Seminar, The Cockcroft Institute, Daresbury Science and Innovation Campus, 6 December 2006

1. Seminar, The Cockcroft Institute, Daresbury Science and Innovation Campus, 6 December 2006 Seminar at THE COCKCROFT INSTITUTE, Daresbury Science and Innovation Campus, 6 December 2006

2. Outline • REFRESHER ON (Modern) RADIOTHERAPY • DOSE DISTRIBUTIONS – the bottom line • RADIOBIOLOGY – what’s this? • THE TECHNOLOGY REQUIRED • COMPARATIVE PLANNING STUDIES • CLINICAL RESULTS TO DATE • WHAT THE UK NEEDS – highly conformal protons • SUMMARY/CONCLUSIONS

3. REFRESHER ON (Modern) RADIOTHERAPY • 50% of cancer patients treated with radiotherapy, or roughy 1 in 6 of us • Today it’s very ‘high tech’ • Everything is under computer control • Ultra sophisticated medical imaging: CT. MR, PET • Highly sophisticated 3‘treatment planning systems’ • CLINICAL RESULTS TO DATE • WHAT THE UK NEEDS – highly conformal protons

4. REFRESHER ON (Modern) RADIOTHERAPY • 50% of cancer patients treated with radiotherapy, or roughy 1 in 6 of us • Today it’s very ‘high tech’ • Everything is under computer control • ‘Intensity-modulation’ (photons) has been ‘all the rage’ • Ultra sophisticated medical imaging: CT. MR, PET; now CT on the treatment couch; 4D CT (time-lapse) • Highly sophisticated 3D ‘treatment planning systems’ • WHAT THE UK NEEDS – highly conformal PROTONS

6. The radiotherapy clinical accelerator Beam of photons or electrons e.g. absorbed dose in water determined by measuring charge collected in air cavity of ionisation chamber

7. Since around the late 80s…….. • CONFORMAL THERAPY (CFRT) • CFRT is based on the assumption that complications are reduced if the volume of “normal tissue” is reduced. Hence • - 3-D planning/ B-E-V • - Shaped fields -> MLCs • - IMRT/”inverse planning” • - Stereotactic techniques

8. What is the BASIS OF Conformal Therapy? • Ans: The VOLUME effect Smaller volume irradiated means HIGHER Tolerance Dose BAD BETTER

9. A (3D) dose distribution • Normal-tissue sparing • High dose to all of the target

10. Physico-biological Optimisation Example: H&N case

11. Physical optimisation • Goal: • Tumor: Mean Dose = 68 Gy • Upper Target : Min Dose = 65 Gy • Lower Target : Min Dose = 54 Gy 7 equally spaced beams

12. Physico-biological Optimisation • Results: • NTCPparotid : 3%  2% • NTCPsubmand : 22%  2% • NTCPcord : 24%  1% • - inhomogeneity : 3%  4% (Dagertun & Larsson, 2002)

16. WHAT COULD “HEAVY PARTICLES” DO FOR US THAT CURRENT STATE-OF-THE-ART PHOTON (AND ELECTRON) BEAMS CANNOT? DO SO-CALLED HEAVY PARTICLES STILL HAVE A ROLE IN THIS ERA OF HIGHLY CONFORMAL (incl. IMRT) megavoltage PHOTON THERAPY?

17. Kraemer, Jaekel et al “From ion tracks to ion radiotherapy” Lisbon workshop, June 2002.

18. Joiner M C (2002) Particle beams in radiotherapy. In Basic Clinical Radiobiology 3rd Edition (GG Steel Ed.) London: Arnold.

19. Fractionation High-LET qualities yield survival curves with very little shoulder i.e. high values of a/b for both tumour and NTs and therefore no advantage to be gained by using small fractions. Can one therefore use a small number of large fractions with high LET beams? YES provided that:  Re-oygenation not compromised (where important)  Positioning accuracy very high – no “help” from random errors due to fractionation  Acute effects not exacerbated beyond tolerance

22. The Oxygen effect revisited…………… For neutrons OER seems close to unity For ‘light ions’ e.g. Carbon, in the SOBP, the OER seems to be close to 2 For low LET qualities (linac x-rays, electrons, protons) at relevant fraction sizes of 2 Gray, the OER is also close to 2 - possibly slightly below (Nahum et al 2003) CONCLUSION: NO SIGNFICANT ADVANTAGE EXPECTED FOR LIGHT IONS OVER 2-GY FRACTIONATED ‘LOW-LET’ TREATMENTS regarding hypoxic tumour cells

24. Lee M., Wynne C., Webb S., Nahum A.E. and Dearnaley D.P. (1994) A comparison of proton and megavoltage x-ray treatment planning for prostate cancer Radiotherapy and Oncology, 33, 239-253.

