11/27/2017. Proton Therapy for Brain Tumors: Hope or Hype? Financial Disclosures. Objectives. None

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1 Proton Therapy for Brain Tumors: Hope or Hype? 1 Financial Disclosures None 2 Objectives Discuss the rationale and evidence for proton therapy in children and adults Discuss the late effects that can be significantly reduced with proton therapy Demonstrate how proton therapy can help cancer patients 3 1

2 Why Protons? There is no advantage whatsoever to irradiating uninvolved healthy tissue. Direct radiation complications neveroccur in unirradiated tissues. Dr. Herman Suit Suit H, The Grey Lecture 2001: Coming Technological Advances in Radiation Oncology IJROBP, 2002 Protons Stop, Photons Do Not 15MV X-ray Protons A With protons: Lower entrance dose 10 cm 10 cm 30 cm 30 cm R P L No exit dose Fewer toxicities 5 18 y.o. with a Paraspinal Ewing Sarcoma Proton Therapy MRI six weeks after RT 6 2

3 Protons have Lower Total Integral Dose 4 fields 15MV X-ray Protons A With protons, There is lower total integral dose 10 cm 10 cm 30 cm 30 cm R P L 7 Proton Therapy Growth >1 million patients treated 2010s with proton therapy Breast Pancreas, Esophagus >40% of US children Lymphoma, Reirradiation treated with RT received Head and Neck and More proton therapy in s: Lung, Liver 1990s: Prostate 1970s: Rare Cancers Skull base, Paraspinal, Sarcomas, Uveal Melanomas, Pediatrics 70 s 80 s 90 s Progress in Pediatric Cancer Treatment Cancer is the second most common cause of death in US children (#1 is Accidents) 5-year overall survival in 1975: 58% 5-year overall survival in 2010: 85% Siegel R, CA: A Cancer Journal for Clinicians, 2013 and

4 Progress in Pediatric Cancer Treatment Five Leading Causes of Cancer Death Male (Age<20) Female (Age<20) CNS Tumors Leukemia Bone Tumors Soft Tissue Tumors NHL Siegel R, CA: A Cancer Journal for Clinicians, Applications of Proton Therapy Pediatric cancers ~50% receive RT 65% of long-term survivors develop serious chronic health conditions Neurocognitive deficits, endocrine deficiencies, heart disease, stroke, infertility, and secondary cancers QOL is compromised by late effects 20% mortality from treatment-related complications and secondary cancers Oeffinger, NEJM, 2006 Armstrong, JCO, How can Protons improve RT delivery? 1. Escalate dose Example: Cure more skull base chordomas without causing blindness 2. Reduce collateral radiation damage Example: Cure the same number of medulloblastomas but reduce damage to heart and lungs Protons significantly reduce the amount of normal tissue exposed to radiation 12 4

5 Applications of Proton Therapy Risk of serious (Grade 3-5) chronic toxicities were significantly increased in long-term childhood cancer survivors compared to siblings, across all disease sites Armstrong, JCO, Trends in the Use of RT in Pediatric Cancers Jairam V, IJROBP, Protons Have No Exit Dose Deliver therapeutic tumor dose and spare normal tissues Conventional RT Proton Therapy 15 5

6 Proton Therapy for CNS Tumors Hearing/Vision Neurocognitive Development and IQ Endocrine Second Cancers Vascular Radiation Sensitive 16 Lower Normal Tissue Doses with Protons RT Technique Dose to Cochlea Dose to 50% of Heart Conventional RT 101.2% 72.2% IMRT 33.4% 29.5% Proton Therapy 2.4% 0.5% RT Technique Risk of Secondary Cancer IMRT 30% Electron Beam 21% Conventional RT 20% Proton Therapy 4% St. Clair, IJROBP 2004 Miralbell, IJROBP 2002 Mu, Acta Oncol Proton Therapy Reduces Decline in IQ Merchant TE, Pediatr Blood Cancer,

7 Proton Therapy Reduces Decline in IQ 1. Age matters 2. Protons may mitigate the age effect 3. Protons & older child IQ preservation Merchant TE, Pediatr Blood Cancer, y.o. with Craniopharyngioma IMRT Proton Therapy 20 Proton Therapy Reduces Decline in IQ Reduction in dose to the temporal lobes preserves task efficiency, processing speed, and memory Merchant TE, Pediatr Blood Cancer,

