SSS Tümörleri. Ufuk ABACIOĞLU Acıbadem Altunizade Hastanesi 10 Aralık 2017, İstanbul

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1 SSS Tümörleri Ufuk ABACIOĞLU Acıbadem Altunizade Hastanesi 10 Aralık 2017, İstanbul

2 Major Themes Radiation therapy for CNS diseases have evolved with increasing options for more conformal therapy With hopefully less toxicity With possibly improved tumor control New (and old) systemic therapies may offer improved disease control but can also be at the trade off of increased/new toxicities, especially in the multimodality treatment setting Cooperative groups enable higher quality investigations of rare diseases and provide opportunity to address new ideas

3 Abstract 1 Rogers: (214.5) High-Risk Meningioma: Initial Outcomes from NRG Oncology/RTOG-0539 Abstract 2 Krauze: (217) Does the Addition of Valproic Acid to Concurrent Radiation Therapy and Temozolomide Improve Patient Outcome? Correlative Analysis of RTOG 0525, SEER, and a Phase 2 NCI Trial Abstract 3 Bell: (215) MGMT Promoter Methylation Status Independently Predicts Overall Survival in Anaplastic Astrocytoma in NRG Oncology/RTOG 9813: A Phase 3 Trial of Radiation Plus Nitrosourea Versus Radiation Plus Temozolomide Abstract 4 Kim: (342) The Risk of Radiation Necrosis Following Stereotactic Radiosurgery With Concurrent Systemic Therapies Abstract 5 Marcrom: (1007) Focal Management of Large Brain Metastases and Risk of Leptomeningeal Disease Abstract 6: (1006) Implications of HER2 Status on Local Control and Adverse Radiation Effects After Stereotactic Radiosurgery for Brain Metastases of Breast Cancer Abstract 7 Ghia: (337) Phase 1 Study of Spinal Cord Constraint Relaxation With Single Session Spine Stereotactic Radiosurgery in the Primary Management of Patients With Inoperable, Previously Unirradiated Metastatic Epidural Spinal Cord Compression Abstract 8: (339) Imaging-Based Outcomes for 24 Gy in 2 Daily Fractions for Patients With De Novo Spinal Metastases Treated With Spine Stereotactic Body Radiation Therapy: An Emerging Standard

4 Meningiomas CBTRUS Rogers L et al. JNS 2015 Perry A. in Russell & Rubinstein s Pathology 2006 Ostrom QT et al. Neuro Oncol 2015

5 High-risk meningioma: Initial outcomes from NRG Oncology/RTOG-0539 Rogers CL, Zhang P, Vogelbaum MA, Perry A, Ashby L, Modi J, Alleman A, Galvin JM, Fogh SE, Youssef EF, Deb N, Kwok Y, Robinson CG, Shu HK, Fisher B, Panet-Raymond V, McMillan W, degroot J, Mehta MP This project was supported by U10CA and U10CA from the National Cancer Institute (NCI).

6 NRG Oncology / RTOG-0539 Schema Phase II Trial of Observation for Low-Risk Meningiomas, and of Radiotherapy for Intermediate and High-Risk Meningiomas Opened June 19, 2009 Group 1 Observation Required Sample Size: for each Group Strata Group 2 3D-CRT or IMRT 54 Gy / 30 Patients enrolled: Group 1 65 CLOSED Group 2 56 CLOSED Group 3 57 CLOSED Group 3 IMRT 60Gy / 30 Average Monthly Accrual: Group Group Group Rogers ASTRO 2017 Group 1 (Low Risk): New WHO Grade 1, GTR or STR Group 2 (Interm Risk): Recurrent Grade 1, GTR or STR New WHO Grade 2, GTR Group 3 (High Risk): Any WHO Grade 3, GTR or STR Recurrent Grade 2, GTR or STR New Grade 2, STR Study endpoints: 3 yr PFS 3 yr OS Toxicity

