University of Groningen
Long-term cardiovascular effects of breast cancer treatment
Boerman, Liselotte
DOI:
10.33612/diss.116880323
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Boerman, L. (2020). Long-term cardiovascular effects of breast cancer treatment. University of Groningen. https://doi.org/10.33612/diss.116880323
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Ǧ
2
The work described in this thesis was conducted at the Department of General Practice and department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands
The study described in this thesis was funded by a grant from Pink Ribbon and stichting De Friesland.
Publication of this thesis was financially supported by SHARE, RUG and UMCG © Copyright 2020 L.M. Boerman, The Netherlands
All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the written permission of the author or, when appropriate, of the publishers of the publications.
Cover design: A. Polgar Printed by: Ridderprint
ISBN 978-94-034-2230-5 (printed version) ISBN 978-94-034-2229-9 (electronic version)
Proefschrift
Ǧ
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 12 februari 2020 om 11.00 uur
door
Liselotte Mirjam Boerman
geboren op 19 april 19894
Promotores
Prof. dr. G.H. de Bock Prof. dr. M.Y. Berger C Copromotor Dr. A.J. Berendsen Beoordelingscommissie Prof. dr. J.J. Assendelft Prof. dr. J.A. Langendijk Prof. dr. A.H.E.M. Maas
Copromotor
Beoordelingscommissie
6
Chapter 1
General Introduction p. 9
Part I: Long--term prevalence of cardiovvascular disease and cardiac dysfunction
Chapter 2 Long-term follow-up for cardiovascular disease after
chemotherapy and/or radiotherapy for breast cancer in an unselected population
p. 19
Chapter 3 Long-term outcome of cardiac function in a population-based cohort of early breast cancer survivors: a cross-sectional study
p. 35
Part II: Risk assessment
Chapter 4 Troponin and (NT-pro)BNP as predictors for the occurrence of asymptomatic and symptomatic cardiac dysfunction during or after breast cancer treatment: a systematic review
p. 57
Chapter 5 Long-term survivors of breast cancer treated with
chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls
p. 79
Chapter 6 Summary, general discussion and recommendations p. 99
Chapter 7 Nederlandse samenvatting p. 113
Appendices References p. 121
Dankwoord p. 145
Curriculum Vitae p. 151
Lijst deelnemende praktijken p. 155
Research Institute SHARE p. 159
General introduction
Chapter 1
10
The main focus of this thesis is to study the long-term cardiovascular effects of
chemotherapy and radiotherapy in breast cancer survivors in general practice. Thereby, the aim is to study the prevalence and the risk of cardiac dysfunction and cardiovascular disease in women treated for breast cancer and compare this to age- and general practitioner (GP) matched controls in primary care. Furthermore, in this thesis an attempt is made to identify which factors are associated with this risk. We, therefore, examined the usefulness of cardiac biomarkers measured at time of breast cancer diagnosis in a systematic review. Furthermore, biomarker profiles were analysed to hypothesize on the possible causal pathway of the development of cardiac dysfunction in breast cancer survivors.
Background
Breast cancer
Breast cancer is the leading cause of cancer among women with about 1.7 million women diagnosed worldwide.1 In the Netherlands, a sharp increase of the incidence of
breast cancer was observed in the early nineties (Figure 1A). This has been explained by the implementation of the breast cancer screening program, by the ageing of the population and probably by the fact that unfavourable lifestyle and reproductive risk factors became more common.2, 3 Examples of unfavourable lifestyle risk factors are:
obesity and physical inactivity. Examples of unfavourable reproductive risk factors are: later age at first childbirth and less breastfeeding.2 A report of the Dutch Cancer Society
published in 2011, observed a steep increase in cancer incidence which was mainly due to aging of the population.3 In 2010 in the Netherlands the life-time risk for developing
Figure 1 Incidence of invasive breast cancer per 100.000 according to European standardised rate* (A) and survival (B) of breast cancer between 1990 and 2015 5
*the rate that would have been found if the population had the same age-composition as a hypothetical European population each year 6
Due to combined increase in incidence and improved survival, the 10-years prevalence of breast cancer also increased.7The current 10-years prevalence in the Netherlands is
12.9 per 1000 women.5This improvement of survival is probably due to advances in
treatment, better staging and early treatment of less advanced stages because of detection through screening.8-11Up to 85% of all women diagnosed today will still be
alive five years after diagnosis12and up to 75% 10 years after diagnosis (figure 1B).13
This implies that a standard Dutch GP practice (which includes 2168 patients) on average includes 20 women with a history of breast cancer.14Of these about 70% have
been treated with chemotherapy, radiotherapy or both.15-18It is important for GPs to
know the cardiovascular problems that these women may experience on the long term.
Risk of cardiotoxicity in breast cancer survivors
Several studies have investigated the risk of cardiotoxicity after chemotherapy and radiotherapy for breast cancer.
