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Long-term side effects of radiotherapy in breast cancer: studies in ischemic heart disease and lung cancer
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Breast cancer (BC) is the most common cancer in women worldwide. Due to early detection and advances in adjuvant therapies, most women diagnosed with early BC will be cured of their disease, and issues of survivorship are of great importance. Adjuvant radiotherapy (RT) in BC is well established and significantly reduces local recurrences and BC mortality. Still, it usually involves some accidental irradiation to the heart and lungs, which may lead to long-term side effects, mainly ischemic heart disease (IHD) and lung cancer (LC). The overall aim with this thesis was to study IHD and radiation-induced LC in women receiving RT for BC from the early 1990s until recently.

In paper I and paper II a cohort of women (n=182) receiving computed tomography (CT)-based RT (3DCRT) for BC during 1992 to 2012, who subsequently were referred to a coronary angiography and treated for coronary stenosis, was studied. Paper I was a reproducibility study with the aim to examine the inter-observer variation in delineation of the coronary arteries (CAs) in CT scans used for 3DCRT planning. All patients treated at one of the participating RT departments (n=32), were selected from the larger cohort, and the CAs were delineated in the patients’ CT-scans by three oncologists independently, with a validated CT-based heart atlas as guideline. Spatial difference between the different delineations, and variance in radiation dose was calculated. The median distance between the centers of the arteries was 2-8 mm for the right coronary artery (RCA), and 1-4 mm for the left main coronary artery (LMCA) and the left anterior descending artery (LAD). The intraclass correlation coefficient (ICC) was derived to quantify the variance in estimated doses. The ICC for mean doses varied from 0.76 to 0.98 for LMCA-LAD, and from 0.73 to 0.92 for RCA, indicating that variation in radiation doses was mainly due to interpatient variation. In conclusion, the study showed high consistency in contouring the CAs in the patients’ planning CTs, in particular the LMCA-LAD. In paper II, the aim was to examine the relationship between radiation dose to the CAs and subsequent coronary stenosis that required a coronary intervention at this location. The CAs were delineated and divided into segments in the 182 patients’ planning-CTs and doses were recalculated based on the dose distribution of the original RT plans. The location of the CA stenosis was identified from the Swedish Coronary Angiography and Angioplasty Register (SCAAR). Mean doses to the heart and the LAD were substantially higher in women receiving left-sided RT compared to right-sided RT. Segment-wise analyses were performed to assess the risk of developing a coronary stenosis that required an intervention at a certain radiation dose. Segments receiving radiation doses < 1 Gray (Gy) were used as reference. The main finding was a five-fold increase in risk of a clinically relevant coronary stenosis in the mid LAD at mean doses over 20 Gy, compared to doses of 0-1 Gy (odds ratio 5.23; 95 % CI (confidence interval) 2.01-13.6). There were iv too few events to calculate increase in risk per Gy. Still, the result of this study supports that the radiation dose to the LAD should be considered at RT planning and kept as low as possible.

In paper III and IV, the BcBaSe cohort was used to examine risk of IHD, and radiation-induced LC after adjuvant RT for BC. The BCBaSe consists of 68089 women diagnosed with BC during 1992 to 2012, and 340352 age-matched women without BC diagnosis. In paper III, Cox regression analyses were performed to estimate risk of IHD, by comparing women with BC to women without BC diagnosis, and by comparing left-sided BC to right-sided BC. Kaplan-Meier analysis was performed to assess cumulative incidence of IHD. Women with BC had a lower risk of IHD compared to women without BC diagnosis at follow-up (hazard ratio (HR) 0.91; 95 % CI 0.88-0.95). Women irradiated for left-sided BC had a higher risk of IHD compared to women irradiated for right-sided BC (HR 1.18; 95 % CI 1.06-1.31). The HRs increased with more extensive lymph node involvement and with addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to rightsided RT, starting from the first years after RT and sustained with longer followup. In paper IV, Kaplan-Meier analyses were performed to assess cumulative incidence of LC and LC-specific survival. Cox regression analyses were performed to estimate risk of LC after adjuvant RT for BC, comparing women with BC to women without BC diagnosis. Women with BC receiving RT had a higher cumulative incidence of LC compared both to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a higher risk of LC compared to women without BC diagnosis (HR 2.35; 95 % CI 1.54-3.59). LCspecific survival was significantly higher in women with a prior BC compared to women without a prior BC diagnosis. In paper III and paper IV information on individual dosimetry data was not available. Most women likely received 3DCRT given with tangential fields and were treated before breathing adaption techniques were implemented in Sweden. The results of these studies emphasize the importance of further development and implementing of RT techniques and regimens that lower the cardiac and lung doses.

