1. Evaluating the Clinical Outcomes of Sixty-Three Patients Treated with Gamma Knife as Salvage Therapy for Glioblastoma Multiforme Erik W Larson, Halloran E Peterson, Wayne T Lamoreaux, Alexander R MacKay, Robert K Fairbanks, Jason A Call, Jonathan D Carlson, Benjamin C Ling, John J Demakas, Barton S Cooke, Ben Peressini, and Christopher M Lee

2. Disclosures  The authors declare no conflict of interest.

3. Background: Glioblastoma Multiforme  Glioblastoma multiforme (GBM) is the most common primary tumor of the brain.  Aggressive upfront therapy includes chemotherapy, whole brain radiation, and gross total resection  Despite these initial interventions, tumors tend to recur in 6 months, and many patients will only survive 14-16 months from their initial diagnosis date.  Following the inevitable recurrence of GBM, there are many salvage therapy options, including Gamma Knife radiosurgery (GKRS)  Historical prognosis indicators include age <50 years, Karnofsky Performance Status ≥90, and whether a gross total resection was achieved at presentation

4. Study Goals  Compare overall survival of recurrent Glioblastoma multiforme (rGBM) patients to expected prognosis as indicated by updated Radiation Therapy Oncology Group – Recursive Partitioning Analysis (RTOG-RPA).*  Determine which patient characteristics are associated with better outcomes  Age  Resection extent  KPS * Li J et al, Validation and simplification of the Radiation Therapy Oncology Group recursive partitioning analysis classification for glioblastoma. International journal of radiation oncology, biology, physics. 2011

5. Materials and Methods  Retrospective chart analysis of 63 patients with confirmed rGBM between 2002 and 2011 who received one or more salvage GKRS treatments.  Treatment was performed at Gamma Knife of Spokane using a Model C Leksell 60 Co Gamma Knife.  Survival curves were estimated using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis of selected variables.

6. Patient Population Characteristics CharacteristicBiopsySubtotalGTTotal n=10n=26n=27n=63 Age at diagnosis, median (range)53 (28-85)57 (28-85)52 (23-76)55 (23-85) <50310619 >=507172044 KPS 601023 7029516 8045817 9023712 10008412 Unknown1113 GK Dose (Gy) <1454514 14-1536615 162141329 >160235 Tumor volume (cc) <15371626 ≥15614828 Unknown1539 Clinical Follow-Up, median (range)8.9 (0.0-63.6)

7. Results: Overall Survival  Median survival following initial diagnosis  = 20.2 ± 2.72 months

8. Overall Survival vs. RTOG-RPA Prognosis RTOG- RPA Class Defining Variables Li, et al. 2011 Present Study n95% CI III age <50 y and KPS ≥90.17.1 17.3 6 Not Significant IV age <50 y and KPS <90; age ≥50 y, KPS ≥70, resection, and working. 11.2 20.2 4617.6-22.8 V age ≥50 y, KPS ≥70, resection, and not working; age ≥50 y, KPS ≥70, biopsy only; age ≥50 y, KPS <70. 7.5 11 86.6-15.4

9. Results: Post-Salvage Survival  Median survival following date of first GKRS salvage  = 9.9 ± 3.1 months

10. Results: Univariate Analysis Median Survival Hazard Ratio n95% CI Estimate95% CIP value** Resection extent GT*27 11.9 ± 4.4 reference Subtotal26 9.9 ± 9.2 1.080.59-1.97=0.792 Biopsy10 9.6 ± 1.1 0.880.38-2.02=0.768 Age at diagnosis <50*19 12.3 ± 11.7 reference ≥5044 9.6 ± 2.4 1.440.81-2.54=0.221 KPS 603 3.0 ± 3.2 8.551.08-66.67 =0.021 7016 5.7 ± 2.5 1.210.52-2.81=0.699 80*17 9.3 ± 2.1 reference 9012 11.9 ± 3.7 0.650.28-1.50=0.308 10012 17.9 ± 5.5 0.350.12-0.99=0.034 Unknown3insufficient data 0.740.52-2.81=0.699 GK dose (Gy) <1414 9.6 ± 12.8 0.98 0.48-2.02=0.966 14-1515 7.9 ± 3.8 1.410.68-2.92=0.314 16*29 11.9 ± 2.8 reference >165 4.7 ± 4.5 0.780.24-2.51=0.638 Tumor vol. (cc) <15*26 13.9 ± 4.2 reference ≥1528 7.2 ± 2.7 1.971.06-3.66=0.019 Unknown99.1 ± 4.01.610.61-4.35=0.252

11. Results: Multivariate Analysis Hazard Ratio Estimate95% CIP value** Resection extent GT* reference Subtotal0.970.44-2.150.941 Biopsy0.410.14-1.180.098 Age at diagnosis <50* reference ≥501.380.67-2.850.383 KPS 608.093.69-17.78<0.001 701.471.35-1.61<0.001 80*reference 900.530.19-1.470.230 1000.220.15-0.33<0.001 Unknown1.100.31-3.920.880 GK dose (Gy) <140.710.25-2.070.535 14-151.150.41-3.180.793 16*reference >160.660.14-3.160.602 Tumor volume (cc) <15* reference ≥151.950.81-4.710.138 Unknown3.681.08-12.580.038

12. KPS  Multivariate Hazard Ratios:  60: 8.09, 70: 1.47, 90: 0.53, 100: 0.22

13. Extent of Resection  Multivariate Hazard Ratios:  Subtotal: 0.91, Biopsy: 0.41  Not significant

14. Non-significant factors  Age.  Patients ≥50 years old (p = 0.383)  Extent of Resection.  Subtotal resection (p = 0.941)  Biopsy (p = 0.098)  Tumor Volume.  Tumors ≥15 cc (p = 0.138)  GK Dose  <14 Gy (p = 0.535)  >16 Gy (p = 0.602)

15. Conclusions  Gamma Knife salvage therapy for selected rGBM patients may provide prolonged survival.  Those patients with higher KPS scores tend to have a better prognosis independent of their age, tumor size, and initial resection extent.  This study is limited by its retrospective nature and may represent a selection bias. A randomized, controlled clinical trial is necessary to assess efficacy on a larger population.  Each patient should be counseled on individual medical and surgical treatment options.

16. Acknowledgments  We would like to thank the research support staff of Cancer Care Northwest as well as Eric Reynolds and Jill Adams of Gamma Knife Spokane.

17. Questions?  Please feel free to contact:  Erik W Larson, elar5000@uw.eduelar5000@uw.edu  Christopher M Lee MD, lee@ccnw.edulee@ccnw.edu