The Role of Radiation Therapy in the Treatment of Brain Metastases Matthew Cavey, M.D.
Objectives Provide information about the prospective trials that are driving the treatment of patients with brain metastases. Discuss the toxicities and the diminishing role of Whole-Brain Radiation Therapy (WBRT) for patients with brain metastases.
Overview Background Evolution of radiation therapy: WBRT SRS Adjuvant (WBRT vs. SRS) Definitive Palliative WBRT Future Directions Conclusions
Background
Background As more effective cancer diagnostics and treatments are developed and as the numbers of cancer patients live longer, there is a greater potential for those cancer patients to develop metastases. Metastatic brain tumors are the most common brain tumor in adults. The incidence begins to increase in those ages 45 64 years and is highest in people over 65 years of age. The exact incidence of metastatic brain tumors is not known but is estimated by the American Brain Tumor Association to be between 200,000 and 300,000 people per year. Skin cancer (melanoma), lung cancer and breast cancer are the most frequent to develop brain metastasis and account for 67%-80% of all cancers. http://www.abta.org/brain-tumor-information/types-of-tumors/metastatic-brain-tumor.html, Brown National Patient and Family Conference 2016 5
Background Stereotactic Radiosurgery (SRS) Whole-Brain Radiation Therapy (WBRT) Very effective treatment in brain metastases ~70-90% treated brain met control (local control) The ultimate in targeted therapy Very sophisticated treatment planning and delivery Delivers very high / ablative doses of radiation therapy. 2D or 3D conformal treatment planning - Relatively simplistic Two week course / 10 treatments Used to treat numerous small lesions WBRT has been used for many years and has changed very little over time Was the go to treatment for the majority of brain mets
Management of Solitary Brain Met
Role of Surgical Resection Solitary met definitive resection Mass effect Biopsy if no primary diagnosis
Landmark Trials Patchell / Single Brain Met WBRT +/- Resection 48 pts, KPS>= 70 36 Gy / 12 fx, Co-60 Improved OS 9.2 vs 3.5 mos with addition of surgery (p<0.01) Improved QOL w/ surg rsxn Resection +/- WBRT 95 pts, s/p rsxn w/ GTR 50.4 Gy / 28 fractions WBRT reduced recurrence in op bed (10 vs 46%) and elsewhere in brain (14 vs. 37%) at 1 year f/u OS no different
SRS vs. WBRT after resection N107C/CEC3 Trial: 1 4 Brain Mets Investigation into SRS Brain Mets Emerging Technology Data with equivalent OS despite increased DBF as compared to WBRT Neurocognitive deficits with WBRT n=194 WBRT SRS Randomize
SRS vs. WBRT after resection N107C/CEC3 Trial: 1 4 Brain Mets Results Median follow up 15.6 months No difference OS 11.5 11.8 mos Less cognitive deterioration in SRS WBRT increased LC intracranially but no difference in tumor bed LC SRS = Better QoL SRS = new SOC for patients with resected brain mets?
SRS Alone No clinical trials vs. surgical resection Location independent Lower cost than craniotomy Ability to treat multiple lesion simultaneously Effective as salvage therapy
Multiple Brain Mets- SRS in Addition to WBRT- Is there a role?
RTOG 95-08 RTOG 95-08: 1 3 Brain Mets Brain Mets n=333 Stratify Randomize Results # of Mets WBRT Status of Extracranial disease WBRT + SRS Boost Increased OS in single brain met patients MVA - increased OS in RPA Class I and favorable histology (squamous, NSCLC)
WBRT in Addition to SRS Is there a role?
Adjuvant WBRT SRS effective treatment of brain mets Risk of distant brain failure Adding (adjuvant) WBRT significantly improves intracranial control Is there a survival benefit? Increased toxicities / cognitive deterioration? Brown National Patient and Family Conference 2016
Does WBRT add anything to SRS? Trial # Local Control Distant Brain Control Median Overall Survival (months) Effectiveness of Salvage Therapies EORTC SRS 199 69% 52% 10.9 Did not assess cognitive EORTC SRS + WBRT 81% 67% 10.9 function Japan SRS 132 73% 36% 8 Improved cognitive Japan SRS + WBRT 89% 58% 7.5 function but used nonvalidated instrument MDACC SRS 58 67% 45% 15.2 Imbalance between MCACC SRS + WBRT 100% 73% 5.7 treatment groups No improvement in survival despite significant improvement in intracranial control effectiveness of salvage therapies (SRS) The risk of WBRT (i.e. cognitive impact) becomes paramount in treatment decisions Which has worse cognitive impact: tumor recurrence or WBRT? In Japan trial, postulated tumor progression correlated with cognitive decline Brown National Patient and Family Conference 2016, Kocher JCO 2010, Aoyama JAMA 2006, Chang Lancet Onc 2009
