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. Example:Second Cancers: IMRT vs. 3-D conformal RT Key is the shape of the dose-response relationshipfor radiation-induced carcinogenesis... High doses do matter High doses don’t matter OR Cancer Risk total dose total dose • IMRT minimizing high doses helps • IMRT’s extra lower doses less important • IMRT minimizing high doses doesn’t help • IMRT’s extra lower doses are bad

8. SURVIVAL TRANSFORMATION DOSE The standard model of carcinogenesis at high doses:Competitionbetweenoncogenic 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.... • Estimate the low dose (~2 Gy) age- gender- and organ-specific relative risks from A-bomb survivors • Use standard models to “convert” theselow dose relative risks to apply to Western population / individual of given age and gender • 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 102:13040-5 (2005)

15. Radiation-induced lung cancer: Excess relative risk at high doses Mean exposure age:45 Brenner et al:JNCI 98: 1974-86 (2006) PNAS 102:13040-5 (2005)

16. Example:Second Cancers: IMRT vs. 3-D conformal RT Key is the shape of the dose-response relationshipfor radiation-induced carcinogenesis... High doses do matter High doses don’t matter Cancer Risk total dose total dose • IMRT minimizing high doses helps • IMRT’s extra lower doses less important • IMRT minimizing high doses doesn’t help • IMRT’s 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. Bilateral breast DVH 30 year old female,35 Gy mantle RT,20 fractions + Breast cancer ERR after 20 years 30 year old female,20 fractions Contributions of different doses to the overall risk Koh et al 2007 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. Data from Freedman et al 2005 A potential application:Reducing Second Breast Cancers 1. Second breast cancer in thecontralateralbreast 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 theipsilateralbreast 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 willall 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