1. Heavy charged particles for cancer radiation therapy (HST.187) Introduction (Bragg peak, LET, OER, RBE) I.Physical rationale II.Biological rationale III.Clinical rationale This document: http://gray.mgh.harvard.edu/ (Resources)http://gray.mgh.harvard.edu/

2. Worldwide proton therapy experience

3. Moore’s law of proton therapy Exponential growth: Factor 2 in 10 years

4. Hospitals Chase a Nuclear Tool to Fight Cancer Front page, December 26, 2007 There is a new nuclear arms race under way — in hospitals. Medical centers are rushing to turn nuclear particle accelerators, formerly used only for exotic physics research, into the latest weapons against cancer. Some experts say the push reflects the best and worst of the nation’s market-based health care system, which tends to pursue the latest, most expensive treatments — without much evidence of improved health — even as soaring costs add to the nation’s economic burden…

5. Recommended reading

6. I. Physical rationale - The concept of dose - Dose is a measure of the amount of energy deposited in a small volume at a point of interest as a result of the radiation - be that energy deposited locally, or brought to the point of interest by secondary radiation generated at some distance from the primary interactions. The dose is the energy deposited in a small volume divided by its mass. Dose is expressed in units of Gray (Gy) 1 Gy = 1 Joule/kg

7. Bragg peak Depth Dose Photons Protons

8. Spread-Out Bragg Peak (SOBP)

9. 100% 60% 10% PROTONS PHOTONS Medulloblastoma “dose bath”

10. The proton advantage: Nasopharynx Photons (IMRT)Protons Dose bath

11. The proton advantage: Paraspinal PhotonsProtons Dose bath

12. I. Physical rationale Why charged particles? Why heavy?

13. I. Physical rationale Heavy charged particle therapy can reduce the dose load (“integral dose”) to normal tissues surrounding the tumor target volume by a factor of 2-3 (reduced “dose bath”). Increased “dose conformality”, i.e., dose gradient between tumor target volume and surrounding healthy tissues.

14. II. Biological rationale Recommended reading: –Eric J. Hall, Radiobiology for the Radiologist, Lippincott, 2000 –Chapter 5 in Goitein –Chapter 2 in DeLaney/Kooy –N. Suntharalingam, E.B. Podgorsak, J.H. Hendry: Basic Radiobiology IAEA publications http://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf http://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf

15. II. Biological rationale

16. Linear energy transfer (LET) “LET of charged particles in a medium is the quotient dE/dl, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dl.” ● 250 kVp X rays: 2 keV/μm. ● Cobalt-60  rays: 0.3 keV/μm. ● 3 MeV X rays: 0.3 keV/μm. ● 1 MeV electrons: 0.25 keV/μm. —14 MeV neutrons: 12 keV/μm. —Heavy charged particles: 100–200 keV/μm. —1 keV electrons: 12.3 keV/μm. —10 keV electrons: 2.3 keV/μm. LET < 10 keV /  m low LET LET > 10 keV /  m high LET

17. Oxygen enhancement ratio (OER) well oxygenated well oxygenated hypoxic

18. LET and OER

19. The linear-quadratic model of cell kill S(D) is the fraction of cells surviving a dose D;  is a constant describing the initial slope of the cell survival curve;  is a smaller constant describing the quadratic component of cell killing.

20. The linear-quadratic model of cell kill, fractionation

21. From cells to organs, dose-volume effects “Bath and shower” experiment on rat spinal cord Bijl et al, IJROBP 57:274-281, 2003

22. From cells to organs, dose-volume effects, Equivalent Uniform Dose (EUD)

23. Tumor Control Probability (TCP), Normal Tissue Complication Probability (NTCP) Schematic diagram on how the EUD can be used to estimate TCP

24. What is the difference in biological effectiveness between particles and photons/electrons ?  Considering RBE Relative Biological Effectiveness (RBE)

25. Dose [Gy] Surviving Fraction RBE=D x /D p Definition of RBE X-rays Particles

26. 1.07  0.12 RBE values for protons, in vivo (center of SOBP; relative to 60 Co) Mice data: Lung tolerance, Crypt regeneration, Acute skin reactions,Fibrosarcoma NFSa

27. RBE values RBE generic = 1.1 for protons RBE for heavier particles (carbon ions) can be much higher (>3) RBE dependencies: –Endpoint: RBE ( , survival/mutation in vitro/in vivo) –Dose: RBE increases with decreasing dose (in vivo ?) –LET: RBE clearly increases with depth

28. LET and RBE, “overkill”

29. Clinical potential of proton therapy: Reduce side effects (reduce NTCP) Increase tumor control probability (TCP) through “dose escalation” Facilitate combined modality therapy –Radiation+chemo, Bevacizumab, … Easy re-treatment of disease –Make cancer a chronic disease …

30. Physics projects in proton radiotherapy 1.Range prediction Finite range is the primary feature of proton therapy Range in the patient is uncertain Better dose calculation models needed 2.New challenges in image-guided RT (IGRT) Impact of image artifacts on proton range Impact of weight loss, tumor shrinkage Adaptive planning essential 3.Intensity modulated proton therapy (IMPT) Beam scanning techniques Challenging optimization problems

31. Physics projects in proton radiotherapy 4.From margins to robust plan optimization PTV concept does not work in proton therapy 5.Unique potential for in-vivo measurements Positron activation – PET/CT measurements Spontaneous gamma production 6.Develop new/cheaper acceleration techniques Laser acceleration, DWA Collaborate with laser and plasma physicists 7.Biological modeling Essential in C-12 therapy New fractionation schemes

33. Summary Physical rationale of heavy charged particle therapy –Reduced integral dose (by factor 2-3) –Potentially improved dose conformality Biological rationale: –Based on modeling studies: LET, OER, EUD, TCP/NTCP, RBE –Potentially increased RBE, but only for heavier particles (heavier than protons) Clinical rationale: –Do we need randomized clinical trials?

34. Homework assignment 1.If every radiation therapy patient worldwide* would get proton therapy (instead of x-rays), what would be the annual dose reduction in healthy tissues compared with the dose load from the Hiroshima bomb? 2.Read (and understand) the short review of radiation biology from http://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf http://www-naweb.iaea.org/nahu/dmrp/pdf_files/Chapter14.pdf *Assume that there are 2 million patients receiving x-ray radiation therapy every year

35. Dose Distance (km) Hiroshima (mGy) Nagasaki (mGy) Gamma ray 0.5 1.0 1.5 2.0 35,700 4,220 549 81 83,000 8,620 983 138 Neutron 0.5 1.0 1.5 2.0 6,480 260 9 0.4 2,970 125 5 0.2 Total number of people exposed: Hiroshima: 350,000; Nagasaki: 270,000 Source: Hiroshima international council for healthcare of the radiation exposed