Alleinige Radiochirurgie und alleinige Systemtherapie zwei «extreme» Entwicklungen in der Behandlung von Hirnmetastasen?

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1 Department of Radiation Oncology Chairman: Prof. Dr. Matthias Guckenberger Alleinige Radiochirurgie und alleinige Systemtherapie zwei «extreme» Entwicklungen in der Behandlung von Hirnmetastasen? Matthias Guckenberger Relevance of brain metastases headache (49%) focal weakness (30%) mental disturbances (32%) gait ataxia (21%) seizures (18%) speech difficulty (12%) visual disturbance (6%) sensory disturbance (6%) limb ataxia (6%) Tremendous impact on Quality of life 1 1

2 Developments in Tx of brain metastases Targeted local Tx only Targeted systemic Tx only 2 Developments in Tx of brain metastases Targeted local Tx only Targeted systemic Tx only 3 2

3 Case example NSCLC, pt2 pn1 cm0 Three brain metastasis 2 years after resection Radiosurgery only to all three brain metastases 4 Resection of solitary brain metastases Patchell NEJM 1990 WBI WBI + Neurosurgery Study Inclusion criteria OS Patchell 1990 KPS vs 15 weeks Noordijk 1994 WHO 2 10 mo vs 6 mo Mintz 1996 KPS 50 6 mo vs 6 mo OS survival benefit in good prognosis patients 5 3

4 RTOG 9508: Radiosurgery 1 3 brain metastases KPS patients WBI & SRS WBI only Andrews Lancet 2004 Improved OS in RPA class I compared to WBI only 6 Secondary Analysis of RTOG 9508 GPA All patients GPA Sperduto IJROBP 2014 OS survival benefit only in GPA OS benefit independently from 1 3 metastases 7 4

5 Value of WBI after SRS 1-3 brain metastases stable systemic disease or asymptomatic primary tumors WHO performance status (PS) of 0 to 2 Neurosurgery n=160 Radiosurgery n=199 Kocher JCO 2011 WBI N=180 Observation N=179 8 SRS w/o WBI for 1-4 brain metastases Local control Brain control Functional outcome Overall survival Aoyama JAMA 2006 Chang Lancet Oncol 2009 Kocher JCO 2011 Brown JAMA 2016 Improved Improved NS NS - Improved Worse NS Improved Improved NS NS Improved Improved Worse NS Consistent lack of OS benefit by WBI Willing to undergo regular MRI FU (every 3 months) 9 5

6 SRS for >3/4 brain metastases Prospective observational study n=1194 Inclusion criteria: SRS only for 1 10 brain mets KPS 70 Largest tumor <10ml, <3cm Total cumulative volume 15ml SRS with 1 x 20-22Gy MRI FU every 3 months Yamamoto Lancet Oncol 2014 OS identical in case with 2-4 and 5-10 metastases 10 Local recurrence after neurosurgery Surgery S & WBI S & SRS S & SRT Kocher JCO 2011 Mahajan ASTRO 2016 Brown ASCO 2016 Choi IJROBP 2012 Minniti IJROBP a 1a 59% 55% 2a 2a Kocher JCO % 22% 1a 2a 28% 44% 16% 0mm 3% 2mm 1a 2a 16% 60% risk of local recurrence after surgical resection Substantial reduction by (fractionated) stereotactic RT 11 6

7 Developments in Tx of brain metastases Targeted SRS only Targeted drugs only 12 Case example NSCLC, EGRT mutated Synchronous brain metastases 18 asymptomatic metastases all < 1cm EGFR inhibitor, regular c-mri and salvage WBI 13 7

