understanding radiotherapy-induced second cancers
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Understanding Radiotherapy-Induced
Second Cancers
David Brenner and Igor ShuryakCenter for Radiological ResearchColumbia UniversityNew York
and Potentially Reducing
• 15-year relative survival rate for patients treated for breast or prostate cancer is 75% (c.f., 58% for breast in 2001)
• Estimated risk of developing a radiation-induced second cancer for 10+ year prostate RT survivors treated with RT around the 1980s was ~1.5%**
As younger patients are treated, and with longer life expectancy, RT-induced second malignancies will likely assume increasing importance
There is increasing concern about radiotherapy-related second
cancers
** SEER analysis Brenner et al (2000)
There is also an increasing realization that lifetime cancer risks due to radiation
exposurein middle age may be larger than we
thought
0 10 20 30 40 50 60 70 80Age at Exposure
0
1000
2000
3000
4000
5000
Lifetime attributable cancer risk per
106 individuals exposed to 10 m
Gy
Female
Male BEIR
From BEIR-VII (2006)4000
2000
0 20 40 60 80Age at Exposure
Shuryak et al 2010
BEIR-VII 0
Surgery
Radiotherapy
Prop
ortio
n w
ith n
o se
cond
prim
ary
canc
er
0 5 10 15 20 25Time (years)
1.0
0.8
0.6
0.4
0.2
0.0
2,000 prostate cancer patients treated with RT (1984 to 2005)
vs. matched prostate cancer patients who underwent surgery
Huang et al 2011
Data from William Beaumont Hospital
14%
28%
Estimating second cancer risks after contemporary
radiotherapy
• Retrospective epidemiology necessarily relates to RT protocols several decades ago
– Different prescription doses
– Different fractionation schemes / dose rates
– Different normal-tissue dose distributions
Compared to the older 3-D conformal radiotherapy, modern IMRT techniques minimize the amount of normal tissue getting high doses
But IMRT does result in larger volumes of normal tissue getting lower doses (more fields and more leakage)
Which is preferable in terms of second cancers? Small volumes of normal tissue getting high doses (3D-
CRT)
Larger volumes of normal tissue getting low doses (IMRT)
Example: Second Cancers: IMRT vs. 3-D conformal RT
Key is the shape of the dose-response relationshipfor radiation-induced carcinogenesis...
High doses don’t matter
• IMRT minimizing high doses helps • IMRT’s extra lower doses less important
Example: Second Cancers: IMRT vs. 3-D conformal RT
total dose total dose
• IMRT minimizing high doses doesn’t help• IMRT’s extra lower doses are bad
High doses do matter
Can
cer R
isk
OR
DOSE
The standard model of carcinogenesis at high doses:
Competition between oncogenic transformation & cell killing
Gray 1965
SURVIVAL
ONCOGENIC TRANSFORMATION
However, recent epidemiology suggests that the risks are not small
at large doses
0 5 10 15 20 25 30 35 40 45Dose (Gy)
0
10
20
30
40
50
Bre
ast c
ance
r exc
ess
rela
tive
risk
A-bomb dataHodgkins dataStandard model
Median age at exposure:23 Median attained age: 42B
Hodgkins data:Travis 03,Van Leeuwen 03
RT-induced breast cancer
0 5 10 15 20 25 30 35 40 45Dose (Gy)
0
5
10
15
Lung
can
cer e
xces
s re
lativ
e ris
k
A-bomb dataHodgkins dataStandard Model
Median age at exposure:45 Median attained age: 58
0
5
10
15
20
25
V36
0
40
80
120
A
Hodgkins data:Gilbert 2003
However, recent epidemiology suggests that the risks are not small
at large doses
RT-induced lung cancer
Cell numbers during RT and subsequent normal-tissue
repopulation
Sachs & Brenner 2005
End RT
Radiation-induced pre-malignant cells
We know enough about repopulation mechanisms to be able to add them to the standard (Gray) model of radiation-induced cancer at high doses
Cancer risks at high doses: A 3rd significant mechanism
Proliferation of pre-malignant cells during organ repopulation
Sachs & Brenner 2005
1. Estimate the low dose (~2 Gy) age- gender- and organ-specific relative risks from A-bomb survivors
2. Use standard models to “convert” theselow dose relative risks to apply to Western population / individual of given age and gender
3. Extrapolate these low-dose risks tofractionated high doses using mechanistic models(initiation / killing / repopulation)
How to calculate cancer risks at high doses, which are organ-specific, age-specific, and gender-specific....
