2012-michael joiner-hypofractionation

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2012-michael joiner-hypofractionation

  1. 1. Does the tumour radiobiology help in the move toward hypofractionation? Michael Joiner Wayne State University Radiation Oncology Detroit, Michigan joinerm@wayne.edu
  2. 2. Does the tumour radiobiology hinder in the move toward hypofractionation? Michael Joiner Wayne State University Radiation Oncology Detroit, Michigan joinerm@wayne.edu
  3. 3. What radiobiology? Historically… •  Research has focused on doses per fraction of 1–3 Gy: clinically relevant •  Radiobiology is quite mature •  Little incentive/funding for high-dose research MCJ Aug 12 3
  4. 4. Why reconsider high dose fractions? •  Because we can: Physics •  Patient convenience and demand •  Lower cost of whole treatment •  Evidence that it is very effective •  Evidence of low !/" in some sites The radiobiology has not yet caught up MCJ Aug 12 4
  5. 5. Why not LQ at high doses? •  Reponse is really linear at higher doses? •  Vascular damage? •  Increased apotosis? •  Immunological effects? •  Mixed tumor cell populations with different response characteristics? Answers likely depend on tissue type and tumor type / stage MCJ Aug 12 5
  6. 6. Hypoxic cells in tumors First demonstration: ~1.5% of the cells were hypoxic 0.015 Mouse lymphosarcoma irradiated in vivo (Powers and Tolmach, 1973) MCJ Aug 12 6
  7. 7. The classic concept of reoxygenation during fractionated radiotherapy MCJ Aug 12 7
  8. 8. Reoxygenation during fractionation 0 10 No -reoxygenation -1 10 -2 10 -3 Surviving Fraction 10 -4 10 -5 10 -6 10 -7 10 30 fractions -8 10 No Hypoxic Cells -9 10 -10 10 0 10 20 30 40 50 60 Total Dose (2Gy Fractions) MCJ Aug 12 8
  9. 9. Courtesy: Bert van der Kogel
  10. 10. Courtesy: Bert van der Kogel Vessels (CD31, white) Hoechst 33342, blue Hypoxic marker 1: Pimonidazole (-4.5 h) Hypoxic marker 2: CCI-103F (-2.5h) Overlap: yellow
  11. 11. Acute hypoxia may not affect proliferation Proliferating cells (Ki67) blood vessel (CD31) Hypoxia (pimonidazole) Courtesy: George Wilson MCJ Aug 12 11
  12. 12. Total dose (Gy) – various isoeffects Early Late Yes No Dose/fraction (Gy) Thames et al. Int J Radiat Oncol Biol Phys 1982;8:219 MCJ Aug 12 12
  13. 13. Semin Radiat Oncol 2008;18:234–9 1.  Mechanistic, biologically based No 2.  Few parameters ! practical Yes 3.  Other models predict similar dose-fractionation No 4.  Well-documented predictive value in Lab Yes 5.  Validated up to 10 Gy per fraction, OK to 18 No
  14. 14. Semin Radiat Oncol 2008;18:240–3 1.  LQ model derived mostly in vitro No 2.  LQ underestimates high-dose tumor control ??? 3.  LQ ignores cell subpopulations Yes 4.  LQ mechs don’t reflect vascular, stromal Yes 5.  Need understanding mol mechs and stem cells No
  15. 15. Linear Quadratic model ! ln(S) = " D + # D !/" = 3 Gy -1 Effective D0 -2 1 (! + 2" D) 10 10 Surviving fraction Effective D0 0 10 2 -3 10 LQ -4 10 -5 10 -6 10 -7 10 -8 10 -9 SF2 = 0.5 10 0 5 10 Dose (Gy) 15 20
  16. 16. Effective D0 is too small at high doses MCJ Aug 12 16
  17. 17. -1 10 -2 10 Surviving fraction Linear Quadratic must straighten at high doses 0 10 -3 10 -4 10 -5 10 -6 10 -7 10 LQ -8 10 -9 10 0 5 10 Dose (Gy) 15 20
  18. 18. -1 10 !ln(S) = "D + #D 2 ! $ D 3 -2 10 Surviving fraction The Linear Quadratic Cubic model 0 10 LQC -3 10 -4 10 -5 10 ( ! = " 3DL -6 10 -7 !/" = 3 Gy 10 LQ -8 10 SF2 = 0.5 !ln(S) = "D + #D 2 -9 10 0 5 10 Dose (Gy) 15 20 )
  19. 19. Curtis' LPL model Complex DSB ! Simple DSB " Curtis SB. Radiat Res 1986;106:252
  20. 20. Response heterogeneity Alternative damage response pathways and/or cell types which are dose dependent
  21. 21. Vascular effects occur at high doses 0 Gy 5 Gy 2 Gy 10 Gy Functional intravascular volume Walker 256 tumors (s.c.) grown in legs of Sprague-Dawley rats Single dose radiation 30 Gy 60 Gy Park HJ et al. Radiat Res 2012;177:311–27 MCJ 21 Aug 12
