4/8/2016. Disclosures. Virtual Lectures Planning Committee Disclosure Summary. Mayo Medical Laboratories. Learning Objectives

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1 Virtual Lectures Planning Committee Disclosure Summary Mayo Medical Laboratories Virtual Lectures 2014 MFMER As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of these relevant financial relationships will be published in activity materials so those participants in the activity may formulate their own judgments regarding the presentation. Listed below are individuals with control of the content of this program who have disclosed Relevant financial relationship(s) with industry: None No relevant financial relationship(s) with industry: Robert Foote, MD program presenter Curtis Hanson, MD program planning committee Sharon Preuss program planning committee Bobbi Pritt, MD, MSc, DTMH program planning committee Cara Schmidt program planning committee References to off-label and/or investigational usage(s) of pharmaceuticals or instruments in their presentation: Hitachi Proton Beam Therapy MFMER MFMER Disclosures Robert L. Foote, M.D. relevant financial relationship(s): NONE off label usage: Hitachi Proton Beam Therapy Proton Beam Therapy at Mayo Clinic Beam On! The DLMP Grand Rounds Planning Committee members listed below declare that they have nothing to disclose in relation to this presentation: Loralie J. Langman, Ph.D. Justin D. Kreuter, M.D. Elitza S. Theel, Ph.D. Thomas Huntley Darci R. Block, Ph.D. Anja C. Roden, M.D. Joanne Yi, M.D. Denise Skudlarek Robert L. Foote, MD DLMP Grand Rounds 2 March MFMER MFMER Learning Objectives By the end of this presentation, participants should be able to: Explain the physical advantage of proton beam therapy compared to x-ray therapy Describe the relationship between radiation dose and tumor control, survival and risk for complications Identify the advantages of proton beam therapy in the treatment of a variety of cancers Radiation Oncology in the U.S. today & tomorrow 1.7 million new cancer diagnosis per year ~2 million by 2020 ~1,000,000 receive radiation therapy 75% curative 25% palliative The most common indications Prostate, Breast, Lung, Brain metastases Currently: ~2,700 radiation therapy centers Smith et al, JCO MFMER MFMER

2 Radiation Therapy ~65% of people with cancer receive one or more courses of radiation therapy during the course of their illness X-rays (Photons) have been used since 1896 Protons (first hospital based system 1990) Electromagnetic Spectrum 2012 MFMER MFMER Wilhelm Conrad Röntgen Earnest Rutherford: Protons MFMER MFMER Protons Charged Particles 2012 MFMER MFMER

3 International Space Station View from Space Shuttle 2012 MFMER MFMER Aurora Borealis Protons versus Photons (X-rays, Gamma rays) X-rays: electromagnetic waves Protons: particles (radius:0.84 x m, density:10 18 kg/m 3, stable:t 1/2 >10 34 years) X-rays: massless Protons: massive (1.673 x kg, 2000X electron) X-rays: no electrical charge Protons: positive electrical charge Physical dose distribution 2012 MFMER MFMER slide-16 The Proton Physical Advantage Bragg Peak Indirect Action of X-rays and Protons 2012 MFMER MFMER slide-18 3

4 Linear Energy Transfer Relative Biologic Effectiveness Oxygen Enhancement Ratio Linear Energy Transfer (LET, kev/µm) Ionizing energy transferred per unit length of the track Dependent upon the type of radiation X-rays (photons) and Protons give rise to fast recoil electrons Negative charge, very small mass Sparsely ionizing 2016 MFMER slide MFMER slide-20 Linear Energy Transfer (LET, kev/µm) Relative Biologic Effectiveness (RBE) Absorbed dose (gray, Gy) Equal physical dose does not produce equal biologic effect X-rays (250 kv) are the standard RBE=D X-rays /D radiation to produce the same biologic effect As LET increases, up to 100 kev/µm, RBE increases 2016 MFMER slide MFMER slide-22 Oxygen Enhancement Ratio (OER) Ratio of doses administered under hypoxic to aerated conditions to achieve the same biologic effect X-rays, γ-rays, Protons are sparsely ionizing OER= Heavier charged particles are densely ionizing OER=1 Oxygen Enhancement Ratio (OER) 2016 MFMER slide MFMER slide-24 4

5 Linear Energy Transfer Relative Biologic Effectiveness Oxygen Enhancement Ratio Basic Principles of Radiation Therapy The higher the dose to the tumor, the longer the survival The higher the dose to the tumor, the longer the overall treatment time (9 weeks) 2016 MFMER slide MFMER X-ray Dose Response for Prostate Cancer X-ray Dose Response for Hodgkin Lymphoma and Nasopharyngeal Carcinoma 2012 MFMER MFMER Basic Principles of Radiation Therapy The higher the dose to the tumor, the longer the survival The higher the dose to the tumor, the longer the overall treatment time (9 weeks) The higher the dose to normal tissues and organs, the greater the incidence and severity of acute and late toxicity Cervical Myelopathy Kirkpatrick, International Journal of Radiation Oncology, Biology, Physics 76:S42, MFMER MFMER

6 Brain Necrosis Circulatory Disease Lawrence, International Journal of Radiation Oncology, Biology, Physics 76:S20, MFMER Little, International Journal of Radiation Oncology, Biology, Physics, 84:1101, MFMER Risk of Cancer Following Low Dose Exposure Proton Beam Therapy Facts and Controversy For the same tumor dose, Protons will deliver a lower dose to a smaller volume of normal tissue than X-rays Lack of Phase III clinical trials No equipoise, unethical Are the benefits worth the extra cost? Little, International Journal of Radiation Oncology, Biology, Physics, In Press, MFMER MFMER % of Pediatric Cancer Patients are Cured Pediatric Cancer a tempered success 65% of long-term survivors have chronic health conditions 20% die of 2 nd malignancy or other treatmentrelated event 2012 MFMER Merchant, et al JCO 2009; Armstrong, et al JCO MFMER

7 Medulloblastoma: Conventional X-ray Therapy Intensity Modulated or 3-Dimensional Conformal X-ray Therapy 2012 MFMER MFMER Facial Asymmetry Following X-ray Therapy Proton Beam Therapy Used with parental permission 2012 MFMER MFMER Medulloblastoma: Conventional X-ray Therapy Intensity Modulated or 3-Dimensional Conformal X-ray Therapy 2012 MFMER MFMER

8 Proton Beam Therapy Cost Analysis for Pediatric Medulloblastoma Variable Proton X-ray Difference Radiation cost ( ) 10, , , Adverse event cost ( ) 4, , , Total cost ( ) 14, , , Lundkvist, Cancer 103: , MFMER MFMER Breast Cancer and Cardiovascular Disease: X-rays vs Protons Breast Cancer: Cost per QALY gained Lundkvist, Radiotherapy and Oncology75:179, 2005 Lundkvist, Radiotherapy and Oncology75:179, MFMER MFMER Ocular Melanoma Mayo Clinic Center for the Science of Health Care Delivery: Cost Effectiveness Enucleation-$22,772 I-125 Plaque-$28,662 Protons-$24,894 Value of eye Value of vision Avoid radiation exposure of staff In-patient vs out-patient procedure Radiation-induced Malignancies Retinoblastoma Protons-MGH: 55 children X-rays-Boston Children s Hospital: 31 children year cumulative incidence of RIM Protons-0%; X-rays-14%, p=0.015 Z. Wang, Int J Radiation Oncol Biol Phys 86:18, 2013 JP Moriarty, PLoS ONE 10(5):e , MFMER Sethi, Cancer MFMER

