2015 ASTRO Refresher Course: Adult CNS Tumors
Minesh P Mehta, MD, FASTRO University of Maryland Disclosures 2014-15
• Consultant: Elekta, Novartis, Novocure • Grants: Novellos, Novocure • Stock Options: Pharmacyclics • Board of Directors: Pharmacyclics • Patents: WARF • Royalties: DEMOS Publishers Learning Objectives
• Discuss the incidence, prevalence, mortality, morbidity, and clinical impact of the major malignant and benign adult primary CNS tumors • Recognize the substantial heterogeneity that exists within these tumor types and understand the prognostic and predictive variables allowing for appropriate selection of therapeutic choices, tailored for a specific patient • Explain the major levels of evidence for therapeutic decision-making • Appreciate the role of various therapies, especially surgery radiotherapy and chemotherapy in managing these tumors Glioblastoma Characteristics
• Rapid progression • Enhancing tumor • Surrounding edema – Contains tumor –GTR almost impossible –Median Survival 12-14 mo –SOC: ChemoRT
T1 post-contrast T2 External Beam Radiotherapy for GBM
• Current standard is 60 Gy/2 Gy/fx on GTV + 2 - 3 cm margin • 3D: conformal, multiple fields • Pooling of 6 randomized trials (RT vs no RT) improved survival • Mean survival time 3 - 6 months without RT; 9 - 12 months with RT*
*Walker MD, et al. N Engl J Med. 1980;303:1323-1329. Radiotherapy: Randomized Trials
Author N Schema Results Andersen 1978 108 RT vs best supportive Post-op RT signif improves OS care Walker 1978 303 BCNU vs RT vs BCNU RT significantly longer MS than +RT, vs best supportive BCNU or best supportive care care Walker 1980 467 Semustine vs RT vs RT significantly longer survival semustine + RT vs than semustine alone BCNU +RT Kristiansen 1981 118 RT vs RT + bleomycin vs MS with RT alone 10.2 mo supportive care compared to 5.2 mo supportive care
Andersen AP. Acta Radiol Oncol Radiat Phys Biol. 1978;17:475-484. Walker MD, J Neurosurg. 1978;49:333-343. Walker MD, NEJM 1980;303:1323-1329. Kristiansen K, Cancer. 1981;47:649-652. GBM RT Dose
• MRC: OS 9 mo 45 Gy vs. 12 mo 60 Gy • RTOG 7401: No benefit 70 vs. 60 Gy (600+ patients) • RTOG 9006: No benefit 72 (1.2 BID) vs. 60 Gy (700+ patients) • U Mich: No benefit 90 Gy (90% failed in-field) • Multiple negative Phase III (e.g. brachy)
• 60 Gy is standard • However dose escalation with temozolomide has not been investigated GBM Target Volume Delineation
• SNO: RT-09: TO COMPARE THE TREATMENT OUTCOMES OF TWO DIFFERENT TARGET VOLUME DELINEATION GUIDELINES (RTOG VS MD ANDERSON) IN GLIOBLASTOMA MULTIFORME PATIENTS: A PROSPECTIVE RANDOMIZED STUDY, Narendra Kumar, et al • METHODS: 50 GBM pts were randomized to target volume delineation per RTOG guidelines in Arm A and per MD Anderson guidelines in Arm B. All patients received a total RT dose of 60 Gy in 30 fractions over 6 weeks. • RESULTS: The planning target boost volume was significantly smaller in Arm B (436 vs 246 cc, p= 0.001). Mean overall survival was significantly better in Arm B (18.4 mo, 95% CI 14.76-22.04 vs 14.8 mo, 95% CI 11.25-18.41; p= 0.021). Median overall survival in Arm A was 13 months (95% CI 10.25-15.78), and not reached in Arm B. QOL Questionnaire BN20 and C-30 scores showed significantly better quality of life in Arm B (p =0.005). Radiosurgery: RTOG 9305
• 203 patients with GBM • 60 Gy + BCNU +/- RS boost (15 - 24 Gy) • Median follow up: 61 months • MS: 13.5 vs 13.6 months • General QOL & cognitive function comparable
Radiosurgery has not been proven to prolong survival of GBM patients.
Souhami L. et al. Int J Radiat Oncol Biol Phys. 2004;60:853-860. What about elderly patients?
Do they benefit from radiotherapy? Elderly GBM: RT vs. BSC
R GBM A Supportive Care N >70 yo D KPS >70 O n=85* M I Z E 50.4 Gy
Control RT P-value Median OS 3.9 mo 6.7 mo 0.002
Keime-Guibert (France) et al. NEJM 356:1527-35, 2007. *Trial discontinued early due to planned interim analysis Is it worth 5 ½ weeks of RT?
