Understanding Radiotherapy-Induced Second Cancers and Potentially Reducing Understanding Radiotherapy-Induced Second Cancers  David Brenner and Igor Shuryak Center for Radiological Research Columbia University New York Understanding radiogenic cancers resulting from contemporary radiotherapy protocols

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 From BEIR-VII (2006) 2000 Shuryak et al 2010 BEIR BEIR-VII 0 20 40 60 80 Age at Exposure

2,000 prostate cancer patients treated with RT (1984 to 2005) vs 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

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 relates

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... High doses don’t matter High doses do matter OR Cancer Risk total dose fewer 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 SURVIVAL TRANSFORMATION DOSE Gray 1965 SURVIVAL ONCOGENIC TRANSFORMATION

RT-induced breast cancer However, recent epidemiology suggests that the risks are not small at large doses RT-induced breast cancer Hodgkins data: Travis 03, Van Leeuwen 03

RT-induced lung cancer However, recent epidemiology suggests that the risks are not small at large doses RT-induced lung cancer Repopulation Hodgkins data: Gilbert 2003

Cell numbers during RT and subsequent normal-tissue repopulation End RT is this with treatment on weekends? 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 proliferation of normal cells *during* treatment is also important, because it increases the number of cells at risk during later fractions 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.... Estimate the low dose (~2 Gy) age- gender- and organ-specific relative risks from A-bomb survivors Use standard models to “convert” these low dose relative risks to apply to Western population / individual of given age and gender 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 Mean exposure age: 23 use inititiation/killing/repoulation model – you have room Brenner et al 2006 JNCI 98: 1974-86 (2006) PNAS 102:13040-5 (2005)

Radiation-induced lung cancer: Excess relative risk at high doses Mean exposure age:45 use “initiation, killing, repopulation” – you have room 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 High doses don’t matter Cancer Risk total dose fewer 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 BREAST CNS COLON LUNG PANCREAS RECTUM STOMACH THYROID Brenner et al 2009

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

Based on these approaches, we can make predictions of second-cancer risks for modern radiotherapeutic protocols Koh et al 2007 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 ERR = 2.1 [1.1, 6.1]

A potential application: Reducing Second Breast Cancers

Large genetically-based second-cancer risk in breast-cancer survivors A potential application: Reducing Second Breast Cancers 1. Second breast cancer in the contralateral breast Data from Freedman et al 2005 Large genetically-based second-cancer risk in breast-cancer survivors Mean age at 1st cancer: 57 Brenner et al. JCO 2007

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

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

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

Experimental investigations of PMI MMTV-PyVT mice Relative risk of breast cancer after PMI Relative Breast Cancer Risk 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 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