8 Endocrinopathies Probability of GH Deficiency (peak GH <7ng/ml) by Mean Hypothalamus Dose and Time Time 5Gy 10Gy 15Gy 20Gy 25Gy 30Gy 35Gy 40Gy 45Gy 50Gy 55Gy 60Gy 12 mo 12% 14% 17% 19% 22% 25% 28% 31% 34% 38% 42% 45% 36 mo 11% 18% 26% 37% 48% 59% 70% 79% 86% 91% 95% 97% 60 mo 11% 22% 39% 57% 75% 87% 95% 98% 99% 100% 100% 100% GH deficiency after RT is a serious complication that leads to: Decreased growth and bone maturation Decreased metabolism, hypersecretion of insulin and leptin Disturbance in the autonomic nervous system and neurocognitive deficits 22 Proton Therapy Reduces Hormone Deficiencies Proton Therapy IMRT Mean Hypothalamus Dose: 27 Gy Mean Hypothalamus Dose: 0.8 Gy 23 4 y.o. with Posterior Fossa Ependymoma Proton Therapy IMRT Mean Hypothalamus Dose: 18 Gy Mean Hypothalamus Dose: 0.2 Gy 24 8

9 Endocrine Replacement Therapy Cost of growth hormone replacement: $10,000-25,000 per year Cost of hormone assisted fertility (female): >$10,000 per treatment course Cost of DDAVP, levothyroxine, and hydrocortisone: Thousands of dollars per lifetime Cost of treating heart disease, hearing loss, second malignancies, etc. Lundkvist J, Acta Oncol, 2005 Mailhot Vega R, IJROBP, Quality of Life Health-Related Quality of Life (HRQoL) compared in pediatric patients treated at MGH (Proton) and Stanford Lucille Packard Children s Hospital (Conventional RT) Prospective data collected using the PedsQL scale (n=120) Children who received proton therapy reported significantly: Better overall HRQoL scores (mean 75.9 vs. 65.4, p=0.002) Higher HRQoL was significantly associated with higher IQ scores Better physical health scores (mean 78.4 vs. 68.1, p=0.01) Better psychosocial health scores (mean 74.5 vs. 64.0, p=0.001) Yock TI, Radiother Oncol, 2014 Kuhlthau KA, JCO, 2012 Better Health-Related Quality of Life Compared to healthy controls, QOL scores were 5.0 points lower in the proton population (p=0.024) and 13.3 points lower in the photon population (p<0.001) QOL scores in the proton cohort were similar/better than children with chronic diseases: Diabetes 76.0, Obesity 75.0, and Asthma 68.8 Yock TI, Radiother Oncol,

10 Quality of Life Differences were most notable in children with Medulloblastoma, Ependymoma/High-Grade Glioma, and Low Grade Glioma Yock TI, Radiother Oncol, 2014 But Proton Therapy is too Expensive Modeled cost-effectiveness of proton therapy for medulloblastoma Considered risk of heart disease, IQ loss, hearing loss, hypothyroidism, GH deficiency, osteoporosis, and secondary cancers Proton therapy reduced total cost by 23,600/patient and significantly increased quality-adjusted life years (QALY) Proton therapy dominated (had both lower cost and better outcomes than) conventional RT Lundkvist J, Acta Oncol, But Proton Therapy is too Expensive Proton therapy cost <$5,000/QALY gained in children Proton therapy had both lower costs/higher QALYs than conventional RT Biggest reasons that proton were better Reduced risk of heart failure Reduced risk of hearing loss Reduced risk of secondary cancer Reduced risk of GH deficiency Mailhot Vega R, IJROBP,

11 Pop Quiz! What is the cost of proton therapy in a pediatric medulloblastoma? <$5,000/QALY Cost of an airbag in your car? $61,000/QALY Cost of adding bevacizumab to FOLFOX in metastatic colorectal cancer (for which there is Level I Evidence)? $935,000/QALY Benefit 0.21 QALY at a cost of $98,570/patient Mailhot Vega R, IJROBP, 2015 Graham JD, JAMA, 1997 Goldstein DA, JCO, Soft tissue sarcoma in the Photon Path Real-life case Growing Evidence for Proton Therapy Matched Pairs Analysis 558 Proton patients vs. 558 SEER patients treated with Conventional RT Incidence of Secondary Cancers: 12.8% Photons vs. 6.4% Protons (HR = 2.73; 95% CI = , p<.0001); Absolute reduction of 50% Prospective (Retinoblastoma) 86 Retinoblastoma patients (55 Proton, 31 Conventional) treated since year incidence of RT-induced in-field SMNs: 0% vs. 14% (p=0.015) Chung CS, IJROBP 2013 Sethi RV, Cancer