8 WBI influence on neurocognitive function NCCTG N0574 (Alliance) - randomized phase III trial SRS vs SRS & WBI Cognitive function 3 months SRS SRS + WBI immediate recall 8% 31% delayed recall 20% 51% verbal fluency 2% 19% Neurocognitive function decline already after 3mo Less toxic Tx required for patients with worse OS Brown ASCO Prognosis of Pts with brain metastases Overall Survival RPA Classification KPS 70% Class 1: 2.3 months Class 2: 4.2 months Class 3: 7.1 months Primary controlled Age < 70a Brain metastases only Gaspar IJROBP 1997 RPA & GPA do not consider molecular tumor profile 15 8

9 Chemotherapy added to WBI Study CT OS Response Ushio Neurosurgery 1991 methyl-ccnu, ACNU / Tegafur NS Improved RR Antonadou JCO 2002 TMZ NS Improved RR Guerrieri Lung Cancer 2004 Carboplatin NS NS No added benefit except of added toxicity 16 Lung molecular-gpa Adeno Ca SCC Paradigm change in Adeno Carcinoma 17 9

10 Intra- vs extracranial response Dabrafenib in MBM Response similar good / bad in cranial vs extracranial metastases 18 Targeted radiotherapy and delayed WBI CTLA-4 AB Ipilimumab Margolin Lancet Oncol 2012 Phase II study 72 pat. melanoma +/- symptomatic brain mets PKI Dabrafinib Long Lancet Oncol 2012 Phase II study 172 pat. BRAF-mutant melanoma Asymptomatic brain mets Lapatinib & Cap Bachelot Lancet Oncol 2013 Phase II study 42 pat. HER-2 pos breast Ca No previous WBI Cerebral disease control Asymptomatic pat 24% Symptomatic pat 10% Intracerebral response w/o prior local TX 39% Progressive after 31% local Tx Intracerebral response Overall RR 66% CR 0% Promising response and intracranial DC rates QoL and neurocognition? 19 10

11 CNS activity in ALK positive NSCLC Crizotinib vs CT Alectinib Solomon JCO 2016 Gadgeel Lancet Oncol 2014 Improved CNS penetration of next generation Tx 20 Targetd drugs added to WBI Study CT OS Welsh JCO 2013 Erlotinib (single arm phase II) Response / PFS Sperduto IJROBP 2013 Lee J Natl Cancer Inst 2014 Erlotinib NS NS Erlotinib NS NS No added benefit but added toxicity However, use in unselected patients 21 11

12 Radiotherapy of brain metastases in patients with driver mutations: ALK Johung JCO 2016 Treatment with TKI AND repeated RT achieves excellent OS 22 Radiotherapy of brain metastases in patients with driver mutations: megfr Retrospective single institution study: n=50 Characteristics of brain mets: Critical location and larger size High risk Low risk N=33 N=17 RT followed by TKI TKI intracranial PD Magnuson IJROBP 2016 Hypothesis: RT can be safely delayed in the context of effective systemic Tx 23 12

13 Radiotherapy of brain metastases in patients with driver mutations: megfr RT first TKI first Magnuson IJROBP 2016 Upfront RT, preferably SRS, remains standard 24 Toxicity of SRS & targeted treatments Dr. Kroeze Dr. Fritz SRS and modern targeted drugs well tolerated CAVE: BRAFi 25 13

14 WBI with hippocampus sparing Goal: reduce toxicity of WBI -> memory function / learning Location of function: Hippocampus Neural stem cells in subgranular zone of the dentate gyrus Location of metastases: Only 8.6 % of brain mets located in the hippocampus plus 5mm margin Gondi Radiother Oncol 2010 Feasibility of avoiding: Modern technologies (IMRT) reduce hippocampas dose by >80% Gondi IJROBP WBI with hippocampus sparing RTOG 0933 Prospective phase II trial of hippocampus sparing during WBI with 10 x 3Gy Primary endpoint: Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 months N=113 Gondi IJROBP 2013 Metastatic progression in hippocampus: 4.5% Decline in HVLT-DR from baseline to 4 months: 7.0% 27 14

15 Conclusions Radiation Oncology Neurology Neurosurgery Oncology 28 15