Understanding Radiotherapy-Induced Second Cancers

1
and Potentially Reducing
Understanding Radiotherapy-Induced Second
Cancers
?
David Brenner and Igor Shuryak Center for
Radiological Research Columbia UniversityNew
York
2
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)
3
There is also an increasing realization that
lifetime cancer risks due to radiation
exposurein middle age may be larger than we
thought
4000
From BEIR-VII (2006)
2000
Shuryak et al 2010
BEIR
BEIR-VII
0
0 20 40 60 80 Age at
Exposure
4
2,000 prostate cancer patients treated with RT
(1984 to 2005) vs. matched prostate cancer
patients who underwent surgery
14
28
Data from William Beaumont Hospital
Huang et al 2011
5
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

6
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)

7
Key is the shape of the dose-response
relationshipfor radiation-induced
carcinogenesis...
Example Second Cancers IMRT vs. 3-D conformal
RT
High doses do matter
High doses dont matter
OR
Cancer Risk
total dose
total dose

• IMRT minimizing high doses helps
• IMRTs extra lower doses less important

• IMRT minimizing high doses doesnt help
• IMRTs extra lower doses are bad

8
The standard model of carcinogenesis at high
doses Competition between oncogenic
transformation cell killing
Gray 1965
SURVIVAL
ONCOGENIC TRANSFORMATION
9
However, recent epidemiology suggests that the
risks are not small at large doses
RT-induced breast cancer
Hodgkins data Travis 03, Van Leeuwen 03
10
However, recent epidemiology suggests that the
risks are not small at large doses
RT-induced lung cancer
Repopulation
Hodgkins data Gilbert 2003
11
Cell numbers during RT and subsequent
normal-tissue repopulation
End RT
Radiation-induced pre-malignant cells
Sachs Brenner 2005
12
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
13

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 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)

Sachs Brenner 2005
14
Radiation-induced breast cancer Excess relative
risk at high doses
Mean exposure age 23
Brenner et al 2006JNCI 98 1974-86
(2006) PNAS 10213040-5 (2005)
15
Radiation-induced lung cancer Excess relative
risk at high doses
Mean exposure age45
Brenner et alJNCI 98 1974-86 (2006) PNAS
10213040-5 (2005)
16
Key is the shape of the dose-response
relationshipfor radiation-induced
carcinogenesis...
Example Second Cancers IMRT vs. 3-D conformal
RT
High doses do matter
High doses dont matter
Cancer Risk
total dose
total dose

• IMRT minimizing high doses helps
• IMRTs extra lower doses less important

• IMRT minimizing high doses doesnt help
• IMRTs extra lower doses are bad

17
Such models can do a reasonable job of modeling
radiotherapy-induced second-cancer risks for many
sites
BLADDER
CNS
BREAST
COLON
LUNG
PANCREAS
STOMACH
RECTUM
THYROID
Brenner et al 2009
18
Lifetime absolute risks, as a function of age at
exposure
Blue BEIR VII (2006) Red 2010 analysis
Excess lifetime risks per 0.1 Gy per 105 persons
Shuryak et al JNCI 2010
19
Based on these approaches, we can make
predictions of second-cancer risks for modern
radiotherapeutic protocols

• ERR 2.1 1.1, 6.1

20
A potential application Reducing Second Breast
Cancers
21
A potential application Reducing Second Breast
Cancers
1. Second breast cancer in the contralateral
breast
Large genetically-based second-cancer risk in
breast-cancer survivors
Mean age at 1st cancer 57
Brenner et al. JCO 2007
22
A potential application Reducing Second Breast
Cancers
2. Second breast cancer in the ipsilateral breast
In the ipsilateral breast, the risk of a
genetically-based second-cancer has been
essentially eliminated
Data from Freedman et al 2005
Brenner et al. JCO 2007
23
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

24
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

25
Irradiating healthy normal tissue?????

• The contralateral breast ofa breast cancer
  survivoris not a healthy normal tissue

26
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

Brenner et al. JCO 2007
27
Experimental investigations of PMI
MMTV-PyVT mice
Relative risk of breast cancer after PMI
Relative Breast Cancer Risk
PMI Dose
28
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

29
Implications for current partial breast
irradiation approaches?
Should we be adding a whole-breast PMI dose to
current partial breast irradiation techniques?
30
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

31
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