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Cardiovascular disease incidence in breast cancer survivors
Boekel, N.B.
2018
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Boekel, N. B. (2018). Cardiovascular disease incidence in breast cancer survivors.
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Cardiovascular disease
incidence in breast cancer
survivors
Cardiovascular disease incidence in breast cancer
survivors
The work described in this thesis was performed at the Netherlands Cancer Institute, Amsterdam, the Netherlands.
The research was financially supported by the Dutch Cancer Society [grant number NKI 2008-3994] and Pink Ribbon [grant number 2012.WO39.C143].
Financial support by the Netherlands Cancer Institute, Vrije Universiteit Amsterdam, and the Netherlands Comprehensive Cancer Organization (IKNL) for printing of this thesis is gratefully acknowledged.
Printing: Gildeprint ISBN: 978-94-6323-395-8
Copyright© N.B. Boekel, Amsterdam, the Netherlands.
VRIJE UNIVERSITEIT
Cardiovascular disease incidence
in breast cancer survivors
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad Doctor
aan de Vrije Universiteit Amsterdam,
op gezag van de rector magnificus
prof.dr. V. Subramaniam,
in het openbaar te verdedigen
ten overstaan van de promotiecommissie
van de Factulteit der Geneeskunde
op donderdag 6 december 2018 om 13.45 uur
in de aula van de universiteit,
De Boelelaan 1105
door
Naomi Becka Boekel
promotoren: prof.dr.ir. F.E. van Leeuwen
prof.dr. J.A. Gietema
copromotoren: dr. B.M.P. Aleman
Table of contents Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9
General introduction and outline
Cardiovascular morbidity and mortality after treatment for ductal carcinoma in situ of the breast
J Natl Cancer Inst. 2014 Aug 15;106(8)
Cardiovascular disease risk in a large, population-based cohort of breast cancer survivors
Int J Radiat Oncol Biol Phys. 2016 Apr 1;94(5):1061-72
Methods and experiences of the Netherlands Cancer Institute in the construction of a population-based breast cancer survivor cohort linked with cardiovascular disease and mortality registries
Published online at https://www.biolink-nl.eu
Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer British Journal of Cancer. 2018 Aug 119: 408–418
Heart failure after treatment for breast cancer Submitted
Radiation dose-response for risk of myocardial infarction in breast cancer survivors
Submitted
Prognosis of acute coronary syndromes after radiotherapy for breast cancer
Submitted
Chapter 1
Breast cancer incidence and survival
Breast cancer is the most frequent cancer in women in developed countries. In the Netherlands, around 14,000 women are diagnosed with invasive breast cancer yearly, with 37% of all breast cancers occurring before the age of 55 years. Additionally, some 2,500 women are diagnosed with in situ breast cancer. Over the past decades, survival from breast cancer has substantially improved (Figure 1). This is due to earlier diagnosis, advances in diagnostic imaging and more effective treatment. The improvements of treatment include more effective systemic treatment (both chemotherapy, immunotherapy and endocrine
therapy) and more accurate radiotherapy techniques1-4. Currently, the 10-year survival of
breast cancer is 75-80%5, leading to a long life expectancy for the majority of patients. These
survival rate improvements together with an increasing incidence of breast cancer (Figure 2), have led to an extensive increase in the number of breast cancer survivors (Figure 3).
Figure 1. Breast cancer survival rate in the Netherlands by time since diagnosis and year of diagnosis (Source: Netherlands Cancer Registry, © May 2018; www.cijfersoverkanker.nl)
Treatment of early breast cancer throughout the study period
1
Figure 2. Absolute breast cancer incidence (left) and age standardized incidence (right) in the Netherlands over time (Source: Netherlands Cancer Registry, © May 2018; www.cijfersoverkanker.nl)
Adjuvant systemic chemotherapy was introduced for premenopausal, lymph-node positive patients in 1975. Standard adjuvant chemotherapy consisted of CMF (cyclophosphamide, methotrexate, and fluorouracil); until 1980, twelve cycles were administered, afterward only six. Since the mid-1990s anthracycline-based chemotherapy regimens (including four cycles of AC [doxorubicin, cyclophosphamide], four cycles of EC [epirubicin, cyclophosphamide], five cycles of FAC [AC with 5-flurouracil], and five to six cycles of FEC [EC with 5-flurouracil]) were given to most premenopausal, and later, at the end of the 1990s, also postmenopausal, lymph-node positive patients and lymph-node negative patients with poor prognostic tumor characteristics. Endocrine therapy, consisting of tamoxifen, was introduced for postmenopausal women from 1980 onward, and starting in the 1990s, also for premenopausal women. After the year 2000, aromatase inhibitors were gradually introduced as an alternative, or were combined with tamoxifen. Starting in 2005, targeted therapy was used to treat HER2-positive tumors, such as trastuzumab, often subsequent to adjuvant anthracycline-containing chemotherapy.
Ductal carcinoma in situ was treated with either mastectomy or wide local excision. In case of wide local excision, this was followed by radiotherapy similar to whole-breast radiotherapy following wide local excision for invasive breast cancer.
shown in Figure 4. Incomplete resection or extensive primary tumors were indications for chest wall irradiation after mastectomy, and in the past, the ipsilateral internal mammary chain field was irradiated in case of centrally or medially located tumors and/or axillary lymph node metastasis. Patients who had extensive axillary nodal metastases, and in more recent years, patients with a positive sentinel node, also had irradiation to the axilla with or without supraclavicular nodes. The dose to the internal mammary chain field varied in the years 1970s to 2000 from 40 Gray in 15 fractions to 50 Gray in 25 fractions, using either photon beams or a mixture of photon and electrons. Over the past 15 years, radiation techniques for treatment of the internal mammary chain changed from direct to oblique fields. The chest wall generally received 35-45 Gray in 15-20 fractions, usually using electrons. Breast irradiation generally consisted of a dose of 50 Gray in 25 fractions using two tangential photon beams and a boost on the tumor bed (brachytherapy or external beam). Radiation during deep inspirational breath hold was not yet routinely performed during the study period.
Figure 3. Ten- and twenty-year breast cancer prevalence in the Netherlands over time (Source: Netherlands Cancer Registry, © May 2018; www.cijfersoverkanker.nl)
1
Figure 4. Typical locoregional radiotherapy fields following (A) lumpectomy and (B) mastectomy
Cardiovascular disease after radiotherapy
Radiotherapy is an essential component of the management of breast cancer and
significantly reduces the risk of local recurrence, and overall mortality6,7. However, patients
treated with radiotherapy have been shown to be at increased risk of various cardiovascular diseases, especially ischemic heart disease, but also other diseases such as valvular heart
disease, pericarditis and arrhythmias8-12. Most studies, however, provided only data on
cardiovascular mortality rather than morbidity. Moreover, breast cancer treatment has been considerably adapted since the 1980s, with less exposure of the heart to radiation and the introduction of anthracycline-based chemotherapy. In studies including patients
treated after 1990, increased risks of cardiovascular morbidity (ischemic heart disease13,14
and valvular heart disease14) were shown, with rate increases ranging from 1.2- to 1.5-fold.
