Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer

ABSTRACT BACKGROUND: Radiation-related heart disease and lung cancer can occur following radiotherapy for breast cancer but the duration of any mortality risk is uncertain. METHODS:

Mortality ratios, by laterality of breast cancer, were estimated using Poisson regression for 558 871 women recorded with breast cancer during 1973–2008 in the Surveillance, Epidemiology and

End Results (SEER) cancer registries and followed until 01 January 2009. RESULTS: For women diagnosed with breast cancer during 1973–1982 and given radiotherapy shortly afterwards, the

cardiac mortality ratios, left-sided _vs_ right-sided, were 1.19 (1.03–1.38), 1.35 (1.05–1.73), 1.64 (1.26–2.14) and 1.90 (1.52–2.37) at <10, 10–14, 15–19 and 20+ years since diagnosis

(2_p_ for trend: <0.001). The lung cancer mortality ratios, ipsilateral _vs_ contralateral, in these women were 1.05 (0.57–1.94), 2.04 (1.28–3.23) and 3.87 (2.19–6.82) at <10, 10–19

and 20+ years, respectively, (2_p_ for trend: 0.002). For women irradiated during 1983–92 there was evidence of radiation-related mortality for lung cancer, but not for heart disease. For

women irradiated since 1993 there is, as yet, little evidence of any radiation-related mortality. CONCLUSION: In this population, the radiation-related risks were larger in the third decade

after exposure than during the first two decades. SIMILAR CONTENT BEING VIEWED BY OTHERS HEART-RELATED MORTALITY AFTER POSTOPERATIVE BREAST IRRADIATION IN PATIENTS WITH DUCTAL CARCINOMA IN

SITU IN THE CONTEMPORARY RADIOTHERAPY ERA Article Open access 02 February 2021 RISK OF PRIMARY LUNG CANCER AFTER ADJUVANT RADIOTHERAPY IN BREAST CANCER—A LARGE POPULATION-BASED STUDY Article

Open access 01 June 2021 CONSEQUENCES OF IONIZING RADIATION EXPOSURE TO THE CARDIOVASCULAR SYSTEM Article 10 July 2024 MAIN In early breast cancer, radiotherapy can reduce the risk of death

from breast cancer itself (Early Breast Cancer Trialists' Collaborative Group (2011)). However, the treatment usually involves some incidental irradiation of the heart and lungs which

may increase the subsequent risks of heart disease and lung cancer. Mortality among women registered with breast cancer in the Surveillance, Epidemiology and End Results (SEER) cancer

registries during 1973–2001 has previously been reported, giving insight into radiation-related mortality during the first two decades after exposure (Darby et al, 2005). We now present

mortality up to 01 January 2009 providing, for the first time, information on the risks of death from radiation-related heart disease and lung cancer in this population during the third

decade after exposure. MATERIALS AND METHODS Information on cause-specific mortality in women registered with invasive breast cancer (localised or regional) during 1973–2008 was obtained

from the SEER public-use data set (Surveillance, Epidemiology and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973–2008), National Cancer Institute, DCCPS, Surveillance

Research Program, Cancer Statistics Branch (released January 2011)). Women aged 20–79 years at breast cancer diagnosis were included unless they had previously been registered with a

different cancer, their cancer was bilateral, of unknown laterality, metastatic, diagnosed at autopsy, or ascertained only from the death certificate. All deaths certified as due to heart

disease (ICD-10 I00–09, I11, I13, I20–51) were included in the analysis. Deaths from metastatic breast cancer can sometimes be registered as lung cancer. Therefore, deaths certified as due

to lung cancer (ICD-10 C34) were included only if microscopically confirmed lung cancer was recorded in the SEER data set. Women with breast cancer who are selected for radiotherapy may have

different mortality rates from those who are not selected for reasons unrelated to radiotherapy (McGale and Darby, 2008). Comparisons that avoid these selection effects can, however, be

performed, as the radiation dose to the heart is generally greater in left-sided than in right-sided breast cancer (Taylor et al, 2007). Therefore, a comparison of cardiac mortality in

irradiated women with left-sided cancer _vs_ irradiated women with right-sided cancer can give a valid indication of the extent of any radiation-related mortality (Vandenbroucke, 2004).

Similarly, the radiation dose to the ipsilateral lung from breast cancer radiotherapy is generally greater than to the contralateral lung. Thus a comparison of mortality from ipsilateral

lung cancer compared with contralateral lung cancer among irradiated women can be used to assess the presence of any radiation-related increase in lung cancer mortality. Each woman’s

contribution to the person-years at risk ran from the date of breast cancer diagnosis to the earliest of 1st January 2009, death, loss to follow-up, or 85th birthday. Mortality ratios were

estimated using Poisson regression with stratification by calendar year of diagnosis, time since diagnosis, age (all in 5-year groups), and race (white, black, other/unknown).