12 Growing Evidence for Proton Therapy Proton therapy reduces the risk of second cancers Chung CS, IJROBP 2013 Sethi RV, Cancer 2014 Eaton BR, IJROBP Growing Evidence Prospective clinicalstudies have demonstrated the benefit of protons vs. conventional RT in reducing normal tissue doses for: Brain Tumors (Prospective) Retinoblastoma (Prospective) Rhabdomyosarcoma (Prospective) Orbital rhabdomyosarcoma (Prospective) Hodgkin lymphoma (Prospective) Chordoma and Chondrosarcoma (Prospective) Ewing sarcoma in the Pelvis/Spine Neuroblastoma Macdonald SM, Neuro Oncol 2013 Yock TI, Lancet Oncol 2015 Merchant T, IJROBP 2011 Hoppe BH, IJROBP Proton therapy is not Experimental Pubmed accessed on Oct 8, 2017 Articles: pediatric cancer proton : 455 pediatric cancer IMRT : 105 pediatric cancer proton outcomes : 72 pediatric cancer IMRT outcomes : 14 >1 million patients have been treated with proton therapy >40% of US children treated with RT with curative intent received proton therapy in

13 Protons Reduce Dose to Heart during CSI Conventional RT Proton Therapy 37 Heart Dose = Cardiac Toxicity Darby (Breast Cancer) Relative risk of major coronary events increased by 7.4% per Gy mean heart dose Darby S, N Engl J Med Heart Dose = Cardiac Toxicity van Nimwegan (Hodgkin) Relative risk of major coronary events increased by 7.4% per Gy mean heart dose van Nimwegan FA, JCO

14 Pediatric Proton Therapy in the US: The typical proton therapy patient is a child <10 years old with a curable brain tumor or axial sarcoma who requires anesthesia and/or concurrent chemotherapy Experience Matters Children with brain tumors treated in high volume hospitals have better survival than at low volume hospitals (Level 1). This lower mortality risk is most pronounced in children <2 y.o. It is likely that children with Ewing sarcoma, osteosarcoma, leukemia, Neuroblastoma, and Wilms Tumor have better survival in high volume centers and when treated by high case volume providers (Level 2). The quality of radiotherapy is related to the volume of patients treated Knops RRG, Annals Oncol, Caring for Children with Cancer To care for children with cancer, you need a team Pediatric Radiation Oncologist Pediatric RNs Pediatric Anesthesiologists Pediatric Recovery Room RNs Child Life Specialist Pediatric Social Worker Radiation Therapists with Pediatric Experience Pediatric Oncologists Pediatric Neurosurgeons Pediatric Surgeons Pediatric Radiologists 42 14