7 NRG Oncology / RTOG-0539, Group 3 Enrollment Consort Diagram Enrolled (n=57) Treated on Protocol (n=53) Initial WHO II: 11 (20.8%) Initial WHO III: 17 (32.1%) Recur WHO II: 8 (15.1%) Recur WHO III: 5 (9.4%) Imaging Only: 12 (22.6%) Ineligible (n=4) Registered to the wrong group (n=1) Multiple meningiomas (n=1) Not meet protocol timeframe (n=1) Not receive protocol treatment (n=1) Withdrew/Lost follow-up Before 3y (n=2), each w/o recurrence Evaluable Primary Endpoint, 3yPFS (n=51) Rogers ASTRO 2017

8 NRG Oncology / RTOG-0539, Group 3 Patient Characteristics Characteristic Group III (n=53) n % Age: median 62y (19-94) < 49 years years years > 70 years % 28.3% 28.3% 22.6% Gender female male % 47.2% Zubrod Performance Status % 47.2% Neurologic Function no symptoms minor symptoms moderate symptoms % 39.6% 17.0% 83% Rogers ASTRO 2017

9 Progression-Free Survival (%) NRG Oncology / RTOG-0539, Group 3 Median follow up 4 years Primary Endpoint: 3y PFS % % 59.2% 50.6% 47.2% Years After Registration Patients at Risk Years After Registration Rogers ASTRO 2017

10 Overall Survival (%) Overall Survival (%) NRG Oncology / RTOG-0539, Group 3 Overall Survival 96.2% 84.5% 78.6% 69.4% 59.1% OS: initial WHO gr 3 vs recur WHO gr 2 p= 0.38 HR= % CI= Overall Survival / 82.4% / / / 71.4% 76.0% / / / / / 47.6% Years After Registration Patients at Risk Patients at Risk Recurrent WHO II Initial WHO III Years after Registration 8 17 Dead Total Recurrent WHO II 3 8 Dead Total Recurrent II 3 8 Initial WHO WHO III III Years Rogers ASTRO 2017

11 NRG Oncology / RTOG-0539, Group 3 Adverse Events Acute or Late Overall Highest Grade Group 3 (n=53) n and (%) of patients by AE Grade (CTCAE 3.0) (24.5%) 24 (45.3%) 6 (11.3%) 0 (0%) * 1 (1.9%) * necrosis, identified 376 days after RT, reported due to protocol therapy Rogers ASTRO 2017

12 Authors Conclusions Patients with high-risk meningioma treated with RT (60 Gy/30) on this trial experienced 3yPFS 59.2% and 3yOS 78.6%, comparable to historic results in the literature Toxicities were mostly limited to grades 1-3, with one necrosis-related grade 5 event Recurrent WHO II disease have inferior outcomes as compared to new diagnosis WHO III meningioma Management and outcomes for high-risk meningiomas remains suboptimal, strongly supporting further investigations to optimize management Rogers ASTRO 2017

13 Comments Strengths: Prospective multi-center study Best quality data reaffirming what many practitioners feel: that high grade meningiomas are aggressive tumors with high risk of recurrence that is not typically salvageable Limitations: Single arm study that defines the outcome of current common practice Does not advance beyond known clinical Future directions: Supports exploring new approaches Higher radiation doses (e.g., EORTC 22042, RT 60 Gy & 70 Gy) Molecular profile driven target therapies (Alliance trial: SMO, AKT, NF2)

14 EORTC Rogers ASTRO 2017

15 Phase II trial of SMO/AKT1/FAK inhibitors in progressive meningiomas with SMO/AKT1/NF2 mutations Residual, recurrent or progressive meningiomas SMO mutation NF2 mutation AKT mutation SMO inhibitor: Vismodegib FAK inhibitor: GSK AKT inhibitor: Afuresertib Brain MRI every 2 months Complete response, partial response or stable disease: Continue on therapy Progressive disease or significant toxicity: Off study Courtesy of P Brastianos

16 Does the addition of Valproic acid to concurrent radiation therapy and temozolomide improve patient outcome? correlative analysis of RTOG 0525, SEER and a phase II NCI trial Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, Tofilon PJ, Fine H, Rowe L, Gilbert M, Camphausen K National Cancer Institute, NIH Krauze ASTRO 2017