Up till now, most studies on long-term cardiotoxic effects of chemotherapy in breast cancer survivors included specific groups. This can be considered as a limitation of the generalizability of these studies. Furthermore, most studies investigating cardiac dysfunction after chemotherapy lack information on long-term follow-up.19-27Studies
comprising selected populations had follow-up information on patients who contributed to randomized controlled trials, which may have influenced the risk estimates.28-31 Others examined the frequency of diagnosed cardiac dysfunction
without knowing cardiovascular risk factors, which may have led to inconsistencies and
0 20 40 60 80 100 120 140 160 N u m b er o f wo m e n p e r 100.00 0 Year of diagnosis A 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 Pe rc e n ta ge o f w o m e n a li v e
Number of years after diagnosis
B 1989-1993 1994-1998 1999-2003 2004-2007
1
Chapter 1
12
clinical difficulties in the interpretation of risks.32-37 Furthermore, risks may have been
overestimated as most studies lacked data on the prevalence of (a)symptomatic cardiac dysfunction in a population of women without breast cancer treatment.38-41
Adverse effects of radiotherapy to the heart have been known after their wide-spread introduction in the end of the sixties.42 As newer radiation schemes are
introduced, risks of cardiovascular morbidity and mortality due to radiation seem to decrease.32, 36, 43-45 However, also with modern schemes small parts of the heart may be
situated in the radiated field, and small doses to the heart may also give an increased risk of cardiovascular morbidity.46 Up till now, studies on modern schemes (after 1980)
have been inconclusive and lack sufficient follow-up to show the adverse effects on morbidity and survival. 36, 47-52
The majority of studies investigating the effects of chemo- and/or radiotherapy by echocardiography have focussed on the effects of treatment on the left systolic function of the heart. However, scarring and fibrosis due to these therapies, could also lead to dysfunction of the diastolic or the right ventricular function.41 Both are
associated with an increased mortality.53 With echocardiography the systolic and
diastolic function of the left ventricle as well as systolic function of the right ventricle can be assessed, and may show changes early in the course of disease.52
Pathophysiology of cardiotoxicity due to cancer treatments
Several pathways have been proposed as possible mechanisms through which chemotherapy and radiotherapy for breast cancer lead to damage to the heart, and therewith are associated with an increased risk of developing cardiovascular disease.54
Nowadays, anthracyclines (either doxorubicin or epirubicin) are the most frequently used type of chemotherapy given to breast cancer patients.55 The leading
hypothesis of the pathophysiological mechanism leading to cardiotoxicity in anthracycline-treated patients is formation of free radicals and alcohol metabolites, through several pathways. Finally, these pathways lead to oxidative stress and damage to the cardiac muscle.56 Furthermore, the impairment of pro-survival pathways may
lead to premature cardiomyocyte death. Besides, cardiac progenitor cells may be affected leading to impaired response to further injury by cardiotoxic treatments or pathologic stress caused other cardiac risk factors.56 This may cause cardiomyopathy,
which in time leads to a reduced left ventricular ejection fraction and is associated with heart failure, severe arrhythmias and heart valve damage57-59, especially when higher
cumulative doses were adminstererd.60
Also, other chemotherapeutic agents, like alkylating agents (e.g. cyclophosphamide) and taxanes (e.g. paclitaxel and docetaxel), have cardiotoxic
effects.61, 62 Cardiotoxicity leading to left ventricle dysfunction due to alkylating agents
usually occurs shortly after initial administration.62 Taxanes, on the other hand, may
potentiate the effect of anthracyclines by interfering with their metabolism and excretion62 and by enhancing the formation of alcohol metabolites leading to potential
increased risk on the long-term as well.63 Another therapy which has a cardiotoxic
effect is trastuzumab. Targeted therapy with trastuzumab, given to patients with an overexpression of HER-2-Neu, may lead to cardiac dysfunction especially when given during or directly following anthracyclines-therapy. This effect is possibly due to a blockage of the repair mechanism of the heart caused by trastuzumab, which prevents the heart repairing the damage due to anthracyclines.64 This dysfunction appears
during treatment, and is highly reversible when treatment with trastuzumab is (temporarily) suspended.64
During radiation therapy, especially in left-sided treated patients, a part of the cardiac muscle may be situated in the radiation field, leading to direct exposure of the heart.54 Exposure to radiation may induce an initial inflammatory response, which is
followed by fibroblast proliferation and remodeling.65 This may lead to the
development of pericardial fibrosis and micro- and macrovascular damage.42, 56, 66
Microvascular damage, can lead to ischemia and ultimately fibroses. This myocardial fibrosis leads to cardiomyopathy and congestive heart failure.54 In turn, macrovascular
damage leads to coronary artery disease, resulting in ischemic heart disease such as angina pectoris and myocardial infarction.54 Besides, myocardial infarction and
cardiomyopathy, arrhythmias and cardiac valve disease are mentioned as consequences of radiation therapy. 33, 67, 68
Thus, chemotherapy and radiotherapy are supposed to have a direct effect by damaging the cells as described above. Furthermore, an indirect effect (not directly due to the treatments itself) is described by Jones et al. called the multiple-hit hypothesis.69, 70 The first hit may be caused by the direct effect of cardiotoxic treatments. This direct
damage might decrease the cardiac reserve which may lead to a decreased capability of the cardiac muscle to cope with additional damage. As additional hits are added – for instance due to the effect of diabetes or hypertension – the cardiac reserve might become even smaller (Figure 2). In contrast, a decreased cardiac reserve at start of breast cancer treatment, due to the effects of other risk factors, such as diabetes, may increase the adverse effects of breast cancer treatment as well. The more hits received, the more strain on the heart arises. This may lead to a lower reserve ending in cardiomyopathy and heart failure.
Chapter 1
14
Figure 2 Decrease in cardiac reserve across breast cancer survivors according to multiple hit theory
Cardiac dysfunction as a result of cardiotoxic therapy can be present in the short-term (during breast cancer treatment), but also years (> 5 years) after diagnosis. The short-term effects may be due to the direct damage, while long-short-term consequences may be due to the combined effects of direct and indirect damage. It remains uncertain, especially on the long-term, to what extend these therapies impair the cardiac function. Follow-up care of breast cancer patients
In the Netherlands, follow-up of patients who have been curatively treated for breast cancer focusses on two topics: early detection and survivorship-care.
Early detection of recurrences and contralateral primary tumours is mainly performed by medical specialists in the hospital in the first five years after treatment. Patients above the age of 60 are then referred back to the national screening program in case of an ablation of the breast or to the GP when they had breast conserving surgery.14
Survivorship-care is delivered by both care providers in the hospital as well as the GP. The focus of a this care is monitoring treatment-related side-effects, and providing care and support.14Monitoring side-effects include treating lymphedema and
shoulder pain, side effects of anti-hormonal medication and (underlying causes of) fatigue. Care and support should be given to women with psychosocial distress, an increase of body weight, with anticonception or hormonal therapy wishes, with problems related to sexuality or returning to work.
Cardiotoxicity is mentioned as a potential side-effect of treatment in the breast cancer guideline of the Dutch College of General Practitioners.14 However, no
recommendations are made regarding routine cardiac follow-up or incorporating cardiotoxicity in the cardiovascular risk assessment. This is because prevalence in primary care is unknown. Studies on the risk of cardiac dysfunction due to breast cancer
Ca rd ia c re se rve vo lu m e Controls Breast cancer patients b rea st c a n c er tr ea tm en t 1st hit 2th hit Time asymptomatic dysfunction heart failure
therapy do not reflect the population of breast cancer survivors in general practice. Therefore, it is uncertain whether long-term routine cardiac follow-up is useful. Furthermore, before determining whether to add chemo- and/or radiotherapy treatment for breast cancer to the cardiovascular risk management (CVRM) guideline of the Dutch College of General Practitioners (NHG), the prevalence must be known. 71 Objectives and outline of the thesis
The main focus of this thesis is to estimate the burden of cardiac dysfunction in women treated for breast cancer with chemo- and/or radiotherapy in the general population compared to age- and GP-matched controls. In addition, this thesis aims to find methods to identify women who are at increased risk of developing cardiac dysfunction, and biomarkers are explored to give more insight in the possible aetiology of the occurrence of cardiovascular disease after breast cancer treatment.