Sachs & Brenner 2005
Radiation-induced breast cancer: Excess relative risk at high doses
0 5 10 15 20 25 30 35 40 45Dose (Gy)
0
10
20
30
40
50
Bre
ast c
ance
r exc
ess
rela
tive
risk
Hodgkins dataRepopulation modelSimplified model
Median age at exposure:23 Median attained age: 42B
Brenner et al 2006JNCI 98: 1974-86 (2006)PNAS 102:13040-5 (2005)
Mean exposure age: 23
Radiation-induced lung cancer: Excess relative risk at high doses
0 5 10 15 20 25 30 35 40 45Dose (Gy)
0
5
10
15
Lung
can
cer e
xces
s re
lativ
e ris
k
Median age at exposure:45 Median attained age: 58
0
5
10
15
20
25
0
40
80
120Hodgkins dataRepopulation modelSimplified model
A
Brenner et al:JNCI 98: 1974-86 (2006)PNAS 102:13040-5 (2005)
Mean exposure age:45
Key is the shape of the dose-response relationshipfor radiation-induced carcinogenesis...
High doses don’t matter
• IMRT minimizing high doses helps • IMRT’s extra lower doses less important
Example: Second Cancers: IMRT vs. 3-D conformal RT
total dose total dose
• IMRT minimizing high doses doesn’t help• IMRT’s extra lower doses are bad
High doses do matter
Can
cer R
isk
0 20 40 60Dose (Gy)
0
2
4
6
ERR
Stomach Cancer
DataModel
0 20 40 60Dose (Gy)
0
4
8
12ER
R
Lung Cancer
DataModel
0 20 40 60Dose (Gy)
0
1
2
3
ERR
Colon Cancer
DataModel
0 20 40 60Dose (Gy)
0
1
2
3
4
5
ERR
Rectal Cancer
DataModel
0 20 40 60Dose (Gy)
0
2
4
6
ERR
Pancreatic Cancer
DataModel
0 20 40 60Dose (Gy)
0
1
2
3
4
ERR
Bladder Cancer
DataModel
0 20 40 60Dose (Gy)
0
5
10
15
20
25
ERR
Thyroid Cancer
DataModel
0 20 40 60Dose (Gy)
0
10
20
30
40
50
ERR
Breast Cancer
DataModel
0 20 40 60Dose (Gy)
0
20
40
60
ERR
CNS Cancers
DataModel
Such models can do a reasonable job of modeling radiotherapy-induced second-cancer risks for
many sites
Brenner et al 2009
BLADDER BREAST CNS
COLON LUNG PANCREAS
RECTUM STOMACH THYROID
Lifetime absolute risks, as a function of age at exposure
0
1000
2000
3000
4000ALL CANCERS
0
20
40
60
80LIVER CANCER
0
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300 COLON CANCER
0 20 40 60 800
400
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1200 BREAST CANCER
0 20 40 60 800
40
80
120 STOMACH CANCER
0 20 40 60 800
100
200
300BLADDER CANCEREx
cess
life
time
risk
Age at exposure (years)
0 20 40 60 800
200
400
600 LUNG CANCER
0
2000
4000
6000ALL CANCERS
Excess lifetime risks per 0.1 Gy per 105 persons
Shuryak et al JNCI 2010
Blue = BEIR VII (2006)Red = 2010 analysis
Based on these approaches, we can make predictions of second-cancer risks for modern
radiotherapeutic protocols
ERR = 2.1 [1.1, 6.1]
Koh et al 2007
0 1000 2000 3000 4000
V1
Dose (cGy)
Volu
me
expo
sed
to g
iven
dos
e
Bilateral breast DVH
30 year old female,35 Gy mantle RT,20 fractions
0 1000 2000 3000 4000
V3
ERR
con
trib
utio
n / u
nit d
ose
Dose (cGy)
Contributions of different doses to the overall risk
0 1000 2000 3000 4000
V5
0
1
2
3
4
5
6
7
Dose (cGy)
Exce
ss re
lativ
e ris
k af
ter 2
0 ye
ars
Breast cancer ERR after 20 years
30 year old female,20 fractions
+
A potential application: Reducing Second Breast Cancers
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Contralateral B
reast Cancer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Contralateral B
reast Cancer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
Data from Freedman et al 2005
A potential application: Reducing Second Breast Cancers
1. Second breast cancer in the contralateral breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Contralateral B
reast Cancer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Contralateral B
reast Cancer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Con
tral
ater
al B
reas
t Can
cer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
Con
tral
ater
al B
reas
t Can
cer R
isk
Contralateral breast. Age at treatment: 57
Second cancer risk in breast cancer patientsBackground cancer risk in healthy womenPredicted radiation-induced riskPredicted radiation-induced risk
Measured risk in breast cancer patientsBreast cancer risk in healthy women
Age 57 at first cancer
Second Breast Cancer: Contralateral Breast
Brenner et al. JCO 2007
Mean age at 1st cancer: 57Large genetically-based second-cancer risk in
breast-cancer survivors
A potential application: Reducing Second Breast Cancers
2. Second breast cancer in the ipsilateral breast
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsilateral Breast C
ancer Risk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsilateral Breast C
ancer Risk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsilateral Breast C
ancer Risk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsilateral Breast C
ancer Risk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
Brenner et al. JCO 2007
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsi
late
ral B
reas
t Can
cer R
isk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
0 5 10 15 20Years Post Radiotherapy
0.00
0.05
0.10
0.15
0.20
0.25
Total ipsilateral second cancer riskRisk of independent second cancerPredicted radiation-induced risk
Ipsi
late
ral B
reas
t Can
cer R
isk
Ipsilateral breast. Age at treatment: 57Second Breast Cancer: Ipsilateral Breast
All second ipsilateral breast cancerAll genetically-independent second ipsilateral breast cancerPredicted radiation-induced breast cancer
Age 57 at first cancer ----
In the ipsilateral breast, the risk of a genetically-based
second-cancer has been essentially eliminated
Data from Freedman et al 2005
Why is there no genetically-based second-cancer risk in the ipsilateral
breast?
