The Ultimate Healing Beam: The Future is Now

1. The Ultimate Healing Beam:The Future is Now John Han-Chih Chang, MD Radiation Oncologist CDH Proton Center, a ProCure Center Primary Investigator for the Radiation Therapy Oncology Group Primary Investigator for the Children’s Oncology Group Children’s Memorial Hospital Vice Chair of the Midwest Children’s Brain Tumor Clinic

2. Road Map • Background • History – When and Where • Proton Mechanics – How to • Applications/Prostate Cancer – What for • Conclusion

3. High End Image Guided Glorified Tanning Booths

4. Techniques to Improve Radiation Delivery Radiation Modality Modality and Delivery Must Work Together OPTIMAL RADIATION THERAPY

5. Protons through the Ages

6. Bragg PeakNamed after the British physicistWilliam Henry Bragg (1862 - 1942)

7. Protons: “Ancient” History 101 Hydrogen Atom R.R. Wilson, Radiology 1946; 47:487-491

8. Scientists have been perfecting proton therapy as a treatment for cancer for 65 years • Robert R. Wilson, PhD • "Radiological Use of Fast Protons" (Radiology 1946:47:487-91) • Berkeley and Harvard • Fermilab

9. Protons: History 101 1946 – Robert Wilson proposes using protons clinically 1955 – The first patient is treated at Berkley 1961 – The Harvard Cyclotron Lab (HCL) begins therapy 1991 – Loma Linda (LL) operates the first proton gantry 2001 – HCL closes  NPTC opens

10. Protons: “Modern” History 101 • Loma Linda Univ Medical Center – Loma Linda, CA 1990 • MGH – NPTC Boston, Massachusetts 2002 • MPRI – Bloomington, Indiana 2004 • MDAH – Houston, Texas 2006 • FPTI – Jacksonville, Florida 2006 • PPC – Oklahoma City, Oklahoma 2009 • RPTC – Philadelphia, Pennsylvania 2010 • HUPTI – Hampton, VA 2010 • CDH – Chicago, IL 2010

11. Proton therapy found its first clinical home in California • Loma Linda • First patient 1990 • First facility designed as patient treatment center

12. The CDH Proton Center, A Procure Center, Warrenville, Ill. We are dedicated to providing exceptional care in a healing environment to patients with cancer

13. Mechanism of Action

14. In order for photons to reach a prescribed dose at the tumor depth, healthy tissue gets four times the radiation as the tumor Protons put 80% of their energy into the tumor and only 20% into healthy tissue Protons have Fewer Side Effects than Photons There is no reason to irradiate healthy tissue Photons deposit only 20% of their energy in the tumor Protons deposit more than 80% of their energy in the tumor

15. The Physics of Protons Depth Dose Curves for Different Treatment Types High Energy X-Rays Spread Out Bragg Peak (SOBP) 100 80 Relative Dose 60 40 200 MeV Protons 20 Tumor Healthy Tissue Healthy Tissue 0 0 5 10 15 20 25 30 Depth in Tissue (cm)

16. The Value of Protons • Protons are physically superior to X-rays • Protons behave differently than x-rays: • Protons • X-Rays do not • Protons improve the “therapeutic ratio” • maximizing tumor control while minimizing side effects • At a given radiation dose to a tumor protons deliver, on average, less than half the radiation dose to normal tissues than do x-rays 1 (1) Jay Loeffler, Massachusetts General Hospital, “Proton Therapy 2009”

18. Evidence of Distal Range Stopping Before treatment Treatment plan After treatment

19. Why would we chose Protons?

20. Cyclotron (spiral path) Constant magnetic field Variable Radius Continuous Beam Production of Clinically-Useful Proton Beams Proton Accelerators

21. Treatment Delivery

22. Production of Clinically-Useful Proton Beams Proton Accelerators - CYCLOTRON

23. Production of Clinically-Useful Proton Beams Beam Line Energy Selection System (230 MeV  70 MeV) Beam Transport and Switching System

24. Gantry 1 NPTC- Harvard Snout (with aperture & compensator) Nozzle 6-axis patient positioner

25. Robotic Table

26. Protons are delivered to patients in specialized treatment rooms Fixed Beam Room Gantry Room

27. Current Pediatrics Paraspinal Ewing’s Optic pathway glioma Optic nerve meningioma Prostate/Pelvic RMS Exophytic BSG Craniospinal irradiation Suprasellar NGGCT Prostate Head and Neck/Base of Skull Intracranial Meningioma Paraspinal/Sacrum Chordoma Planned Lung Organ motion Density changes Tumor response Inspiration: Expiration GI Organ motion Density changes Breast - API Lymphoma Ocular Clinical Indications