To answer these questions, a retrospective study, a cross-sectional study, and a systematic review have been performed. The majority of the chapters (2, 4 and 5) are based on data of the BLOC (Breast Cancer Long-term Outcome Cardiac dysfunction) study: a cross-sectional cohort study of 350 long-term breast cancer survivors treated with chemo- and/or radiotherapy and 350 age- and GP matched controls derived from general practice. This large study contained echocardiographic data, blood samples and questionnaires of all 700 participants. In this study we were able to compare outcomes of breast cancer survivors with those of control women to contribute to a more accurate assessment of risks.
Chapter 1
16
Part I Prevalence
The first part of this thesis focusses on the main research question regarding the prevalence of cardiac dysfunction of breast cancer survivors, and presents the results of two studies:
1. Long-term follow-up for cardiovascular disease after chemotherapy and/or radiotherapy for breast cancer in an unselected population
In this retrospective analysis of electronic patient files of GPs the aim was to assess the risk of congestive heart failure, vascular cardiac diseases, and ‘other’ cardiac diseases in an unselected population of women curatively treated for breast cancer, compared with an age- and general-practice matched random sample of women. In addition, breast cancer survivors treated with radiotherapy were compared to those threated without radiotherapy and breast cancer survivors with chemotherapy were compared to survivors without chemotherapy. 2. Long-term outcome of cardiac function in a population-based cohort of early
breast cancer survivors: a cross-sectional study [BLOC-study]
This cross-sectional study, derived from the BLOC-study, assessed the prevalence of long-term echocardiographic-based cardiac dysfunction among early breast cancer survivors treated with chemotherapy (± radiotherapy) or radiotherapy only, and compared that with the prevalence of cardiac dysfunction among matched control women in a primary care setting. In addition, the prevalence of cardiovascular disease and prescribed cardiovascular medication was assessed among survivors and controls.
Part II Risk assessment
In the second part of the thesis, the goal was to gain more insight into factors that are associated with long-term cardiac dysfunction, and therewith identify factors associated with higher risk of long-term cardiac dysfunction and cardiovascular disease among the long-term survivors.
3. Troponin and (NT-pro)BNP as predictors for the occurrence of asymptomatic and symptomatic cardiac dysfunction during or after breast cancer treatment: a systematic review
This systematic review evaluated whether an increased value of troponin or (NT-pro)BNP during breast cancer treatment could predict the occurrence of subsequent cardiac dysfunction. Thereby, it may
serve as a tool to identify a high risk cohort within the group of breast cancer survivors.
4. Long-term survivors of breast cancer treated with chemotherapy are
characterized by a pro-inflammatory biomarker profile compared to matched controls [BLOC study]
This aim of this analysis was to search for differences in biomarker profiles between breast cancer survivors and women without a history of cancer and to identify whether these profiles relate to their cardiac function, and therewith give clues to the pathophysiology of cardiotoxicity.
Finally, the last chapter contains a summary and general discussion on the most important results of this thesis.
Chapter 1
Long-term follow-up for cardiovascular disease after
chemotherapy and/or radiotherapy for breast cancer in an
unselected population
L.M. Boerman A.J. Berendsen P van der Meer J.H. Maduro M.Y. Berger G.H. de Bock
Chapter 2
20 Abstract
Purpose
Whereas earlier research focused on specific patient groups, this study assessed the risk of cardiovascular disease (CVD) in an unselected population curatively treated for breast cancer (BC), compared with an age-matched random sample of controls.
Methods
Risks were determined in BC survivors and controls. CVD was divided into three categories: congestive heart failure, vascular cardiac diseases and ‘other’ cardiac diseases. Hazard ratios (HR) and 95% confidence intervals (95%CI) adjusted for age, CVD and CVD risk factors at baseline, were determined by Cox regression analyses.
Results
All 561 survivors of BC experienced surgery of whom 229 received (neo)adjuvant radiotherapy, 145 chemotherapy (with or without radiotherapy), and 187 received no adjuvant therapy. During follow-up (median 9; range 5-57 years), CVD occurred in 176/561 (31%) survivors and in 398/1,635 (24%) controls. After radiotherapy, no increased risks of congestive heart failure (HR 0.5; 95%CI 0.2-1.8), vascular cardiac diseases (HR 1.1; 95%CI 0.7-1.7) or other cardiac diseases (HR 1.3; 95%CI 0.8-2.3) were found compared with controls. Similar results were found after chemotherapy for congestive heart failure (HR 1.8; 95%CI 0.6-5.8), vascular cardiac diseases (HR 1.1; 95%CI 0.5-2.3) and other cardiac diseases (HR 1.2; 95%CI 0.3-5.5).
Conclusions
In an unselected population of BC survivors, no significant increased risk of CVD after radiotherapy and/or chemotherapy was found compared with controls. However, the HR after chemotherapy was in line with previous studies. Future studies should include more detailed information on treatment and more specific outcome measures.
Introduction
The current lifetime risk for women in Western countries to develop breast cancer is about 1 in 8. Due to earlier detection through screening and advances in treatment, the overall survival of women with breast cancer has substantially increased.10, 11, 72 Most
women with early breast cancer are treated with surgery combined with radiation.15
Young women more often receive chemotherapy due to clinical preferences and biological factors of the tumor (e.g. in case of more advanced and aggressive tumors).17, 18 As survival and incidence increases, the long-term effects of treatment have become
apparent. Treatment with radiotherapy and chemotherapy, although very effective, carries the risk of increased cardiovascular morbidity and mortality, even many years after treatment.73-75
Cardiovascular disease (CVD) after radiotherapy is mainly associated with acute myocardial infarction, arrhythmias, cardiomyopathy, coronary artery disease and cardiac valve disease.33, 67, 68 Much research has focused on the cardiotoxic effects of
radiotherapy. Studies have shown that patients who received left-sided radiotherapy are at increased risk to develop CVD as compared with right-sided radiotherapy; this correlates with the probability of the inclusion of parts of the heart in the radiotherapy field.76-78 Furthermore, every few years a large meta-analysis is performed by the Early
Breast Cancer Trialists' Collaborative Group (EBCTCG).75, 79 The 2005 meta-analysis
showed an excessive mortality of CVD among women treated for breast cancer.43 A
proportional 30% increase in cardiac mortality was seen in patients treated in the 1960s and 1970s. In these latter studies, most women had been treated with the older radiation schemes, which involved higher doses of radiation, and a larger proportion of the heart was positioned in the radiation field. However, the most recent study of the EBCTCG (published in 2010) did not detect an enhanced mortality due to CVD 10 years post treatment.79
The increased incidence of CVD after chemotherapy is mostly due to the effects of anthracyclines.73, 80, 81 The use of anthracyclines may cause cardiomyopathy, which
leads to a reduced left ventricular ejection fraction and is associated with heart failure, severe arrhythmias and heart valve damage.57-59 However, most studies on the
long-term cardiotoxic effects of chemotherapy in breast cancer survivors included a highly selected group of patients, which may limit the generalizability of these studies. In ƐŽŵĞ ƐƚƵĚŝĞƐ͕ ǁŽŵĞŶ ĂŐĞĚ ш ϲϱ LJĞĂƌƐ ŽĨ ĂŐĞ ǁĞƌĞ ŝŶĐůƵĚĞĚ34, 35, 37, whereas
chemotherapy is often prescribed to younger women. Other studies included women who participated in large randomized controlled trials with strict inclusion
Chapter 2
22
criteria26, 82, 83, or did not compare the risks of developing CVD in breast cancer patients
with a control group without a history of cancer.25
The present study assesses the risk of CVD in an unselected population of women curatively treated for breast cancer, compared with an age- and general-practice matched random sample of women. In addition, different regimens of breast cancer treatment are compared with each other.