Can we do the RT quicker? “Elderly” GBM: Short vs. Std Course RT
R A 60 Gy/30 N D GBM O >60 yo M n=100* I Z E 40 Gy/15
60 Gy 40 Gy French Median OS 5.1 mo 5.6 mo 6.7 mo
Roa (Canada) et al. JCO 22:1583-88, 2004. *KPS = 70 How about chemotherapy instead? “Elderly” HGG Trial NOA-08 Temozolomide vs. Std RT R A 54-60 Gy HGG N >65 yo D O n=373* M I Z E TMZ week on/week off
RT TMZ Median OS 9.6 mo 8 mo
Wick (German) et al. JCO 28:180S, 2010. *~90% were GBM. Median age 71 GBM in the Elderly: MGMT
• THE NOA-08 TRIAL, Michael Weller, et al • mOS [HR, =1.09] and EFS [HR = 1.15] of TMZ vs RT did not differ. • Pts with MGMT methylation had longer EFS with TMZ (8.4 vs 4.6 mo). • Pts without methylation had longer EFS with RT (4.6 vs 3.3 mo). This effect persisted for OS. • Combined TMZ-RT remains unaddressed Elderly GBM TMZ vs. Std RT vs. Hypofx RT
R A 60 Gy/30 N D HGG 34 Gy/10 >60 yo O n=342* M I Z TMZ d1-5q28d E 60 Gy 34 Gy TMZ Median OS 6 mo 7.5 mo 8 mo
Malmstrom et al. JCO 28:180S, 2010. GBM in the Elderly: Chemo vs RT, Meta-analysis
• Yin A, et al; J Neuroncol. 2013 Nov 1. [Epub ahead of print]: A meta-analysis of temozolomide versus radiotherapy in elderly glioblastoma patients. • Systematic lit search of studies comparing TMZ vs RT (≥65 years; 2 RCTs, 3 comparative studies): OS advantage for TMZ (HR 0.86, 95 % CI 0.74-1.00). • Sensitivity analysis only support non-inferiority (HR 0.91, 95 % CI 0.66-1.27). • A clear increase in G3-4 toxicities with TMZ, with similar QOL between groups. • Methylated tumors had longer OS with TMZ (HR 0.50, cf unmethylated); TMZ was more beneficial than RT for OS for methylated tumors (HR 0.66) but the opposite was true for unmethylated tumors (HR 1.32). Impact of Resection on Survival
R A Resection w/ 5-ALA N D O HGG* M n=322 I Z E Resection w/ White Light 5-ALA Standard P-value GTR 65% 36% <0.001 6 mo PFS 41% 21% <0.001 Median OS 15.2 mo 13.5 mo 0.1 Stummer W (Germany) et al. Lancet Oncology 7:392-401, 2006. 5-ALA=aminolevulinic acid; *97% GBM Level 1: Gross-total resection (OS) 30 patients, age >65, radiographic findings suggestive of glioblastoma
Randomized to biopsy/resection 23 patients with histologically confirmed glioblastoma 13 biopsied 10 resected
2.8 v 5.7 mo
Vuorinen, Acta Neurochir , 2003; 145:5 Radiation +/- Temozolomide
Concomitant Adjuvant TMZ TMZ/RT*
R 0 6 10 14 18 22 26 30 Weeks
RT Alone
Temozolomide 75 mg/m2 po qd for 6 weeks, then 150-200 mg/m2 po qd day 1-5 q 28 days for 6 cycles Focal RT daily — 30 x 200 cGy Total dose 60 Gy
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase. EORTC/NCIC PIII GBM Trial: Overall Survival
100 90 80 P<0.0001 70 60 50 Percentage 40 30 TMZ/RT 20 N=573 10 RT 0 0 6 12 18 24 30 36 42 months
Stupp R, et al. N Engl J Med. 2005;352:987-996. Predictive Value of MGMT
% 6-mo PFS % 2-yr survival MGMT RT +TMZ RT +TMZ Overall 36 54 10 26 Unmethylated 35 40 2 14 Methylated 48 69 23 46
GBM patients with methylated MGMT from EORTC trial 2-year survival 14 vs 46%.