17 Study Objective Valproic Acid (VPA) is an antiepileptic agent with HDACi (histone deacetylase inhibitor) activity shown to radiosensitize glioblastoma (GBM) cells The initial study evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in a two center, open-label, phase II study (NCI-06-C-0112) The intent of this study was to compare patient outcomes across NCI results with modern standard of care (RTOG 0525), and general population data (SEER ) Krauze ASTRO 2017

18 Study Design Comparison of outcomes for patient with new diagnosis GBM: 37 patients from phase II NCI trial, daily VPA (25 mg/kg) + concurrent RT/TMZ, patients from RTOG 0525, treated on standard TMZ dose arm, patients from SEER database, adult patients (age > 15) with diagnostic codes (third edition (IDC-O-3) diagnosed Endpoints: OS and PFS Krauze ASTRO 2017

19 Patient characteristics Krauze ASTRO 2017 NCI n % RTOG 0525 n % P-value Age (y), median (range) 54.3 (31-72) 57 (22-84) Sex RPA KPS Surgery MGMT status Bevacizumab use Male Female unknown GTR STR biopsy methylated unmethylated unknown no yes unknown < <0.001

20 Results: PFS & OS Progression free survival Overall survival p = p < Younger age, class V RPA and MGMT status were significant for both PFS in both the NCI cohort and the RTOG 0525 cohort, in addition KPS was also significant for OS Krauze ASTRO 2017

21 Results: Superior PFS & OS in NCI vs RTOG 0525 Study or SEER NCI (n=37) RTOG 0525 (n=411) SEER (n=6083) PFS OS PFS OS OS # of events (%) 30 (81) 27 (73) 374 (91) 320 (78) 5359 (88) median (months)(95% CI) 11.1 (8.0,51.9) 30.9 (22.2,65.6) 7.5 (6.9, 8.2) 18.9 (16.8, 20.3) 11 6 months (%) 78.4 (66.2,92.8) 97.3 (92.2,100) 61 (56.5,65.9) 91.9 (89.3,94.6) 65.5 (64.3,66.7) 12 months (%) 45.9 (32.4,65.2) 91.7 (83.2,100) 30 (25.9,34.8) 70.4 (66.1,75) 45.5 (44.2,46.7) 24 months (%) 37.8 (25,57.2) 56.4 (41.9,75.8) 14.4 (11.3,18.2) 34.2 (29.9,39.2) 20.7 (19.6,21.8) P-value* <0.001** Krauze ASTRO 2017

22 Authors Conclusions PFS and OS in NCI phase II study with the addition of VPA to concurrent RT/TMZ was superior in comparison to both a trial population receiving standard of care (RTOG 0525) and a contemporary SEER cohort These results warrant further consideration of VPA for analysis in a phase III trial Krauze ASTRO 2017

23 Comments Strengths: NCI outcomes compared to prospective standard of care data (RTOG 0525 control), next best thing to a prospective randomized study Proposes a cost effective therapy with potential symbiotic intervention with regards to antiepileptic effects of VPA Limitations: NCI VPA study cohort of 37 patients is small Patients in NCI study were not similar to other cohorts and had better KPS, lower RPA, and greater use of bevacizumab may account for differences in outcomes Future directions: Validation/further testing of hypothesis is required, ideally in a larger prospective and randomized study

24 MGMT promoter methylation status independently predicts overall survival in anaplastic astrocytoma in NRG Oncology/RTOG 9813: a phase III trial of radiation plus nitrosourea vs radiation plus temozolomide E. H. Bell, M. Won, S. M. Chang, G. Cairncross, M. Gilbert, J. P. Bahary, C. Dolinskas, K. Aldape, J. McElroy, J. Fleming, L. Ashby, H. A. Shih, G. K. Hunter, W. A. Yung, S. P. Howard, K. Belanger, M. L. Siker, B. D. Kavanagh, Y. Chen, and A. Chakravarti The Ohio State University & NRG Bell ASTRO 2017

