The Clinical Perspective: Does Proton/Ion Beam Therapy Work?

1. Targeting Tumors: Ion Beam Accelerators Take Aim at Cancer The Clinical Perspective: Does Proton/Ion Beam Therapy Work? Hak Choy, M.D. University of Texas Southwestern Medical Center Dallas, Texas

2. Stephen Peggs, Brookhaven National Laboratory Advances in Accelerator Science Deliver Precision Beams for Cancer TherapyKathryn D. Held, Massachusetts General Hospital Charged Particles for Cancer Treatment: The Benefits of Ions over Photons

3. Targeting Tumors: Ion Beam Accelerators Take Aim at Cancer: The Clinical Perspective

4. Deaths and percentage of total deaths for the 10 leading causes of death: US, 2013 • Heart Diseases 597,689 24.2 • Cancer 574,743 23.3 • Respiratory diseases 138,080 5.6 • Cerebrovascular diseases 129,476 5.2 • Accidents (Unintentional injuries) 120,859 4.9 • Alzheimer’s disease 83,494 3.4 • Diabetes mellitus . 69,071 2.8 • Kidney disease 50,476 2.0 • Influenza and pneumonia 50,097 2.0 • Suicide 38,364 1.6 Rank Cause of Death No. And % of all deaths US 1990 Heart Diseases 723,636 34 Cancer 496,545 23 National Vital Statistics Reports, Vol. 62, No. 6, December 20, 2013

5. Lifetime Probability of Developing Cancer, by Site, Men and Women US, 1998-2000 Women Men All sites 1 in 2 Prostate 1 in 6 Lung & bronchus 1 in 13 Colon & rectum 1 in 17 Urinary bladder 1 in 29 Non-Hodgkin lymphoma 1 in 48 Melanoma 1 in 55 Leukemia 1 in 70 Oral cavity 1 in 72 Kidney 1 in 69 Stomach 1 in 81 All sites 1 in 3 Breast 1 in 7 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 57 Ovary 1 in 59 Pancreas 1 in 83 Melanoma 1 in 82 Urinary bladder 1 in 91 Uterine cervix 1 in 128 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI, 2003. http://srab.cancer.gov/devcan

6. How do we treat our Cancer Patients ? • Surgery • Chemo/Targeted therapy • Radiation Therapy • Conventional Radiation Therapy • Proton • Carbon ? • Combination of 1,2 &3

7. What is Radiation Therapy ? Something to do in the Basement with Radiation Oncologists, Physicists & Engineers

8. Radiation Oncologist Physicist Engineer

9. Technological Innovations with Conventional Radiation Treatment 1990’s 1980’s 1960’s 2000’s 1970’s Computerized 3D CT Treatment Planning The First Clinac Functional Imaging Cerrobend Blocking Electron Blocking Multileaf Collimator Dynamic MLC and IMRT High resolution IMRT Standard Collimator IMRT Evolution evolves to smaller and smaller subfields and high resolution IMRT along with the introduction of new imaging technologies Blocks were used to reduce the dose to normal tissues Technological improvements in radiotherapy have aimed to improve tumor control while limiting healthy normal tissue damage. MLC leads to 3D conformal therapy which allows the first dose escalation trials. The linac reduced complications compared to Co60 Computerized IMRT introduced which allowed escalation of dose and reduced compilations McKenna, WG

10. Characteristics of Photon Improve Depth Dose ! to improve tumor control while limiting healthy normal tissue damage 1920’s 1960 1970 1980 1990

11. Characteristics of Photon and Proton Bragg Peaks: Significant Improvement in Depth Dose ! 1920’s 1960 1970 1980 1990

12. Provide a lethal dose to the tumor… …while sparing the surrounding healthy tissue

13. Depth of tumor Provide a lethal dose to the tumor… …while sparing the surrounding healthy tissue

14. Depth of tumor Provide a lethal dose to the tumor… …while sparing the surrounding healthy tissue

15. Why protons for treatment of pediatric malignancies? lower overall normal tissue dose, which should result in fewer long term side effects: Growth abnormalities Hearing acuity Endocrine disorders Neurocognitive and psychosocial functioning lesser second malignancy risk

16. Dose Distribution Comparison

17. Protons appear to decrease the risk of most side effects compared to conventional Radiation Therapy All intact treated orbits have excellent vision (impaired in 50%+ with XRT). No cataracts thus far (compare to 50%+ with XRT) No neuroendocrine issues (60%+ with XRT) No painful dry eye (10% with XRT) Only mild orbital asymmetry Yock et al, IJROBP 63:1161,2005 Oberlin et al. JCO 19:197-204, 2001

18. Dose Distribution Comparison

21. ASTRO 9-2013

23. Global Proton Centers

24. Proton Therapy Centers in US Hampton Univ. Beaumont. Mich MGH Chicago Central U Penn Bloomington , IN Pro Cure Oklahoma Loma Linda Univ. of Florida MD Anderson

25. Particle Therapy 2000 and beyond 1920’s 1960 1970 1980 1990 Carbon-ion beam is approx. 3-4 time more biologically effective compared to protons and can potentially overcome tumor hypoxia

26. World Wide Carbon Centers How many in US ? None ! Italy: CNAO, Pavia; Germany: HIT, Heidelberg Japan: HIMAC, Chiba;  HIBMC, Hyogo;  GHMC, Gunma;  SAGA-HIMAT, Kyushu China: Shanghai and Lanzhou

