1. ‘A little to a lot or a lot to a little’ ­ the crucial question to be raised in conformal radiation therapy Professor Dag Rune Olsen, PhD Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo

2. Conformal Radiation Therapy Conformal radiation therapy aims at limiting the radiation dose to the targeted volume, and minimise the radiation dose to normal tissues and organs Conformal radiation therapy offers therefore a possibility of limiting the long-term side effects following radiation therapy. Brahme A. Int J Radiat Oncol Biol Phys. 58:603- 16,2004.

3. Conformal Radiation Therapy “Conformity index” is a measure of how well the high dose volume is confined to the target volume: CI=V target /V treated CI of conventional RT is low, for conformal RT medium, for IMRT medium-to-high, for proton therapy high. V target V treated

4. D. Dearnaley at al. Lancet 1999 Conformal Radiation Therapy Dearnaley et al. have shown, in a CRT comparing conventional with conformal RT of prostate cancers, that conformal RT lowered the late rectal toxicity as compared to conventional RT.

5. Dose maps: virtual rectum unfolding Open each orthogonal contour 66 Gy 21 Gy 9 Gy 44 Gy 61 Gy Hoogeman, MS et al. AVL, Amsterdam

6. Mean dose maps: conventional vs. conformal ConformalConventional 64-70 Gy 59-64 Gy 53-59 Gy 48-53 Gy 42-48 Gy 36-42 Gy 31-36 Gy 25-31 Gy Hoogeman, MS et al. AVL, Amsterdam

7. Conformal Radiation Therapy The crucial question: ‘a little to a lot or a lot to a little’ Which DVH corresponds to the lowest NTCP ? dose Rectal volume conv. IMRT

8. The normal tissue volume effect Dose response relationship for rectal bleeding following radiation therapy, demonstrating a significant volume effect. Rancati T, et al. Radiother Oncol. 73:21-32, 2004

9. N = total number of FSUs k = number of intact FSUs necessary to maintain organ function k/N = critical fraction serial k = N k < N parallel N k k < N mix Tissue organization and the normal tissue volume effect The concept of Functional Sub Units (FSU) Olsen DR, et al. Br J Radiol. 67:1218-25, 1994

10. Tissue organization and the normal tissue volume effect Is the tissue organization and thus the volume effect an inherent biological characteristics of the tissue, or does it vary with: –end-point –location within the organ (i.e. is the tissue organization uniform within the organ)

11. Tissue organization of the rectum – clinical study Sixty-six cancer prostate patients were treated with external radiation therapy with a mean dose to the planning target volume (PTV) of 66 Gy Late radiation effects in the rectum were assessed by a mailed ad hoc designed questionnaire to be completed by the patients 1–2 years after their radiotherapy Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.

12. Tissue organization of the rectum – clinical study Descriptive values calculated from the dose- volume histograms of the 66 pts. used in the analysis. Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.

13. Late toxicity in the rectum is dependent on the tissues functional architecture Tissue organization of the rectum – clinical study Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.

14. Tissue organization of the rectum – experimental study Experimental study on the effect of irradiated volume on late normal tissue damage in the rat rectum Male Fischer rats (CDF[F344]/CrLBR SPF) weighing 280–300 g were used for the experiments. Irradiation parameters and the numbers of cases in recent experiments are summarized on the left.

15. Tissue organization of the rectum – experimental study Cumulative dose-volume histograms of total rectal volume. "Unshielded" denotes the dose-volume histogram of the unshielded 8/2.5-mm step size configuration. "Shielded" and "Short" denote the dose-volume histograms of the shielded 8/2.5-mm step size and unshielded 2/2.5-mm step size configurations, respectively.

16. Tissue organization of the rectum – experimental study Dose response for single-dose and three- fractionated endocavitary irradiation with three different brachytherapy field configurations.

17. Tissue organization of the rectum – experimental study Histopathologic scores for: (a) single dose and (b) three-fractionated brachytherapy, with the unshielded configuration. U = ulceration PCP = proctitis cystica profunda VS = vascular sclerosis F = fibrosis AER = atypical epithelial regeneration CIS = colon injury score (total score). A B

18. Tissue organization of the rectum – experimental study Modelling demonstrated a considerable volume dependence of the occurrence of rectal stenosis. The mean functional reserve, 50, of 0.53 is consistent with a typical parallel functional volume organization. Rectum has thus a large functional reserves and expresses a threshold-type dose-volume relationship.

19. Tissue organization of the rectum Clinical study: –Mild end-points: –Serial structure Experimental study –Severe end-points: –Parallel structure Tissue organization and thus volume effect may thus depend on end-point !

20. Tissue organization and the normal tissue volume effect Is the tissue organization and thus the volume effect an inherent biological characteristics of the tissue, or does it vary with: –end-point –location within the organ (i.e. is the tissue organization uniform within the organ)

21. Is tissue organization uniform ? Radiation-induced pneumonitis in mouse lung Two end points: –elevated breathing rate after 22 weeks (‘elBR’) –lethality within 28 weeks (‘dead’) Single doses (11 - 22 Gy) Different subvolumes irradiated –size (% of total lung volume) –location (measured from base or apex) Lethality data analysed by Tucker et al. (1997) –volume effect model / target cell concept –estimated ‘target cell distribution’ base apex Lung: 50% base 70% apex Travis EL, et al. Int J Radiat Oncol Biol Phys. 38:1045-54, 1997.

22. SF = surviving fraction D = dose K and D 0 : radiosensitivity parameters Normal tissue complication probability: Is tissue organization uniform ? N = total number of FSUs n = number of irradiated FSUs k = critical number (k/N = critical fraction) p = FSU inactivation probability

23. Travis EL, et al. Int J Radiat Oncol Biol Phys. 38:1045- 54, 1997. Analysis performed by Sue Tucker, MD Anderson Cancer Centre, indicated a variable volume effect over the lung; could this variation be due to variation in: –density of FSUs –critical fraction of FSUs –Inactivation probability of FSUs Is tissue organization uniform ?

24. (N) Is tissue organization uniform ?

25. 30% base30% apex Is tissue organization uniform ?

26. 30% base30% apex Is tissue organization uniform ?

27. ‘A little to a lot or a lot to a little’ ? the question can only be answered if you know the tissue organization of the normal tissue or organ in question, and the answer depend on the end-point chosen and may even vary within the organ The crucial question: