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Clinical Benefits

Brain Lung 31% increase in disease control for aggressive tumors 35% relative increase in overall survival for Stage II & III lung cancer14 1 at base of skull (chordomas) at 5 years 56% relative reduction in incidences of serious (grade 3) pain with 50% less likely to have secondary from treatment2,3 swallowing (esophagitis)13 55% reduction in average dose to the hippocampi Up to 4-week reduction in treatment time for select cases15 (memory function) in treatment of meningioma3 Esophageal 10% increase in overall survival at 5 years in stage I-III disease16 Head and Neck 10% increase in local control at 5 years in stage II-III16 in overall risk of needing a feeding tube for 27% reduction 15% decrease in distant metastasis at 5 years in stage II-III16 oropharyngeal cancer4 26% reduction in pulmonary toxicity compared with X-ray therapy (IMRT)17 Fewer side effects first 3 months after treatment, quicker return to normal function in patients with oropharyngeal cancer5 21% reduction in the risk of severe, treatment related lymphopenia, particularly in lower esophagus19 45% reduction in overall risk of needing a feeding tube for nasopharyngeal cancer6 3-4-day reduction in average hospital stay after surgery18 Dramatic reduction of negative impact on taste, nausea, and painful changes to the mouth in salivary gland treatment7 Prostate 44% relative increase in disease free survival rate for nasal and 5% higher 5-year overall survival in intermediate risk20 paranasal sinus cavity at 5 years8 Patients who received proton therapy report highest quality of life compared to surgery, x-ray, or patients21 radiation to the bladder and 59% less radiation to the rectum22 Breast 35% less 42% reduction in relative risk of developing a secondary malignancy20 88% less radiation dose to the heart for left sided breast cancer9,10 50% reduction in treatment related bowel frequency and urgency at 2 years23 44% reduction in clinically significant radiation doses to the lung10 21% lower risk of urinary toxicity at 2 years24 90% of partial breast cases result in good to excellent 24 cosmetic outcomes at 5 years11 25% lower risk of erectile dysfunction at 2 years Well tolerated - Less than 4% serious side effects (grade 3) in locally advanced breast cancer10 Rectal/Anal More than 50% reduction in radiation dose to critical 25 Liver structures including bone marrow Associated with excellent local control and favorable survival rates12 Able to treat larger tumors (>6cm) ineligible for stereotactic radiation Overall (SBRT) or ablation12 31% relative reduction in occurrence of secondary cancers after treatment26

Results from separate studies compared in some instances. The benefits of proton therapy for each individual patient will vary based on their individual diagnosis. A personal consultation with a proton-experienced is recommended in all cases. See Proton Therapy Clinical Benefits Sources and Citations or visit ProtonBenefits.com for more information. 1/2019 BREAST ESOPHAGEAL