15 Caution: Unexpected Toxicity -- Brainstem Pediatric Brainstem Radionecrosis 313 patients treated with Proton Therapy at UFPTI 11/313 patients developed brainstem toxicity Seven with Grade 2, Three with Grade 3-4, One Grade 5 2-year cumulative incidence Any brainstem toxicity: 3.8% ± 1.1% Grade 3+ brainstem toxicity: 2.1% ± 0.9% Symptoms stabilized/resolved in 9/10 living patients Indelicato DJ, Acta Oncol, Caution: Unexpected Toxicity -- Vasculopathy 3-year cumulative incidence Any Vasculopathy: 7.5% Stroke or Revascularization: 2.6% Hall MD, IJROBP, Make Patient Safety a Priority More conservative guidelines are needed in pediatric patients receiving proton therapy than are currently used by COG Spinal Cord Absolute dose at 0.5cc 1.7 Gy Goals= 55, 60 Gy Optic Chiasm Absolute dose at 0.1cc 28.3 Gy Goals= 55, 60 Gy Solutions: Brainstem Surface Absolute dose at 0.1cc 46.4 Gy Goals= 59, 64 Gy Brainstem Core Absolute dose at 0.1cc 46.4 Gy Goals= 54, 57 Gy Retina Left Absolute dose at 0.1cc 0 Gy Goals= 50, 55 Gy 1. Normal tissue guidelines Retina Right Absolute dose at 0.1cc 0 Gy Goals= 50, 55 Gy Optic Nerve Left Absolute dose at 0.1cc 13.8 Gy Goals= 55, 60 Gy Optic Nerve Right Absolute dose at 0.1cc 21.6 Gy Goals= 55, 60 Gy 2. Rigorous QA Cochlea Left Mean absolute dose 31 Gy Goals= 30, 36 Gy Cochlea Right Mean absolute dose 18.9 Gy Goals= 30, 36 Gy Lacrimal Gland Left Mean absolute dose 0 Gy Goals= 34, 41 Gy 3. Expert Team Lacrimal Gland Right Mean absolute dose 0 Gy Goals= 34, 41 Gy Temporal Lobe Left Relative volume at 20Gy 59.7 % Goal= 10 % Pediatric Fellowship Training Temporal Lobe Right Relative volume at 20Gy 60.8 % Goal= 10 % Hippocampus Tail Left Mean absolute dose 41.8 Gy Goal= 20 Gy Hippocampus Tail Right Mean absolute dose 44.9 Gy Goal= 20 Gy PENTEC Late Effects Project Hippocampus Head Left Mean absolute dose 33.7 Gy Goal= 5 Gy Hippocampus Head Right Mean absolute dose 36.1 Gy Goal= 5 Gy CAYAHL Harmonization Project Hypothalamus Mean absolute dose 41.8 Gy Goal= 5 Gy COG Late Effects Working Group Pituitary Mean absolute dose 25.9 Gy Goal= 30 Gy Mastoid Air Cell Left Mean absolute dose 11.1 Gy Goal= 30 Gy Mastoid Air Cell Right Mean absolute dose 10.3 Gy Goal= 30 Gy Posterior Nasopharynx Mean absolute dose 1.8 Gy Goal= 30 Gy Scalp Absolute volume at 30Gy 0 cc Goal= 5 cc Brain Relative volume at 115% dose 0 % Goal= 0 % Brain Mean absolute dose 19.2 Gy As low as possible Non Target Brain Mean absolute dose 14.2 Gy As low as possible Supratentorial Brain Rel volume getting 0-1Gy 14.8 % As low as possible Supratentorial Brain Rel volume getting 1-20Gy 41.3 % As low as possible Supratentorial Brain Rel volume getting 20-40Gy 34.3 % As low as possible Supratentorial Brain Rel volume getting >40Gy 9.6 % As low as possible 45 15

16 Pediatric Anesthesia At pediatric proton therapy centers, up to 50% of patients may require anesthesia 7 fellowship-trained pediatric anesthesiologists Pediatric recovery room (3 pediatric nurses/day) No current limit on anesthesia case capacity 46 The Value of a Certified Child Life Specialist At UFPTI, 62.3% of children aged 5-8 required anesthesia in ; 28.8% of children aged 5-8 required anesthesia in after a child life specialist was hired An average 6-week course of pediatric anesthesia costs $50,000/patient The average annual cost to employ one child life specialist is $50,000/year Employing a child life specialist and reducing anesthesia results in an expected cost savings to the healthcare system exceeds $950,000 in a program treating 100 pediatric patients per year Smith MT. IJROBP The Value of a Certified Child Life Specialist A Child Life Specialist Reduces the need for anesthesia and makes treatment faster Pediatric CNS case: 30 minutes Pediatric CNS case with anesthesia: 45 minutes Improves patient and family experience Represents the standard of care in a pediatric radiation oncology program 48 16

17 Conclusions Patients derive no benefit from the irradiation of normal developing tissues Proton therapy can significantly reduce the volume of normal tissue receiving collateral radiation Clinical data continues to mature, but already verifies the modeled benefits in children Appropriate patient selection maximizes the absolute benefit achieved in patients receiving proton therapy. This benefit is greatest in children. 49 Miami Cancer Institute Thank you! Matthew D. Hall, M.D., MBA Radiation Oncology Baptist Health South Florida Cell: (618)