1 radiobiological rationale of hypofractionation, clinical relevance, risk of late toxicities, and...
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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 Pins26 Juin 2009
2Claudius Regaud
(1870-1940)
http://www.pasteur.fr/infosci/archives/
e_reg0.html
3Hall, Radiobiology for the
Radiologist, 2000
4
Henri Coutard
(1876-1950)radonc.ucsd.edu/.../
historyImages/Coutard.jpg
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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 indeeply situated and not markedly radiosensitive malignant tumors. Coutard reduced this handicap by applying to practice the principle of fractionatingand 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 testesby Regaud.
6Strandquist Acta Radiol 55 (suppl):1, 1944
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Total Dose = (NSD) T 0.11 N 0.24
N = number of fractionsT = overall time
NOMINAL STANDARD DOSE (NSD) SYSTEM
Ellis, Br J Radiol 44:101, 1971
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What’s Wrong with the NSD System
and the Resulting Time, Dose and Fractionation
(TDF) Tables?
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1.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.
2.The time factor is underestimated for tumors and early‑responding tissues.
3.The time factor is overestimated for late‑responding tissues.
THE TIME FACTOR
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1.N0.24 does not predict the severe late damage that occurs for larger fraction sizes.
2.The impact of fractionation is underestimated for late-responding tissues and possibly some forms of cancer.
3.Fraction size, not number, is the important parameter.
THE FRACTION NUMBER
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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.
GENERAL CRITICISM
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How can we more accurately estimate the
impact of fraction size for tumor control as well as early and late effects?
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BIOLOGICALLY EFFECTIVE DOSE (BED)
BED = nd[1+(d//)]
n = number of fractionsd = 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.
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Where do / values come from?
15Withers, Cancer 55:2086,
1985
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Calculation of /
Values
(n1d1)[1+(d1//)] = (n2d2)[1+(d2//)]
/ = (D2d2-D1d1)/(D1-D2)
http://www.dkfz-heidelberg.de/en/medphys/appl_med_rad_physics/images/Biology_1_re.jpg
18Hall, Radiobiology
for the Radiologist, 2000
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Normalized Total Dose (NTD)
or2 Gy Equivalent Dose
The total dose delivered in 2 Gy fractions that corresponds to a particular BED.
NTD = BED/[1+(2 Gy//)]
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What is the impact of treatment time?
21Withers et al., Acta
Oncologica 27:131, 1988
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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 timeTk ("kick-off" time) - time at which compensatory proliferation or accelerated repopulation begins. - parameter associated with cellular radiosensitivityTpot – time required for cells comprising the tumor or normal tissue to double in number
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LATE EFFECTSPROTOCOL DESCRIPTION BED
(Gy4
)
2 Gy Eq Dose
25 fx X 2 Gy (32 days) Standard whole breast 75 5023 X 2 Gy (30 days) Standard whole breast 69 46
12 X 3.94 Gy (37 days)
Scandinavian 1970s post-mastectomy
94 6313 X 3.2 Gy (32 days) The Start Trialists’ Group
Lancet Oncol 9:331, 200875 50
15 x 2.67 Gy (18 days)
The Start Trialists’ Group Lancet 371:1098, 2008
67 4516 x 2.6 Gy (22 days) Whelan et al JNCI 94:1143,
200271 47
10 x 3.85 Gy (5 days) RTOG 0413; rtog.org/members/protocols/0413/041
3.pdf76 51
15 x 2.7 Gy (19 days) Formenti et al. JCO 16:2236, 2007 (NYU Prone AIMRT)
68 455 x 6 Gy (10 days) Formenti et al. IJROBP 60:493,
2004 (NYU Prone Partial Breast)
75 50
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TUMOR CONTROL
PROTOCOL DESCRIPTION BED (Gy4
)
2 Gy Eq Dose
25 fx x 2 Gy (32 days) Standard whole breast 71 4730 fx x 2 Gy (39 days) Standard with 7 fx X 2 Gy
boost84 56
12 x 3.94 Gy (37 days)
Scandinavian 1970s post-mastectomy
88 5913 x 3.2 Gy (32 days) The Start Trialists’ Group
Lancet Oncol 9:331, 200871 47
15 x 2.67 Gy (18 days)
The Start Trialists’ Group Lancet 371:1098, 2008
67 4516 x 2.6 Gy (22 days) Whelan et al JNCI 94:1143,
200271 47
10 x 3.85 Gy (5 days) RTOG 0413; rtog.org/members/protocols/
0413/0413.pdf
76 51
15 x 3.2 Gy (19 days)
5 x 6 Gy (10 days)
Formenti et al. JCO 16:2236, 2007 (NYU Prone AIMRT)
Formenti et al. IJROBP 60:493, 2004 (NYU Prone Partial
Breast)
8675
5750
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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
BED CALCULATIONS, ALTHOUGH A USEFUL GUIDE FOR RESEARCH PURPOSES OR TO SERVE AS A
YARDSTICK BY WHICH TO JUDGE NEW FRACTIONATION SCHEMES, ARE NOT TO BE CONSIDERED A
SUBSTITUTE FOR CLINICAL JUDGEMENT AND TRAINING.