28. Prostate Cancer

29. Radiation Treatment Options • Radiation therapy options include • Brachytherapy (BT) is vastly underutilized • Effective • Safe (in the appropriately selected patients) • Convenient (1 to 2 day procedure) • External Beam Radiation Therapy (EBRT): Proton beam is superior to IMRT • Higher cure rates • Lower complication rates • Stereotactic Body Radiotherapy (SBRT) • Effective • Convenient (3 to 5 day non-invasive procedure) • Safety seems to be similar to IMRT (it is still X-rays)

31. Invasive Non-Invasive But, don’t forget about active surveillance!

32. Misconceptions About Proton Therapy “Just because someone keeps saying it doesn’t make it true.” • The typical quote: “The DVH of IMRT is better than the DVH of protons in the high dose region, and that’s what really counts” • FACT: Protons, regardless of delivery method, and with equivalent PTVs, should yield superior DVH curves without overlap • The typical quote: “There is no data showing protons have better control rates” • FACT: Protons do have better control • By definition, protons will never have worse control rates than x-rays

33. Misconceptions About Proton Therapy “Just because someone keeps saying it doesn’t make it true.” • The typical quote: “There is no data showing that side effects and complications (“toxicity”) are lower with protons” • FACT: At a similar treatment dose and volumes, the toxicity is lower with protons • The typical quote: “Protons are 2x to 5x times more expensive than IMRT” • FACT: Protons are at most 40% – 60% more than IMRT, based on Medicare, and offer a much better value • The lifetime costs of protons are much less than IMRT • Patient access must not be based on misconceptions. We must rely on science and data to drive these decisions.

34. In order for photons to reach a prescribed dose at the tumor depth, healthy tissue gets four times the radiation as the tumor Protons put 80% of their energy into the tumor and only 20% into healthy tissue Protons have Fewer Side Effects than Photons There is no reason to irradiate healthy tissue Photons deposit only 20% of their energy in the tumor Protons deposit more than 80% of their energy in the tumor

35. “Direct Radiation Complications Never Occur In Unirradiated Tissues” Dr. Herman Suit1 IMRT immerses more healthy tissue with radiation Radiation Therapy Plans for Prostate Cancer IMRT - 7-field co-planer Proton Therapy - 2-field DS Blue – 13% Green – 51% Purple – 63% Yellow – 76% Red – 95% Tumor Higher dose bath to healthy tissue with IMRT:Pelvis, rectum and bladder Less healthy tissue exposed to radiation compared to IMRT • Herman Suit, “The Grey Lecture 2001: Coming Technological Advances in Radiation Oncology,” International Journal of Radiation Oncology Biology Physics 53 No. 4 (2002): 798-809.

36. Prostate Cancer Treatment Plans IMRT- Protons: Excess dose for IMRT Protons IMRT Protons for rectum and bladder-dose is much lower Dose -% of dose IMRT immerses more healthy tissue with low to intermediate dose bath

37. The Data: Photons vs Protons

38. Prostate Cancer Proton Therapy vs. Conventional Radiation (by dose) in Locally Advanced Prostate Cancer Source: Presentation by Dr. N. Mendenhall, University of Florida, IBA

39. Rectum The limit of the photon modality IMRT - MSK 3D CRT - MSK IMRT - MGH IMRT - UFPTI Proton - MGH Proton - UFPTI Adapted from Zelefsky 2000, Trofimov 2007 and Vargas 2008

40. Rectal dose comparison Zelefsky et al Radiotherapy and Oncology 2000; 55:241-249 Trofimov et al IJROBP 2007; 69:pp. 444–453, Zhang et al IJROBP 2007; 67: 620–629 Vargas et al IJROBP 2008; 70: pp. 744–751

41. University of Florida Dosimetry Data Show Protons Reduce Dose To The Rectum By 59% IJROBP 2008 Radiation dose to the rectum – proton therapy and IMRT1 • Background on study • First prostate patients seen at University of Florida Proton Therapy Institute (“UFPTI”) • Both proton and IMRT plans were planned prospectively for each patient • The results • Relative and absolute mean rectal dose savings of 59.2% and 20.1%, respectively, with proton therapy • Why this is important • Entire Dose Volume Histogram (“DVH”) does matter, not just high the dose region • Rectal wall volume irradiated at 32.4 Gy is biggest predictor of rectal toxicity2 • Extremely high correlation between rectal volume irradiation to 70 Gy and 5-year toxicity rates3 90% 80% IMRT 70% 60% 50% Rectal Volume Receiving Radiation (%) Dose to rectum is more than 2x with IMRT vs. protons at 32 Gy 40% 30% Dose to rectum is almost 2x with IMRT vs. protons at 70 Gy 20% Proton 10% 0% 0 10 20 30 40 50 60 70 80 90 Radiation Dose (CGE/Gy) • Carlos Vargas et al., “Dose-Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer,” International Journal of Radiation Oncology Biology Physics 70 No.3 (2008): 744-751. • Susan Tucker, Lei Dong, Rex Cheung, et al., “Comparison of Rectal Dose-Wall Histogram Versus Dose-Volume Histogram for Modeling the Incidence of Late Rectal Bleeding After Radiotherapy,” International Journal of Radiation Oncology Biology Physics 60 (2004): 1589-1601. • Mark Storey, Alan Pollack, Gunar Zagars et al., “Complications from Radiotherapy Dose Escalation in Prostate Cancer: Preliminary Results of a Randomized Trial,” International Journal of Radiation Oncology Biology Physics 48 (2000): 635-642.