Results on cardiovascular disease mortality, however, varied6,15. It is not clear whether
these results apply to contemporary radiotherapy regimens, as radiotherapy techniques have been refined even further with methods such as oblique fields for internal mammary chain radiotherapy, intensity modulated radiotherapy and deep inspirational breath
hold16,17. Nevertheless, part of the heart may still receive a considerable radiation dose.
Data on radiation doses to the heart in relation to cardiovascular disease risk are gradually
emerging. In a large case-control study13 a linear relationship between typical whole
does not emerge until at least ten years after treatment11-13,15.
Data on the effects of classic cardiovascular risk factors on the risk of treatment-associated
cardiovascular diseases are still sparse. Hooning et al.12 showed that smoking and
radiotherapy together were associated with a more than additive effect on risk of myocardial
infarction. Harris et al.18 have reported a higher risk to develop cardiovascular diseases in
left-sided breast cancer patients with hypertension at start of adjuvant radiotherapy. Darby
et al.19, however, observed only differences in absolute risk increases and not in relative risk
increases between patients with and without classic cardiovascular risk factors.
The mechanism of radiation-induced cardiovascular disease is thought to be through damage of the macro- and microvasculature. This initiates local endothelial activation, and a process of atherosclerosis and (vascular) fibrosis, which may lead to myocardial ischemia,
and subsequent acute coronary syndrome.20
Cardiovascular disease after systemic therapy
Anthracyclines are highly effective and commonly used chemotherapy agents in the
(neo)adjuvant treatment for breast cancer1,3. However, both acute and late, dose-related
cardiotoxicity has been reported after anthracycline-based chemotherapy, specifically
congestive heart failure21-24. Previous studies on anthracycline-related cardiovascular
disease had important limitations such as focus on chemotherapy effects in general rather than on anthracycline-based chemotherapy and inclusion of few patients treated with
anthracycline-based chemotherapy alone23,24. Also, the long-term (ten or more years) effects
of anthracycline-based chemotherapy are essentially unknown. Whether cardiotoxic effects from anthracycline-based chemotherapy and radiotherapy are additive or synergistic is still unclear. Several clinical studies in Hodgkin lymphoma patients showed that anthracycline-based therapy may further increase the radiotherapy-related risk of congestive heart failure
and valvular disorders by two- to three-fold compared to radiotherapy alone25,26 this effect
may also be more than additive.27 The chemotherapy regimen CMF, predominantly used in
the 1980s-1990s, is not considered cardiotoxic. Hooning et al.12 did observe an increased
rate of heart failure after CMF (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.25-2.73); this, however, has not been confirmed.
Anthracycline-based chemotherapy causes direct damage to the cardiomyocytes. Damage to the left ventricle wall leads to depressed overall function of the left ventricle, as
measured by a decreased left ventricular ejection fraction (LVEF)28. Anthracycline-induced
cardiomyopathy may acutely, or with a symptom free interval throughout the years, result
1
Trastuzumab subsequent to anthracycline-based chemotherapy has substantially improved
survival in HER2-positive breast cancer patients30,31. However, it is also known to affect the
LVEF and cause heart failure31-33, with the onset already during treatment. Because of this,
LVEF measurement before and during trastuzumab treatment is advised in Dutch breast
cancer treatment guidelines (www.oncoline.nl). The reduced LVEF and heart failure caused
by trastuzumab, however, mostly seem to be reversible.21,34,35
Endocrine therapy using tamoxifen has not been shown to increase the risk of cardiovascular
disease36,37. Cardiovascular risks after treatment with aromatase inhibitors, however, are
less clear. Increased cardiovascular disease rates have been observed in some studies38,39,
but not in others40,41, and long-term risks have not yet been examined.
Data sources for breast cancer and cardiovascular disease
For the studies included in this thesis, two cohorts of breast cancer survivors were constructed; a population-based cohort and a hospital-based cohort, each with different data sources for both breast cancer and cardiovascular disease. The population-based cohort (n=70,230 patients with invasive breast cancer and n=10,468 patients with ductal carcinoma in situ) was set up using breast cancer diagnosis and treatment data from
the Netherlands Cancer Registry42. Detailed radiotherapy information was collected from
radiation treatment facilities, clinical trials, and regional studies that had electronically available treatment information. Information on morbidity and mortality from cardiovascular disease was acquired through linkage with Statistics Netherlands, which records cause of death, the Cardiac Intervention Registry maintained by the Steering Committee Heart Interventions Netherlands, which registers all heart interventions (including for instance
open heart surgery and percutaneous coronary interventions)43, and the Dutch Hospital
Data (DHD), which holds data on all hospital discharges.
The hospital-based cohort (n=14,645) includes patients treated at the Netherlands Cancer Institute, Amsterdam, the Netherlands (NKI) and the Erasmus MC Cancer Center, Rotterdam, the Netherlands. The first part of this cohort of patients diagnosed in the period 1970 to
1986 was compiled previously12,44,45. For this thesis, this existing cohort was expanded with
Rationale and outline of this thesis
This thesis has the objective to evaluate long-term morbidity and mortality from cardiovascular disease in survivors of invasive breast cancer and ductal carcinoma in situ of the breast. More specifically, this thesis aims to assess the incidence of various specific cardiovascular diseases for more contemporary breast cancer treatments, the onset of treatment-related cardiovascular disease risk, and the interaction between different treatments and with cardiovascular risk factors.
In Chapter 2 and Chapter 3, we studied morbidity and mortality of specific cardiovascular
diseases in population-based cohorts of patients treated for ductal carcinoma in situ of the breast and invasive breast cancer. These large cohorts were established through linkage of several nation-wide registries and electronically kept data files. This was a complex process, also because we were the first to perform linkages for research purposes with one of the used registries; the process involved many different parties and regulations to secure the privacy
of patients. Chapter 4 describes the linkage procedures that were used and the challenges
that were addressed. In Chapter 5 we took a closer look at the cardiovascular risks after
different treatment regimens, e.g. internal mammary chain irradiation and anthracycline-based chemotherapy, using our hospital-anthracycline-based cohort with detailed treatment information. In this cohort, we also studied the interaction between radiotherapy and chemotherapy, and between classic cardiovascular risk factors and radiotherapy.