Hegi ME, et al. N Engl J Med. 2005;352:997-1003. Temozolomide Intensification: RTOG 0525
All eligible 1120
All randomized 833
Gilbert, et al. abstract #2006, oral presentation ASCO 2011. NOTE: All had resection (NO biopsy only) RTOG 0525-Results
Overall survival Arm 1 vs Arm 2 Prog free survival Arm 1 vs Arm 2 100 100 Dead Total Dead Total Arm 1 320 411 Arm 1 374 411 Arm 2 332 420 Arm 2 379 420 p (1-sided) = 0.63 p (2-sided) = 0.06 75 75 HR (95% CI) =1.03 (0.88, 1.20) HR (95% CI) =0.87 (0.75, 1.00)
50 50
Overall Survival (%) 25 25
Progression-free Survival (%)
0 0 0 12 24 36 48 0 12 24 36 48 Months after Randomization Patients at Risk Months after Randomization Patients at Risk Arm 1 411 257 121 32 7 Arm 1 411 107 50 19 5 Arm 2 420 256 123 40 5 Arm 2 420 132 56 18 2
Arm 1 = standard adjuvant. Arm 2 = dose dense Confirmed MGMT as a Prognostic Marker Pseudo-Progression • Imaging progression shortly after RT + TMZ – Unknown if “true disease progression” – Should one continue adjuvant TMZ or declare progression and switch to different chemo
• Very Common – 1/3 to 1/2 of patients – 1/2 stabilize/improve with further TMZ
Taal W., et al. abstract #2009, oral presentation ASCO 2007. Pre-RT and TMZ 4 wks after RT/TMZ 4 wks after RT/TMZ 3 mo after RT/TMZ RTOG 0825: Role of Bevacizumab
Closed 978 pts
30 Gy + R# TMZ (75 TMZ (200 mg/m2) d 1- A mg/m2 qd x 21 N 5 of 28-d cycle + d) + Placebo GBM 30 Gy + D Placebo Tissue TMZ (75 O 12 cycle max mg/m2 qd M available x 21 d)* I 30 Gy + Z TMZ (75 TMZ (200 mg/m2) d 1- E 2 mg/m qd x 5 of 28-d cycle + Bev 21 d) + Bev 12 cycle max (10 mg/kg q 2wks) *Analysis for MGMT methylation, molec profile # Stratify by: (Random 10d post start RT) Recursive partitioning analysis (RPA) class (III vs IV vs V) MGMT methylation status Molecular profile Primary Outcomes by Treatment
Median overall survival Median progression free survival Placebo: 16.1 months Placebo: 7.3 months Bevacizumab: 15.7 months Bevacizumab: 10.7 months HR (bev/placebo:1.13 (95%CI:0.93,1.37)) HR (bev/placebo:0.79 (95%CI:0.66,0.94)) Neither OS or PFS achieved pre-specified endpoints
Presented by: Mark R. Gilbert, MD Outcomes by MGMT Status: Both Arms Pooled
Median overall survival Median progression free survival Methylated: 23.2 months Methylated: 14.1 months Unmethylated: 14.3 months Unmethylated: 8.2 months HR (unmeth/meth:2.10 (95%CI:1.65,2.68) HR (unmeth/meth:1.67 (95%CI:1.36,2.05)
Presented by: Mark R. Gilbert, MD 2014: Banner Year for Positive Trials
• GBM: – EF-14 Optune (Novo-TTF) study – ICT 107 vaccine study – BELOB study (rGBM) – Rindopepimut (rGBM) ReACT Trial
Randomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine versus Lomustine in patients with recurrent Glioblastoma
R A Bevacizumab every 2 weeks N + f D Lomustine every 6 weeks o O l M l 1st recurrence I Bevacizumab every 2 weeks o Glioblastoma Z w A T u I p O Lomustine every 6 weeks N
Stratification: age, PFS Taal et al, Lancet Oncol 2014 OS 9 mo, median OS, PFS 6 mo, ORR
Endpoint Lomustine Bevacizumab Bev/Lom 90 Bev/Lom all 9 mo OS 43% (29-57%) 38% (25- 51%) 59% (43-72%) 63% (49-75%)
Median OS 8 mo 8 mo 11 mo 12 mo
6 mo PFS 13% (5- 24%) 16% (7 – 27%) 41% (26-55%) 42% (29-55%) ORR* 2:41 (5%) 18:48 (38%) 14:41 (34%) 19:49 (39%) (Between brackets: 95% confidence interval) *local diagnosis; 138 patients evaluable for response Phase II “ReACT” Study Design
Bevacizumab naïve Study vaccine + Randomization (1:1) (n=70) bevacizumab No prior bevacizumab or VEGF/ VEGF Double-blind treatment receptor-targeted agents Control + bevacizumab
Bevacizumab refractory (Initial cohort: n=25 Open-label treatment Study vaccine + Expansion cohort: n=up to 73) bevacizumab Progression during or within two months of bevacizumab
41 41 Overall Survival Bevacizumab-Naïve Relapsed GBM
Median (95% CI) Study Vaccine + Bevacizumab (n=35) 12.0 (9.7, --) Control + Bevacizumab (n=37) 8.8 (6.8, 11.4)
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M o n t h s 42 Anaplastic Astrocytoma
•Incidence: • 2,000 diagnosed annually in US - Median age 5th decade •Median Survival: •2 - 3 years
•Histology: •Increased astrocytic cellularity •Cellular atypia and mitosis, no necrosis Anaplastic Astrocytoma •Notes: •Tissue sampling a major issue •Progression to glioblastoma frequent •Significant difficulties with pathological identification - In contrast to GBM, ~30% “AA patients” misdiagnosed •Genetics • Less than 5% 1p19q co-deleted… • MGMT methylation ~ GBM • IDH mutation frequent