QOL Study: SRS +/- WBRT - N0574 Primary Objective: To quantify the cognitive deterioration 3 months versus SRS combined with WBRT Brain Mets Stratify Age (18 to 59 vs. 60+) Extra-cranial Disease Controlled ( 3 > 3 Months) Number of brain mets (1 vs. 2 vs. 3) Institution Randomize SRS Arm A (SRS only): Lesions < 2.0 cm - 24 Gy Lesions 2 2.9 cm - 20 Gy SRS + WBRT Arm B (SRS and WBRT): Lesions < 2.0 cm - 22 Gy Lesions 2 2.9 cm - 18 Gy WBRT: 30 Gy/12 Brown National Patient and Family Conference 2016, Brown JAMA 2016
Adjuvant WBRT- N0574 Mean QOL Change Baseline to 3-month Functional Wellbeing SRS SRS + WBRT 3-22 Overall -0.1-12.0 100.00% Cognitive Deterioration 80.00% 60.00% 40.00% 20.00% 0.00% SRS SRS + WBRT 3 Mo 12 Mo Brown National Patient and Family Conference 2016, Brown JAMA 2016
Adjuvant WBRT Limited Brain Mets Adding WBRT had no impact on survival Adding WBRT showed worse cognitive function and QOL There was no role for WBRT if SRS was feasible What about multiple brain mets (4-10)? Can we avoid WBRT? Brown National Patient and Family Conference 2016
Radiosurgery versus WBRT Multiple (4+) Brain Metastases SRS disadvantage Does not address micrometastases More labor intensive Greater cost? SRS Advantage Less acute toxicity Shorter delays initiating systemic therapy Less cognitive deterioration No Prospective Phase III Trials Brown National Patient and Family Conference 2016
JLGK0901 Prospective SRS Trial Trial Information Findings 1,194 brain met patients 1-10 brain mets (limited volume) <10cc + <3cm Total vol <15 cc SRS alone 92% Died Systemic Disease Progression Better systemic dz control more role for SRS Mets Median OS (Months) 1 met 14 2 4 mets 11 5 10 mets 11 Brown National Patient and Family Conference 2016, Yamamoto Lancet Oncol15 (4):387 395, 2014
Palliative WBRT
Quartz Trial Palliative WBRT vs. Supportive Care NSCLC Brain Mets* n=538 Randomize WBRT + Supportive Care Supportive Care *Not suitable for resection or SRS. 38% KPS < 70. WBRT 20Gy/5. Group WBRT + Support Results Median OS (Days) 65 43 Support 57 41 No difference in steroid use over time QALY** (Days) No benefit WBRT in poor prognosis brain met patients **QALY - quality adjusted life years, generated Brown National Patient and Family Conference 2016, Mulvenna ASCO 2015
Indications for WBRT Is there still a need for WBRT? Numerous lesions / high volume disease? Poor PS / uncontrolled systemic disease Prophylactic cranial irradiation (SCLC) Insurance denies SRS Brown National Patient and Family Conference 2016
Future Direction
SRS Studies Phase I dose escalation studies (single fx and mult fx for larger lesions) Combination with targeted therapies (Sutent) and/or chemotherapy (Temozolomide)
SRS: Pre- or Post- Resection Multi-institutional retrospective review Brain Mets n=180 Cohorts Pre-resection SRS Target definition Less seeding (LMD) Less necrosis (no margin) Better oxygenated tumor / less dose Post-resection SRS More data Smaller target Results No difference in OS / LC / DBF Less symptomatic radionecrosis with pre-resection SRS Lower rates of leptomeningeal disease in pre-resection SRS
WBRT +/- Memantine RTOG 0614 Brain Mets n=508 Stratify Randomize Results RPA Class I RPA Class II 20 mg Memantine Daily and WBRT Week 1: 5 mg memantine Week 2: 10 mg memantine Week 3: 15 mg memantine Week 4-24: 20 mg memantine WBRT: 37.5 Gy in 15 fractions Placebo and WBRT WBRT: 37.5 Gy in 15 fractions Brown National Patient and Family Conference 2016, Brown NO 2013
Cognitive Function Hippocampal Avoidance Hippocampal Avoidance Phase II Hippocampal neurogenesis vital to memory Hippocampal stem cells sensitive to RT Conformal avoidance hippocampus may reduce cognitive deficits RTOG 0933 Memory deficits reduced from 30% to 7% Gondi V, JCO 2014, Brown National Patient and Family Conference 2016
Cognitive Function: Hippocampal Avoidance NRG CC001: Phase III Trial Memantine and WBRT with or without Hippocampal Avoidance in Patients with Brain Metastases Brain Mets n= 518 RPA Prior Therapy Stratify Randomize WBRT 30 Gy/10 + Memantine Hippocampal Avoidance WBRT 30 Gy/10 + Memantine Primary End Point: Time to Cognitive Failure HVLT-R, COWA, TMT A and B Brown National Patient and Family Conference 2016, Brown NRG Oncology
Case Study
Case Study 71 year old woman diagnosed in 4/2012 with Adenocarcinoma of the lung (T2 N3 M1, Stage IV) MRI solitary left frontal brain met Craniotomy and GTR 5/1/12 SRS boost, 1800 cgy 5/23/12 Tarceva NED systemically NED in brain til 11/2016 No NSGY intervention recommended SRS 2700 cgy, 3 fx, 12/8/2016
Case Study 71 year old woman diagnosed in 4/2012 with Adenocarcinoma of the lung (T2 N3 M1, Stage IV) MRI 5/10/17 Recurrence versus radionecrosis? PET 6/6/2017 hypometabolic Management with steroids MRI 8/16/17 Resolution of edema and enhancement
Conclusions & Questions
Conclusions Paradigm has shifted (Radiosurgery >> WBRT) Limited role for WBRT Cognitive impact demonstrated in clinical trials Investigations to limit cognitive impact underway (Memantine, Hippocampal avoidance). Brown National Patient and Family Conference 2016
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