In Chapter 6 and Chapter 7, we present the results of two case-control studies nested in
the hospital-based cohort for, respectively, heart failure and myocardial infarction. In these studies we specifically focused on the radiation dose-response effects, for which individual dosimetry was performed for cardiac radiation dose, but also on the (dose-response) effects of anthracycline-based chemotherapy, trastuzumab, and endocrine therapy. These data on dose-response relationships are crucial for future steps in translating results from late-effect studies to more individual predictions of cardiovascular disease risks and for patients with different exposures tot he heart than in our study.
Previous studies have shown that radiotherapy increases the risk of acute coronary syndrome. However, it is currently unknown if radiation-induced acute coronary syndrome
is different from acute coronary syndrome in the general population. Therefore, in Chapter
8, we studied the prognosis of acute coronary syndrome in women irradiated for breast
1
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1
Oncol 26:5561-5568, 2008
Chapter 2
Cardiovascular morbidity and mortality
after treatment for ductal carcinoma in
situ of the breast
Naomi B. Boekel
Michael Schaapveld
Jourik A. Gietema
Emiel J.T. Rutgers
Michel I.M. Versteegh
Otto Visser
Berthe M.P. Aleman
Flora E. van Leeuwen
Abstract
Background: Recent concerns about potential overdiagnosis and overtreatment of ductal
carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients.
Methods: Data on all incident DCIS cases in the Netherlands between 1989 and 2004,
diagnosed before the age of 75 years, were obtained (n=10,468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within cohort comparisons were based on multivariate competing-risk regression.
Results: Compared with the general population, five-year survivors of DCIS had a similar risk
of dying due to any cause (standardized mortality ratio (SMR)=1.04 95% confidence interval (CI) 0.97-1.11), but a lower risk of dying of CVD (SMR=0.77 95%CI 0.67-0.89). No difference in CVD risk was found when comparing five-year survivors treated with radiotherapy to surgery only. Left-sided versus right-sided radiotherapy did also not increase this risk (hazard ratio (HR)=0.94 95%CI 0.67-1.32 In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005 we were able to account for history of CVD and did not observe a risk difference between treatment groups (left- versus right-sided radiotherapy HR=0.94 95%CI 0.68-1.29).
Conclusion: After a median follow-up of ten years, we did not find an increased risk for
2
Introduction
Since the introduction of breast cancer (BC) screening programs, the number of non-invasive BC diagnoses has increased substantially mainly due to increased incidence of
ductal carcinoma in situ of the breast (DCIS)1-4. Although DCIS is generally thought to be a
precursor of invasive BC, it remains unclear what proportion would progress into invasive BC
if left untreated5. Nevertheless, current practice is to treat all DCIS patients. Consequently,
an unknown but substantial proportion of these patients may be overtreated, rendering knowledge about late adverse effects after DCIS treatment of great importance.
Treatment of DCIS typically consists of surgery, and in the case of wide local excision (WLE), this is often followed by radiation using tangential breast fields. Previous research has shown that radiation exposure of the heart, for instance in patients treated for Hodgkin
lymphoma6-8 and invasive BC9,10, can increase the long-term risk of cardiovascular disease
(CVD). Also exposures to lower doses (<2 Gy) have been shown to increase the risk of CVD, although this concerned whole body irradiation with potential vascular damage to other
organs (e.g. kidneys)11,12. Recently, a dose-effect relationship for ischemic heart disease
(IHD) was shown in BC patients treated with radiotherapy13. Radiation in DCIS treatment will
result in exposure of the heart, but with relatively low doses (estimated mean heart dose
during study period is approximately 6 Gy for left-sided disease and 2 Gy for right-sided)14
compared to e.g. exposure from treatment for invasive BC including also nodal fields. Yet,
until now, only three studies have examined treatment-related CVD in DCIS patients15-17 and
the results were inconsistent. Because these studies examined cardiovascular mortality
rather than morbidity15,16 or included rather few patients17, it remains unclear if patients
treated with radiotherapy for DCIS are at increased risk for CVDs. We therefore studied the risk of cardiovascular morbidity and mortality in a large population-based cohort of patients treated for DCIS.
Methods
Data collection procedures
The Dutch population-based DCIS cohort consists of 10,468 female patients diagnosed with DCIS as their first neoplasia before the age of 75 years between 1989 and 2004. Patient selection was performed by the Netherlands Cancer Registry (NCR). The NCR has a coverage of at least 96% of invasive malignant neoplasms and selected non-invasive
cancers, including DCIS, occurring in the Netherlands since 198918. The NCR performs an
and death, topography, morphology, differentiation, stage, type of surgery, chemotherapy yes/no, and radiotherapy yes/no.
Linkages with two different population-based registries were performed for CVD information (see Supplementary Methods for linkage details). First linkage was with the Cardiac Intervention Registry maintained by the Steering Committee Heart Interventions Netherlands (BHN). This population-based registry collects data on all heart interventions (including open heart surgery and percutaneous coronary interventions) performed in the
Netherlands since 199519.
After linkage with BHN, the cohort was sent to Statistics Netherlands where linkages were performed for cause of death and with the second registry with information on CVD, the Dutch Hospital Data (DHD). This registry provides data on all hospital discharges. Diagnoses are coded by local hospital staff according to the International Classification of Diseases,
9th revision (ICD-9-CM)20. Because the DHD does not contain a unique personal identifier or
patient names, linkage with the DHD could be performed only for patients who were uniquely identifiable using the variables available in the registry i.e. birth date, sex, and four-digit postal code (90.7% of the cohort, see Supplementary Methods and Supplementary Figure 1). Lack of histological confirmation (n=9) or treatment including chemotherapy (n=15) were reasons for exclusion. The analytical cohort comprised 10,444 DCIS patients.
A cardiovascular event was defined as cardiovascular-related hospital admission/surgical intervention/death. The first hospitalization of each specific CVD was used in the analyses. Follow-up on second neoplasias, vital status, cardiovascular interventions, and hospital admissions were complete until at least January 1, 2010. The study was approved by the review boards of the NCR, BHN, and Statistics Netherlands.
Treatment
DCIS was treated with surgery (either mastectomy or WLE) and, in case of WLE, this was, especially in the later years, frequently followed by tangential breast field irradiation to a prescribed dose equivalent of 50 Gy in 25 fractions. The percentage of DCIS patients treated with radiotherapy changed considerably during the study period: from 20% in 1989, to 46% in 2004.
Statistical analysis
2
only, radiotherapy for right-sided DCIS, radiotherapy for left-sided DCIS.
We compared cardiovascular mortality in the study population with that in the Dutch female population, taking into account person-years of observation in the cohort (by age, calendar period, and follow-up interval). From the results of the person-years analysis, we calculated standardized mortality ratios (SMRs) as ratios of observed and expected numbers of cardiovascular deaths, and absolute excess risk (AER) as observed minus expected, divided by the number of person-years at risk, times 10,000. To quantify the effects of different treatments on CVD risk, within cohort comparisons were performed using competing-risk
regression models21 with death due to other causes than the event of interest as a competing
risk and including age at DCIS treatment (continuous) and year of DCIS treatment in the model as covariates. The assumptions of proportionality were verified by comparing log-log survival curves. Competing-risk regression models were fitted with the use of Stata/ SE 11.0 (StataCorp LP, College Station, TX) and a P-value <0.05 was considered statistically significant.
To examine whether patients with a history of CVD are at increased risk for developing radiation-induced CVD, as well as to rule out confounding by indication, we aimed to take into account history of CVD. However, because CVD incidence information was available from 1995 onwards only, history of CVD before BC diagnosis was not available for all patients and the number of years with information on history of CVD increased with year of diagnosis after 1995; therefore, a subgroup analysis for patients diagnosed between 1997 and 2005 was performed.
Because CVD incidence data in the first five years after treatment were not available for the entire cohort and since most studies did not find an increased risk in these first years after
radiotherapy 9,22-24 time at risk of all patients started five years after DCIS diagnosis in the
Total Left-sided DCIS Right-sided DCIS
Characteristic No.* % No. % No. %
No. of patients 10,444 100.0 5,613 53.9 4,825 46.1
Age at DCIS diagnosis
<49 years 2,090 20.0 1,122 20.0 967 20.0
49-59 years 4,242 40.6 2,258 40.2 1,982 41.1
60-69 years 3,073 29.4 1,687 30.1 1,385 28.7
70-74 years 1,039 9.9 546 9.7 491 10.2
Attained age at end of follow-up
<50 years 586 5.6 309 5.5 277 5.7
50-59 years 1,923 18.4 998 17.8 924 19.2
60-69 years 3,567 34.2 1,919 34.2 1,648 34.2
70-79 years 3,180 30.4 1,758 31.3 1,419 29.4
≥80 years 1,188 11.4 629 11.2 557 11.5
Treatment period DCIS
1989 -1993 1,382 13.2 757 13.5 625 13.0
1993 -1997 2,373 22.7 1,268 22.6 1,102 22.8
1997 - 2000 3,096 29.6 1,702 30.3 1,394 28.9
2000 - 2005 3,590 34.4 1,886 33.6 1,704 35.3
Follow-up time, median (years) 10 10 10
Patients treated with radiotherapy, median (years) 8 8 8
Follow-up interval 0 years 7 0.1 3 0.1 4 0.1 <5 years 481 4.6 251 4.5 230 4.8 5-9 years 4,653 44.6 2,487 44.3 2,165 44.9 10-14 years 3,366 32.2 1,834 32.7 1,528 31.7 ≥15 years 1,937 18.5 1,038 18.5 898 18.6
Primary DCIS treatment
Surgery only 7,466 71.5 3,985 71.0 3,476 72.0
Mastectomy 4,434 42.5 2,318 41.3 2,113 43.8
Lumpectomy 2,014 19.3 1,113 19.8 900 18.7
Type of surgery unknown† 1,018 9.7 554 9.9 463 9.6 Surgery & radiotherapy 2,899 27.8 1,584 28.2 1,314 27.2 Mastectomy & radiotherapy 111 1.1 63 1.1 48 1.0 Lumpectomy & radiotherapy 2,543 24.3 1,393 24.8 1,149 23.8 Type of surgery unknown† & radiotherapy 236 2.3 126 2.2 110 2.3
Untreated‡ 79 0.8 44 0.8 35 0.7
Vital status
Alive 8,916 85.4 4,775 85.1 4,135 85.7
Dead 1,319 12.6 724 12.9 595 12.3
Emigrated 209 2.0 114 2.0 95 2.0
2
Total Left-sided DCIS Right-sided DCIS
Characteristic No.* % No. % No. %
Patients ever uniquely identifiable during follow-up§ 9,470 90.7 5,081 90.5 4,389 91.0
Laterality Left 5,613 53.7 Right 4,825 46.2 Unknown 6 0.1 Differentiation DCIS Well-differentiated 968 9.3 537 9.6 430 8.9 Moderately differentiated 1,715 16.4 909 16.2 805 16.7 Poorly differentiated 2,788 26.7 1,462 26.0 1,326 27.5 Unknown|| 4,973 47.6 2,705 48.2 2,264 46.9
History of cardiovascular disease¶ 182 1.7 97 1.7 84 1.7
DCIS diagnosis 1989 - 1993# n.a. n.a. n.a.
DCIS diagnosis 1993 - 1997# 9 0.1 4 0.1 5 0.1
DCIS diagnosis 1997 - 2000 58 0.6 33 0.6 35 0.5
DCIS diagnosis 2000 - 2005 114 1.1 60 1.1 54 1.1
Second primary neoplasia 2,124 20.3 1,188 21.2 936 19.4 Abbreviation: DCIS, ductal carcinoma in situ of the breast; n.a., not available.
* The numbers of left- and right-sided DCIS do not add up to the total because of six patients with missing laterality † Type of surgery was not registered in every region during the first years of the registry
‡ Excluded from analyses
§ Linkage with the Hospital Discharge Registry is only possible for patients who were ever unique based on postal code, date of birth and sex
|| Time dependent, with “unknown” coded more often during older years of diagnoses
¶ History of cardiovascular disease defined as a hospital admission for cardiovascular disease or cardiovascular surgery prior to the DCIS diagnosis
# Data on cardiovascular disease is available since 1995
Results
Patient characteristics
Nearly 54% of the patients were diagnosed with left-sided DCIS. (Table 1) Patient characteristics did not differ between left- and right-sided DCIS. Median follow-up time was ten years, and eight years when restricting to patients treated with radiotherapy. Almost 28% of the cohort was irradiated, mostly following WLE. During follow-up, 1,319 patients died and 2,124 were diagnosed with a second neoplasia. Few patients (1.7%) had a history of CVD prior to their DCIS diagnosis.
In total, 950 patients experienced a cardiovascular event, of whom 814 were admitted to the hospital, 255 underwent a cardiovascular intervention, and 282 died due to CVD. (Table 2) Considering events occurring ≥five years after DCIS diagnosis only, 684 events remained for analyses, of which 574 were hospital admissions, 170 cardiovascular interventions, and 204 cardiovascular deaths.
Table 2. Cardiovascular events in the population-based ductal carcinoma in situ of the breast cohort
Cardiovascular event ICD-10 Total, n 5-year survivors*, n
Any cardiovascular event† 950 684
Cardiovascular death I00-99 282 204
Myocardial infarction I21-22 76 48
Other ischemic heart disease I20, 23-25 25 15
Other heart disease I30-52 78 63
Pericarditis I30-32 0 0
Valvular dysfunction I34-38 17 15
Cardiomyopathy I42 2 2
Arrhythmia I47-49 10 6
Congestive heart failure I50 23 18
Cerebrovascular disease I60-69 68 55
Hospital admission for cardiovascular disease‡ I20-25, 30-52 814 574
Ischemic heart disease I20-25 411 268
Acute myocardial infarction I21-22 137 83
Angina pectoris I20 146 88
Valvular dysfunction I34-38 52 39
Arrhythmia I47-49 308 215
Congestive heart failure I50 154 120
Surgical intervention for cardiovascular disease§ 255 170 Percutaneous coronary intervention 158 101
Coronary artery bypass surgery 56 36
Valvular dysfunction 53 41
Arrhythmia 4 3
Abbreviation: ICD-10, International Classification of Diseases, 10th revision * Time at risk started five years after DCIS diagnosis.
† Cardiovascular death, hospital admission for cardiovascular disease, or surgical intervention for cardiovascular disease.
‡ Data available since 1995, for patients who were unique based on date of birth, sex, and postal code at time of the hospital discharge
§ Data available since 1995
Comparison with the general population
2
Table 3. Standardized mortality ratios in population-based cohort of five-year survivors of ductalcarcinoma in situ of the breast
Cause ICD-10 Observed SMR 95% CI AER
All causes* A00-Y89 941 1.04
0.97 - 1.11 5.7
Unknown cause 6
Circulatory system I00-99 195 0.77 0.67 - 0.89 -10.2 Myocardial infarction I21-22 43 0.83 0.60 - 1.11 -1.6 Other ischemic heart disease I20, 23-25 15 0.78 0.44 - 1.29 -0.7 Other heart disease I30-33, 39-52 47 0.69 0.50 - 0.91 -3.8 Cerebrovascular disease I60-69 52 0.77 0.58 - 1.01 -2.7 Other cardiovascular disease I00-15, 26-28, 34-52, 70-99 38 0.83 0.59 - 1.14 -1.4 Abbreviations: ICD-10, International Classification of Diseases, 10th revision; SMR, standardized mortality ratio; CI, confidence interval; AER, Absolute excess risk per 10,000 patients per year
Time at risk started five years after DCIS diagnosis. Patients were censored at diagnosis of a second neoplasia treated with chemotherapy or radiotherapy above the diaphragm or date of emigration
* Without taking censoring for second neoplasia into account
Within cohort comparison
When comparing patients treated with radiotherapy to patients treated with surgery only and patients treated with left-sided vs right-sided radiotherapy, no statistically significantly increased risks were found for the combined group of any cardiovascular event (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32), or for cardiovascular death, cardiovascular surgical intervention, hospital discharge diagnoses of CVD, myocardial infarction, other heart disease, valvular dysfunction, arrhythmia, or congestive heart failure separately (Table 5). Risks of hospital discharge diagnoses for IHD and angina pectoris were increased for patients treated with right-sided radiotherapy compared to surgery only (HR=1.47 95%CI 1.01-2.13 and HR=2.53 95%CI 1.46-4.41, respectively). However, no statistically significant differences were seen comparing left- versus right-sided radiotherapy (HR=0.78 95%CI 0.48-1.27 for IHD and HR=0.57 95%CI 0.27-1.23 for angina pectoris). Although statistically non-significant, risks of cardiovascular mortality, IHD, congestive heart failure, and cardiovascular surgical interventions tended to be lower for patients treated with radiotherapy to the left breast than for patients irradiated to the right breast. Conversely, risks of valvular dysfunction and arrhythmia were somewhat higher, although statistically non-significantly, for left- versus right-sided radiotherapy.
Table 4 . Risk s o f diff er en t car dio vascular diseases in fi ve -y ear sur vi vor s o f D CIS, b y ag e, f ollo w -up in ter val, tr ea tmen t, and la ter ali ty Cir cula tor y s ys tem * My ocar dial inf ar ction †
Other ischemic hear