25 NRG Oncology/RTOG 9813 Background A phase III study of RT + temozolomide (TMZ) versus RT+nitrosourea (NU) in grade III anaplastic astrocytoma Age 1. <50 2. >50 KPS Surgery 1. Biopsy 2. Resec. Arm 1: RT: 59.4 Gy + TMZ 200 mg/m 2 daily on days 1-5 of the first week of RT. Repeat TMZ every 28 days for a total of 12 cycles. Arm 2: RT: 59.4 Gy + NU [BCNU 80mg/m 2 IV days 1-3 every 8 weeks OR CCNU 130mg/m 2 p.o. every 8 weeks] Chang, S. et al., Neuro-oncology 2016 Bell ASTRO 2017

26 Background MGMT promoter methylation prognosticates responsiveness to alkylating chemotherapy in glioblastoma Significance of MGMT status in anaplastic gliomas is not well defined Bell ASTRO 2017

27 Study Objective To determine the proportion of patients with MGMT promoter methylation in NRG/RTOG 9813 To determine the prognostic significance in the setting of anaplastic gliomas (astrocytoma dominant) in a prospective phase III trial using rigorous multivariable analysis with well-annotated clinical data Bell ASTRO 2017

28 Study Design RTOG 9813 subjects reviewed for tissue availability for molecular testing Samples assessed by Illumina 450K Methylation Array MGMT-STP27 prediction model was used to calculate MGMT promoter methylation status Bell ASTRO 2017

29 Results 58 eligible and randomized patients identified 36 (62%) MGMT methylated 22 (38%) MGMT unmethylated No significant difference was observed on age or performance status at baseline between methylated and unmethylated patients Bell ASTRO 2017

30 Results MGMT methylation trended with improved OS Progression-free Survival Overall Survival Correlative Data Obtained in Chakravarti Lab, The Ohio State CCC/Arthur G. James Cancer Hospital HR(95% CI) = 1.29 ( ). p= 0.41 HR(95%CI) = 1.78( ), p= 0.08 Bell ASTRO 2017

31 Results: Multivariable Analyses Cox Proportional Hazards Model for Progression- Free Survival, Stepwise Cox Proportional Hazards Model for Overall Survival, Stepwise Variable (Bolded value has favorable outcome) MGMT Status (Unmethylated vs. Methylated) p-value Hazard Ratio (95%CI) (0.80, 2.73) Age (<50 vs 50+) (0.22, 0.89) Race (White vs. Other) (0.11, 0.97) Treatment, surgery status, KPS, gender, neurologic function, and mental status dropped out during stepwise selection Variable (Bolded value has favorable outcome) MGMT Status (Unmethylated vs. Methylated) p-value Hazard Ratio (95%CI) (1.15, 4.55) Age (<50 vs 50+) < (0.14, 0.60) Treatment, surgery status, KPS, gender, race, neurologic function, and mental status dropped out during stepwise selection Lack of association with PFS may be indicative of limitations of progression defined by imaging (pseudoprogression) Bell ASTRO 2017

32 Authors Conclusions MGMT promoter methylation was an independent prognostic biomarker for OS upon MVA of anaplastic astrocytomas treated with radiation plus nitrosourea or radiation plus temozolomide This is the first study to validate the prognostic significance of MGMT promoter methylation on OS in a phase III study of grade III anaplastic glioma (astrocytoma dominant) patients treated with radiation plus TMZ or NU using rigorous MVAs with prospectively-collected, well-annotated clinical data Bell ASTRO 2017

33 Comments Strengths: Secondary analyses of rigorously treated and followed glioma patients Affirms our understanding of MGMT prognostic significance for GBM and now extended to slightly lower grade (III) gliomas Supports incorporating existing data (MGMT status) into guiding clinical practice Limitations: Small sample size (36) Unclear how distinct an entity astrocytic anaplastic gliomas are will require integration with IDH mutational data Future directions: MGMT status should be factored in future (anaplastic) glioma studies MGMT clinical significance will need to be defined relative to IDH & 1p/19q

34 Future Directions Grade II/III Glioma Include MGMT status? IDH1/2 - mutated IDH1/2 wild-type 1p/19q del 1p/19q intact MGMT meth MGMT unmeth RT + PCV (or RT + TMZ?) RT + PCV (or RT + TMZ?) RT/TMZ TMZ RT? or biomarker-driven clinical trials Bell ASTRO 2017