• Likely explanation is related to the ~46 Gy fractionated dose to the ipsilateral breast
• Only about 1 in 106 cells will survive this fractionated dose
• So assuming there at most a few thousands of background pre-malignant stem cells in the breast, they will all be sterilized
Prophylactic mammary irradiation (PMI) to the contralateral breast
• If whole breast irradiation has eliminated all the background pre-malignant stem cells in theipsilateral breast ....
prophylactic mammary irradiation (PMI) to the contralateral breast would have the potential toeliminate the large background risk in that breast
PMI would need much lower dose than the ~46 Gy ipsilateral breast dose, as we are only trying to kill relatively small numbers of pre-malignant cells,not millions of tumor cells
Irradiating healthy normal tissue?????
The contralateral breast ofa breast cancer survivor
is not a healthy normal tissue
What PMI dose to the contralateral breast would be needed?
Brenner et al. JCO 2007
• So a realistic PMI fractionated dose would be around 20 Gy
• Much lower than the standard post-lumpectomy RT dose
• Need to consider the risk of radiation-induced cancer• Predicted PMI-induced breast cancer risk is ~4% at 20 yrs
• So if PMI eliminates a ~15% contralateral breast cancer risk, it would have a favorable benefit / risk ratio
0 250 500 750 1000
V3
10
15
20
25
Total PMI D
ose (Gy, 10 fractions)
Number of Background Pre-Malignant Cells in Breast
Experimental investigations of PMI
Prophylactic Mammary Irradiation (PMI) Dose to the Contralateral Breast (Gy)
Rel
ativ
e R
isk
of C
ontr
alat
eral
Se
cond
Bre
ast C
ance
r
0 20 40
1
A B C
Schematic: Contralateral Breast Cancer Risk as a Function of PMI Radiation Dose
DOSE REGIONFOR WHICH CONTRALATERALSECOND BREASTCANCER RISK ISREDUCED
0
LEAD SHIELD
LEAD
SHI
ELD
MMTV-PyVT mice Relative risk of breast cancer after PMI
Rel
ativ
e B
reas
t Can
cer R
isk
PMI Dose
PMI for BRCA1/2 carriers
• Second contralateral breast cancer in BRCA1/2 carriers is very frequent.... ~40% at 15 years
• The benefit / risk balance for contralateral PMI is probably even more favorable for BRCA1/2 carriers,but there are uncertainties
• Major pluses for BRCA1/2 carriers are that PMI is
– estrogen independent
– a breast conserving option, compared with prophylactic contralateral breast mastectomy
Implications for current partial breast irradiation
approaches?
Should we be adding a whole-breast PMI dose to current partial breast irradiation techniques?
Prophylactic Mammary IrradiationConclusions
• Low-dose PMI of the contralateral breast, given at the same time as conventional post-lumpectomy RT,may significantly reduce the large risk of second cancerin the contralateral breast of breast cancer survivors
• Independent of estrogen status
• Cost effective
• Need to balance the risk of radiation-induced cancer but overall PMI is likely to have a favorable benefit / risk balance
• Benefit / risk ratio is likely to be still better for BRCA1/2 patients, who are subject to very large second-cancer risks
• PMI is a breast-conserving option, c.f. prophylactic contralateral breast mastectomy
Overall Conclusions
As long-term cancer survival rates increase, there are increasing concerns about radiation-induced second cancers
Better models are giving us a better understandingabout whether we need to be more concerned about large doses to small volumes of normal tissue, or about smaller doses to larger volumes…
We can potentially use our understanding of radiation-induced cancers to combat a major problem, contralateral second breast cancer, through prophylactic mammary irradiation
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