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THE Gene-PARE PROJECT
Genetic Predictors of Adverse Radiotherapy Effects
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HYPOTHESISPeople 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.
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OVERALL GOALS
1. 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.
2. 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.
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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
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SINGLE NUCLEOTIDE
POLYMORPHISM
SNP
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Humans are 99.9% Identical Genetically
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...but, 100% of Humans Differ Genetically
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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.
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RADIOGENOMICS
Predicting radiotherapy response
of cancer patients based upon genetic
profiles
37Mark et al., Nature Reviews Genetics 9, 356-369, 2008
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CANDIDATE GENE STUDIES
1998-2008
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RADIATION RESPONSE RADIATION RESPONSE GENES SCREENEDGENES SCREENED
ATMATM – – regulation of cell cycle checkpoints following irradiationregulation of cell cycle checkpoints following irradiation
SOD2SOD2– Response to reactive oxygen speciesResponse to reactive oxygen species
RAD21RAD21– Repair of DNA double strand breaksRepair of DNA double strand breaks
TGFB1TGFB1– Fibrosis, proliferation, differentiation, angiogenesis and Fibrosis, proliferation, differentiation, angiogenesis and
wound healingwound healing
XRCC1XRCC1– Base excision repairBase excision repair
XRCC3XRCC3– Recombinational repair of DNA double strand breaksRecombinational repair of DNA double strand breaks
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DANISH POST-MASTECTOMY BREAST CANCER PATIENTS
WHO RECEIVED A HYPOFRACTIONATED
PROTOCOL
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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
Low apoptotic response (≤16%)
Intermediate apoptotic response (16-24%)
High apoptotic response (>24%)
Ozsahin et al, Clin Cancer Res 2005
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Distribution of SNPs According to Radiation-Induced Late Effects
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THE PROBLEMS WITH
CANDIDATE GENE STUDIES
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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.
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2. There is relative ignorance of the full spectrum of genes and proteins that are associated with the development of radiation injury.
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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.
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4. Critical SNPs associated with radiosensitivity may not even be located within genes, but in regulatory portions of the DNA.
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Genome-Wide SNP Association Studies
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THE AGNOSTIC APPROACH
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53IlluminaAffymetrix
SNP (Genotyping) Arrays
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Cost of SNP Genotyping
1998 - $4 per SNP2009 - $0.0004 per SNP
~10,000-fold decrease in the cost of SNP genotyping in the past decade!!!
