GAMMA KNIFE RADIOSURGERY PREDICTORS FOR OVERALL SURVIVAL FOR BRAIN METASTASES PREDICTORS FOR OVERALL SURVIVAL Cornel Tancu, GK Clinical Research Fellow

Brief History 2012: partnership between University College London Hospitals NHS Foundation Trust and Medical Equipment Solutions Limited Company October 2012 The first GK procedure April 2013 Official opening of our centre November 2014 300th patient treated June 2016 QSRC/UCLH – 7 years contract with NHS England to treat all 4 tiers as a new NHS implementation plan October 2016 First paediatric patient treated for AVM March 2018 1000 procedures

GK INDICATIONS Benign tumours: Vascular: Functional: Metastases Vestibular Schwannoma Meningioma Pituitary adenoma Other benign (other schwannoma, haemangioblastoma, glomus tumour, etc) Metastases Vascular: Arterio-venous malformations (AVM) Cavernoma Paediatric AVM Functional: Trigeminal Neuralgia

GK procedures 917 procedures until the end of December 2017 27% 19% 25% 13.5% 15% 19% 44 22 69 182 185 167 248 917 20% 21 121 161 150 187 277

GK SRS for BRAIN METASTASES - BACKGROUND GK SRS became a well-established treatment for brain metastases (BM). Recent studies have demonstrated its non-inferiority for survival in multi- metastatic patients (5-10 comparing with 2-4 BM) . (Yamamoto et al., Lancet 2014). Emerging data suggest that total Tumor Intracranial Volume (TIV) of BM is an important predictor of disease burden and outcome.

Material and Methods Population: 156 consecutive patients with BMs treated between 29/10/2012 and 31/12/2017 Mean follow-up period: 12.5 months (0.3 –43mths) Method: Prospective & retrospective data collection from CDR, PACS and Leksell Gamma Plan Station Excel table Kaplan-Meier estimation of survival, Log-Rank test and Cox regression in SPSS 17 OBJECTIVE : OVERALL SURVIVAL AND PREDICTORS LOCAL TUMOUR CONTROL ADVERSE RADIATION EFFECTS (ARE)

Procedures: 182 Patients: 156 Metastases: 619 POPULATION Procedures: 182 Patients: 156 Metastases: 619 Total intracranial volume of BM Mean BMs/procedure: 4 Range: 1 – 20 Range= 25mm to 25cc Mean TIV= 3.5cc; Median=2cc

Example of good response of a large BM 6 weeks post GK

Example of good response of a large BM 6 weeks post GK 6 weeks post GK 6 weeks post GK

Fractionated treatment for large BM (N=3) 10Gy x3 # GK 1st #, TV=24.3cc 2nd #, TV=13.7cc 3rd #, TV=8.5cc 6 weeks after, TV=6cc

I. LOCAL TUMOUR CONTROL (n=333 metastases) OVERALL RATE OF CONTROL FOR EACH TREATED METASTASIS: 94.6% LCR in old BM series Institution BM/pts Med. Dose Crude LCR% UCSF 219/100 18 82 Pittsburgh 229/130 16 89 Karolinska 105/85 27 94

Target Volume was the main predictor parameter for ARE (p<0.0001) III. ADVERSE RADIATION EFFECTS (ARE) (Tumour swelling, increased perilesional oedema or radionecrosis) Overall rate of any ARE =8.7% (29/333 lesions) Target Volume was the main predictor parameter for ARE (p<0.0001) By example, for lesions with a TV>0.25cc (D≈8mm) ARE=16.7% (22/132)

III. OVERALL SURVIVAL (N=152) Older series: Kondziolka (1999): SRS+WBRT 11mths Chidel (2000): SRS alone 10.5mths Sneed (2002): 11.3 mths Sneed (39): 14 mths (15.2mths for RPA class1) Yamamoto - RCT JLGK0901 (2014): 12mths Median Overall Survival 15.6 mths

THE NUMBER OF BRAIN METASTASES AT TREATMENT p= 0.144 Log Rank test Univariate Cox regression: The groups of 2-4 and >5 metastases did not show a statistically significant difference in overall survival- p=0.230

Total Intracranial Volume of BMs Total volume: Median: 2cc; Mean: 3.5cc; Range: 0.025-24.8cc 3 categories – equal number of patients Volume categ (cc) Nb Estimated Median survival (months) Small <0.14cc 49 27.7 Medium 0.15-3.6 52 15.6 Large >3.6 51 9.5 Overall 152 p=0.002 Log Rank test

II.OVERALL SURVIVAL– Prognostic Factors VARIABLE (continuous) Univariate Cox proportional hazard regression model  MULTIVARIATE Cox regression Hazard ratio (95% Confidence Limits) p value Total Intracranial Volume 1.085, 1.032-1.139 0.001 1.073, 1.019-1.129 0.008 Primary (Lung vs Others) 1.59, 1.022-2.491 0.04 1.518, 0.959-2.403 0.075 Number of metastases (continous) 1.024, 0.982-1.069 0.270 1.023, 0.977-1.072 0.330 (Single vs Multiple) 0.630, 0.381-1.04 0.071 0.641, 0.385-1.069 0.088 Total Intracranial Volume was found to be the only independent intracranial parameter for overall survival.

DISCUSSION – Total Intracranial Volume Gonda, Yamamoto,Chen et al, European Journal of Cancer 2014: ‘The cumulative tumour volume independently associated with overall survival (p < 0.001)’. Baschnagel A et al, JNS 2017: ‘The total brain metastasis volume was a strong and independent predictor for overall survival, distant brain failure, and local control, even when considering the number of metastases’.

‘On demand’ GK SRS CONCLUSIONS GOOD OVERALL SURVIVAL (MEDIAN=15.6 MONTHS) THE TOTAL INTRACRANIAL VOLUME OF METASTASES, BUT NOT THE NUMBER OF METASTASES, WAS A NEGATIVE PREDICTOR OF THE SURVIVAL. LOCAL TUMOUR CONTROL OF >94% TARGET VOLUME WAS THE MAIN INDEPENDENT PREDICTOR OF LOCAL CONTROL RATE AND OF SIDE-EFFECTS ‘On demand’ GK SRS

Future developments with the GK ICON for BM Possibility to treat larger metastases/ postoperative cavities, with lower side-effects Reduced doses for organs at risk by using fractionation, when required Staged treatments for patients with large number of BM Mask treatments for repeated GK procedures and/or for anxious patients

GK CyberKnife ?

Thank you QSRC Team Consultant Neurosurgeons Therapeutic Radiographers QSRC Executive Director Lynne Brooks Consultant Neurosurgeons Mr N Kitchen – Medical Director Mr R Bradford Miss J Grieve Miss M Murphy Mr A McEvoy Mr L Thorne Miss H Sethi Mr J Hyam Mr G James – paediatric Mr M Tisdal - paediatric Physicists – Medical Physics Limited Ian Paddick Alex Dimitriadis Phil Tapper Clinical Fellow C. Tancu Local Manager Mike Allcock Therapeutic Radiographers Katie Jeanson A. Polonsky W. Kinnaird Elise Arnett Administrative Emily Brooks Consultant Neuroradiologists Dr K Miszkiel Dr P Rangi Dr. P. Cowley Dr S. Bisdas Dr F Roberson - paediatric Dr A Rennie - paediatric MDT Coordinator Sam Atrey Nurse: Glenda Jimenez