  22. 22. Vascular effects occur at high doses Breast cancer patients Endothelial cells from normal breast or cancer Normal Cancer Normal Cancer Park HJ et al. Radiat Res 2012;177:311–27 MCJ 22 Aug 12
  23. 23. Vascular effects occur at high doses hypoxic oxic resistant endothelial sensitive endothelial Park HJ et al. Radiat Res 2012;177:311–27 MCJ 23 Aug 12
  24. 24. Endothelial cell apoptosis at high doses Lung 20 Gy Wild type p53 –/– ASMase –/– Intestines 15 Gy Wild type p53 –/– ASMase –/– Kolesnick R & Fuks Z. Oncogene 2003;22:5897–906 MCJ 24 Aug 12
  25. 25. Same tumor, different mice Garcia-Barros M et al. Science 2003;300:1155–59 MCJ 25 Aug 12
  26. 26. High doses not low doses per fraction Fuks Z & Kolesnick R. Cancer Cell 2005;8:89–91 MCJ 26 Aug 12
  27. 27. Immunological effects at high doses A549 Human NSCLC in lungs of nude mice 27 days after 12 Gy single dose Hematoxylin-Eosin Masson-Trichrome IF H F H x20 Tumor Small tumor nodules (arrows) with degenerative changes in nuclei and cytoplasm. Multiple large vacuoles, hemorrhages [H] and scattered inflammatory infiltrates x40 Normal lung Heavy infiltration of inflammatory cells [IF] mostly lymphocytes and neutrophils. Fibrous tissue [F] in midst of inflammatory infiltrates x40 C Normal lung Extensive fibrotic tissue [C] and hemorrhages [H] Hillman GG et al. Radiother Oncol 2011;101:329–36 MCJ Aug 12 27
  28. 28. Response heterogeneity Mixed target cell populations with different sensitivites
  29. 29. Radiotherapy and Oncology, 9 (1987) 241- 248 Elsevier 241 RTO 00341 An explanatory hypothesis for early- and late-effect parameter values in the LQ model T. E. Schultheiss, G. K. Zagars and L. J. Peters Division of Radiotherapy, The University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, TX 77030, U.S.A. (Received 3 November 1986, revision received 17 February 1987, accepted 17 February 1987) 1.  Higher-order terms (e.g. LQC) result from response heterogeneity Key words: Cell survival; lsoeffect: LQ model; Late effect Summary The isoeffect equation increase in “measured” value linear and 2.  Leads dose. derived from the linear-quadratic that higher-order cell survival containsof !/" to Experimental studies have shown (LQ) model of terms may also be present. These quadratic terms in terms have been previously attributed to the fact that the LQ model may be the first two terms in a power series approximation to a more complex model. This study shows that higher-order terms are introduced as a result of heterogeneity in the response of the cell population being irradiated. This heterogeneity is modeled by assuming that the parameters ! and " in the LQ model are distributed according to a bivariate normal distribution. Using this distribution, the expected value of cell survival contains third- and fourth-order terms in dose. These terms result in the previously observed downward curvature of Fe plots. Furthermore, these higher-order terms introduce bias in the estimated values of ! and ", if only the linear and quadratic terms of the LQ model are used, and higher-order terms are ignored. The bias is such that the estimated value of ! /" is substantially increased. Thus the higher values of ! /" observed for early effects as compared to late effects may be due to greater heterogeneity of response in early-responding tissues than in later-responding tissues. This differential effect is maintained even if the two cell populations have the same average values of ! and ". 3.  Leads to “linearization” of the “cell survival curve” at higher doses 4.  Explains the higher !/" for early effects and in some tumors
  30. 30. Response heterogeneity 30% 70% –20 –15 MCJ Aug 12 30
  31. 31. Response heterogeneity 30% 70% MCJ Aug 12 31
  32. 32. Put more of this heterogeneity modeling in?