9 Radiation-induced Malignancies Protons-Harvard Cyclotron ( ) 558 proton patients SEER cancer registry 558 matched X-ray patients Adjusted hazard ratio 0.52 (C.I , p=0.009) Nasal Cavity and Paranasal Sinus Cancers Mayo Clinic Center for the Science of Health Care Delivery Comparative effectiveness analysis Protons: significantly fewer recurrences Protons: significantly prolonged survival International Journal of Radiation Oncology, Biology, Physics; Chung, MFMER SH Patel, Lancet Oncology 15:1027, MFMER Tumor at Diagnosis Mayo Clinic Proton Beam Treatment Program Decrease dose to normal organs, decrease acute and late toxicity Decrease costs of treating side effects, improve quality of life and function Increase dose to tumor, decrease recurrence, increase survival Decrease costs of treating recurrent cancer Decrease overall treatment time, decrease out of pocket expenses and emotional distress to patient 18 Months After Treatment Nearly identical location (in front of kidney) 2012 MFMER MFMER David Living Life to its Fullest! Patient Demand in Rochester in 2015 Over 137,000 adults and children each year within the US 20,000 within 500 miles of Rochester 2400 within 120 miles of Rochester Capacity: 1240 patients per year 4 treatment rooms Pencil beam scanning 2012 MFMER MFMER

10 X-rays (Photons) vs Protons Patient Demand in Arizona in ,500 to 3,000 patients in Arizona 2,300 in Colorado 870 in New Mexico 1,200 in Nevada 6,870-7,370 total patients Capacity: 1,240 patients per year 4 treatment rooms Pencil beam scanning 2012 MFMER MFMER year old male with esophageal cancer, ECOG PS 0, CAD, MI, PTCA, A. Fib. 6 week history of dysphagia EGD with EUS: circumferential, friable, 4 cm exophytic distal esophageal mass, T3, N1 Biopsy: Adenocarcinoma, background of Barrett s esophagus CT CAP: 3.8 cm distal esophageal mass PET/CT: FDG avid distal esophageal mass Dutch CROSS trial 366 pts operable esophageal ca 84% PS=0 75% ACA 82% distal/gej R 81% ct3 64% cn1 Neoadjuvant CRT 41.4 Gy/23 fx RT* Weekly carboplatin (AUC 2) + paclitaxel (50 mg/m2) Esophagectomy * Compared to US standard of care, RT was reduced dose (41.4 Gy) and reduced field (no celiac LN coverage) Esophagectomy Van Hagen P et al. N Engl J Med 2012;366(22): MFMER MFMER Dutch CROSS trial 50 Gy in 25 fractions over 5 weeks Carboplatin and Paclitaxel Re-evaluate 5-6 weeks later for surgery Van Hagen P et al. N Engl J Med 2012;366(22): MFMER MFMER

11 Post-operative morbidity Cause of death Recurrent cancer 85% Other causes 15% Sepsis Cardiac failure Respiratory insufficiency Kidney failure Second malignancy Fistula Treatment-related Van Hagen P et al. N Engl J Med 2012;366(22): Van Hagen P et al. N Engl J Med 2012;366(22): MFMER MFMER Pulmonary toxicity 444 esophageal cancer patients Cardiac morbidity 2,000 breast ca pts followed for 10+ years 80 gm Hydrogen 6 X protons/gram ~5 X protons ~5 X protons/pt ~10 X patients 1200 patients/year ~8 X 10 9 years Wang, International Journal of Radiation Oncology, Biol., Phys. 86 (5):885-91, MFMER Darby SC et al. NEJM 2013;368(11): MFMER Why proton beam therapy for esophageal cancer? Target volume surrounded by non-target normal tissues lungs, heart, kidneys, liver, bowel 2012 MFMER MFMER

