Download Second Cancers - HPS Chapters

and Potentially Reducing
Understanding Radiotherapy-Induced

Second Cancers
David Brenner and Igor Shuryak
Center for Radiological Research
Columbia University
New York
•
•
There is increasing concern about
radiotherapy-related second cancers
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
** SEER analysis Brenner et al (2000)
There is also an increasing realization that
lifetime cancer risks due to radiation exposure
in middle age may be larger than we thought
4000
Lifetime attributable cancer risk per
10 6 individuals exposed to 10 mGy
5000
From BEIR-VII (2006)
4000
Female
3000
2000
Shuryak et al 2010
2000
Male
1000
BEIR BEIR-VII
0
0
0
0
10
20
30
40
50
Age at Exposure
60
70
80
20
40
60
80
Age at Exposure
Proportion with no second primary cancer
2,000 prostate cancer patients treated with RT (1984 to 2005)
vs. matched prostate cancer patients who underwent surgery
1.0
Surgery
14%
0.8
28%
Radiotherapy
0.6
0.4
0.2
0.0
Data from William
Beaumont Hospital
0
5
10
15
Time (years)
20
25
Huang et al 2011
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
Example:
Second Cancers: IMRT vs. 3-D conformal RT
 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 relationship
for radiation-induced carcinogenesis...
Cancer Risk
High doses don’t matter
High doses do matter
OR
total dose
total dose
•
•
IMRT minimizing high doses doesn’t help
IMRT’s extra lower doses are bad
•
•
IMRT minimizing high doses helps
IMRT’s extra lower doses less important
The standard model of carcinogenesis at high doses:
Competition between oncogenic transformation & cell killing
Gray 1965
SURVIVAL
SURVIVAL
ONCOGENIC
TRANSFORMATION
TRANSFORMATION
DOSE
However, recent epidemiology suggests that
the risks are not small at large doses
B
Breast cancer excess relative risk
Median age at exposure:23 Median attained age: 42
A-bomb data
Hodgkins data
Standard model
50
40
RT-induced
breast cancer
30
20
10
0
0
5
10
15
20
25
Dose (Gy)
30
35
40
45
Hodgkins data:
Travis 03,
Van Leeuwen 03
However, recent epidemiology suggests that
the risks are not small at large doses
A
15
25
A-bomb data
Hodgkins data
Standard Model
120
20
RT-induced
lung cancer
10
15 80
V36
Lung cancer excess relative risk
Median age at exposure:45 Median attained age: 58
10
5
40
5
0
0
0
5
10
15
20
25
Dose (Gy)
30
35
40
45
0
Hodgkins data:
Gilbert 2003
Cell numbers during RT
and subsequent normal-tissue repopulation
End RT
Radiation-induced
pre-malignant cells
Sachs &
Brenner 2005
Cancer risks at high doses: A 3rd significant mechanism
Proliferation of pre-malignant cells during organ repopulation
We know enough about repopulation mechanisms to be able to
add them to the standard (Gray) model of radiation-induced
cancer at high doses
Sachs & Brenner 2005
How to calculate cancer risks at high doses,
which are organ-specific, age-specific,
and gender-specific....
1.
Estimate the low dose (~2 Gy) age- gender- and
organ-specific relative risks from A-bomb survivors
2.
Use standard models to “convert” these
low dose relative risks to apply to Western
population / individual of given age and gender
3.
Extrapolate these low-dose risks to
fractionated high doses using mechanistic models
(initiation / killing / repopulation)
Sachs & Brenner 2005
Radiation-induced breast cancer:
Excess relative risk at high doses
B
Breast cancer excess relative risk
Median age at exposure:23 Median attained age: 42
Hodgkins data
Repopulation model
MeanSimplified
exposuremodel
age: 23
50
40
30
20
10
0
0
5
10
15
20
25
Dose (Gy)
30
35
40
45
Brenner et al 2006
JNCI 98: 1974-86 (2006)
PNAS 102:13040-5 (2005)
Radiation-induced lung cancer:
Excess relative risk at high doses
A
Median age at exposure:45 Median attained age: 58
Lung cancer excess relative risk
15
25
Hodgkins data
Repopulation model
Mean
exposure
age:45
Simplified
model
120
20
10
15 80
10
5
40
5
0
0
0
5
10
15
20
25
Dose (Gy)
30
35
40
45
0
Brenner et al:
JNCI 98: 1974-86 (2006)
PNAS 102:13040-5 (2005)
Example:
Second Cancers: IMRT vs. 3-D conformal RT
Key is the shape of the dose-response relationship
for radiation-induced carcinogenesis...