PROTON THERAPY 9. ClinicalTrials.gov Identifier: NCT02603341 Compare the 19. Lin SH, Merrell KW, et al. Multi-institutional analysis of radiation effectiveness of proton vs. therapy in reducing major modality use and postoperative outcomes of neoadjuvant Clinical Benefits cardiovascular events (MCE), defined as atherosclerotic chemoradiation for . Radiotherapy and coronary heart disease or other heart disease death, Oncology. 2017;123;3;376 - 381. Sources & Citations myocardial infarction, coronary revascularization, or hospitalization for major cardiovascular event (heart PROSTATE failure, valvular disease, arrhythmia, or unstable angina). 20. Hartsell W, Bentefour H, Dooling D,Mendenhall N. Proton 10. Cuaron JJ, Chon B, Tsai H, et al. Early Toxicity in Patients Therapy Is Associated with Superior Survival and Decreased Risk BRAIN Treated With Postoperative Proton Therapy for Locally of Complications Compared to IMRT for Intermediate Advanced . International Journal of Radiation Risk : A Medicare/SEER Database Study. 1. Ares C, Hug E, Lomax A, et. al. Effectiveness and Safety of Oncology • Biology • Physics. 2015;Volume 92;Issue 2;284 - 291. [abstract] Presented at PTCOG-NA October 25, 2017 at National Spot Scanning Proton for Chordomas and Conference in Chicago. http://ptcog-na.org. Chondrosarcomas of the Skull Base: First Long-Term Report. 11. Bush D, Do S, et. al. Partial Breast Radiation Therapy International Journal of Radiation Oncology • Biology • Physics. With Proton Beam: 5 Year Results With Cosmetic Outcomes 21. Bryant Research. Awareness and Impressions of Selected 2008;75;4;1111 - 1118. International Journal of Radiation Oncology • Biology • Physics. Prostate Cancer Treatment Options Survey. 2013. 2014;Volume 90;Issue 3;501 - 505. Dennis ER, Bussière MR, Niemierko A, et. al. A Comparison 2. 22. Vargas C, Fryer A, Mahajan C, et al. Dose–volume comparison of Critical Structure Dose and Toxicity Risks in Patients with LIVER of proton therapy and intensity-modulated radiotherapy for Low Grade Gliomas Treated with IMRT versus Proton Radiation prostate cancer. International Journal of Radiation Oncology • Therapy. Technology in Cancer Research & Treatment. 2013;12;1– 12. Hong TS, Wo JY, Yeap BY, et. al. Multi-Institutional Phase II Biology • Physics. 2008;70;3;744 - 751 9. https://doi.org/10.7785/tcrt.2012.500276 Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresected Hepatocellular 23. Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative 3. Arvold ND, Niemierko A, Broussard GP, Adams J, at al. Carcinoma and Intrahepatic Cholangiocarcinoma. Jour Clin Onc. effectiveness study of patient reported outcomes after proton Projected second tumor risk and dose to neurocognitive 2016;34;5;460-468. therapy or intensity-modulated radiotherapy for prostate cancer. structures after proton versus photon radiotherapy for benign Cancer. 2014;120:1076-1082. meningioma. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e495- 500. doi: 10.1016/j.ijrobp.2011.10.056. Epub 2012 Jan 26. LUNG 24. Pan H, Jiang J, Hoffman D, et. al. Comparative toxicities and 13. Higgins KA, O’Connell K, et. al. National Cancer Database cost of intensity-modulated radiotherapy, proton radiation, and HEAD & NECK Analysis of Proton Versus Photon Radiation Therapy in Non-Small sterotactic body radiotherapy among younger men with prostate Cell Lung Cancer. International Journal of Radiation Oncology cancer. Journal of Clinical Oncology. 2018;36;18;1823-1830. 4. Frank SJ, Rosenthal DI, Ang K, et al. Gastrostomy Tubes Biology Physics. 2017. 97;1;128-137. https://doi.org/10.1016/j. Decrease by Over 50% With Intensity ijrobp.2016.10.001 Modulated Proton Therapy (IMPT) During the Treatment RECTAL/ANAL of Oropharyngeal Cancer Patients: A Case–Control Study. 14. Chang JY, Verma V, Li M, et al. Proton Beam Radiotherapy 25. Anand A, Bues M, Rule WG, et. al. Scanning proton beam [abstract]. International Journal of Radiation Oncology • Biology and Concurrent Chemotherapy for Unresectable Stage III Non– therapy reduces normal tissue exposure in pelvic radiotherapy • Physics. 2013;87;2;S144 Small Cell Lung Cancer: Final Results of a Phase 2 Study . JAMA for anal cancer. [abstract]. Radiotherapy & Oncology. 2015. Dec; Oncol. 2017;3(8):e172032. doi:10.1001/jamaoncol.2017.2032 117 (3): 505-8. doi: 10. 1016/j.radonc.2015.10.027. Epub 2015 Nov 5. Sio T, Lin H-K, et. al. Intensity-Modulated Proton Therapy 17. (IMPT) versus Intensity-Modulated Photon Radiotherapy 15. Bush DA, Cheek G, Zaheer S, et. al. (2013). High-dose (IMRT) for Oropharyngeal Cancer: First Comparative Results of hypofractionated proton beam radiation therapy is safe and OVERALL Patient-Reported Outcomes. International Journal of Radiation effective for central and peripheral early-stage non-small cell Oncology*Biology*Physics. 2016. 95;4;1107-1114; http://dx.doi. lung cancer: results of a 12-year experience at Loma Linda 26. Chung C, Yock T., et. al. Incidence of second malignancies org/10.1016/j.ijrobp.2016.02.044. University Medical Center. Int J Radiat Oncol Biol Phys. 2013 Aug among patients treated with proton versus photon radiation. Int 1;86(5):964-8. doi: 10.1016/j.ijrobp.2013.05.002. J Radiat Oncol Biol Phys. 2013 Sep 1;87(1):46-52. doi: 10.1016/j. 6. Holliday EB, Garden A, Rosenthal D, et al. Proton therapy ijrobp.2013.04.030. Epub 2013 Jun 15. reduces treatment realated toxicities for patients with nasopharyngeal cancer: A case-match control study of intensity- ESOPHAGEAL modulated proton therapy and intensity-modulated photon 16. Xi M, Xu C, Zhongxing L, Chang JY, et. al. Comparative therapy. Int J Part Ther 2015;2(1):1-10. Outcomes After Definitive Chemoradiotherapy Using Proton Beam Therapy Versus IMRT for Esophageal Cancer: A 7. Romesser PB, Cahlon O, Scher E, Zhou Y, et. al. Proton Retrospective, Single-Institutional Analysis. Internat Jour of Rad beam radiation therapy results in significantly reduced toxicity Onc bio phy. 2017;99;3;667-676. compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiotherapy 17. Lester SC, Lin SH, Chuong M, et. al. A Multi-institutional & Onc Eur Soc of Rad and Onc. 2016;118;2;286-292. Analysis of Trimodality Therapy for Esophageal Cancer in Elderly Patients. Internat Jour of Rad Onc bio phys. 2017;98;4;820-828. 8. Patel SH, Wang Z, et. al. Charged versus photon therapy for paranasal sinus and nasal cavity malignant 18. Fang P, Shiraishi Y, Verma V, et. al. Lymphocyte-Sparing diseases: a systematic review and meta-analysis. Lancet Oncol. Effect of Proton Therapy in Patients with Esophageal Cancer 2014 Aug;15(9):1027-38. doi: 10.1016/S1470-2045(14)70268-2. Treated with Definitive Chemoradiation.International Journal of Epub 2014 Jun 26. Particle Therapy. 2018;4;3;23-32.