Methods
Context
The study included 10 general (group) practices in the northern part of the Netherlands with a total population of ± 94,000 patients. In the Netherlands every citizen should be registered with one primary care practice. Most patients have a long-standing relationship with their practice and general practitioner (GP).84 All primary care practices in the Netherlands have a high level of information technology and store information encrypted. Furthermore, an electronic medical record is at their disposal in which referral letters to and from medical specialists, admission and discharge information from hospitals, communication with pharmacies, and information exchange with the after-hours cooperatives are available.84
Data for the present study included patient contacts recorded by participating GPs using the International Classification of Primary Care (ICPC) version 185 and referrals by specialty. The ICPC codes are linked to each patient based on information from the specialist, or on a diagnosis made by the GP (e.g. clinical symptoms, radiology and laboratory tests).
Patients and controls
Women were included in the study if they were diagnosed with breast cancer and received a curative treatment before 2007 (minimal follow-up period of 5 years) and after 1970 (due to outdated treatment or incomplete data). Patients were excluded if ƚŚĞLJǁĞƌĞĂŐĞĚшϴϬLJĞĂƌƐĂƚƚŝŵĞŽĨĚŝĂŐŶŽƐŝƐ;ďĞĐĂƵƐĞŽĨĂŶĞdžƉĞĐƚĞĚŚŝŐŚĨƌĞƋƵĞŶĐLJ ŽĨ s ĂŶĚ Ă ůŝĨĞ ĞdžƉĞĐƚĂŶĐLJ ŽĨ ч ϭϬ LJĞĂƌƐͿ Žƌ ǁŚĞŶ ƚŚĞLJ ǁĞƌĞ ƚƌĞĂƚĞĚ ǁŝƚŚ chemotherapy for other indications. When the therapy regimen for breast cancer was unknown, these patients were also excluded (n=8).
Of the total population, 561 women with breast cancer met the inclusion and exclusion criteria and were included in the present study. Three female patients (controls) without a previous diagnosis of cancer enlisted in the same general practice were matched (using a random generator) with each eligible patient for age at inclusion
(in 5-year intervals). For controls, the same exclusion criteria were applied as for included patients. Relevant data were retrieved from patients’ medical records and entered into a separate, anonymous, password-protected database. According to Dutch law this means that no further approval from our Institutional Review Board was required.86
Data and definitions
Cardiovascular diagnoses (and the date of their first occurrence) were extracted from the electronic medical records of the GPs and divided into three categories based on the ICPC codes: congestive heart failure, vascular cardiac diseases, and other cardiac diseases.
‘Congestive heart failure’ includes acute and chronic congestive heart failure. ‘Vascular cardiac diseases’ include unstable and stable angina pectoris, acute myocardial infarction, other chronic ischemic heart diseases (coronary artery sclerosis), transient ischemic attack (TIA) and cerebrovascular attack (CVA). The ‘other cardiac diseases’ category includes atrial fibrillation, paroxysmal tachycardia, non-rheumatic valve disease, and other CVD (e.g. cardiomyopathy, aneurysm aorta, and arteriosclerosis). Hypertension, diabetes, hyperlipidemia and CVD before baseline were considered to be risk factors for CVD. The presence of any of these factors, as well as the date of occurrence, was noted on a predefined form.
Letters sent by medical specialists to GPs were read to assess the stage of the cancer and the treatment received. This treatment, the date of diagnosis, TNM stage, and localization of the tumor (left or right) were registered.
In general, because the electronic patient files of GPs do not contain information on deceased patients, the main analysis focused on patients who were alive at the date of inclusion at end 2011. However, 3 of the 10 participating general (group) practices take part in the Registration Network Groningen (RNG), which contains information on about 30,000 patients. The database of the RNG contains information on the cause of death for patients who died before the inclusion date and after the start of the registration network in 1998; these latter data were used for an additional analysis.
Data analyses
The selected patients treated for breast cancer were divided into three groups based on therapy regimes: surgery combined with adjuvant radiotherapy (without chemotherapy), surgery combined with (neo)adjuvant chemotherapy (with or without
Chapter 2
24
radiotherapy), and surgery alone. Prevalence of risk factors for CVD, and CVD at time of diagnosis, as well as age at time of diagnosis were determined for these groups and the matched controls.
Follow-up times were calculated. For patients the baseline was date of diagnosis of breast cancer; for controls without a history of cancer this was set at the median time of diagnosis of breast cancer of their matched (5-year) patient group. The endpoint was the date of the first cardiovascular event of the specific cardiac category after the date of diagnosis of breast cancer, or the date of data retrieval. Cox regression analyses were used to determine the hazard ratios (HR) and 95% confidence intervals (95% CI) to assess the time to CVD for patients compared with controls.
In the first analysis, patients treated with radiotherapy were compared with controls without a history of cancer. Secondly, the same patients were compared with patients with breast cancer who did not receive radiotherapy. We focused on vascular and other cardiac diseases as these are mainly associated with radiotherapy. In the third and fourth analyses, patients treated with chemotherapy were compared with controls without a history of cancer and with patients with breast cancer who did not undergo chemotherapy. In these analyses we focused on heart failure, as this is mainly associated with chemotherapy.
All HRs are adjusted for age at the time of diagnosis of breast cancer, the presence of CVD, and risk factors for CVD at baseline. All analyses are performed in total groups as well as in subgroups of patients treated 5-ϭϬLJĞĂƌƐĂŐŽĂŶĚшϭϬLJĞĂƌƐ ago.
