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Radiobiological Rationale of Hypofractionation, Clinical Relevance, Risk of Late Toxicities, and

Radiobiological Rationale of Hypofractionation, Clinical Relevance, Risk of Late Toxicities, and Prediction Possibilities Barry S. Rosenstein, Ph.D. Departments of Radiation Oncology, Mount Sinai School of Medicine and NYU School of Medicine

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Radiobiological Rationale of Hypofractionation, Clinical Relevance, Risk of Late Toxicities, and

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  1. Radiobiological Rationale of Hypofractionation, Clinical Relevance, Risk of Late Toxicities, and Prediction Possibilities Barry S. Rosenstein, Ph.D. Departments of Radiation Oncology, Mount Sinai School of Medicine and NYU School of Medicine Deuxieme Rencontre du Cercle Des Oncologues Radiotherapeutes du Sud Meridien Juan les Pins 26 Juin 2009

  2. Claudius Regaud (1870-1940) http://www.pasteur.fr/infosci/archives/e_reg0.html

  3. Hall, Radiobiology for the Radiologist, 2000

  4. Henri Coutard (1876-1950) radonc.ucsd.edu/.../historyImages/Coutard.jpg

  5. DISCUSSION.-DR. MAURICE LENZ (New York): It had been realized for a long time that large doses were essential for clinical arrest of cancer by roentgenotherapy. This could frequently not be carried out because of concomitant roentgen ray injury to adjacent normal tissues, especially in deeply situated and not markedly radiosensitive malignant tumors. Coutard reduced this handicap by applying to practice the principle of fractionating and protracting the total dosage over a longer period. This he did- at the suggestion, and on the basis, of experimental work carried out on ram's testes by Regaud.

  6. Strandquist Acta Radiol 55 (suppl):1, 1944

  7. NOMINAL STANDARD DOSE (NSD) SYSTEM Total Dose = (NSD) T 0.11 N 0.24 N = number of fractions T = overall time Ellis, Br J Radiol 44:101, 1971

  8. What’s Wrong with the NSD System and the Resulting Time, Dose and Fractionation (TDF) Tables?

  9. THE TIME FACTOR • T0.11 predicts a large increase of isoeffect dose at first, then increasing more slowly. The biological fact is just the opposite: it shows no increase at first and then a rapid rise of isoeffect dose as proliferation accelerates. • The time factor is underestimated for tumors and early‑responding tissues. • The time factor is overestimated for late‑responding tissues.

  10. THE FRACTION NUMBER • N0.24 does not predict the severe late damage that occurs for larger fraction sizes. • The impact of fractionation is underestimated for late-responding tissues and possibly some forms of cancer. • Fraction size, not number, is the important parameter.

  11. GENERAL CRITICISM TDF tables were too easy to use without thinking rigorously about the impact of fraction size, proliferation rates and the potential for incomplete repair between fractions.

  12. How can we more accurately estimate the impact of fraction size for tumor control as well as early and late effects?

  13. BIOLOGICALLY EFFECTIVE DOSE (BED) BED = nd[1+(d//)] n = number of fractions d = dose per fraction / = parameter, in units of Gy, characteristic of the impact of fraction size on the particular tissue or tumor BED = (total dose)(relative effectiveness) BED is the quantity by which different fractionation regimens can be compared.

  14. Where do / values come from?

  15. Withers, Cancer 55:2086, 1985

  16. Calculation of /Values (n1d1)[1+(d1//)] = (n2d2)[1+(d2//)] / = (D2d2-D1d1)/(D1-D2)

  17. http://www.dkfz-heidelberg.de/en/medphys/appl_med_rad_physics/images/Biology_1_re.jpghttp://www.dkfz-heidelberg.de/en/medphys/appl_med_rad_physics/images/Biology_1_re.jpg

  18. Hall, Radiobiology for the Radiologist, 2000

  19. Normalized Total Dose (NTD) or 2 Gy Equivalent Dose The total dose delivered in 2 Gy fractions that corresponds to a particular BED. NTD = BED/[1+(2 Gy//)]

  20. What is the impact of treatment time?

  21. Withers et al., Acta Oncologica 27:131, 1988

  22. ALLOWANCE FOR CELLULAR PROLIFERATION BED=nd[1+(d//)] – [(loge2) (T-Tk)/Tpot ] = (Total Dose) (Relative Effectiveness) – (loge2/) (Number Cell Doublings During Treatment) T - total treatment time Tk ("kick-off" time) - time at which compensatory proliferation or accelerated repopulation begins.  - parameter associated with cellular radiosensitivity Tpot – time required for cells comprising the tumor or normal tissue to double in number