12 MD Anderson, Mayo Clinic, U of Maryland Esophageal Cancer Study 582 patients Institution 335 MDACC 200 Mayo 47 Maryland Radiotherapy modality 471 photon (81%) 256 IMRT 215 3DCRT 111 proton (19%) 2012 MFMER MFMER Pathologic outcomes Post-operative complications Outcome Photon (n=471) Proton (n=111) P-value R0 resection (%) NS pcr (%) NS Outcome Photon (n=471) Proton (n=111) P-value Hospital LOS, mean, days 12 9 < Post-operative complications (%) Any Pulmonary Cardiac Gastrointestinal Wound MFMER MFMER Overall Survival by RT Modality Median f/u after surgery: 2.3 years 70% Proton 58% Photon Log-rank p=0.03 Acute Toxicity-CTCAE v4 Physician reported: Grade 1 dysphagia Grade 2 constipation Grade 1 dermatitis Patient reported: LASA 3: QOL 8/10, Pain 0/10, Fatigue 1/10 Severe constipation 2012 MFMER MFMER

13 First day of treatment: 23 yo female, incompletely resected growth hormone secreting pituitary adenoma First patient treated with proton beam therapy Insulin-like Growth Factor 1: 867 to 605 ng/ml (normal ) Growth Hormone: 19 to 2.45 ng/ml (normal ) Acute and late toxicity: grade 1 fatigue, resolved 2012 MFMER MFMER First patients treated on June 22, 2015: 2 treatment rooms 3 rd room-december 7, th room-june 2016 Phoenix: March 14 2 rooms As of December 31, 2015: 117 patients treated 88 have completed treatment Median age 43 years (15 months to 85 years) 32 (27%) pediatric patients 19 (16%) young adults 18 (15%) prior RT 2012 MFMER MFMER Ramp up plan vs actual 70 Patients Treated Per Quarter/Year Ramp up plan vs actual 30 Average Patients Treated Per Day FEA Actual FEA Actual YR1 Q1 (6/22-9/30/15) YR1 Q2 (10/1-12/31/15) 0 YR1 Q1 (6/22-9/30/15) YR1 Q2 (10/1-12/31/15) 2012 MFMER MFMER

14 Liver cancer 2% Lymphoma 7% Esophageal cancer 8% Head and Neck cancer 9% Prostate cancer 12% Anal 3% Rectal 1% Colon cancer 1% Breast cancer 13% Brain tumors 30% Sarcoma 14% Geographic distribution of patients as of December 31, each: AZ, CO, DC, HI, KS, MD, MO, NY 8 2 each: FL, IL, IN, MT, NE, NC 12 South Dakota, 3 Michigan 4 North Dakota 6 Wisconsin 6 Iowa 13 International - Equador, Kuwait, SA 4 Minnesota MFMER MFMER Department of Radiation Oncology Procedural Volumes N =494 11% increase Protons = 117 Protons = 23% of increase Insurance coverage 185 patients (66 insurance companies) 166 approved (90%) 19 denied (10%) 18 treated at Mayo with photons 1 paid out of pocket for protons Commercial: 68% Government: 28% International: 4% MFMER MFMER Patient registry: 766 patients approached 693 (90%) patients enrolled (585 blood for biobank) 614 photon patients 79 proton patients Patient reported outcomes Started April 2015 PROMIS 10 LASA 3 Disease specific PRO 786 conventional radiation therapy patients 117 proton patients 2012 MFMER MFMER

15 Provider reported outcomes Started August 2013 CTCAE v conventional radiation therapy patients 92 proton patients Clinical Research/Trials : IRB approved prospective patient registry and biobank: : Esophageal Cancer: : Breast Cancer APBI (3 tx): : Malignant glioma F-DOPA: : CTA (coronary artery): MFMER MFMER Phase III clinical trials (photons vs protons) MD Anderson Stage III-IV Oropharynx Cancer NRG Oncology Inoperable stage II-IIIB NSCLC PCORI (UPenn) Stage II or III Breast Cancer UPenn/MGH Prostate cancer 42 peer-reviewed manuscripts 2012 MFMER MFMER Beam On! On schedule Under budget Ramping up 2012 MFMER