In an additional analysis, the cause of death and median age at time of death is reported of the deceased breast cancer patients and controls. Furthermore, HRs were determined for the population recruited in these practices, including data from the deceased patients, in the same way as described before.
The proportional hazard assumption of the Cox analysis was tested and held true. All analyses were performed with SPSS version 20.0.
Results
Of the 561 patients with breast cancer, 229 received adjuvant radiotherapy (without chemotherapy), 145 received (neo)adjuvant chemotherapy (with or without radiotherapy), and 187 received surgery alone (Table 1). Furthermore, larger tumor size and more lymph node involvement were more often present in women who received (neo)adjuvant chemotherapy (Table 1).
Table 1 Tumor and therapy characteristics of the breast cancer patients (n=561)
Radiotherapy only (n=229) Chemotherapy ± radiotherapy (n=145) Surgery alone (n=187) n (%) n (%) n (%) Tumor size 1 156 (72.2) 58(42.0) 97 (72.9) 2 56 (25.9) 63 (45.7) 33 (24.8) 3 1 (0.5) 11 (8.0) 3 (2.3) 4 3 (1.4) 6 (4.3) 0 (0) Unknown 13 (-) 7 (-) 54 (-)
Involved lymph nodes
0 176 (81.1) 36 (25.9) 132 (89.2) 1 39 (18.0) 94 (67.6) 16 (10.8) >2 2 (0.9) 9(6.5) 0 (0) Unknown 12 (-) 6(-) 39 (-) Side Left 107 (46.9) 72 (49.7) 89 (49.2) Right 120 (52.6) 73 (50.3) 90 (49.7) Both 1 (0.4) 0(0) 2 (1.1) Unknown 1 (-) 0(-) 6 (-) Surgery Lumpectomy 200 (87.3) 72 (49.7) 22 (11.8) Mastectomy 27 (11.8) 72 (49.7) 165 (88.2) None 2 (0.9) 1 (0.6) 0 (0) Adjuvant therapy Chemotherapy 0 (0) 145 (100) 0 (0) Radiotherapy 229 (100) 105 (72.4) 0 (0) Hormone therapy 49 (21.5) 85 (58.6) 25 (13.3) Trastuzumab 0 (0) 4 (2.8) 0 (0) Decade of treatment 1970-1979 2 (0.9) 2 (1.4) 17 (9.1) 1980-1989 15 (6.5) 7 (4.8) 25 (13.4) 1990-1999 72 (31.4) 39 (26.9) 89 (47.6 ) 2000-2006 140 (61.1) 97 (66.9) 55 (29)
Women who received (neo)adjuvant chemotherapy (with or without radiotherapy) were on average 8 years younger than patients with breast cancer who did not receive this therapy. Women who received chemotherapy (with or without
Chapter 2
26
radiotherapy) had less cardiovascular risk factors at baseline compared with the other treatment groups and with controls. However, the prevalence of hypertension was higher in women in this group compared with the other treatment groups and with controls (Table 2).
Table 2 Baseline risk factors of the patients (n=561) and controls (n=1635)
Radiotherapy only (n=229) Chemotherapy ± radiotherapy (n=145) Surgery alone (n=187) Controls (n=1635) Median age in years at
time of diagnosis (range)
56 47 53 54 (22-77) (27-67) (27-79) (27-67)
n (%) n (%) n (% ) n (%)
Risk factors for CVD-
combined 44 (19.2) 25(17.2) 25 (13.5) 269 (16.5)
Lipid dysfunction 13 (5.7) 6 (4.1) 13 (7.0) 74 (4.5)
Diabetes mellitus 15 (6.6) 4 (2.8) 3 (1.6) 50 (3.1)
Hypertension 26 (11.4) 21 (14.5) 17 (9.2) 199 (12.2)
Total CVD at baseline 11 (4.8) 5 (3.4) 14 (7.5) 72 (4.4)
In the chemotherapy group (the youngest age group), after diagnosis of breast cancer 3.5% developed congestive heart failure, 6.9% vascular cardiac diseases, and 7.6% developed other cardiac diseases. The percentages of CVD found in the radiotherapy group and control group were similar. On average, the surgical group (the oldest age group) developed the highest number of CVD (Table 3).
Table 3 Cardiovascular events of patients (n=561) and controls (n=1635) at inclusion
Radiotherapy only (n=229) Chemotherapy ± radiotherapy (n=145) Surgery alone (n=187) Controls (n=1635) n (%) n (%) n (%) n (%)
Congestive heart failure 5 (2.2) 5 (3.5) 20 (10.7) 49 (3.0)
Vascular cardiac diseases 27 (11.8) 10 (6.9) 43 (23.0) 198 (12.1)
Other cardiac diseases 24 (10.5) 11 (7.6) 31 (16.6) 151 (9.2)
Radiotherapy group
The risk ratio to develop a vascular cardiac disease was not increased in the radiotherapy group compared with controls without a history of cancer (HR 1.1; 95%CI 0.7-1.7) and with other breast cancer patients without radiotherapy (HR 0.7; 95%CI 0.4-1.1). For the group treated 5-10 years ago, the HR was 2.2 (95%CI 0.2-22.5); however, due to this wide CI this HR cannot be seen as enhanced. The risk ratio for patients
ĚŝĂŐŶŽƐĞĚшϭϬLJĞĂƌs ago was also not enhanced (HR 1.0; 95% CI 0.6-1.6). The risk ratio for other cardiac diseases was also not enhanced compared with controls without a history of cancer and with other breast cancer patients; the same applies for the risk ratio of congestive heart failure (Table 4).
The risk ratio to develop a vascular cardiac disease was non-significantly higher in patients treated with radiotherapy with or without chemotherapy compared with the other breast cancer patients without radiotherapy (HR 1.5; 95% CI 0.9-2.4); the same applies to the risk ratio to develop congestive heart failure (HR 1.7; 95% CI 0.8-3.6) (Table 4). When comparing left-sided and right-sided treated patients in the group treated with radiotherapy with or without chemotherapy, no increased risk of congestive heart failure (HR 0.98; 95%CI 0.3-3.6), vascular cardiac diseases (HR 0.7; 95%CI 0.3-1.4) or other cardiac diseases (HR 0.8; 95%CI 0.4-1.7) was found.