42. GI (Rectal) Side Effects and Complications The probability of damage to the GI tract is much higherwith x-rays than protons Chronic Radiation Proctitis in the GI tract Inflammation causedby radiation Necrosis and ulcer

43. Dose Escalation Trials Support the Use of Protons for Prostate Cancer Protons offer better control and lower toxicity than X-Rays The best outcome for control AND toxicity was achieved using protons • DA Kuban, SL Tucker, L Dong et al., “Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer,” International Journal of Radiation Oncology Biology Physics 70 (2008): 67-74. (Note: toxicity updated from Viani et al, ref 6) • ST Peters, WD Heemsbergen, PC Koper et al., “Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy,” 24 (2006): 1990-1196. • DP Dearnaley, MR Sydes, JD Graham et al, “Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT101 randomized controlled trial,” Lancet Oncology 8 (2007): 475-487. • Anthony L. Zietman, “Correction: Inaccurate analysis and results in a Study of Radiation Therapy in Adenocarcinoma of the Prostate,” JAMA 299 No. 8 (2008): 898-900. Anthony L. Zietman et al., “Comparison of Conventional-Dose vs. High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate. A Randomized Controlled Trial,” JAMA 294 No. 10 (2005): 1233-1239. • Beckendorf V, Guerif S, Le Prise E, et al. The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate cancer: Feasibility and acute toxicity. Int J Radiat Oncol Biol Phys 2004;60: 1056–1065. (Note: no 5-year control rates given) • Viani GA et al. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1405-18.

44. Reviewing the Data

45. Protons are Safer and More Effective Protons significantly decrease the risk of secondary malignancies in prostate cancer treatment over 5 year period A 2008 MGH study determined that protons decreases the risk of patients developing a secondary cancer by 50%(1) “According to the study, 6.4 percent of patients who underwent proton therapy developed a secondary cancer while 12.8 percent of patients who had photon treatment [x-rays] developed another type of cancer.” • “Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy,” presented by Nancy Tarbell, M.D. at ASTRO 2008 (Chung et al. study) • SEER data • McGee et al., “Comparison of Second Cancer Risk in Prostate Cancer Patients Treated with Neutron/Photon Irradiation, Photon Irradiation, or Prostatectomy,” International Journal Radiation Oncology Biology Physics 66 (2006): S318-S319 • Fontenot et al., “Risk of secondary malignant neoplasms from proton therapy and intensity-modulated x-ray therapy for early-stage prostate cancer,” International Journal Radiation Oncology Biology Physics 74 (2009): 616-622 • Chung et al., “Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy,” International Journal Radiation Oncology Biology Physics 72 (2008) :S8

46. Prostate Cancer Summary • Protons are AN option for prostate cancer treatment • Protons are superior to IMRT • Protons are different from surgery and brachytherapy • Active surveillance is perfectly acceptable for many men with prostate cancer • Discussions should be had with patients about ALL the options

47. Parting Shots • Take home points: • All cancers should be approached in a multi-specialty or multi-disciplinary fashion • Patient care should be performed in team approach: • Concierge/Receptionists, Nurses, Therapists, Physicists/Dosimetrists, Physicians • State of the Art Radiation Therapy @ CDH/Procure • FULL Spectrum of Radiation Treatment options • HDR Brachytherapy • SBRT/SRS • IMRT/3D CRT/IGRT • Proton Beam Therapy

48. Parting Shots • Photons/Electrons will still be needed • Brachytherapy will still be utilized • Image guidance will remain critical for all modalities of radiation therapy • Proton beam therapy can improve the side effects profile in many of the disease we currently treat with photon radiation. • We are seeing just the tip of the iceberg

49. Tumors we are and will be able to treat: • Head / Neck • Eye • Sinus/nasal • Throat • Ear • Pediatric • Brain • Spinal Cord • Bone • Neurologic • Brain • Spinal Cord • Other Solid Tumors • Breast Cancer (2011) • Lung Cancer (2011) • Colorectal Cancer • Prostate

50. Questions