Understanding Radiotherapy-Induced Second Cancers David Brenner and Igor Shuryak Center for...

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 80

Age at Exposure

0

1000

2000

3000

4000

5000

Lifetime attributable cancer risk per

106

individuals exposed to 10 mG

y

Female

Male BEIR

From BEIR-VII (2006)4000

2000

0 20 40 60 80

Age at Exposure

Shuryak et al 2010

BEIR-VII 0

Surgery

Radiotherapy

Pro

port

ion

with

no

seco

nd p

rim

ary

canc

er

0 5 10 15 20 25

Time (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


total dose total dose

• IMRT minimizing high doses doesn’t help

• IMRT’s extra lower doses are bad

High doses do matter

Can

cer

Ris

k

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)

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50

Bre

as

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an

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xc

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s r

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isk

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 45

Dose (Gy)

0

5

10

15

Lu

ng

ca

nc

er

ex

ce

ss

re

lati

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ris

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A-bomb dataHodgkins dataStandard Model

Median age at exposure:45 Median attained age: 58

0

5

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20

25

V3

6

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


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....


Radiation-induced breast cancer: Excess relative risk at high doses

0 5 10 15 20 25 30 35 40 45

Dose (Gy)

0

10

20

30

40

50

Bre

as

t c

an

ce

r e

xc

es

s r

ela

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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 45

Dose (Gy)

0

5

10

15

Lu

ng

can

cer

exce

ss r

elat

ive

risk

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


total dose total dose

• IMRT minimizing high doses doesn’t help

• IMRT’s extra lower doses are bad

High doses do matter

Can

cer

Ris

k

0 20 40 60Dose (Gy)

0

2

4

6

ER

R

Stomach Cancer

DataModel

0 20 40 60Dose (Gy)

0

4

8

12

ER

R

Lung Cancer

DataModel

0 20 40 60Dose (Gy)

0

1

2

3

ER

R

Colon Cancer

DataModel

0 20 40 60Dose (Gy)

0

1

2

3

4

5

ER

R

Rectal Cancer

DataModel

0 20 40 60Dose (Gy)

0

2

4

6

ER

R

Pancreatic Cancer

DataModel

0 20 40 60Dose (Gy)

0

1

2

3

4

ER

R

Bladder Cancer

DataModel

0 20 40 60Dose (Gy)

0

5

10

15

20

25

ER

R

Thyroid Cancer

DataModel

0 20 40 60Dose (Gy)

0

10

20

30

40

50

ER

R

Breast Cancer

DataModel

0 20 40 60Dose (Gy)

0

20

40

60

ER

R

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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0 20 40 60 800

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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 CANCER

Exces

s life

tim

e 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)

Vo

lum

e e

xp

os

ed

to

giv

en

do

se

Bilateral breast DVH

30 year old female,35 Gy mantle RT,20 fractions

0 1000 2000 3000 4000

V3

ER

R c

on

trib

uti

on

/ u

nit

do

se

Dose (cGy)

Contributions of different doses to the overall risk

0 1000 2000 3000 4000

V5

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Dose (cGy)

Ex

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ea

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Breast cancer ERR after 20 years

30 year old female,20 fractions

+

A potential application: Reducing Second Breast Cancers

0 5 10 15 20

Years Post Radiotherapy

0.00

0.05

0.10

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Co

ntralateral B

reast Can

cer Risk

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 20


0.00

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Co

ntralateral B

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Data from Freedman et al 2005


1. Second breast cancer in the contralateral breast

0 5 10 15 20


0.00

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Co

ntralateral B

reast Can

cer Risk






0 5 10 15 20


0.00

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Co

ntralateral B

reast Can

cer Risk






0 5 10 15 20


0.00

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Co

ntr

alat

eral

Bre

ast

Can

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Ris

k






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0.00

0.05

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Co

ntr

alat

eral

Bre

ast

Can

cer

Ris

k






Brenner et al. JCO 2007

Mean age at 1st cancer: 57

Large genetically-based second-cancer risk in

breast-cancer survivors


2. Second breast cancer in the ipsilateral breast

0 5 10 15 20


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 B

reast Can

cer 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


----

0 5 10 15 20


0.00

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0.25


Ipsilateral B

reast Can

cer Risk




----

0 5 10 15 20


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Ipsilateral B

reast Can

cer Risk




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0 5 10 15 20


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Ipsilateral B

reast Can

cer Risk




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0 5 10 15 20


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Ipsi

late

ral

Bre

ast

Can

cer

Ris

k




----

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0.00

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Ipsi

late

ral

Bre

ast

Can

cer

Ris

k




----

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?


• 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 PM

I Dose (G

y, 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

LEA

D S

HIE

LD

MMTV-PyVT mice Relative risk of breast cancer after PMI

Re

lati

ve

Bre

as

t C

an

ce

r 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 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 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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Understanding Radiotherapy-Induced Second Cancers David Brenner and Igor Shuryak Center for...

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