Chemotherapy group
Breast cancer survivors treated with chemotherapy (with or without radiotherapy) had a risk ratio of 1.8 (95%CI 0.6-5.8) to develop congestive heart failure compared with controls. This risk ratio was mainly present in the group of patients who were diagnosed ш ϭϬ LJĞĂƌƐ ĂĨƚĞƌ ĚŝĂŐŶŽƐŝƐ ;,Z 1.8; 95%CI 0.5-7.2). The risk ratio of developing congestive heart failure showed a non-significant increase compared with breast cancer patients without chemotherapy (HR 2.2; 95%CI 0.8-6.4). This risk ratio showed a non-significant increase at 5-10 years after diagnosis (HR 1.4; 95% CI 0.1-19.6) as well ĂƐĂƚшϭϬLJĞĂƌs thereafter (HR 2.9; 95%CI 0.9-9.7). The risk ratio for vascular and other cardiac diseases was also not enhanced (Table 5).
Deceased patients
In the general practices of the RNG, 249 women with breast cancer were found of whom 50 died before the inclusion date and after 1998; 9 (18%) died due to a cerebrovascular accident (mean age 83 years) and 7 (14%) died of another CVD (mean age 84 years). The risk ratio for congestive heart failure after chemotherapy decreased from 1.8 (95%CI 0.6-5.8) to 0.9 (95%CI 0.3-2.9) after analysing the group including deceased women compared with controls without a history of cancer. Other calculated HRs did not differ from earlier reported HRs.
Chapter 2
28
Table 4 Hazard ratios (HR) of patients who received adjuvant radiotherapy (n=229) and patients who received radiotherapy±chemotherapy (n=334) compared with controls without a history of cancer (n=694) and with breast cancer(BC) survivors who did not receive adjuvant radiotherapy (n=227)
CVD Comparison Patients Radiotherapy
only HR (95% CI) Radiotherapy ± chemotherapy HR (95% CI) Congestive heart failure Radiotherapy patients vs. controls Total Controls 1 1 Radiotherapy 0.5 (0.2- 1.8) 0.8 (0.4 -1.8) 5-10 yr. Controls 1 1
Radiotherapy Not calculated† Not calculated†
шϭϬLJƌ͘ Controls 1 1 Radiotherapy 0.4 (0.1-1.7) 0.8 (0.4-2.0) Radiotherapy patients vs. breast cancer patients without radiotherapy
Total Other BC patients 1 1
Radiotherapy 0.4 (0.2-1.1) 1.7 (0.8-3.6)
5-10 yr. Other BC patients 1 1
Radiotherapy 0.5 (0.1-4.1) 1.4 (0.2- 8.9) шϭϬLJƌ͘ Other BC patients 1 1 Radiotherapy 0.3 (0.1-1.0) 1.7 (0.7-4.2) Vascular cardiac diseases Radiotherapy patients vs. controls Total Controls 1 1 Radiotherapy 1.1 (0.7-1.7) 1.0 (0.7-1.5) 5-10 yr. Controls 1 1 Radiotherapy 2.2 (0.2-22.5) 0.3 (0.03-3.0) шϭϬLJƌ͘ Controls 1 1 Radiotherapy 1.0 (0.6-1.6) 1.0 (0.6-1.6) Radiotherapy patients vs. breast cancer patients without radiotherapy
Total Other BC patients 1 1
Radiotherapy 0.7 (0.4-1.1) 1.5 (0.9- 2.4)
5-10 yr. Other BC patients 1 1
Radiotherapy 0.9 (0.3-2.5) 1.3 (0.5-3.5) шϭϬLJƌ͘ Other BC patients 1 1 Radiotherapy 0.6 (0.3-1.1) 1.6 (0.9-2.7) Other cardiac diseases Radiotherapy patients vs. controls Total Controls 1 1 Radiotherapy 1.3 (0.8-2.3) 0.7 (0.5-1.1) 5-10 yr. Controls 1 1
Radiotherapy Not calculated† 0.5 (0.1-1.9)
шϭϬLJƌ͘ Controls 1 1 Radiotherapy 1.3 (0.7-2.3) 0.7 (0.4-1.2) Radiotherapy patients vs. breast cancer patients without radiotherapy
Total Other BC patients 1 1
Radiotherapy 0.9 (0.5-1.6) 0.9 (0.5-1.6)
5-10 yr. Other BC patients 1 1
Radiotherapy 1.2 (0.3-4.2) 0.8 (0.3-2.6)
шϭϬLJƌ͘ Other BC 1 1
Radiotherapy 0.9 (0.5-1.7) 0.9 (0.5-1.7)
* HRs are adjusted for age, risk factors for cardiovascular disease, and cardiovascular disease at the time of diagnosis †Not calculated because of no significant numbers of events
Table 5 Hazard ratios (HR) of patients who received (neo) adjuvant chemotherapy (n=145) compared with controls without a history of cancer (n=417) and with breast cancer survivors who did not receive (neo) adjuvant chemotherapy (n=416)
CVD Comparison Patients Chemotherapy
± radiotherapy HR (95% CI) Congestive heart failure Chemotherapy patients vs. controls Total Controls 1 Chemotherapy 1.8 (0.6-5.8) 5-10 yr. Controls 1
Chemotherapy Not calculated†
шϭϬLJƌ͘ Controls 1 Chemotherapy 1.8 (0.5-7.2) Chemotherapy patients vs. breast cancer patients without chemotherapy
Total Other breast cancer patients 1
Chemotherapy 2.2 (0.8- 6.4)
5-10 yr. Other breast cancer patients 1
Chemotherapy 1.4 (0.1 -19.6)
ш 10 yr. Other breast cancer patients 1
Chemotherapy 2.9 (0.9-9.7) Vascular cardiac diseases Chemotherapy patients vs. controls Total Controls 1 Chemotherapy 1.1 (0.5-2.3) 5-10 yr. Controls 1
Chemotherapy Not calculated†
шϭϬLJƌ͘ Controls 1 Chemotherapy 1.7 (0.7-3.8) Chemotherapy patients vs. breast cancer patients without chemotherapy
Total Other breast cancer patients 1
Chemotherapy 0.8 (0.4-1.6)
5-10 yr. Other breast cancer patients 1
Chemotherapy 0.2 (0.03-1.7)
шϭϬ yr. Other breast cancer patients 1
Chemotherapy 1.3 (0.6-2.8) Other cardiac diseases Chemotherapy patients vs. controls Total Controls 1 Chemotherapy 1.2 (0.3-5.5) 5-10 yr. Controls 1 Chemotherapy 1.3 (0.3-5.5) шϭϬLJƌ͘ Controls 1 Chemotherapy 1.7 (0.6-4.8) Chemotherapy patients vs. breast cancer patients without chemotherapy
Total Other breast cancer patients 1
Chemotherapy 1.4 (0.7-2.7)
5-10 yr. Other breast cancer patients 1
Chemotherapy 0.7 (0.2-2.6)
шϭϬLJƌ͘ Other breast cancer patients 1
Chemotherapy 1.8 (0.8-4.4)
* HRs are adjusted for age, risk factors for cardiovascular disease and cardiovascular disease at the time of diagnosis †Not calculated because of no significant numbers of events
Chapter 2
30
Discussion
To our knowledge this is the first study of its kind in an unselected population of patients from general practice with breast cancer, to assess the risk of CVD among women who received chemotherapy and/or radiotherapy, compared with age- and general practice matched controls.