  33. 33. A model is a lie that helps you see the truth - Howard Skipper Thanks Patrick McDermott
  34. 34. D0 = 1.42 Gy
  35. 35. In vivo survival curves linear at high dose Tissue D0 (Gy) Ref 1.65 Kember 1965, 1967 1.3-1.4 Withers 1967 Colon 1.42 Withers 1974 Spermatogenic tubules 1.74 Withers 1974 Telogen hair follicles 1.35 Griem 1979 Jejunum 1.3 Hendry 1983 Kidney tubules 1.25 Withers 1986 Cartilage growth plate Skin from HD Thames MCJ Aug 12 35
  36. 36. Why does this make a difference? High-dose log-linear (HDLL) model predicts higher isoeffect dose than LQ as the curve goes linear HDLL LQ At what dose does this divergence become significant? MCJ Aug 12 36
  37. 37. Approach •  Consider three tumor sites (breast, prostate, lung) where hypofractionation or SBRT is being used •  Identify relevant !/" values of tumor and NTs, and doses per fraction used clinically •  Choose HDLL models consistent with parameters •  Estimate size of dose per fraction at which 10% or greater disparity between predicted isoeffect doses occurs •  Compare this with doses actually in use clinically MCJ Aug 12 37
  38. 38. Fractionation in breast cancer Mean = 4.0 [CL 1.0 – 7.8]
  39. 39. Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 1, pp. 1–9, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter doi:10.1016/j.ijrobp.2010.08.035 Fraction size 2.66 – 3.3 Gy, 6 Gy in FAST trial CRITICAL REVIEW HYPOFRACTIONATED WHOLE-BREAST RADIOTHERAPY FOR WOMEN WITH EARLY BREAST CANCER: MYTHS AND REALITIES JOHN YARNOLD, F.R.C.R.,* SØREN M. BENTZEN, D.SC.,y CHARLOTTE COLES, PH.D.,z { AND JOANNE HAVILAND, M.SC. *Section of Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom; yDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; zOncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; {Institute of Cancer Research Clinical Trials and Statistics Unit, Section of Clinical Trials, Sutton, United Kingdom INTRODUCTION Hypofractionation for treatment of women with early breast cancer is being used again after addressing past causes of failure. Data from randomized trials confirm the safety and efficacy of schedules using fraction sizes of around 3 Gy, provided the correct downward adjustments to total dose are made. Unjustified concerns relating to heart tolerance, nonuniform dose distribution, and duration of follow-up need not discourage the routine adoption of a 15- or 16-fraction schedule. Potential benefits of the overall shorter treat- total dose must be reduced in order to maintain the same level of antitumor or normal tissue effect. True, the dose reduction is relatively modest for epidermis and some tumors, as correctly estimated by the Ellis isoeffect formula proposed in the late 1960s (1). When a regimen is changed from 25 Â 2.0-Gy fractions to a 15-fraction regimen delivered over the same overall treatment time, the Ellis formula estimated a dose reduction from 50 Gy to 45 Gy in 15 fractions of 3.0 Gy to match acute skin reactions. Ellis felt that the healing of skin epithelium reflected ‘‘the condition of
  40. 40. Fractionation in prostate cancer Int J Radiat Oncol Biol Phys 2011;79:195–201 Mean = 1.55 [CL 0.46 – 4.52]
  41. 41. Fractionation in prostate cancer 1.55 (0.46–4.52) Gy 5093 patients Proust-Lima C PSA evolution median follow up 4.7 years d/f < 2.8 6 institutional datasets, no risk-group dependence Int J Radiat Oncol Biol Phys 2011;79:195-201 1.48 Gy 1.4 (0.9–2.2) Gy 5969 patients Miralbell R Biochem relapse free survival at 5 years d/f < 6.7 7 institutional datasets, no risk-group dependence Int J Radiat Oncol Biol Phys 2012;82:e17-e24 1.86 (0.7–5.1) Gy 274 patients Leborgne F Biochem disease free survival at 5 years d/f < 3.15 Single institution, no risk-group dependence Int J Radiat Oncol Biol Phys 2012;82:1200-7
  42. 42. Relevant parameters for prostate trials !/" values Tumor: 1.48 Gy Proust-Lima, Miralbell, Leborgne GU and GI toxicity: 5 Gy Joiner & Bentzen 2002, Brenner 2004 Doses per fraction 3.1 Gy Arcangeli et al 2010 3 Gy Dearnaley et al 2007 Prostate Cancer Symposium Orlando FL abstract #303 2.7 Gy Pollack et al 2009 MCJ Aug 12 42
  43. 43. Treatment of NSCLC with SBRT Early-stage or palliative Reference (1st author) Dose per fraction (Gy) x Number fractions Minimum total dose to PTV (Gy) Timmerman (2006) 20-22 x 3 (80% isodose) 60-66 Timmerman (2003) 18-20 (80% isodose) 54-60 Nyman (2006) 15 x 3 (PTV periph) 45 Xia (2006) 5 x 10 (50% isodose) 50 Zimmermann (2005) 12.5 x 3 (60% isodose) 37.5 Wulf (2005) 12.5 x 3 (65% isodose) 37.5 Hara (2006) 30-34 x 1 (min PTV) 30-34 Fritz (2006) 30 x 1 (isocenter) 24 Hof (2003) 19-26 x 1 (isocenter) 15.2-20.8 Nagata (2005) 12 x 4 (isocenter) 48 to isocenter MCJ Aug 12 43
  44. 44. Results Breast: For dose/fraction 2.7-3.3 Gy, LQ predictions of isoeffect doses are approximately correct for tumor response and toxicity, but too low for higher doses per fraction (>6 Gy) Prostate: For dose/fraction of 2.7-3.1 Gy, LQ predictions of isoeffect doses are approximately correct for tumor response and toxicity, but too low for higher doses per fraction (>4 Gy). This undermines to some extent the LQ-predicted therapeutic gain from hypofractionation Lung: For dose/fraction < 10 Gy, LQ predictions of isoeffect doses are approximately correct for tumor response and early toxicity, but too low for higher doses per fraction (>12 Gy) Courtesy: Howard Thames MCJ Aug 12 44
  45. 45. Hypofractionation can work in 2012 ? •  Physics enables: -  improved dose definition -  image guidance •  Biology is catching up: -  low “!/"” of some tumors… -  vascular and immunological effects -  is LQ good for high dose fractions? MCJ Aug 12 45

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