t disease ‡ Other hear t disease § O SMR 95% CI AER O SMR 95% CI AER O SMR 95% CI AER O SMR 95% CI AER Ag e at D CIS diag nosis , y ears <49 0 0. 0 0. 00 -0.56 -5 .0 0 0. 0 0. 00 -2.1 9 -1. 3 0 0. 0 0. 00 -10 .12 -0 .3 0 0. 0 0. 00 -2.30 -1. 2 50-59 23 0. 6 0.38 -0. 91 -6 .5 8 0. 9 0.37 -1. 69 -0. 6 2 0.7 0. 08 -2. 44 -0. 4 6 0.7 0. 24 -1. 41 -1 .4 60-69 97 0.7 0.58 -0.87 -2 3.0 17 0. 6 0.35 -0. 97 -6 .5 6 0. 6 0.21 -1. 24 -2 .7 22 0. 6 0.38 -0. 92 -8 .3 7 0-75 75 1. 0 0.82 -1.30 7. 3 18 1. 4 0.83 -2.20 13 .8 7 1. 3 0.54 -2.7 5 4.8 23 0. 9 0.55 -1.31 -8 .2 Treatment period D CIS 1989 -1992 66 0.7 0.56 -0. 91 -1 7. 4 13 0.7 0.37 -1.1 7 -4 .0 5 0.7 0. 24 -1. 69 -1. 3 32 0. 9 0.58 -1.20 -3 .7 1993 -1996 69 0. 8 0. 63 -1. 03 -7. 9 16 0. 9 0.52 -1. 48 -0 .8 5 0. 8 0.25 -1.82 -0 .7 26 0.7 0. 45 -1. 01 -5 .7 199 7 - 2000 36 0. 8 0.56 -1.1 0 -7. 5 8 0. 9 0.38 -1. 72 -0. 9 4 1. 2 0.32 -2.9 9 0. 5 20 0. 9 0.52 -1.32 -2 .5 2001 - 2005 24 0. 8 0. 49 -1.1 4 -7. 5 6 0. 9 0. 34 -2.0 3 -0 .5 1 0. 4 0. 01 -2.33 -1 .4 14 0. 9 0.53 -1.55 -0. 9 Follow -up inter val, y ears 5-9 96 0. 8 0. 63 -0. 96 -7. 4 28 1. 0 0. 67 -1. 46 0.1 7 0.7 0.30 -1. 51 -0 .7 23 0. 8 0. 48 -1.1 3 -2 .1 10-15 75 0. 8 0. 66 -1. 04 -9 .1 14 0. 8 0. 44 -1. 34 -2 .1 4 0. 6 0.1 6 -1.52 -1. 6 16 0. 6 0.36 -1. 03 -5 .6 >1 5 24 0. 6 0.39 -0. 90 -37 .3 1 0.1 0. 00 -0.83 -13 .8 4 1. 4 0.39 -3.6 6 2.9 8 0. 6 0.28 -1.27 -1 0. 6 D
CIS treatment Surg
er y only 159 0. 8 0. 65 -0.89 -10 .8 35 0. 8 0. 57 -1.1 4 -1. 2 13 0. 8 0. 44 -1. 42 -0. 6 82 0. 8 0. 66 -1. 02 -3 .7 Radiotherap y 36 0. 8 0.55 -1.1 0 -8 .0 8 0. 8 0.37 -1. 67 -0. 6 2 0. 6 0. 07 -2.0 9 -1. 2 11 0.7 0.36 -1.29 -3 .5 Rig ht -sided radiotherap y 19 0. 9 0.55 -1. 43 -3 .4 2 0. 5 0. 06 -1. 67 -4 .3 2 1. 3 0.1 5 -4.56 0. 8 7 1. 0 0.39 -2.0 1 -0 .3 L ef t-sided radiotherap y 17 0.7 0. 40 -1.1 0 -11 .8 6 1. 2 0. 43 -2.54 1. 3 0 0. 0 0. 00 -1. 97 -2 .9 4 0. 5 0.1 4 -1.27 -6 .1 Surg er y only , rig ht -sided 82 0.7 0.59 -0. 92 -1 1. 9 17 0.7 0. 43 -1.1 9 -2 .4 2 0. 2 0. 03 -0.86 -2 .6 43 0. 8 0. 57 -1. 07 -4 .4 Surg er y only , lef t-sided 77 0. 8 0. 63 -1. 00 -9 .4 18 0. 9 0. 51 -1. 44 -0 .8 11 1. 5 0.7 6 -2.7 1 1. 8 39 0. 9 0. 62 -1.1 8 -2 .8 Abbreviations: O, obs er ved; SMR , standardiz ed mor tality ratio; CI, confidence inter val; AER , absolute e xcess risk per 10 ,000 patients per y ear .
Time at risk star
ted fi ve y ears af ter D CIS diag nosis . P atients w ere censored at diag nosis of a second neoplasia treated with chemotherap y or radiotherap y abo ve the diaphrag m or date of emig ration
* I00-99 International Classification of Diseases
, 10th revision
†
I21-22 International Classification of Diseases
, 10th revision
‡I20
,
23-25 International Classification of Diseases
, 10th revision
§I30-33
, 39-52 International Classification of Diseases
2
Table 4 . Risk s o f diff er en t car dio vascular diseases in fi ve -y ear sur vi vor s o f D CIS, b y ag e, f ollo w -up in ter val, tr ea tmen t, and la ter ali ty Cir cula tor y s ys tem * My ocar dial inf ar ction †Other ischemic hear
t disease ‡ Other hear t disease § O SMR 95% CI AER O SMR 95% CI AER O SMR 95% CI AER O SMR 95% CI AER Ag e at D CIS diag nosis , y ears <49 0 0. 0 0. 00 -0.56 -5 .0 0 0. 0 0. 00 -2.1 9 -1. 3 0 0. 0 0. 00 -10 .12 -0 .3 0 0. 0 0. 00 -2.30 -1. 2 50-59 23 0. 6 0.38 -0. 91 -6 .5 8 0. 9 0.37 -1. 69 -0. 6 2 0.7 0. 08 -2. 44 -0. 4 6 0.7 0. 24 -1. 41 -1 .4 60-69 97 0.7 0.58 -0.87 -2 3.0 17 0. 6 0.35 -0. 97 -6 .5 6 0. 6 0.21 -1. 24 -2 .7 22 0. 6 0.38 -0. 92 -8 .3 7 0-75 75 1. 0 0.82 -1.30 7. 3 18 1. 4 0.83 -2.20 13 .8 7 1. 3 0.54 -2.7 5 4.8 23 0. 9 0.55 -1.31 -8 .2 Treatment period D CIS 1989 -1992 66 0.7 0.56 -0. 91 -1 7. 4 13 0.7 0.37 -1.1 7 -4 .0 5 0.7 0. 24 -1. 69 -1. 3 32 0. 9 0.58 -1.20 -3 .7 1993 -1996 69 0. 8 0. 63 -1. 03 -7. 9 16 0. 9 0.52 -1. 48 -0 .8 5 0. 8 0.25 -1.82 -0 .7 26 0.7 0. 45 -1. 01 -5 .7 199 7 - 2000 36 0. 8 0.56 -1.1 0 -7. 5 8 0. 9 0.38 -1. 72 -0. 9 4 1. 2 0.32 -2.9 9 0. 5 20 0. 9 0.52 -1.32 -2 .5 2001 - 2005 24 0. 8 0. 49 -1.1 4 -7. 5 6 0. 9 0. 34 -2.0 3 -0 .5 1 0. 4 0. 01 -2.33 -1 .4 14 0. 9 0.53 -1.55 -0. 9 Follow -up inter val, y ears 5-9 96 0. 8 0. 63 -0. 96 -7. 4 28 1. 0 0. 67 -1. 46 0.1 7 0.7 0.30 -1. 51 -0 .7 23 0. 8 0. 48 -1.1 3 -2 .1 10-15 75 0. 8 0. 66 -1. 04 -9 .1 14 0. 8 0. 44 -1. 34 -2 .1 4 0. 6 0.1 6 -1.52 -1. 6 16 0. 6 0.36 -1. 03 -5 .6 >1 5 24 0. 6 0.39 -0. 90 -37 .3 1 0.1 0. 00 -0.83 -13 .8 4 1. 4 0.39 -3.6 6 2.9 8 0. 6 0.28 -1.27 -1 0. 6 D
CIS treatment Surg
er y only 159 0. 8 0. 65 -0.89 -10 .8 35 0. 8 0. 57 -1.1 4 -1. 2 13 0. 8 0. 44 -1. 42 -0. 6 82 0. 8 0. 66 -1. 02 -3 .7 Radiotherap y 36 0. 8 0.55 -1.1 0 -8 .0 8 0. 8 0.37 -1. 67 -0. 6 2 0. 6 0. 07 -2.0 9 -1. 2 11 0.7 0.36 -1.29 -3 .5 Rig ht -sided radiotherap y 19 0. 9 0.55 -1. 43 -3 .4 2 0. 5 0. 06 -1. 67 -4 .3 2 1. 3 0.1 5 -4.56 0. 8 7 1. 0 0.39 -2.0 1 -0 .3 L ef t-sided radiotherap y 17 0.7 0. 40 -1.1 0 -11 .8 6 1. 2 0. 43 -2.54 1. 3 0 0. 0 0. 00 -1. 97 -2 .9 4 0. 5 0.1 4 -1.27 -6 .1 Surg er y only , rig ht -sided 82 0.7 0.59 -0. 92 -1 1. 9 17 0.7 0. 43 -1.1 9 -2 .4 2 0. 2 0. 03 -0.86 -2 .6 43 0. 8 0. 57 -1. 07 -4 .4 Surg er y only , lef t-sided 77 0. 8 0. 63 -1. 00 -9 .4 18 0. 9 0. 51 -1. 44 -0 .8 11 1. 5 0.7 6 -2.7 1 1. 8 39 0. 9 0. 62 -1.1 8 -2 .8 Abbreviations: O, obs er ved; SMR , standardiz ed mor tality ratio; CI, confidence inter val; AER , absolute e xcess risk per 10 ,000 patients per y ear .
