1. Neutron Therapy Treatment For Advanced and Radioresistant Tumors Fighting Cancer with Neutrons

2. Neutron Therapy at Fermilab One of two (three ?) neutron therapy facilities in the US Operated in partnership with NIU Located in the Linac Gallery Have been treating since 1976, not experimental Radioresistant – not well controlled by conventional photon (x-ray) therapy Depends on the type of tissue that is cancerous Location & type

3. Neutron Therapy at Fermilab Patients from both physician and self referral Also referred to as “fast” neutron therapy First trials of neutron therapy in 1938 used lower energy neutrons than what is used today.

4. FAST NEUTRON THERAPY Why is it necessary? Why is it necessary? Why Fermilab? Why Fermilab? How is it done? How is it done? Clinical Results Clinical Results

5. Why Radiation Therapy? Why is it Necessary?

6. Cancer Stages & Treatment Stages Local Tumor Regional Metastasis Locally advanced Systemic Disease Treatment Surgery Radiation Therapy Chemotherapy

7. What is Radiation Therapy? (External Beam Therapy) Radiation directed at the tumor from outside the body

8. Conventional photon (x-ray) therapy

9. What is Radiation Therapy? (External Beam Therapy) Radiation directed at the tumor from outside the body Two critical components Where the energy is deposited The type of damage produced

10. Where is the Energy Deposited? Photons Neutrons Protons

11. Neutrons

12. Large radioresistant tumors are not well controlled by photon (or proton) therapy Resting cells are radioresistant Resting cells are radioresistant Hypoxic (low oxygen) cells are radioresistant Hypoxic (low oxygen) cells are radioresistant Neutron therapy is less affected by cell cycle or oxygen content Why are Neutrons Needed?

13. How Do Neutrons Overcome Resistance? The Type of Damage Produced Cell killing mechanisms are complicated DNA damage Free radicals Bystander effect Inflammation Genetics Focus on DNA damage through: Radiation Quality Linear Energy Transfer - LET

14. Radiation Quality Photons and Charged Particles Neutrons Low LETHigh LET

15. 2 nm10 nm 30 nm 2 μm Optimum LET 100 eV/nm ~3 ip ~200 nm DNA Damage

16. LET Comparison (Linear Energy Transfer) Belli, et. al., Molecular Targets in Cellular Response to Ionizing Radiation and Implications in Space Radiation Protection, J. Radiat. Res.,43:Suppl.,S13-S19 (2002) Photons & Protons Neutrons

17. How can we turn LET, radiation quality, and all the other complexities of cell killing into something we can understand?

18. Preliminary Blazek, et al Factor of 3 Relative Biological Effectiveness Neutrons Photons

19. Relative Biological Effectiveness - RBE - is the reason for pursuing Neutron Therapy

20. So What is the Best Therapy? LET LowHigh Dose Distribution Bragg Exponential Photons Protons Neutrons Ions $$$ $$$$$$$($) Cost-effective High RBE Therapy

21. Why Fermilab? Robert Wilson – 1 st director of Fermilab Article in Radiology in 1946 proposing protons Paper by Louis Rosen of LASL Use of accelerators for other than physics research – PAC ‘71 Prof. Lester Skaggs – U of C & Argonne Cancer Hospital Organized discussions looking at p, ions, π –1971 Clinical results from Hammersmith Hosp With neutrons - RBE September 7, 1976 – 1 st patient treatment With neutrons

22. How is radiation therapy done?

23. Electron linear accelerator for photon therapy

24. Proton linear accelerator for neutron therapy

25. Proton linear accelerator for Neutron therapy

26. Proton linear accelerator for neutron therapy

27. Photon & Neutron Collimators

29. Some Clinical Results How good is Neutron Therapy? It depends.

30. Before Neutron Therapy Prostate Tumor Bladder (with contrast) displaced CT scan of prostate cancer

31. After 12.25 Gray of neutrons Bladder (no contrast) Normal position

32. Beginning Of TreatmentEnd of Treatment Soft Tissue Sarcoma

33. Two Months After Treatment

34. Squamous Cell Carcinoma

35. Results of Neutron Clinical Trials Reference - Nuclear data for neutron therapy: Status and future needs - IAEA TECDOC 992 (1997) Reference - Nuclear data for neutron therapy: Status and future needs - IAEA TECDOC 992 (1997) “ ” (page 24) “The proportion of patients suitable for neutrons ranges from 10-20%, but this is probably a lower limit…with high energy modern cyclotrons neutron therapy will be useful for a larger proportion of patients. ” (page 24) Tumors where fast neutrons are superior to conventional x-rays are: Salivary - locally extended, well differentiated Paranasal sinuses - adenocarcinoma, mucoepidermoid, squamous, adenoid cystic Head and Neck - locally extended, metastatic Soft tissue, osteo, and chondrosarcomas Locally advanced prostate (page 23) Inoperable/recurrent melanomas (page 23)

36. Results of Neutron Clinical Trials IAEA TECDOC 992 (1997) - (continued ) Tumors where more research is needed Inoperable Pancreatic Bladder Esophagus Recurrent or inoperable rectal Locally advanced uterine cervix Neutron boost for brain tumors (pp 13-19)

37. Review of the loco-regional rates for malignant salivary gland tumors treated with radiation therapy. Fast Neutrons AuthorsNumber of Patients Loco-regional control (%) Saroja et al. (1987)11371(63%) Catterall and Errington (1987) 6550(77%) Battermann and Mijnheer (1986) 3221(66%) Griffin et al. (1988)3226(81%) Duncan et al. (1987)2212(55%) Tsunemoto et al. (1989)2113(62%) Maor et al. (1981)96(67%) Ornitz et al. (1979)83(38%) Eichhorn (1981)53(60%) Skolyszewski (1982)32(67%) Overall310207(67%) Low-LET Radiotherapy Photon and/or Electron beams and/or Radioactive Implants AuthorsNumber of Patients Loco-regional control (%) Fitzpatrick and Theriault (1986) 506(12%) Vikramet et al. (1984)492(4%) Borthne et al. (1986)358(23%) Rafla (1977)259(36%) Fu et al. (1977)196(32%) Stewart et al. (1968)199(47%) Dobrowsky et al. (1986)177(41%) Shidnia et al. (1980)166(38%) Elkon et al. (1978)132(15%) Rossman (1975)116(54%) Overall25461(24%) Table III. from IAEA-TECDOC-992, “Nuclear data for neutron therapy: Status and future needs,” December 1997, pg. 12.

39. Side Effects

40. Incidence of Life-Threatening or Fatal late normal tissue toxicity in the head and neck by prescribed tumor dose.

41. An Important Point for Potential Health Care Consumers Neutron Therapy is NOT a treatment of last resort. Healthy tissue can only tolerate a certain amount of any type of radiation. A specific tumor site cannot be retreated if it has already been treated with photons. Patients from both physician and self referral We presently treat up to 20 patients per year Very underutilized

42. How to find us neutrontherapy.niu.edu Or neutrontherapy.org

43. Does Fermilab Still Have a Role? Not tied to a major Hospital Good and Bad Large source to isocenter distance Continuity in physician support Inventive environment Presently developing upgrades Until an optimized, dedicated facility is built, Fermilab is (almost) the only game in town.

44. The End – Thank you Marty Murphy