Transcript Document

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
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26 Juin 2009
Claudius Regaud
(1870-1940)
http://www.pas
teur.fr/infosci/a
rchives/e_reg0.
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html
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Hall, Radiobiology for the Radiologist,
Henri Coutard
(1876-1950)
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radonc.ucsd.edu/.../histor
yImages/Coutard.jpg
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
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by Regaud.
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Strandquist Acta Radiol 55 (suppl):1, 1944
NOMINAL STANDARD DOSE
(NSD) SYSTEM
Total Dose = (NSD) T 0.11 N 0.24
N = number of fractions
T = overall time
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Ellis, Br J Radiol 44:101, 1971
What’s Wrong with the NSD System
and the Resulting
Time, Dose and Fractionation (TDF)
Tables?
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THE TIME FACTOR
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
late-responding tissues.
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for
THE FRACTION NUMBER
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.
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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.
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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 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
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regimens can be compared.
Where do / values come from?
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Withers, Cancer 55:2086, 1985
Calculation of / Values
(n1d1)[1+(d1//)] = (n2d2)[1+(d2//)]
/ = (D2d2-D1d1)/(D1-D2)
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http://www.dkfz-heidelberg.de/en/medphys/appl_med_rad_physics/images/Biology_1_re.jpg
Hall, Radiobiology
for
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the Radiologist, 2000
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//)]
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What is the impact of treatment time?
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Withers et al., Acta
Oncologica 27:131, 1988
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
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LATE EFFECTS
PROTOCOL
DESCRIPTION
BED
(Gy4)
25 fx X 2 Gy (32 days)
Standard whole breast
23 X 2 Gy (30 days)
Standard whole breast
12 X 3.94 Gy (37 days)
Scandinavian 1970s postmastectomy
13 X 3.2 Gy (32 days)
2 Gy
Eq Dose
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94
50
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The Start Trialists’ Group Lancet
Oncol 9:331, 2008
75
50
15 x 2.67 Gy (18 days)
The Start Trialists’ Group Lancet
371:1098, 2008
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16 x 2.6 Gy (22 days)
Whelan et al JNCI 94:1143, 2002
10 x 3.85 Gy (5 days)
RTOG 0413;
rtog.org/members/protocols/0413/0413.pdf
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76
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15 x 2.7 Gy (19 days)
Formenti et al. JCO 16:2236, 2007
(NYU Prone AIMRT)
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5 x 6 Gy (10 days)
Formenti et al. IJROBP 60:493, 2004
(NYU Prone Partial Breast)
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50
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TUMOR CONTROL
PROTOCOL
DESCRIPTION
BED
(Gy4)
25 fx x 2 Gy (32 days)
Standard whole breast
30 fx x 2 Gy (39 days)
Standard with 7 fx X 2 Gy boost
12 x 3.94 Gy (37 days)
2 Gy
Eq Dose
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84
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Scandinavian 1970s postmastectomy
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13 x 3.2 Gy (32 days)
The Start Trialists’ Group Lancet
Oncol 9:331, 2008
71
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15 x 2.67 Gy (18 days)
The Start Trialists’ Group Lancet
371:1098, 2008
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16 x 2.6 Gy (22 days)
Whelan et al JNCI 94:1143, 2002
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10 x 3.85 Gy (5 days)
RTOG 0413; rtog.org/
members/protocols/0413/0413.pdf
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15 x 3.2 Gy (19 days)
Formenti et al. JCO 16:2236, 2007
(NYU Prone AIMRT)
5 x 6 Gy (10 days)
Formenti et al. IJROBP 60:493, 2004
(NYU Prone Partial Breast)
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2450
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
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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.
THE Gene-PARE PROJECT
Genetic Predictors of Adverse
Radiotherapy Effects
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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.
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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
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development of adverse effects.
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
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Mark et al., Nature Reviews Genetics 9, 356-369, 2008
CANDIDATE GENE
STUDIES
1998-2008
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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
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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
Low apoptotic response (≤16%)
Intermediate apoptotic response (16-24%)
High apoptotic response (>24%)
Cumulative incidence of grade 2 or more late side effects according to
radiation-induced CD8 T-lymphocyte apoptosis in 399 patients
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Ozsahin et al, Clin Cancer Res 2005
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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SNP (Genotyping) Arrays
Affymetrix
Illumina
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Cost of SNP Genotyping
1998 - $4 per SNP
2009 - $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
BIG
Biorepositories 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/Databank
NIH- 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
Memorial Sloan-Kettering Cancer
Center, New York
Breast cancer patients treated at MSKCC
Alice Ho
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
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
Thomas Merchant
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The
RaPiD
International 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
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resulting from radiotherapy.
STUDY INVESTIGATORS
American Collaborators
Mount Sinai School of Medicine
David Atencio, Ph.D.
Ryan Burri, M.D.
Jamie Cesaretti, M.D.
Grace Fan, M.D.
Sheryl Green, 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.
NYU School of Medicine
Silvia Formenti, M.D.
Harry Ostrer, M.D.
Yale/UMDNJ
Bruce Haffty, M.D.
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INTERNATIONAL COLLABORATORS
Aarhus University Hospital, Denmark
Jan Alsner, M.D.
Nicolaj Andreassen, M.D.
Jens Overgaard, M.D.
Marie Overgaard, M.D
Institute for Cancer, England
Roger A’Hern, M.Sc.
Soren Bentzen, Ph.D. (Wisconsin)
Lone Gothard, H.N.D.
Jo Haviland, M.Sc.
Roger Owen, M.D.
Georges Sumo, M.S.
Mark Sydenham, B.Sc.
John Yarnold, M.B.B.S.
CRLC Val d'Aurelle, France
David Azria, M.D., Ph.D.
Nigel Crompton, Ph.D.
Jean-Bernard Dubois, Ph.D.
Andrew Kramar, Ph.D.
Françoise Mornex, M.D.
André Pèlegrin, M.D.
CHUV, Lausanne, Switzerland
René-Olivier Mirimanoff, M.D.
Mahmut Ozsahin, M.D., Ph.D
Rambam Medical Center, Israel
Abraham Kuten, M.D.
Karen Drumea, M.D.
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