High doses do matter
Cancer Risk
High doses don’t matter
total dose
total dose
•
•
IMRT minimizing high doses doesn’t help
IMRT’s extra lower doses are bad
•
•
IMRT minimizing high doses helps
IMRT’s extra lower doses less important
Such models can do a reasonable job of modeling
radiotherapy-induced second-cancer risks for many sites
Bladder Cancer
BLADDER
50
3
40
2
30
1
Data
Model
40
20
20
0
20
40
60
0
0
0
Dose (Gy)
20
40
Dose (Gy)
Lung Cancer
Colon Cancer
0
60
12
Data
Model
2
20
40
60
Dose (Gy)
Pancreatic Cancer
LUNG
COLON
3
PANCREAS
Data
Model
Data
Model
6
8
1
ERR
ERR
ERR
Data
Model
60
10
0
4
0
20
40
0
0
60
4
2
0
0
20
40
60
0
20
40
Dose (Gy)
Dose (Gy)
Dose (Gy)
Rectal Cancer
Stomach Cancer
Thyroid Cancer
STOMACH
RECTUM
Data
Model
4
6
ERR
3
2
60
THYROID
25
Data
Model
Data
Model
20
4
ERR
5
ERR
CNS
ERR
Data
Model
ERR
ERR
4
CNS Cancers
Breast Cancer
BREAST
15
10
2
1
5
0
0
0
20
40
Dose (Gy)
60
0
0
20
40
Dose (Gy)
60
0
20
40
60
Dose (Gy)
Brenner et al 2009
Lifetime absolute risks, as a function of age at exposure
Excess lifetime risk
4000
6000
3000
4000
2000
ALL CANCERS
CANCERS
ALL
80
LIVER
CANCER
60
COLON
CANCER
300
40
200
400
2000
1000
20
100
200
00
0
0
0
BREAST
CANCER
1200
STOMACH
CANCER
120
80
200
400
40
100
0
0
20
40
60
80
0
0
20
40
60
80
Age at exposure (years)
Excess lifetime risks per 0.1 Gy per 105 persons
0
0
20
40
60
80
BLADDER
CANCER
300
800
LUNG
CANCER
600
0
20
40
60
80
Blue = BEIR VII (2006)
Red = 2010 analysis
Shuryak et al JNCI 2010
Bilateral breast DVH
30 year old female,
35 Gy mantle RT,
20 fractions
0
1000
2000
3000
+
4000
Excess relative risk after 20 years
Volume exposed to given dose
Based on these approaches, we can make predictions of
second-cancer risks for modern radiotherapeutic protocols
7
6
5
4
Breast cancer ERR
after 20 years
3
2
30 year old female,
20 fractions
1
0
0
1000
Dose (cGy)
 ERR = 2.1 [1.1, 6.1]
Koh et al 2007
ERR contribution / unit dose
V1
2000
3000
4000
Dose (cGy)
Contributions of different
doses to the overall risk
V5
0
1000
2000
Dose (cGy)
3000
4000
A potential application:
Reducing Second Breast Cancers
A potential application:
Reducing Second Breast Cancers
1. Second breast cancer in the contralateral breast
0.20
Contralateral Breast Cancer Risk
Contralateral
breast. Age
at treatment:Breast
57
Second
Breast Cancer:
Contralateral
patients
Measured
risk inrisk
breast
cancer
Second cancer
in breast
cancer
patients
Breast
cancercancer
risk inrisk
healthy
women
Background
in healthy
women
Predicted
risk
Predicted radiation-induced
radiation-induced risk
Large genetically-based
second-cancer risk in
breast-cancer survivors
0.15
Age 57
at first
Mean
age
at 1stcancer
cancer: 57
0.10
0.05
Data from Freedman et al 2005
0.00
0
5
10
15
20
Years Post Radiotherapy
Brenner et al. JCO 2007
A potential application:
Reducing Second Breast Cancers
2. Second breast cancer in the ipsilateral breast
0.25
Ipsilateral
Age
at treatment:
57
Breast breast.
Second
Cancer:
Ipsilateral
Breast
Ipsilateral Breast Cancer Risk
In the ipsilateral breast,
the risk
---- of a genetically-based
second-cancer has been
essentially eliminated
All second ipsilateral breast cancer
Total ipsilateral second cancer risk
AllRisk
genetically-independent
of independent second cancer
second
ipsilateral
breast cancer
Predicted
radiation-induced
risk
Predicted radiation-induced breast cancer
0.20
0.15
Age 57 at first cancer
0.10
0.05
0.00
0
5
10
15
20
Years Post Radiotherapy
Data from Freedman et al 2005
Brenner et al. JCO 2007
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 the
ipsilateral breast ....
 prophylactic mammary irradiation (PMI) to the
contralateral breast would have the potential to
eliminate 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 of
a breast cancer survivor
is not a healthy normal tissue
Total PMI Dose (Gy, 10 fractions)
What PMI dose to the contralateral breast
would be needed?
25
• So a realistic PMI fractionated
20
dose would be around 20 Gy
15
• Much lower than the standard
post-lumpectomy RT dose
10
0
250
500
750
1000
Number of Background Pre-Malignant Cells in Breast
•
•
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,
V3
it would have a favorable benefit / risk ratio
Brenner et al. JCO 2007
Experimental investigations of PMI
MMTV-PyVT mice
DOSE REGION
FOR WHICH
CONTRALATERAL
SECOND BREAST
CANCER RISK IS
REDUCED
1
LEAD SHIELD
A
0
0
B
20
PMI Dose
Prophylactic Mammary Irradiation (PMI)
Dose to the Contralateral Breast (Gy)
C
40
LEAD SHIELD
Relative Risk of Contralateral
CancerRisk
Breast
Second
Cancer
Breast
Relative
Schematic: Contralateral Breast Cancer Risk
as a Function
of PMI Radiation
Relative
risk of breast
cancer Dose
after PMI
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 Irradiation
Conclusions
•
•
•
•
•
•
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 cancer
in 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 understanding
about 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