ESTRO 36 5-9 May 2017, Vienna Austria, Accuray Symposium Treating Multiple Brain Metastases (BM) with CyberKnife System Frederic Dhermain MD PhD, Radiation Oncologist Gustave Roussy University Hospital, Villejuif, France Frederic.dhermain@gustaveroussy.fr 1
Conflict of Interest An honorarium is provided by Accuray for this presentation The views expressed in this presentation are those of the presenters and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated or any of its subsidiaries of any vendor, products or services contained in this presentation is intended or should be inferred. 2
Our experience at Gustave Roussy Radiation Therapy Dept: 4 Linacs, 2 Tomos 1 Novalis Tx, 1 CyberKnife System M6 with InCise MLC All ages, all locations +200 BM patients/ Yr N 1: NSCLC, N 2: Melanomas, N 3: Breast K Last Yrs: dramatic increase in Systemic control More long survivors exposed to risk of BM s 3
Rationale favoring Radiosurgery (RS) for Multiple (> 4) BM patients (1) First step: RS (+/- WBRT) for 1-4 BM Brown: Prospective trial: RS +WBRT vs RS only [1] Worse Neurocognitive outcome, Same Survival Next step : RS only for 1 to 8-10 BM! Yamamoto: RS only for multiple (5-10) BM [2] Same Local control & median Survival: 10,8 mths Kondziolka: the number of BM does not matter [3] CKN for Intra- / Extra-CNS metastases The only machine dedicated for real-time Tracking For What Patient s clinical interest? [1] Brown P. JAMA 2016; 316:401-409 [2] Yamamoto M. Lancet Oncol 2014; 387-95 [3] Knoll MA. Am J Clin Oncol 2016; June 2 (epub ahead of print) 4
Rationale favoring Radiosurgery (RS) for Multiple BM patients (2) Accuracy < 1 mm: key for BM < 3 mm from OaR dosimetrically comparable plans [1] with GKN: HI, nci Feasibility: frameless = ambulatory delivery Efficacy: 1 Yr Local control ~ 80-90% comparable to GKN,! NSCLC # Melanoma: molecular # Toxicity: consider all post-rs adverse events! % of Gr 3+ Radionecrosis, Headache & Seizures / 1-4 BM? Volumetric Increase if too early MRI evaluation (> 3 mths) Dose delivered to Normal Brain [2] depends on # factors QoL after RS for Multiple BM: decline [3]? Not Vs WBRT [1] Sio T. J Appl Clin Med Phys 2014; 15:14-26 [2] Ma L. J Neurosurg 2011; 114:1580-84 [3] Miller JA. Neurosurgery 2017; Febr 23 (epub ehead of print) 5
Rationale favoring Radiosurgery (RS) for Multiple BM patients (3) Serious Challengers of RS Partners! WBRT with Hippocampal sparing Especially when 1-2 BM > 3 cm and non operable Combined to RS to decrease Intra-cranial failures Systemic TT s: Targeted TTs and ImmunoTT s Combined + RS, not (yet?) Concomitant : toxicity? Supportive Care: an alternative if KPS < 70 Quartz, UK [1]: no need for 5 fractions of WBRT [1] Mulvena P, Lancet 2016;388:2004-2014 6
RS for Multiple BM: a review [1] of 10 Trials No level I evidence but [1] Sahgal A. SRS alone for Multiple BM, Neuro-Oncol 2017; 19:ii2-ii15. 7
Ongoing & Future International Trials on RS in Multiple BM NCT 01731704: WBRT / RS alone > 4 BMs, Total Volume < 15 cc closed because? Primary endpoint Cognitive Function at 6 months NCT 01592968 (MDAH): WB / RS alone Ongoing, 4 to 15 BMs (Max Total Volume of BMs?) Endpoints Cognitive (HTLVR) + Local control 4 mths NCT 02353000 (Maastricht): WB / RS alone Ongoing, 4-10 BM, Total Volume < 20 cc Primary endpoint: Quality of Life (EQ-5D-5L) Toronto: RS frontline => WBRT or no WBRT 8
IN OUR PRACTICE: # Groups of Pts Perfect indications Non Indications BEST indications: of key value for patients! REASONABLE indications: our daily practice DEBATABLE indications: tbd case by case NON indications: ideally < 10% of patients Meningitis, KPS < 70, Asymptomatic + Stable, Urgency 9
CKN & Multiples BM BEST indications: ~ 20% Fit patient: KPS > 80, Young age, GPA-DS > 3 Symptoms + but controlled: steroids, anti-epileptics Clearly Progressing or New BM on F.U. MRI s Ideally NO or really Stable Extra-CNS disease Non Bulky Extra-CNS Mets: < 4 # organs Low Burden of BM: total Volume < 10-15 cm3 Located within 3 mm of a critical organ! 10