  23. LATE EFFECTS

  24. TUMOR CONTROL

  25. Are BED Calculations Appropriate for Protocols Using Fraction Sizes >8Gy • PROBABLY NOT! • / ratios determined for protocols using fraction sizes <8Gy • Does not adequately take into account microvasculature; doses >8Gy produce endothelial cell damage due to activation of acid sphingomyelinase triggering apoptosis • Cancer stem cells resistant to doses <8Gy • Radiosurgery doses that produce adequate tumor control would have been predicted as insufficient 25

  26. BED CALCULATIONS, ALTHOUGH A USEFUL GUIDE FOR RESEARCH PURPOSES OR TO SERVE AS A YARDSTICK BY WHICH TO JUDGE NEW FRACTIONATION SCHEMES, ARE NOTTO BE CONSIDERED A SUBSTITUTE FOR CLINICAL JUDGEMENT AND TRAINING.

  27. THE Gene-PARE PROJECT Genetic Predictors of Adverse Radiotherapy Effects 

  28. HYPOTHESIS People who are carriers of certain single nucleotide polymorphisms (SNPs) may be more likely to develop adverse radiation effects compared with individuals who do not possess these DNA markers.

  29. OVERALL GOALS • To develop an assay capable of predicting, with a high level of sensitivity and specificity, which cancer patients are most likely to develop radiation injuries resulting from treatment with a standard radiotherapy protocol. • To obtain information to assist with the elucidation of the molecular pathways responsible for radiation-induced normal tissue toxicities through identification of genes possessing SNPs associated with the development of adverse effects.

  30. If we can identify SNPs associated with radiosensitivity and develop a predictive assay, what can be done with this information? • Receive a strictly surgical treatment, if feasible • Receive more of a conformal treatment (i.e. IMRT, protons, etc.) • Could be ideal radiotherapy candidates as their cancers may also be radiosensitive; standard treatment overdoses

  31. SINGLE NUCLEOTIDE POLYMORPHISM SNP

  32. Humans are 99.9% Identical Genetically

  33. ...but, 100% of Humans Differ Genetically

  34. PERSONALIZED MEDICINE The use of detailed information about a person’s genotype in order to select a medication, therapy or preventative measure that is particularly suited specifically to that individual.

  35. RADIOGENOMICS Predicting radiotherapy response of cancer patients based upon genetic profiles

  36. Mark et al., Nature Reviews Genetics 9, 356-369, 2008

  37. CANDIDATE GENE STUDIES 1998-2008

  38. RADIATION RESPONSE GENES SCREENED ATM – regulation of cell cycle checkpoints following irradiation SOD2 Response to reactive oxygen species RAD21 Repair of DNA double strand breaks TGFB1 Fibrosis, proliferation, differentiation, angiogenesis and wound healing XRCC1 Base excision repair XRCC3 Recombinational repair of DNA double strand breaks 39

  39. DANISH POST-MASTECTOMY BREAST CANCER PATIENTS WHO RECEIVED A HYPOFRACTIONATED PROTOCOL

  40. Low apoptotic response (≤16%) Intermediate apoptotic response (16-24%) High apoptotic response (>24%) Low lymphocyte apoptosis = increased late side effects Cumulative incidence of grade 2 or more late side effects according to radiation-induced CD8 T-lymphocyte apoptosis in 399 patients Ozsahin et al, Clin Cancer Res 2005

  41. Distribution of SNPs According to Radiation-Induced Late Effects

  42. THE PROBLEMS WITH CANDIDATE GENE STUDIES

  43. 1. Although a number of studies have detected correlations between possession of a minor SNP allele with an increased incidence of radiation toxicity, the results of early studies have not always been validated in subsequent work.

  44. 2. There is relative ignorance of the full spectrum of genes and proteins that are associated with the development of radiation injury.

  45. 3. Even if all of the important genes that encode the essential protein products associated with radiation toxicity were included in candidate gene studies, it is not certain whether all of these genes would possess SNPs that would both alter protein function and be present at a high enough frequency in the population to be of importance.

  46. 4. Critical SNPs associated with radiosensitivity may not even be located within genes, but in regulatory portions of the DNA.

  47. Genome-Wide SNP Association Studies

  48. THE AGNOSTIC APPROACH

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