27. What is the Evidence for Clinical Benefit of Carbon therapy in Cancer patients ? Thanks to NIRS, Chiba Japan

28. Clinical studies of skull based chordomas Slide Courtesy of Dr. Masashi Koto (NIRS)

29. Clinical studies of skull based chordomas Slide Courtesy of Dr. Masashi Koto (NIRS)

30. Clinical studies of skull based chordomas Slide Courtesy of Dr. Masashi Koto (NIRS)

31. Local Control and Survival Rates with Different Modalities for Adenoid Cystic Carcinoma Slide Courtesy of Dr. Azusa Hasegawa (NIRS)

32. Local Control and Survival Rates with Different Modalities for Adenoid Cystic Carcinoma Slide Courtesy of Dr. Azusa Hasegawa (NIRS)

33. Local Control and Survival Rates with Different Modalities for Adenoid Cystic Carcinoma Slide Courtesy of Dr. Azusa Hasegawa (NIRS)

34. Local Control and Survival Rates with Different Modalities for Mucosal Malignant Melanoma Slide Courtesy of Dr. Azusa Hasegawa (NIRS)

35. Local Control and Survival Rates with Different Modalities for Mucosal Malignant Melanoma Slide Courtesy of Dr. Azusa Hasegawa (NIRS)

36. Charged Particle Therapy for Hepatocellular Carcinoma Slide Courtesy of Dr. Shigeo Yasuda (NIRS)

37. Phase 1 study evaluating the treatment of patientswith hepatocellular carcinoma (HCC) with carbonion radiotherapy: The PROMETHEUS-01 trial

38. Chemoradiotherapy for Locally Advanced Pancreatic Cancer GEM: Gemcitabine Slide Courtesy of Dr. Shigeru Yamada (NIRS)

39. Chemoradiotherapy for Locally Advanced Pancreatic Cancer GEM: Gemcitabine Slide Courtesy of Dr. Shigeru Yamada (NIRS)

40. Two-year overall survival for carbon ion radiotherapy group and conventional multimodality treatment group for Locally Recurrent Rectal Cancer Gunma Heavy Ion Therapy Medical center

41. Controversial Issues with Particle Therapy lack of phase III clinical trials In most cases, too few centers and patients are involved to draw firm conclusions on the clinical effectiveness Ethical issues also arise when contemplating a randomized trial that randomize patients to a potentially suboptimal conventional radiation delivery. (Pediatric Cancers !) In small subtypes (ocular melanoma, adenoid cystic carcinoma and chordomas or chondrosarcomas of the base of the skull) the evidence is already sufficient to conclude that proton or C-ion therapies are superior to Conventional RT For other common tumor types, we need prospective Clinical Trials which include randomized phase III studies

42. Texas Center for Advanced Radiation Therapy (TCART): Carbon Conventional, Proton, $ 286 million Appox. $ 200-300 million $ 92 million Under Construction Planning Phase Under Construction National Particle Therapy Research Center

43. National Particle Therapy Research Center(NPTRC) will provide unique opportunity for major advancements in Cancer Research and Patient Care Private Funding Gov’t Federal (?) State Acadmic UTSouthwestern Texas Center for Advanced Radiation Therapy (TCART)

45. Total Radiation Therapy cost Approx $ 4-5 billions

46. Phase III: Overall SurvivalPhase III Trial of Carbo/paclitaxel +/- Bevacizumab in Non-Squamous NSCLC 1.0 12 mo 24 mo PC 44.4% 15.4% 6.6% Diff at 2 yrs. 0.8 BV/PC 51.0% 22.0% HR: 0.80, P = 0.003 0.6 2 months 60 days Proportion surviving Medians: 10.3, 12.3 0.4 0.2 0.0 12 24 36 0 6 18 30 42 48 Patients at risk PC 190 36 5 444 318 104 9 1 0 BV/PC 216 54 8 434 340 127 25 3 0 Survival (months)

47. Phase III: Overall SurvivalPhase III Trial of Carbo/paclitaxel +/- Bevacizumab in Non-Squamous NSCLC 1.0 12 mo 24 mo PC 44.4% 15.4% 6.6% Diff at 2 yrs. 0.8 BV/PC 51.0% 22.0% HR: 0.80, P = 0.003 0.6 2 months 60 days Proportion surviving Medians: 10.3, 12.3 0.4 0.2 0.0 12 24 36 0 6 18 30 42 48 Patients at risk PC 190 36 5 444 318 104 9 1 0 BV/PC 216 54 8 434 340 127 25 3 0 Survival (months)

48. 35-75 times less cost with Carbon Tx than other Tx. If the cost of Carbon Tx. in US is 10X of Japan, It will be still 3.5 to 7.5 times Cheaper !

49. Perhaps, We can do a “Whole lot better” with Carbon Therapy With much reduced Cost and Side Effects Heidelberg, Germany Carbon Therapy Center NIRS Chiba, Japan Carbon Therapy Center Shanghai Proton and Heavy Ion Center  CNAO Payvia, Italy Carbon Therapy Center

50. In Summary: More than 50% of all cancer patients receive conventional radiotherapy as part of their cancer treatments But it’s effectiveness is limited by unavoidably side effects. Technological improvements in radiotherapy have aimed to improve tumor control while limiting healthy normal tissue damage. Protons and heavy ions allow a higher local control of the tumor, a lower probability of damage to healthy tissue,(physical and biological effects in the Bragg peak) Although East Asia and Europe are heavily investing in heavy-ion centers, None in the US ..just thinking about it !! Funding to support clinical, physics, socio-economic, cost benefit research are also needed. Funding to build the clinical C-ion are desperately needed in US.