glioma recurrence from posttreatment radiation effect: direct correlation between image-guided tissue histopathology and localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging measurements. AJNR Am J Neuroradiol 30:552–558PubMedCrossRefGoogle Scholar
  40. 40.
    Zeng QS, Li CF, Zhang K et al (2007) Multivoxel 3D proton MR spectroscopy in the distinction of recurrent glioma from radiation injury. J Neurooncol 84:63–69. doi: 10.1007/s11060-007-9341-3 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Nader Pouratian
    • 1
  • R. Webster Crowley
    • 1
  • Jonathan H. Sherman
    • 1
  • Jay Jagannathan
    • 1
  • Jason P. Sheehan
    • 1
    Email author
  1. 1.Department of Neurological SurgeryUniversity of VirginiaCharlottesvilleUSA

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