Over-dispersion tests were performed, but no adjustments were needed. Tests for trend were performed using variance-weighted least squares assuming Poisson variation. Significance tests were

two-sided. Calculations used Stata version 12. RESULTS A total of 558 871 women were included in the analysis. Similar proportions of women with left-sided and right-sided breast cancer

were recorded as receiving radiotherapy (left-sided: 45.8% (130 285 women), right-sided: 46.2% (126 691 women) (Table 1)). For women not recorded as receiving radiotherapy, there was little

evidence that mortality from heart disease differed in women with left-sided and right-sided cancer (cardiac mortality ratio, left-sided _vs_ right-sided: 1.02, 95% confidence interval (CI)

0.99–1.06, 2_p_=0.16). However, for women recorded as receiving radiotherapy, there was an excess of cardiac deaths following left-sided cancer (cardiac mortality ratio, left-sided _vs_

right-sided: 1.08, 95% CI 1.03–1.14, 2_p_=0.002). Considering only women recorded as receiving radiotherapy during 1973–1982, the cardiac mortality ratio, left-sided _vs_ right-sided, was

raised during the first decade after cancer diagnosis (1.19, 95% CI 1.03–1.38) and subsequently increased further, taking values 1.35 (1.05–1.73), 1.64 (1.26–2.14), and 1.90 (1.52–2.37),

respectively, in periods 10–14, 15–19 and 20+ years since breast cancer diagnosis (2_p_ for trend<0.001, see Figure 1). For women receiving radiotherapy after 1982, there was little

evidence of any radiation-related increase in heart disease mortality either during the first decade after breast cancer diagnosis or later, although follow-up is, as yet, incomplete. For

women not recorded as receiving radiotherapy, the lung cancer mortality ratio, ipsilateral _vs_ contralateral, was 0.97 (95% CI 0.89–1.06, 2_p_=0.50), while for irradiated women it was 1.30

(95% CI 1.16–1.45, 2_p_<0.001). For women diagnosed with breast cancer during 1973–1982 and irradiated, the lung cancer mortality ratio, ipsilateral _vs_ contralateral, increased with

time since breast cancer diagnosis, taking values 1.05 (95% CI 0.57–1.94), 2.04 (1.28–3.23), and 3.87 (2.19–6.82) in the first, second, and third decades since breast cancer diagnosis (2_p_

for trend=0.002, see Figure 2). For women diagnosed during 1983–92 and irradiated, the lung cancer mortality ratio, ipsilateral vs contralateral, also showed a substantial increase more than

20 years after exposure (3.87, CI 1.24–11.31, data not shown). DISCUSSION Several studies of mortality from radiation-related heart disease and lung cancer have suggested that where there

is a risk, it may continue for many years after exposure (Inskip et al, 1994; Preston et al, 2003; Early Breast Cancer Trialists' Collaborative Group 2005; Prochazka et al, 2005;

Bouillon et al, 2011). However, no study has demonstrated so clearly a progressive increase in risk with time since exposure lasting into the third decade. In this population, the

radiation-related increases in mortality are very clear for women irradiated during 1973–82. For women irradiated during 1983–92 there is evidence of radiation-related mortality for lung

cancer, but not for heart disease. Follow-up of those irradiated since 1993 reveals, as yet, no increase in risk. Individual radiation doses are not available for the women in this study.

Average mean doses to the heart and lungs for women diagnosed with breast cancer in a given decade depend mainly on the prescribed dose, the targets irradiated and the techniques used. There

has been little variation in prescribed dose in the United States over the past few decades (Solin et al, 1991; Shank et al, 2000). However, the radiotherapy targets and techniques have

changed. One of the main determinants of heart and lung doses has been the use of radiotherapy to the internal mammary nodes. In previous decades, internal mammary irradiation has delivered

around 13–17 Gy and 3–10 Gy to the heart for left and right-sided radiotherapy, respectively, and around 13–24 Gy and 3–11 Gy to the ipsilateral and contralateral lungs, respectively, where

the tumour dose is 50 Gy (Prochazka et al, 2005). The use of internal mammary radiotherapy has declined in the United States at least since the 1980s: in a survey of radiation oncology

practice, the internal mammary chain was irradiated in 62% of women after breast conserving surgery in the 1980s, but in only 1% of such women in the 1990s. This reduction may explain, at

least in part, the reductions in radiation-related cardiac and lung cancer mortality. The eventual risks for breast cancer patients given radiotherapy today are, as yet, unknown, but will

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ACKNOWLEDGEMENTS This work was funded by Cancer Research UK. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Clinical Trial Service Unit (CTSU), University of Oxford, Richard Doll Building,

Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK, K E Henson, P McGale, C Taylor & S C Darby Authors * K E Henson View author publications You can also search for this author

inPubMed Google Scholar * P McGale View author publications You can also search for this author inPubMed Google Scholar * C Taylor View author publications You can also search for this

author inPubMed Google Scholar * S C Darby View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to K E Henson. RIGHTS AND

PERMISSIONS This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit

http://creativecommons.org/licenses/by-nc-sa/3.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Henson, K., McGale, P., Taylor, C. _et al._ Radiation-related mortality from

heart disease and lung cancer more than 20 years after radiotherapy for breast cancer. _Br J Cancer_ 108, 179–182 (2013). https://doi.org/10.1038/bjc.2012.575 Download citation * Received:

17 August 2012 * Revised: 13 November 2012 * Accepted: 20 November 2012 * Published: 20 December 2012 * Issue Date: 15 January 2013 * DOI: https://doi.org/10.1038/bjc.2012.575 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * epidemiology * breast cancer radiotherapy * radiation-related heart disease * radiation-related lung cancer *

long-term effects * mortality