The radiotherapy group had no increased risk of developing congestive heart failure or vascular cardiac diseases (HR 1.1; 95%CI 0.7-1.7). In women treated with chemotherapy (with or without radiotherapy) we found a risk of congestive heart failure of 1.8 (95%CI 0.6-5.8) compared to controls without a history of cancer. This risk showed no significant change when deceased women were included, i.e. 0.9 (95%CI 0.3-2.9).
Radiotherapy
In the present study, the risk of vascular cardiac disease for women treated with radiotherapy was not increased (HR:1.1; 95%CI:0.7-1.7). Earlier studies of women treated before 1980 found an increased risk ratio of dying of CVD ranging from 1.20-1.76 (95%CI:1.04-2.31)32, 43, 76, 78, 79, 87-89 and another study found an increased risk of ischemic heart disease in women mainly treated before 1990.46 After 1980, the risk of CVD declined towards uniformity32, 36, 77, probably due to the advances in radiotherapy techniques.51, 90, 91
In the present study, women treated with radiotherapy showed no overall increased risk of congestive heart failure if they were treated 5-ϭϬLJĞĂƌƐŽƌшϭϬLJĞĂƌƐ ago, compared with controls without a history of cancer and other women with breast cancer. Another study reported a risk ratio of 1.72-2.66 (95%CI 1.22-5.61)36; however, all these latter patients were treated between 1970 and 1986, whereas in our population 92% of all breast cancer survivors were treated after 1990; therefore, these data on risks are probably not comparable.
Comparison of our entire radiotherapy group (i.e. including patients who received chemotherapy) and the other breast cancer patients (i.e. receiving only chemotherapy, or only surgery) shows that the HR are higher than those of patients treated with radiotherapy alone. This is in line with earlier studies in suggesting that chemotherapy and radiotherapy influence each other in enhancing the risk of CVD.36
Chemotherapy
The most frequently mentioned side-effect in relation to chemotherapy is congestive heart failure. In the present study, there was a non-significant increased risk of congestive heart failure of 1.8 (95% CI 0.6-5.8) compared with controls without a history of cancer. Although in this study the enhanced risk is non-significant, the magnitude of the HR is in line with earlier studies reporting a significant risk ranging from 1.25 to 1.85 (95% CI 1.07-2.73).34-37
Among women with breast cancer, those selected to receive chemotherapy are often a healthier group.35, 92 From that viewpoint, a hazard ratio of 1.8 may indicate a clinically relevant increased risk. Future research on this topic should include larger numbers of women treated with chemotherapy and focus on other determinants of CVD (e.g. smoking); it should also be noted that the dose and type of some chemotherapeutic agent (e.g. anthracyclines) may be more cardiotoxic than other types of chemotherapy (e.g. cyclophosphamide and taxanes).57 Also, there is a large inter-individual variability of sensitivity to chemotherapy, as some women react strongly to a small dose while others receive high doses without consequences. As this inter-individual variability is probably due to genetic predisposition93, this factor should also be taken into consideration.
In the present study the risk of congestive heart failure was enhanced mainly ŝŶ ƚŚĞ ŐƌŽƵƉ ƚƌĞĂƚĞĚ ш ϭϬ LJĞĂƌƐ ĂŐŽ͘ KƚŚĞƌƐ ĂůƐŽ ĨŽƵŶĚ ƚŚĂƚ ƚŚĞ ƌŝƐŬ ǁĂƐ ŵĂŝŶůLJ increased after the first decade after treatment.34, 35 We found a decreased risk for congestive heart failure in deceased patients; this might be explained by the old age of these patients (age >80 years) as the incidence of congestive heart failure is higher in older women.94 Another study reported that, among women aged 71-80 years treated with chemotherapy, there was no enhanced risk for congestive heart failure.35
In the present study, the overall risk of developing other cardiac diseases in women treated with chemotherapy compared with controls without a history of cancer was 1.2 (95%CI 0.3-5.5). This was highest in the ŐƌŽƵƉƚƌĞĂƚĞĚшϭϬLJĞĂƌƐĂŐŽ;,Z 1.7; 95%CI 0.6-4.8). Other studies found a risk of cardiomyopathy of 1.95-2.48 (95%CI 1.44-2.93).34, 37 However, these latter studies were performed in a population aŐĞĚ ш ϲϱ years in whom cardiomyopathy might more frequently be present.
Chapter 2
32
Strengths and limitations
The present study was performed in an unselected population of patients with breast cancer (in general practice), which means that the risks found are relatively unbiased and similar to ‘true’ risks. As only breast cancer survivors were included, our estimates might be biased because deceased patients could not be taken into account. However, the risks calculated with deceased patients included (whenever possible) did not differ from risks calculated without these deceased patients, except for the risk of congestive heart failure in the group that received chemotherapy (perhaps because of the older age of these deceased patients). Data on deceased patients are, however, limited to patients who died after 1998. Therefore, the risk of CVD we found might be underestimated because patients who died before 1998 could not be included in the analysis.
The data were extracted from the electronic patient files of GPs. Information on CVD and CVD risk factors depends on the individual discipline of the GP to link a code to the diagnosis. Fortunately, almost all practices participating in this study are affiliated to the national coding network, which ensures and preserves excellence in data collection 84. If there were absent codes, this will apply equally to patients and
controls and will therefore not seriously influence the results.