Stupp et al., Onc Hem 63:72-80, 2007. Wick et al. JCO 27:5874-5880, 2009. RT 60 Gy/30 •318 patients – 1/2 Astrocytoma, 1/3 oligoastrocytoma, 1/8 oligodendroglioma 80% power to detect 50%improvement TTF w/ chemo one sided level 0.05 NOA-04 Phase III Results
PCV/TMZ RT
Median TTF* 43.8 mo 42.7 mo Median PFS 31.9 mo 30.6 mo 4 year OS 64.6% 72.6%
Wolfgang et al. JCO 27:5874-5880, 2009. * TTF defined as failure after both chemo AND RT requiring new chemotherapy RTOG 9813
Phase I
Arm 1: XRT + BCNU 200 mg/m2 + TMZ 150 mg/m2 x 5d q 8 wks 15 pts enrolled: 7/10 eligible pts needed dose mods Arm 5: XRT + TMZ 150 mg/m2 x 5d + BCNU 150 mg/m2 q 8 wks 15 pts enrolled. Combination produces unacceptable toxicity
Phase III n=480 Arm 2: XRT + TMZ 150 mg/m2 x 5d q 4 wks Arm 3: XRT + BCNU 80 mg/m2 q 8 wks*
Closed early: 201 patients enrolled
Chang SM, et al. Neuro-Onc 10:826, 2008. *CCNU allowed RTOG 9813
TMZ BCNU P-value Grade 3+4 45% 70% P<0.01 Grade 5 2% 1% NS
TMZ combined with RT significantly better tolerated than BCNU
Chang SM, et al. Neuro-Onc 10:826, 2008 EORTC 26053/22054 Observation
RT Adjuvant TMZ 200mg/M2 Anaplastic Glioma 5 D/28D without 1p/19q deletions
N=680 Observation RT + TMZ • RT = 5940/33fx 75mg/M2/D • Adjuv. TMZ to 12 mo in Adjuvant TMZ responders 200mg/M2 5 D/28D Anaplastic Oligodendroglioma RTOG 9402 EORTC 26951 • Randomized trial 4 • Randomized trial 6 neoadjuvant cycles cycles postradiation intensive PCV standard PCV vs RT followed by RT vs RT alone alone • Central review of • Central review of neuropathology neuropathology • Tissue for 1p 19q • Tissue for 1p 19q available for 70% available for 85%
Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714. van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722. The World of Molecular Markers is Emerging and 1p19q Proves to be Highly Prognostic…..but not Predictive
Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714. van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722. Patience is a Virtue
• 18 years after the first patient was randomized – Median follow-up for the entire cohort is 11.3 years – Persistence has allowed tissue collection for 1p19q analysis in 90% of patients on study. – Data are reanalyzed with longer follow-up and a greater proportion of patients with molecular characterization 2012: OS by Treatment (1p/19q co-del)
100 2006
/ / Practice changing 75 / // / / / / / / // // 50 / Median Survival / PCV+RT: 14.7 years // RT alone: 7.3 years / / / Overall Survival (%) 25
Dead Total PCV+RT 28 59 p= 0.03 0 RT 47 67 HR=0.59 (0.37, 0.95) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization If it’s not in the Mind, the Eye Cannot See: 2012: OS, Non-Co-deleted (N=137) 100 Median Survival / PCV+RT: 2.6 years RT alone: 2.7 years 75 / P = 0.39 /
/ 50 /
Overall Survival (%) 25 / / // / / / /
/ Dead Total / / / PCV+RT 58 76 p= 0.39 0 RT 53 61 HR=0.85 (0.58, 1.23) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization What is Not in the Mind, the Eye Cannot See: 2012: OS, Non-Co-deleted (N=137) 100 Median Survival / PCV+RT: 2.6 years RT alone: 2.7 years 75 / P = 0.39 / Some patients with non-co-deleted AO/AOA live longer after PCV+RT / 50 than RT alone; 10-year: PCV+RT 25% vs. RT 10%, p<0.05 /
Overall Survival (%) 25 / / // / / / /
/ Dead Total / / / PCV+RT 58 76 p= 0.39 0 RT 53 61 HR=0.85 (0.58, 1.23) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization Whole genome sequencing identifies mutation in Isocitrate Dehydrogenase 1 (IDH1) as a Prognostic Marker in GBM
Sequenced 22 GBMs for 20,661 genes Parsons DW, et al. Science 2008 OS by IDH & Co-deletion Status
100 Dead Total Co-del+IDH pos 55 88 Non co-del+IDH pos 50 66 Non co-del+IDH neg 40 44 75 p < 0.001
50
Overall Survival (%) 25
0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization OS by Treatment for IDH Mutated Cases
100 Median Survival PCV+RT: 9.4 years 75 RT alone: 5.7 years P = 0.006
50
Overall Survival (%) 25
Dead Total PCV+RT 45 80 p= 0.006 0 RT 61 76 HR=0.59 (0.40, 0.86) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization Overall Survival (%) 100 25 50 75 OS byTreatment for 0 0 1 IDH is both prognostic and predictive 2 Years after Randomization 3 4 5 RT alone PCV+RT: SurvivalMedian IDH 6 RT PCV+RT P HR= p= = 0.67 = : 1.3 years1.3 7 1.8 years1.8 IntactCases 0.67 1.14 (0.63,2.04) 8 20 26 Dead 9 10 23 31 Total 11 12 Coke vs Pepsi: PCV vs. TMZ?