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We need to develop a large consortium to create
BIGBiorepositories of tissue samples and Databanks
derived from well-characterized irradiated subjects
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Creation of an International Consortium to Establish a Radiotherapy Patient Biorepository/DatabankNIH- Sponsored Conference, March 18, 2008
Presenter Institution RT Populations that may be Contributed to the Biorepository/Databank
David Azria CRLC Val d’Aurelle, Montpellier, France
Breast and prostate cancer patients treated in CO-HO-RT, PHRC and BONBIS European cooperative trials
Yuhchyau Chen University of Rochester Medical Center, Rochester, NY
Patients treated by investigators who are members of CURED (Cancer Survivorship Research and Education)
Karen Drumea Rambam Medical Center, Haifa, Israel
Breast, prostate, head&neck and cervical cancer patients treated at the Rambam
Silvia Formenti NYU Medical Center, New York, NY
Breast cancer patients treated under NYU protocols
Debra Friedman Fred Hutchinson Cancer Research Center,
Seattle, WA
Patients treated with total body irradiation at the Fred Hutchinson Cancer Center
Bruce Haffty_________________
Germaine Heeren
UMDNJ-New Brunswick, NJ___________________________
ESTRO, Brussels, Belgium
Breast cancer patients treated at UMDNJ, Yale and Korea_______________________________________________
Patients enrolled in the GENEPI Biorepository
Alice HoMemorial Sloan-Kettering Cancer
Center, New YorkBreast cancer patients treated at MSKCC
Mayumi Iwakawa National Institute of Radiological Sciences, Chiba, Japan
Breast, prostate, head&neck and cervical cancer patients enrolled in the RadGenomics Biorepository
Shannon MacDonald
Massachusetts General Hospital Boston, MA
Breast and pediatric cancer patients treated at MGH
Thomas Merchant St. Jude Children’s Research Hospital, Memphis, TN
Pediatric patients treated at St. Jude
Mahmut Ozsahin Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Cancer patients treated under EORTC protocols
Matthew Parliament Cross Cancer Institute/University of Alberta, Edmonton, Canada
Prostate, breast and head&neck cancer patients treated at the Cross Cancer Institute
Barry Rosenstein Mount Sinai School of Medicine, New York, NY
Patients enrolled in the Gene-PARE biorepository, the U.K. Start trial and RTOG
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The
RaPiDInternational Consortium
Radiotherapy Patient Biorepository and Databank
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INTERNATIONAL RADIOGENOMICS CONSORTIUM
17-18 November, 2009
Manchester, UK
GOAL
To provide a collaborative structure for the international radiation oncology research community to pool data to discover the genetic basis for individual differences in susceptibility for the development of radiation injuries resulting from radiotherapy.
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STUDY INVESTIGATORS
American Collaborators
Mount Sinai School of Medicine NYU School of MedicineDavid Atencio, Ph.D. Silvia Formenti, M.D.Ryan Burri, M.D. Harry Ostrer, M.D.Jamie Cesaretti, M.D.Grace Fan, M.D. Yale/UMDNJSheryl Green, M.D. Bruce Haffty, M.D.Alice Ho, M.D.Lynda Kusnetz, B.A.Karen Loeb, M.D.Christopher Peters, M.D.Sheila Peters, B.A. Richard Stock, M.D. Nelson Stone, M.D.Sylvan Wallenstein, Ph.D.
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INTERNATIONAL COLLABORATORS
Aarhus University Hospital, Denmark CRLC Val d'Aurelle, FranceJan Alsner, M.D. David Azria, M.D., Ph.D.Nicolaj Andreassen, M.D. Nigel Crompton, Ph.D.Jens Overgaard, M.D. Jean-Bernard Dubois, Ph.D.Marie Overgaard, M.D Andrew Kramar, Ph.D.
Françoise Mornex, M.D.Institute for Cancer, England André Pèlegrin, M.D.Roger A’Hern, M.Sc.Soren Bentzen, Ph.D. (Wisconsin) CHUV, Lausanne, SwitzerlandLone Gothard, H.N.D. René-Olivier Mirimanoff, M.D.Jo Haviland, M.Sc. Mahmut Ozsahin, M.D., Ph.DRoger Owen, M.D.Georges Sumo, M.S. Rambam Medical Center, IsraelMark Sydenham, B.Sc. Abraham Kuten, M.D.John Yarnold, M.B.B.S. Karen Drumea, M.D.
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