In conclusion, we found that radiation doses to the LAD remained high in women receiving 3DCRT for BC between 1992 and 2012, and were associated with an increased risk of clinically relevant CA stenosis. Delineating the LAD was feasible and the results of these studies support that the LAD radiation dose should be considered in RT treatment planning. The register-based studies confirmed that the risk of IHD was significantly increased in women receiving left-sided RT and that the risk of LC after BC RT was significantly increased in this large cohort of women with BC.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2020. , p. 99
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2069
Keywords [en]
breast cancer, radiotherapy, long-term side effects, ischemic heart disease, lung cancer, survivorship
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-167726ISBN: 978-91-7855-194-1 (electronic)ISBN: 978-91-7855-193-4 (print)OAI: oai:DiVA.org:umu-167726DiVA, id: diva2:1390646
Public defence
2020-02-28, Aulan, Sundsvalls sjukhus, Sundsvalls Sjukhus, Sundsvall, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-02-07 Created: 2020-02-02 Last updated: 2020-02-04Bibliographically approved
List of papers
1. Inter-observer variation in delineating the coronary arteries as organs at risk
Open this publication in new window or tab >>Inter-observer variation in delineating the coronary arteries as organs at risk
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2017 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 122, no 1, p. 72-78Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To determine the inter-observer variation in delineating the coronary arteries as organs at risk (OAR) in breast cancer (BC) radiotherapy (RT) and how this variation affects the estimated coronary artery radiation dose.

METHOD: Delineation of the left main and the left anterior descending coronary artery (LMCA and LAD), and the right coronary artery (RCA), by using the heart atlas by Feng et al., was performed by three radiation oncologists in 32 women who had received adjuvant RT for BC. Centres of the arteries were calculated and distances between artery centres were measured and the artery radiation doses were estimated. The intraclass correlation coefficient (ICC) was used to quantify the variability in doses.

RESULTS: Along the extent of RCA, the median distance between centres of arteries varied from 2 to 9mm with similar patterns over pairs of oncologists. For the LMCA-LAD the median distance varied from 1 to 4mm. The estimated maximum radiation doses showed an ICC variation from 0.82 to 0.97.

CONCLUSION: The coronary arteries can be reliably identified and delineated as OARs in BC RT. The spatial variance is limited and the total variation in radiation dose is almost completely determined by the between patient variation.

National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-130163 (URN)10.1016/j.radonc.2016.11.007 (DOI)000395217900013 ()27866849 (PubMedID)
Available from: 2017-01-13 Created: 2017-01-13 Last updated: 2020-02-02Bibliographically approved
2. The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors
Open this publication in new window or tab >>The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors
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2019 (English)In: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 14, article id 40Article in journal (Refereed) Published
Abstract [en]

BackgroundTo assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) for breast cancer (BC).MethodsThe study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location.ResultsThe odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p=0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1Gy to the mid LAD. In women receiving mean doses of 5-20Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20Gy, when compared to women receiving mean doses of 0-1Gy to the mid LAD.ConclusionsIn women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Breast cancer, Radiotherapy, Radiation doses, 3DCRT, Coronary stenosis, Left anterior descending tery
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-157511 (URN)10.1186/s13014-019-1242-z (DOI)000460794000002 ()30845947 (PubMedID)
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2020-02-02Bibliographically approved
3. Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large populationbased cohort
Open this publication in new window or tab >>Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large populationbased cohort
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2020 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 22, no 10, article id 31969169Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: 

Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of ischemic heart disease (IHD). We examined the incidence of IHD in a large population-based cohort of women with BC.

METHODS: 

The Breast Cancer DataBase Sweden (BCBaSe) includes all women diagnosed with BC from 1992 to 2012 (n = 60,217) and age-matched women without a history of BC (n = 300,791) in three Swedish health care regions. Information on comorbidity, educational level, and incidence of IHD was obtained through linkage with population-based registries. The risk of IHD was estimated by Cox proportional hazard regression analyses and cumulative incidence by the Kaplan-Meier method.

RESULTS: 

Women with BC had a lower risk of IHD compared to women without BC with a hazard ratio (HR) of 0.91 (95% CI 0.88-0.95). When women with left-sided BC were compared to right-sided BC, an increased HR for IHD of 1.09 (95% CI 1.01-1.17) was seen. In women receiving RT, a HR of 1.18 (95% CI 1.06-1.31) was seen in left-sided compared to right-sided BC, and the HRs increased with more extensive lymph node involvement and with the addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to right-sided RT, starting from the first years after RT and sustained with longer follow-up.

CONCLUSIONS: 

Women given RT for left-sided BC during 1992 to 2012 had an increased risk of IHD compared to women treated for right-sided BC. These women were treated in the era of three-dimensional conformal RT (3DCRT), and the results emphasize the importance of further developing and implementing RT techniques that lower the cardiac doses, without compromising the beneficial effects of RT.

Place, publisher, year, edition, pages
London: BioMed Central, 2020
Keywords
Breast cancer; Ischemic heart disease; Long-term side effects; Radiotherapy; Survivorship
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-167724 (URN)10.1186/s13058-020-1249-2 (DOI)31969169 (PubMedID)2-s2.0-85078306504 (Scopus ID)
Available from: 2020-02-02 Created: 2020-02-02 Last updated: 2020-02-04Bibliographically approved
4. Risk of primary lung cancer after adjuvant radiotherapy in breast cancera large population-based study
Open this publication in new window or tab >>Risk of primary lung cancer after adjuvant radiotherapy in breast cancera large population-based study
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-167728 (URN)
Available from: 2020-02-02 Created: 2020-02-02 Last updated: 2020-02-04

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23456786 of 8
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