Anaplastic Oligodendroglioma 1p-19q Co-Deleted
Treatment with Chemotherapy Alone PCV N = 21 TemozolomideN = 68
Time To Progression PCV 7.6 y Temozolomide3.3 y
Overall Survival PCV 10.5 y Temozolomide7.2 y
CAUTION: Retrospective, observational study, these are hypothesis-generating results and await further study Lassman AB, et al. Neurooncol 2011; 13: 649-659 RTOG 0131: Phase II Trial of Pre-Irradiation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligodendrogliomas – Updated Survival and Progression Free Survival Analysis
Michael A. Vogelbaum M.D., Ph.D. RTOG BR-0131: Evaluable Patients
• 42 patients enrolled – July 2002 to June 2004 – 40 eligible patients • 1 hospital withdrew from protocol • 1 consented patient refused protocol treatment – Of the 40 eligible patients: • 32 completed protocol treatment and are evaluable • 4 withdrew due to toxicity • 4 withdrew without evidence of toxicity or progression RTOG BR-0131: Temozolomide
• Survival Analysis (2012) – 2 patients who received only pre-RT TMZ (CR or NED) have remained progression-free for over 7 years – 3-year PFS and 6-year OS (Codeleted patients)
Trial 3-year PFS 6-year OS BR-0131 77% 82% 9402 – RT Only 49% 60% 9402 – PCV/RT 68% 67%
Note: Not a protocol-defined analysis Low-Grade Gliomas Key Features • 1,900 low-grade gliomas annually • Mean age: 37 years • Heterogenous population - wide range of median survival times – Diffuse astrocytomas 5 years – Oligoastrocytomas 7.5 years – Oligodendrogliomas 10 years
Shaw EG, et al. J Neuro Oncology 1997;31:273-278. Historic Standard of Care • In the past many patients were observed until sxs dictated resection. • Modern recommendations (EORTC 22844 and 5; NCCTG 86-71-52) , are a maximum safe resection with adjuvant radiotherapy (45-54 Gy) to prolong PFS – Some would delay RT as there is no OS benefit – Prior chemo trials were not positive EORTC “Believers” Trial 22844 45 Gy vs 59.4 Gy
45 Gy 59.4 Gy P-value
5-yr PFS 47% 50% 0.94
5-yr OS 58% 59% 0.73 EORTC “Non-Believers” Trial 22845 Immediate vs Delayed
Control RT P-value 5-yr PFS 35% 55% <0.0001 5-yr OS 66% 68% 0.87 MS 3.3 y 5.3 y + Seizure @ 1Y 41% 25% 0.03
Van den Bent, et al. Lancet. 2005.Updated results 7.8 median F/U RTOG 98-02 Intergroup Trial
Low risk:Arm 1 observe Age <40 and GTR LGG Arm 2: RT High risk: 54 Gy R Age >40 or ~111 low risk 254 Arm 3: RT + 6 high risk STR/biopsy P60 mg/m2 CCNU cycles PCV 110mg/m2 VCR 1.4 mg/m2 JCO 2012: Overall Survival
HR = 0.72 p=0.33 (Wilcoxon) p=0.13 (Log rank)
©2012 by American Society of Clinical Oncology JCO 2012: Progression Free Survival
p=0.06 (Wilcoxon) p=0.005 (Log rank) HR=0.6
©2012 by American Society of Clinical Oncology Long-term Overall Survival
RT Alone RT + PCV Median 7.8 years 13.3 years 5 year 63.1 % 72.3% 10 year 40.1% 60.1%
2012 to 2014: HR improved from .72 to .59 Conclusions • For patients with a. G2 glioma,
R E G 2 I Daily temozolomide (75 mg/m /day) + RT(54 Gy/30 fractions/6 weeks) followed by S temozolomide (150-200 mg/m2 )x 12 cycles T E R
Hypothesis:
43% increase in MS from 40.5 to 57.9 months and 20% increase in 3YS from 54 to 65%; 96% power with a 0.10 1-sided. A Phase II Study of a Temozolomide-Based Chemoradiotherapy Regimen for High EORTCRisk SurvivalLow-Grade Gliomas: by Preliminary Pignatti Results of RTOGCategory 0424
Pignatti F et al. JCO 2002:20;2076-2084 RTOG 0424 OS by Risk Group EORTC 22033-26033
S R 50.4 Gy* T A R N A D 1p Status O LGG T I etc. M n=466 F I Y Z E TMZ x 12
*Age> 40 years; radiologically proven progressive lesion, new or worsening neurological symptoms, intractable seizures Completed accrual 03/2010 EORTC 22033 2013 ASCO Abstract 2007 • 477 pts, RT (240) vs TMZ (237). • TMZ DOES NOT improve PFS in these high-risk low grade glioma patients. • 1p deletion was confirmed to be a positive prognostic factor with either treatment – p-value stratified by treatment, progression-free survival: p = 0.0003; HR = 0.59, 95% CI (0.45 - 0.78), – overall survival: p = 0.002; HR = 0.49, 95% CI (0.32 - 0.77). Abstract 2007 EORTC 22033 2013 ASCO