Time at risk star
ted fi ve y ears af ter D CIS diag nosis . P atients w ere censored at diag nosis of a second neoplasia treated with chemotherap y or radiotherap y abo ve the diaphrag m or date of emig ration
* I00-99 International Classification of Diseases
, 10th revision
†
I21-22 International Classification of Diseases
, 10th revision
‡I20
,
23-25 International Classification of Diseases
, 10th revision
§I30-33
, 39-52 International Classification of Diseases
, 10th revision
Table 5. Competing risk regression analyses for different cardiovascular events in five-year survivors of DCIS
Risk factor ICD-10 No. events HR 95% CI
Any cardiovascular event*,† 613
Surgery only 475 Ref.
Right-sided radiotherapy 65 1.08 0.83 - 1.41
Left-sided radiotherapy 73 1.01 0.79 - 1.30
Left- vs. right-sided radiotherapy 138 0.94 0.67 - 1.32 Cardiovascular death‡ I20-25, 30-52 125
Surgery only 101 Ref.
Right-sided radiotherapy 13 1.29 0.72 - 2.31
Left-sided radiotherapy 11 0.89 0.48 - 1.66
Left- vs. right-sided radiotherapy 24 0.70 0.31 - 1.56 Hospital discharge diagnosis of cardiovascular disease† I20-25, 30-52 542
Surgery only 416 Ref.
Right-sided radiotherapy 59 1.12 0.85 - 1.48
Left-sided radiotherapy 67 1.07 0.82 - 1.38
Left- vs. right-sided radiotherapy 126 0.95 0.67 - 1.36 Hospital discharge diagnosis of ischemic heart disease† I20-25 253
Surgery only 189 Ref.
Right-sided radiotherapy 33 1.47 1.01 - 2.13
Left-sided radiotherapy 31 1.15 0.78 - 1.68
Left- vs. right-sided radiotherapy 64 0.78 0.48 - 1.27 Hospital discharge diagnosis of acute myocardial infarction† I21 75
Surgery only 62 Ref.
Right-sided radiotherapy 8 1.13 0.54 - 2.40
Left-sided radiotherapy 5 0.59 0.24 - 1.48
Left- vs. right-sided radiotherapy 13 0.52 0.17 - 1.63 Hospital discharge diagnosis of angina pectoris† I20 82
Surgery only 55 Ref.
Right-sided radiotherapy 16 2.53 1.46 - 4.41
Left-sided radiotherapy 11 1.43 0.76 - 2.71
Left- vs. right-sided radiotherapy 27 0.57 0.27 - 1.23 Hospital discharge diagnosis of other heart disease† I30-52 340
Surgery only 266 Ref.
Right-sided radiotherapy 31 0.89 0.61 - 1.31
Left-sided radiotherapy 43 1.05 0.76 - 1.46
Risk factor ICD-10 No. events HR 95% CI
Hospital discharge diagnosis of valvular dysfunction† I34-38 37
Surgery only 29 Ref.
Right-sided radiotherapy 3 0.83 0.25 - 2.71
Left-sided radiotherapy 5 1.18 0.47 - 2.94
Left- vs. right-sided radiotherapy 8 1.51 0.36 - 6.28 Hospital discharge diagnosis of arrhythmia† I47-49 205
Surgery only 157 Ref.
Right-sided radiotherapy 20 0.91 0.57 - 1.48
Left-sided radiotherapy 28 1.09 0.73 - 1.64
Left- vs. right-sided radiotherapy 48 1.20 0.67 - 2.15 Hospital discharge diagnosis of congestive heart failure† I50 107
Surgery only 87 Ref.
Right-sided radiotherapy 10 1.04 0.53 - 2.03
Left-sided radiotherapy 10 0.87 0.45 - 1.67
Left- vs. right-sided radiotherapy 20 0.83 0.34 - 2.03 Cardiovascular surgical intervention‡ 164
Surgery only 125 Ref.
Right-sided radiotherapy 20 1.44 0.89 - 2.36
Left-sided radiotherapy 19 1.12 0.69 - 1.82
Left- vs. right-sided radiotherapy 39 0.78 0.41 - 1.46 Abbreviations: ICD-10. International Classification of Diseases, 10th revision; HR, hazard ratio; CI, confidence interval; Ref, reference group.
* Cardiovascular death, hospital admission for cardiovascular disease, or surgical intervention for cardiovascular disease.
† Time at risk started at the first moment of becoming uniquely identifiable, with a minimum of five years after DCIS diagnosis.
‡ Time at risk started five years after DCIS diagnosis.
With death treated as a competing risk. Adjusted for age at DCIS diagnosis and year of DCIS diagnosis. Patients were censored at diagnosis of a second neoplasia treated with chemotherapy or radiotherapy above the diaphragm or date of emigration. Multiple cardiovascular events per person possible.
right-sided radiotherapy HR=0.94 95%CI 0.68-1.29; Table 6). Additionally, the risk in the first five years after treatment did not differ from the risk more than five years after treatment (HR=0.63 95%CI 0.42-0.94). In stratified analyses, similar risks were found for patients with and without a history of CVD (HR=0.88 95%CI 0.37-2.06 and HR=0.94 95%CI 0.67-1.33, respectively). When taking into account history of CVD within two years prior to DCIS diagnosis only, and thus equaling the number of years with information on history of CVD for all patients, a statistically non-significant risk increase of 1.85 was seen for patients with a history of CVD (95%CI 0.50-6.82), while no increased risk was seen for patients without a history of CVD (HR=0.95 95%CI 0.68-1.33). However, the number of patients available for this analysis was only small.