35 The Risk of Radiation Necrosis following Stereotactic Radiosurgery with Concurrent Systemic Therapies Joseph M Kim, Jacob A. Miller, Rupesh Kotecha, Roy Xiao, Aditya Juloori, Matthew C. Ward, Manmeet S. Ahluwalia, Alireza M. Mohammadi, David M. Peereboom, Erin S. Murphy, John H. Suh, Gene H. Barnett, Michael A. Vogelbaum, Lilyana Angelov, Glen H. Stevens, Samuel T. Chao Cleveland Clinic Kim ASTRO 2017

36 Study Objective With increased survival and use of novel systemic therapies for brain metastases patients, radiation necrosis (RN) is a toxicity of SRS with unclear risk with concurrent use of other therapies To demonstrate the rate of radiographic RN after SRS and specifically in context with: The addition of concurrent systemic therapies The addition of concurrent systemic therapies + WBRT The addition of concurrent targeted agents Kim ASTRO 2017

37 Study Design Retrospective single institution cohort study Newly-diagnosed brain metastasis between who underwent SRS +/- WBRT or resection All cytotoxic, hormone, cytokine, and targeted systemic therapies were assessed Concurrent systemic therapy was defined as an agent administered within 5 biological half-lives of the date of SRS Kim ASTRO 2017

38 Results 1650 patients with 2843 brain metastases treated with SRS 445 patients with some concurrent therapy Overall radiographic RN 8% of which 54% are symptomatic 12-month rate of radiographic RN yes no p-value Concurrent systemic therapy 6.6% 5.3% 0.14 Concurrent systemic therapy + WBRT 8.7% 3.7% 0.04 Concurrent VEGFR TKI 14.3% 6.6% 0.04 Concurrent EGFR TKI 15.6% 6.0% 0.01 Concurrent Her2 Ab 9.0% 5.3% 0.03 Kim ASTRO 2017

39 Unadjusted hazard ratios for RN Agent HR 95% CI N* Any Concurrent Therapy Upfront WBRT No Upfront WBRT Cytokine Therapy Targeted Therapy VEGF Antibody VEGFR TKI HER2 Antibody EGFR TKI ALK TKI BRAF Inhibitor mtor Inhibitor PD-1/CTLA-4 Inhibitor Cytotoxic Chemotherapy Alkylating Agent Nucleoside Analog Folate Analog Intercalating Agent Platinum Agent Taxane Topoisomerase Inhibitor Vinca Alkaloid Hormone Therapy Hazard Ratio For Radiation Necrosis! Kim ASTRO 2017

40 Cumulative Incidence 0 % 5 % 10 % 15 % 20 % Cumulative Incidence 0 % 5 % 10 % 15 % 20 % Cumulative incidences of RN +/- concurrent systemic therapies A! 0 1 No Concurrent Systemic Therapy Concurrent Systemic Therapy With WBRT At umber Risk at-risk No Concurrent 0: Concurrent 1: B! Time (months) No Concurrent Systemic Therapy Concurrent Systemic Therapy Without WBRT At Risk No Concurrent Concurrent Time (months) Kim ASTRO 2017

41 Authors Conclusions As compared to patients receiving SRS alone, radiographic RN: Is not increased among patients receiving concurrent cytotoxic chemotherapy, hormone therapy, and cytokine therapies Is increased among patients who have received prior WBRT + systemic therapy Is significantly increased with the addition of concurrent specific targeted therapies (VEGFR TKI in renal mets, EGFR TKI in lung mets, Her2 Ab in breast mets) Kim ASTRO 2017

42 Comments Strengths: Large patient numbers Include a large selection of systemic therapies Limitations: Retrospective design, yet the best way to first pursue a clinical question Future direction: Mindful combination of therapies, both for patients with or at risk of brain metastases; consider timing and dose of RT and of new drugs More studies need to incorporate brain metastases as an increasing new norm of patients with metastatic disease and longer term survival Adverse effect data is imperative in prospective studies