EORTC 22033 RT TMZ N 240 237 Med PFS (mo) 47 (40, 56) 40 (35, 44) 1p intact PFS 41 (32, 55) 30 (24, 40) 1p deleted PFS 58 (41, 67) 55 (38, N) OS NR 74 9802 RT RT/PCV Med PFS (mo) 48 (37, 66) 125 (73, NR) Mol Abnormalities in LGG
Type Frequency Wildtype IDH 19% IDH mut 81% MGMT unmet 30% MGMT met 70% p53 wt 73% p53 mut 27% 1p19q int 76% 1p19q LOH 24%
Leu, NeuroOncol, 2013 HR for Death by Mol Subtype (G2/3)
Parameter Frequency HR for Death IDH wt 33 % 1 IDH mut/MGMT met 20 % 0.33 IDH mut/MGMT met/1p19q 25 % 0.18 LOH (Triple positive) IDH mut/MGMT met/p53+ 13% 0.88 Others* 9 %
Leu, NeuroOncol, 2013 Pilocytic Astrocytoma
• WHO grade I tumors • Well circumscribed, enhancing cerebellar lesions typically in kids – Few adult studies • Surgical resection alone 10 yr OS >80% – Most important intervention Pilocytic Astrocytomas Recommendations • Observation after GTR or STR
• Radiation (50.4 Gy) recommended after biopsy or recurrence after STR – Especially if symptomatic
• Malignant transformation rare event – As many reports of malignant transformation after radiation as after surgery alone
Brown et al., IJROBP 58 (4):1153-1160, 2004 Intracranial Ependymoma
• 5% brain tumors; image entire CNS axis • Historical standard post-op RT • BNI: 45 post fossa image defined resection • 71% GTR; 29% STR 10 yr LC 10 yr OS GTR + RT 100% 83% GTR 50% 67% STR + RT 36% 43%
Mork, Loken Cancer 40:907-915, 1977 Rogers (Barrow Neurologic Institute) JNS 102:629-636, 2005. 96% Low grade tumors. Intraspinal Ependymoma • 63% intramedullary spine tumors
• Image entire CNS axis
• En bloc resection (not piecemeal) curative, but not easy to achieve – Up to 95% DFS Grade II
Hanbali (MDAH) 51:1162-1174, 2002 Myxopapillary Ependymoma – MDAH
Adjuvant RT Observation
10 yr LC 86% 46%* 10 yr PFS 75% 37%*
• Authors recommend post-op RT for all patients due to irregular shape, nerve root involvement
Akyurek J Neuro-Onc 80:177-183, 2006. Median RT dose 50.4 Gy; *P<0.05 Myxopapillary Ependymoma RARE CANCER NETWORK
Observation <50.4 Gy >50.4 Gy
5 yr PFS 50% 68%* 82%**
Pica, Miller, et al. IJROBP 74:1114–1120, 2009. Median RT dose 50.4 Gy * P=0.4 compared to surgery alone **P=0.05 compared to surgery alone Schild et al, IJROBP 53(3): 787, 2002. Mayo also found benefit >50 Gy Spinal Cord Astrocytoma - Mayo Clinic • 200-300 intramedullary spinal cord astrocytomas annually • 136 patients treated Mayo, 1962-2005 • No role of adjuvant RT for pilocytic • RT for all infiltrative astrocytomas – Grade 2 – 50.4 Gy local field – Grade 3 – 55.8 Gy local field – Grade 4 – 59.4 Gy local field
Minehan, Brown, Scheitauer IJROBP 73(3):727-33, 2009 Craniopharyngioma
• Locally extensive, benign tumor from remnant of Rathke’s pouch, with cystic and solid portions • 1-3% of all intracranial tumors; 10% of peds • Biomodal distribution – Childhood 5-14 years, Adult 55-65 years • Male = Female • Histologic types: – Adamantinomatous – Squamous papillary – Mixed Treatment: Surgery
• GTR most likely for – <3cm – Pre or intrachiasmatic lesions – Solid component – No hypothalamic extension • Retrochiasmatic tumors have higher mortality with sx • Trans-sphenoid approach gives higher GTR • 10 yr LC with GTR=90%, STR=30% Treatment: Surgery + RT
• Recurrence after STR about 50-70%
Series % LR STR % LR STR+RT Richmond 37 4 Weiss 60 13 Karavitaki 62 23
• In modern series, local recurrence after Sx and RT is < 10% • Timing of RTcontroversial; some argue for immediate RT
Richmond et al. Neurosurgery. 6(5):513-17. 1980; Weiss et al. IJROBP. 17(6):1313-21 Karavitaki et al. Clin Endocrinol. 62(4):397-409. Apr 2005; Mark et al. Radiology. 197(1):195-8. Oct 1995 Craniopharyngioma: RT Dose/Timing
• Used for inoperable, partial resection, or recurrent disease • 54 Gy/1.8 Gy per fraction. – >55 Gy increase optic neuropathy – <54 Gy lower control rates (44 vs 16% recurrence)* – 78% 20 yr OS for those treated for primary disease vs 25% for recurrence