2
Table 6. Risk of any cardiovascular event* in subgroup analysis for all patients with DCIS diagnosedbetween 1997 and 2005 taking into account history of cardiovascular disease†
Risk factor No. patients No. events HR 95% CI
1997-2005, total 6,676 477
Surgery only 4,352 324 Ref.
Right-sided radiotherapy 1,061 71 1.02 0.78 - 1.33
Left-sided radiotherapy 1,263 82 0.96 0.75 - 1.23
Left- vs. right-sided radiotherapy 2,324 153 0.94 0.68 - 1.29 1997-2005, without history of cardiovascular disease 6,504 413
Surgery only 4,240 281 Ref
Right-sided radiotherapy 1,034 61 1.02 0.77 - 1.36
Left-sided radiotherapy 1,230 71 0.97 0.74 - 1.26
Left- vs. right-sided radiotherapy 2,264 132 0.94 0.67 - 1.33 1997-2005, with history of cardiovascular disease 172 64
Surgery only 112 43 Ref
Right-sided radiotherapy 27 10 1.06 0.53 - 2.13
Left-sided radiotherapy 33 11 0.98 0.51 - 1.91
Left- vs. right-sided radiotherapy 60 21 0.88 0.37 - 2.06
Abbreviations: HR, hazard ratio; CI, confidence interval; Ref, reference group
Time at risk started at the first moment of becoming unique. Death was treated as a competing risk. Adjusted for age at DCIS diagnosis, year of DCIS diagnosis and history of hospital admission for cardiovascular disease. Patients were censored at diagnosis of a second neoplasia treated with chemotherapy or radiotherapy above the diaphragm or date of emigration.
* Cardiovascular death, hospital admission for cardiovascular disease, or surgical intervention for
cardiovascular disease
† History of cardiovascular disease defined as a hospital admission for cardiovascular disease prior to
the DCIS diagnosis
Discussion
history of CVD. Due to the low number of patients with a history of CVD in this analysis, this may be a chance finding.
Contrary to our expectations, we did not find a risk increase of IHD incidence or mortality following radiotherapy for DCIS, possibly because of the relatively short follow-up duration. Excess risks for valvular dysfunction, arrhythmia, and congestive heart failure were not expected because of the expected low mean heart dose.
Although we did not collect information on radiation fields, it is plausible to assume that patients treated with radiotherapy were irradiated using tangential breast fields only. In the Netherlands DCIS and invasive BC are treated with similar tangential fields; therefore our results also apply to invasive BC patients provided internal mammary nodes are not included.
The Early BC Trialists’ Collaborative Group15 compared DCIS patients (n=3,729) treated with
radiotherapy to patients treated with surgery only and found a slight but statistically non-significant risk increase in cardiovascular mortality. Although we had a comparable follow-up duration, we were not able to confirm this finding. Our results are, however, in line with the
two other CVD studies in DCIS patients16,17. Ernster et al.16 found a similarly decreased SMR
for CVD using the Surveillance, Epidemiology and End Results database (n=7.072). However, they were not able to make any further distinctions based on laterality or treatment. Also in
invasive BC patients, lower SMRs were found22,24. Possible explanations for lower SMRs for
CVD are differences in CVD risk factors between DCIS patients and the general population, e.g. higher socio-economic status, later age at menopause, or more health-conscious, or the adoption of a healthier lifestyle after DCIS diagnosis.
Park et al.17 compared cardiovascular morbidity and mortality in a small patient group (n=129)
treated with radiotherapy for left- versus right-sided DCIS and did not find a difference. Studies looking at the effect of tangential breast field irradiation for invasive BC showed
mixed results25,26. Our results are in contrast to Darby et al.’s13 recently published increase of
2
patients treated with radiotherapy on CVD risk factors10. However, due to the excellent Dutch
health insurance system and the small distances to radiation facilities, only comorbidity could have influenced the treatment choice, next to DCIS disease characteristics and patient preferences. If comorbidity had an influence, the effect was probably small, since the prevalence of a history of CVD before DCIS diagnosis was low (1.7%) in our patient population ≤75 years at DCIS diagnosis. Moreover, patients with a history of CVD did not receive radiotherapy less often than patients without a history of CVD and estimates comparing radiotherapy versus surgery only did not materially differ from those of left- versus right-sided radiotherapy comparisons.
Our study had several strengths and limitations. Unique features of our population-based study include taking into account both cardiovascular morbidity and mortality, performing linkage with two population-based registries with CVD information, and examining the effect of a history of CVD.
There is no reason to assume either confounding by indication or surveillance bias in our study population. There was no difference in use of radiotherapy between left- and right-sided DCIS, history of CVD incidence did not differ by laterality, and DCIS patients irradiated to the breast are not routinely screened for cardiac symptoms in routine clinical care. A limitation of our study is that we missed less severe cases of CVD that did not require hospitalization or cardiac intervention, and did not lead to death. Furthermore, we were unable to perform linkage with the DHD for 9.7% of our cohort because these patients were not uniquely identifiable. There is, however, no reason to assume difference in CVD incidence between identified and non-identified patients, since no differences in patient characteristics or frequency of cardiovascular surgical interventions between the two groups were found.
Because the DHD and the BHN registries were digitalized/initiated in 1995, CVD incidence before 1995 was unavailable for our cohort. Therefore, we included only five-year survivors in our overall analyses. Since earlier research has frequently shown that
radiotherapy-related CVD risk did not become clinically manifest until after 5-10 years9,22-24, no effect of
radiotherapy was expected in the first 5 years after irradiation. In our analyses in patients diagnosed ≥1997, we did not observe risk increases in the first five years after treatment. Unfortunately, we did not have information on CVD risk factors. However, it is unlikely that any possible risk factor would differ by laterality.
Especially since radiation effects on CVD have a long induction period, it is unfortunate that the follow-up in our study was relatively short, with a median of ten years in the total cohort, and eight years for patients treated with radiotherapy. Although restriction of the analyses to patients with a follow-up of ten years or more did not change our results, power was limited in these analyses.
The results of our study are important for the debate with regard to screening for BC and the possibility of overtreating the increasing number of patients diagnosed with DCIS. Possible benefits and risks of BC screening and radiotherapy following breast conserving surgery for DCIS should be weighed carefully. Importantly, radiotherapy after breast-conserving surgery for DCIS approximately halves the rate of ipsilateral breast events during the
subsequent decade with little effect on contralateral or distant events15. Although our
results are reassuring, studies with longer follow-up after breast irradiation are needed before definitive conclusions regarding CVD risk can be drawn.
Funding: This work was supported by the Dutch Cancer Society (grant number NKI 2008-3994). Disclaimers: None of the authors have disclosures or conflict of interest. The sponsor had no role in the study design, data collection and analysis, interpretation of the results, or the preparation of the manuscript.