BEST indication Ms A. 34 yrs old, carcinoid of the Lung Multi-metastatic, slowly evolving for 5 Years M+ Ovarien, breast, cutaneous, initially: 6 BM < 5 mm Focal Surgery, then > 30 cycles of Carbo-VP16 Emergency in 2016: headache, diplopia, left ptosis MRI: 9 BM, total Vol < 10 cm3, 1 close to Brainstem Steroids + switching chemo for 2 cycles of Temozolomide New MRI: several BMs still slowly progressing RS 11
1 x 20 Gy (80%) Total PTV Volume = 15 cc CI = 1,35 12
3 x 7 Gy (80%) 13
BEST indication Ms A. at 18 months Short / mid-term neurologically OK Last MRI: Stable or Responsive BM s Slowly evolving Extra-cranially Still on treatment (Temozolomide) Excellent KPS 14
CKN & Multiples BM REASONABLE indications: ~ 60% KPS > 70, expected Survival > 6 mths Controlled Extra-CNS Disease > 3 months Symptomatic or not: IF Progressing on MRI s +/- Previous Whole Brain RT: > 6 months Low Burden of Extra-CNS Mets: <3 # organs Max diam < 3 cm / Total Vol: < 15-20 cc 15
REASONABLE indications Case 1: Ms A. 45 yrs old, Melanoma. Melanoma Braf. M+ Lung & Liver. 3 BM no symptoms. Pembro 1st line. MR: BM progression. Ipi C1 => RS => C2 16
Complete response of first 2 targets but + 6 new BM s and +/- Asymptomatic Pt 6 mths after Complete response 17
To be noted: RS of first 2 BM irradiated between concomitant C1 - C2 Ipilimumab course 6 mths after 17 mm 18
# Options: WBRT or Multiple RS on 6 BM PB Pembro for Systemic progression on PET Not recommended with WBRT RS with MLC! 6 mths after 19
1 x 20 Gy, Using Incise 2 MLC*, 38 min Total Volume of PTV = 27 cc, CI = 1.25 Stabilisation of all BM at 4 mths 20
REASONABLE indication Case 2 Ms C. 35 yrs Old, KPS 90-100 Breast K HEr2 + since 2005 Recurrences in 2011 Seizures MRI: 2 BM + suspected leptomeningeal M+ May 2016: WBRT (10 x 3 Gy) ACTIVE NURSE Full Time 21
December 2016, 7 mths later: 1 new lesion 3 x 9 Gy 80% 22
Febr. 2017, 2 mths after: 8 new BM s Previous BM RS: 1 x 20 Gy (78%) in 43 min PTV Total: HI = 1.33 and % coverage 98% 23
DEBATABLE indication ~ 10% Mr R. 36 yrs old Active, KPS 80-90, only discrete Headache Melanoma: Initally Multi-metastatic 3 # sites Lymph nodes, Liver mets, slowly progressing 6 peauci symptomatic BM already present Ipi + Nivo failure on Pembro: BM progression Multiple BMs: 9, all < 15 mm, Total Vol 10 cc 24
PTV Total: HI = 1,25 and % coverage 99.4% 25
Debatable indication Feasibility: Yes, 46 minutes total time Short-term Toxicity: correct, just a little dizzy Brain MR at 2 mths: stable / decreasing but Died at 3 months post-rs Hepatic failure No objective evaluation of a very bulky Volume Very short-term prognostic outside the brain 26
Multiples BM & CKN Discussion Individual outcome for this Patient? Predictive Value of GPA-DS ~ 70% at best! Predicting Local control / Recurrence Strict MR follow-up: every 2 months => 1 Yr Waiting too long for definitive diagnosis (6 mths): biomarker? Prevention of Post-SRS Adverse Events Role of Steroids (always?), Anti-epileptics, Bevacizumab SRS + Systemic TTs: > Toxicity or Efficacy? TDM-1 (breast), TKI 2 nd generation (NSCLC), CPI (Melanoma) 27
Multiples BM & CKN Perspectives Individual outcome for this Patient? Imaging biomarker for 1 patient: Perfusion / Diffusion MR Preventing Local & Intra-cranial Failure WBRT with Hippocampal sparing, early rcbv, Radiomics Prevention of Post-SRS Adverse Events Bulky Volumes: automatic tools? 3 x 9 Gy vs 1 x 20 Gy? Steroids, Anti-epileptics, Beva: randomized studies! Interactions of SRS + Systemic TT s TDM-1, TKI 2 nd generation, CPI s: prospective series! [1] Sahgal A. SRS alone for Multiple BM Neuro-Oncol 2017; 19:ii2-ii15. 28
Multiple BM & CKN Take Home Message: Patient First Interdisciplinary Choice: Efficacy/ Toxicity ratio Systemic TT (targeted / immuno) / WBRT / BS Care Neuro-clinical Evaluation for this Patient Direct info on KPS, Neuro Signs, concomitant Drugs Imaging & Technical considerations: OaR? MR s dynamic, Total BM Volume, Dosimetrics: CI Patient opinion Mask Vs I.V. Drugs THANK YOU FOR YOUR ATTENTION 29