*Regine et al. IJROBP. 24(4):611-7.1992 Habrand et al. IJROBP. 44(2):255-63. May 1999 Cavazzuti et al. J Neurosurg. 59(3):409-17. 1983 Vestibular Schwannoma • Tumor of the vestibular nerve sheath – Acoustic neuroma is a misnomer • Symptomatic incidence is ~1/100,000 – 0.2% of MRIs with VS – Represent 80-90% of CPA tumors – Rising incidence • Almost always unilateral and benign – Bilateral is a pathognomonic feature of NF2 • Variable growth rate – Avg 1.9 mm/year – 40% will show no growth or even spontaneous shrinkage on serial images. Observation
• 5% will spontaneously shrink • Some tumors grow only 1-2 mm / year • Serial audiometry and MRI every 1-2 years • May be reasonable in some pts: – Elderly pts with slow-growing tumors confirmed on serial scans – Pts with a lesion in the dominant or sole side of hearing where an intervention would render hearing loss • Risks: – Hearing loss despite minimal growth – 75% of tumors grow within 1 year Surgery
• 50% of patients are treated surgically – Steep learning curve (20-60 cases)
• Mortality ~ 2%
• Cure rates > 95%
• Preservation of facial nerve and hearing is goal – Influenced significantly by tumor size and approach Surgery Complications
Post-op complications ~ 20% 1. CSF leak – 5-15% 2. Meningitis – 2-10% 3. Facial weakness – 4-15% 4. Hearing loss varies according to approach 5. Headache – 10-34% 6. Stroke 7. Brain injury Radiosurgery
– Viable option for patients with tumors <3cm or for growing tumors in medically inoperable patients – 12.5 to 13 Gy • Typically prescribe to 50% IDL with GKS • TV is macroscopic volume seen on MRI – 5 year PFS correlated with tumor size (1.5% decrease per 1 cm3) – >95% local progression free survival > 5 years SRS vs. Microsurgery: France
• Non Randomized prospective series using pre- and post- Rx questionnaires – Minimum follow up 3 years – GKS=97 pts; Microsurgery 110 pts
Rx CN VII CN V Hearing Functional Hosp Work disturbance Disturbance Preserved disturbance stay missed Surgery 37% 29% 37.5% 39% 23 130 GK 0% 4% 70% 9% 3 7
Regis et al. J Neurosurgery. 2002 Nov; 97(5):1091-100 FSRT vs. SRS: TJ Experience
• Retrospective review • N=69 GK and 56 FSRT patients • 12Gy GK vs. 50Gy/25fx
Treatment Tumor Control CN V CN VII Hearing Preservation Preservation Preservation SRS 98% 95% 98% 33% FSRT 97% 93% 98% 81%
Andrews, IJROBP. 2001 Aug 1;50(5):1265-78 FSRT vs. SRS: Amsterdam
• 129 pts from ‘92-’99; mean f/u 33 mo • Pseudorandomization – Dentate patients received 20 or 25Gy/5fx – Edentulous pts received SRS 10 or 12.5 Gy
Treatment Tumor CN V CN VII Hearing Control Preservation Preservation Preservation SRS 100% 92% 93% 75% FSRT 94% 98% 97% 61%
Meijer et al, IJROBP 2003. Aug; 56(5):1390-96 Meningioma
• Second commonest primary brain tumor – ~30% of all primary intracranial tumors • Incidence is about 6/100K • Incidence increases with age • May be higher based on autopsy series (up to 2%) • 90% benign 2007 WHO Grading
Grade I Any major variant other than clear cell, chordoid, papillary, or rhabdoid (benign) 80-90%
Grade II Frequent mitoses (>4 per hpf) (Atypical) OR 5-20% 3+ of the following: sheeting architecture, hypercellularity, prominent nucleoli, small cells with high nuclear:cytoplasm, foci of spontaneous necrosis OR Chordoid, clear cell, or brain invasion
Grade III Excessive mitotic index (>20 per 10 hpf) (Anaplastic or OR Malignant) Frank anaplasia resembling:sarcoma, carcinoma, or melanoma 1-2% OR Papillary or rhabdoid Observation
• Retrospective review of 1,434 patients from 1989-2004 • 603 had asymptomatic lesions • Size, growth over time, appearance of symptoms • 58% of the asymptomatic lesions were observed – Progression noted in 37%, but symptomatic progression in only 16%
Yano S et al, J Neurosurg. 105(4)538-43, 2006 Surgery
• Gross total resection if medically operable • GTR generally thought to give 90% RFS, but depends on Simpson Grade • Recommended for younger patients with surgically accessible lesions • IN GENERAL, convexity lesions are managed with surgery, while base of skull lesions and optic nerve sheath meningiomas are generally not Simpson Grade
Grade 5 year recurrence rate I Removal of tumor bulk, 10% surrounding dura, involved bone II Removal of tumor with 20% diathermy of involved dura III Small focus left in situ 30%