25. Lee M., Wynne C., Webb S., Nahum A.E. and Dearnaley D.P. (1994) A comparison of proton and megavoltage x-ray treatment planning for prostate cancer Radiotherapy and Oncology, 33, 239-253.

26. Induction of Secondary Cancers by Radiotherapy – an ‘old’ problem thoroughly understood or ………. ???

29. Nahum A.E. and Glimelius B. (2001) Biological models applied to the comparison of proton and photon treatments Physica Medica 17, Suppl. 2, 126-130 Protons superior to x-rays for OARs with large volume effect e.g. lung

30. Technology?

31. Kraemer, Jaekel et al “From ion tracks to ion radiotherapy” Lisbon workshop, June 2002. The GSI magetic spot-scanning system cf. PSI, Chiba

32. PROTONS Excellent depth-dose properties thus excellent conformal therapy, especially if spot-scanning employed; integral dose ≈ 0.5 of photon therapy; zero dose beyond the tumour. Radiobiologically speaking: low LET (except at distal edge of Bragg peak) thus normal-tissue sparing achievable by fractionation RBE around 1.05-1.10 ≈ independent of depth Re- hypoxic clonogens, effective OER at 2 Gy ≈ 2 for most tumours Clinical indications: in principle all tumours on which conformal photons are used but especially base of skull (e.g. chordomas) and uveal melanoma; can spare the heart in ca. breast, indicated for ca. lung, and in child cancers Expensive largely due to requirement of a large gantry. Cost per treatment approx. THREE times that of conventional (non-IMRT) linac-based RT. Small number of facilities currently in use ; several new ones planned in the USA and Europe. > 30000 treatments since the early 1950s. Superiority over state-of-the-art photon therapy demonstrated theoretically but no clear phase-III clinical-trial based evidence yet for any common tumours

33. IONS HEAVIER THAN PROTONS (CARBON etc.) I Excellent depth-doses thus excellent CFRT, especially if spot-scanning employed; integral dose ≈ 0.6 of photon therapy (as for protons) BUT nuclear particles beyond the Bragg peak (unlike protons) Radiobiologically speaking: moderate to high LET Variable RBE through SOBP – thus non-uniform dose distributions required to yield uniform biological effect throughout SOBP; RBE lower outside SOBP hence potential differential normal-tissue sparing outside the target volume. Re- hypoxia, effective OER ≈ 2 for most tumours at average LET in SOBP but ≈ no radiobiological experiments done in hypoxic conditions in current clinical beams

34. IONS HEAVIER THAN PROTONS (CARBON etc.) II Very high a/b and hence large fractions possible in theory – but will REOXYGENATION be as effective as with a large number of small fractions?? Clinical indications: in principle all tumours on which conformal photons used; an assumed benefit for hypoxic tumours - no evidence clinically or radiobiologically. No comparative planning studies carried out (due to radiobiological complexity?) and no clear clinical evidence of superiority for any tumours but promising results initially reported for early-stage NSCLC by Chiba group, also for large fractions. NOT CONFIRMED in very recent paper: Koto et al (2004) Radioth. Oncol.71 147-56. EXTREMELY expensive largely due to requirement of a large gantry and sophisticated accelerator technology e.g. variable-energy synchrotron. Cost per treatment approx. FIVE times that of conventional (non-IMRT) linac-based RT. Three facilities currently treating: HIMAC (Chiba) and new one in Hyogo, GSI (Darmstadt); two new ones to be constructed, in Heidelberg and in Pavia.

35. How do we best take advantage of “Improved” dose distributions in risk organs? i. Escalate the Prescription Dose (by adding on a number of 2-Gy fractions) for the same or reduced (late) Complication Rate OR…….. ii. Reduce the number of Fractions FRACTION-NUMBER REDUCTION FRACTION-SIZE ESCALATION

36. SOME RADIOBIOLOGICAL CONSIDERATIONS ON THE POTENTIAL OF IMRT IN NON-STANDARD FRACTIONATION R. Calandrino1, S.Broggi1, G.M. Cattaneo1, C. Fiorino1, A.E. Nahum2, F. Fazio3

37. AN IDEAL ACCELERATOR FOR RADIOTHERAPY • 250-MeV Protons, narrow beam. Monodirectional • Beam currents of the order of 20 nanoamps (to deliver 1 Gy (Joule/kg) per minute in water) • ‘Spot-scanning’ with 100% reliability (in 3D) • Variable (monoenergetic) energy, very fast switching • Isocentric gantry - ESSENTIAL • 100% clinical use (not part of Physics lab) • Several independent treatment rooms per facility • 50 million Euros???