IV Macrosocopic residual disease 40%
V Simple decompression 5 yr PFS after EBRT
Rogers L. Radiation Therapy for Intracranial Meningiomas. 2010 Radiation
• Indications – Subtotal resection – Unresectable tumor – High grade – Recurrent Radiation
• Grade 1 – 50.4 to 54 Gy at 1.8 to 2 Gy fractions (1-2 cm margin) • Grade 2 – 54 to 59.4 Gy at 1.8 to 2 Gy fractions (2-3 cm margin) • Grade 3 – 59.4 to 60 Gy at 1.8 to 2 Gy fractions (2-3 cm margin) SRS and EBRT by Grade
Adapted from Chan, Rogers, Anderson, Khuntia: Chapter 26 Benign Brain Tumors. Clinical Radiation Oncology. In Press 2011. Pituitary Adenomas
• Represent between 10-15% of all CNS neoplasms • Females>males (especially microadenomas) • Usually between ages 45-55 • Benign, invasive, or carcinoma – Majority are benign (greater than 60%) – Invasive adenomas make up 35% – True carcinomas are rare (<0.2%) Size/Secretory Function
• 70% Secretory – Prolactinomas the most common • 30% Non-secretory (non functioning) • Microadenomas are <10mm – Majority are microadenomas • Macro adenomas >10 mm • Giant adenoma > 40 mm Functional Endocrine Definition
1. Prolactinomas 2. ACTH-producing adenomas (somatotrophs) 3. GH-producing adenomas (somatotrophs) 4. TSH-producing adenomas (thyrotrophs) 5. Non functioning adenomas (usually gonadotrophs)
Listed in order of frequency Prolactinomas
• >250 μg/L common (Normal <15 μg/L) – Symptoms not correlated with level • Microadenomas are found in 11% of autopsies with prolactinomas making up 44%
Klibanski, A. NEJM. 262;13, April 1, 2010 Surgery
• Allows prompt decompression of mass effect • Histology • Rapid normalization of hormone levels • Long term control of 80-90% of microadenoma and 25-50% with macroadenomas Medical Management
• Bromocriptine and cabergoline (a dopamine agonist) for prolactin secreting tumors – Can reduce secretion and size in 80% – Can stop after 2 years of normal hormones levels and close f/u • Somatostatin analogs (SSAs: octreotide, lanreotide) for growth hormone secreting – 50-60% success rate in those not responding to surgery – Pegvisomant (IGF inhibitor) costs $150,000/year • For ACTH secreting, mitotane, ketoconazole, metapyrone – Usually less effective than local therapies. Indications for XRT
• Incomplete resection • Recurrent tumors • Inoperable patients • Refractory secretory tumors Radiation Therapy
• Cavernous sinus invasion is probably not amenable to surgery and is better treated with radiation. • EBRT controls hypersecretion in about 80% of patients with acromegaly, 50-80% of those with Cushing’s disease, and about 1/3 of those with hyperprolactinemia • But this can take several years SRS
• Reverses endocrinopathies faster and more predictably than EBRT • Need to hold drug therapy before and during SRS especially for prolactinomas* • Doses range between 12-28 Gy based on size and location. Doses >15 Gy increase LC for secreting tumors (try to achieve 20 Gy if can be done safely) – Secretory tumors 24-28 Gy marginal dose – Non-secretary 14-16 Gy
*Landolt et all. J Neurosurgery. 2000;93,14-18 *Pouratian et al. Neurosurgery. 2006;59(2):255-266 Acromegaly • Resection often curative • Somatostatin analogs used for second-line therapy • Radiation can yield 80% normalization of growth hormone with time (delayed) • SRS yields LC in excess of 95% • Time to normalization is 1.4 years with SRS versus 7.1 years with EBRT • Concurrent octreotide with SRS delays hormonal normalization and should be discontinued 1-2 months prior
Jenkins et al. J Clin Endocrinol Metab 2006;91(4)1239-1245 Landolt et al. J Neurosurg. 1998;88(6)1002-08 Landolt et al. J Clin Endocrinol Metab. 2000;85(3):1287-89 Non Functioning Adenomas
• Most are macroadenoma • Usually present with vision changes so usually surgery is advocated (80-90% LC) • Immediate postop RT yields LC >90% versus LR after STR of 33% at 15 years • SRS yields LC>90% with less than 25% new endocrinopathies
Gittoes et al. Clin Endocrinol. 1998;48(3):331-37 Van den Bergh et al. IJROBP. 2007;67(3):863-69 Thank You