Although risks found in the present study are adjusted for hypertension, hyperlipidemia and diabetes, we could not adjust for other risk factors such as smoking, body mass index, family history of CVD, lifestyle, type and dose of chemotherapeutic agents. Furthermore, the diagnosis of congestive heart failure and cardiomyopathy are based on the ICPC codes and not on echocardiography (the gold standard). Therefore, some of the women could have a reduced ejection fraction or diastolic dysfunction
without being diagnosed by the GP; this implies that the risk of CVD may actually be
higher than that calculated in this study . Furthermore, some of the women might exhibit symptoms of CVD (e.g. fatigue) that are misinterpreted by the GPs, as this is a common complaint after cancer diagnosis due to their past history of cancer 95. Moreover, (dilated) cardiomyopathy (which can lead to congestive heart failure in patients treated with chemotherapy) has been assigned to the ‘other CVD’ category
because of the ICPC classification. Therefore, the risks may in fact be higher than those
calculated in the present study. Due to these limitations, the lack of significant findings in this study does not necessarily rule out the clinically important risks of CVD related to breast cancer treatment. More detailed information on risks factors and more specific outcome measures (e.g. ECG or echocardiographic parameters) may be needed for future research to detect CVD as well as asymptomatic cardiac dysfunction.
Conclusion
This is the first study in a large cohort of an unselected population of women in general practice with breast cancer to examine the cardiovascular effects of radiotherapy and chemotherapy, in which breast cancer survivors are compared with controls without cancer. No increased risk was found among women treated for breast cancer with radiotherapy. Because this finding is supported by earlier studies, it appears that treatment with radiotherapy is currently a relatively safe method of treatment with regard to CVD. In this study, the risk (HR 1.8) for congestive heart failure found after chemotherapy is not significantly increased and is in line with previous studies. However, the lack of significant findings in the present study does not necessarily rule out the clinically important risks of CVD related to breast cancer treatment. Future research should include more detailed information on treatment and more specific outcome measures.
Acknowledgments
The authors thank all the general practitioners and other staff of the general practices for their cooperation. We also thank F. Groenhof, A.E. Oeloff, B.J. Swart and L.D.G. Zwart for collecting the data.
Disclosure
The authors declare that they have no conflict of interest.
Chapter 2
Long-term outcome of cardiac function in a
population-based cohort of early breast cancer survivors:
A cross-sectional study
L.M.Boerman S. W.M.C. Maass P. van der Meer J.A. Gietema J.H. Maduro Y.M. Hummel M.Y. Berger G.H. de Bock A.J. Berendsen
Eur J Cancer. 2017 Aug; 81: 56-65 H &W. 2019 Mar; 62: 26-29 Ned. Tijdschirft voor Oncologie 2019Feb; 16:3-12
Chapter 3
36 Abstract
Purpose
Chemotherapy and radiotherapy for breast cancer may lead to cardiac dysfunction, but the prevalence of long-term echocardiographic evidence of cardiac dysfunction is unknown among survivors.
Patients and methods
In a cross-sectional study in primary care, we included 350 women who survived breast cancer for at least five years after diagnosis (treated with chemotherapy and/or radiotherapy) and 350 matched women (age and primary care physician). The primary outcome was cardiac dysfunction, defined as a left ventricular (LV) ejection fraction <54% and an age-corrected decreased LV diastolic function. Secondary outcomes included serum NT-proBNP levels, newly diagnosed cardiovascular diseases, and cardiovascular medication.
Results
Median age at diagnosis was 63 (IQR 57–68) years for the breast cancer survivors. Median follow-up after diagnosis was 10 (IQR 7–14) years. LV ejection fraction <54% was present in 52 (15.3%) survivors and 24 (7%) controls (OR 2.4, 95%CI 1.4–4.0), but there was no significant increased prevalence of either LV ejection fraction <50% or LV diastolic dysfunction. Serum NT-proBNP levels were increased, cardiovascular disease was more frequently diagnosed, and cardiovascular medication use was more frequent among survivors compared with controls. These associations remained after adjustment for relevant covariates at diagnosis and at follow-up.
Conclusion
In the long term, breast cancer survivors are at increased risk of mild LV systolic dysfunction, increased NT-proBNP levels, and cardiovascular disease compared with matched controls, even after adjustment for cardiovascular risk factors. Previous breast cancer treatment with chemotherapy, radiotherapy, or both should be considered when assessing a patient’s cardiovascular risk profile.
Introduction
Breast cancer is the most common cancer among women, with approximately 0.5 million women affected annually in Europe.2, 96 Courtesy of screening programs and
advances in cancer treatment, the 5-year overall survival rates have increased to 85%12.
Although adjuvant therapies like anthracycline-based chemotherapy, trastuzumab, and radiotherapy are very effective, they may cause cardiac dysfunction decades after treatment.32 This late cardiac dysfunction can remain subclinical because of its gradual
onset and presentation with vague symptoms. Since the prevalence of subclinical cardiac dysfunction is unknown among long-term survivors of breast cancer, and no interventions have been established to manage it, there are no specific follow-up recommendations. Timely diagnosis of cardiac dysfunction is important because early treatment of associated risk factors may prevent further deterioration and improve prognosis.97
Previous long-term studies among adult female breast cancer survivors have focused on the frequency of only diagnosed cardiac dysfunction, which may have underestimated the prevalence of cardiac dysfunction.32-37 By contrast, studies in
selected hospital populations may have overestimated the prevalence of cardiac dysfunction in these women.28-31 This is exacerbated by the lack of controlled long-term
studies assessing the incidence of undiagnosed cardiac dysfunction in adult female breast cancer survivors with echocardiographic data in non-hospital settings.41
Therefore, we assessed the prevalence of long-term echocardiographic-based cardiac dysfunction among breast cancer survivors treated with chemotherapy (± radiotherapy) or radiotherapy only, and compared that with the prevalence of cardiac dysfunction among matched controls in a primary care setting.
Chapter 3
38 Methods
Study design
We performed a cross-sectional, population-based study to assess the frequency of cardiac dysfunction in a primary care setting. All inhabitants of the Netherlands are enlisted in a electronical record of a primary care physician (PCP), who registers everything according to International Classification of Primary Care (ICPC)85 and
Anatomical Therapeutic Chemical (ATC) classification codes.98
Relevant data were retrieved from patients’ medical records at primary care practices and were entered into a separate, anonymous, password-protected database. In practices contributing to data registries, we were able to retrieve information from non-respondents. The medical ethics committee of the University Medical Center Groningen (UMCG) approved this study, and all participants gave written informed consent. The study was also registered at clinicaltrials.gov [ID:NCT01904331].
Participants
Women were considered breast cancer survivors if they were diagnosed with breast cancer stage I –III, had been free of disease for at least five years, and were included from the electronic patient records of 80 PCPs in the north of the Netherlands. When women had been diagnosed with a local/loco-regional recurrence of breast cancer, they were included if they had been free of disease for at least five years. The inclusion criteria were treatment for breast cancer with chemotherapy, radiotherapy, or both. The exclusion criteria were metastatic disease at time of breast cancer diagnosis, breast cancer treatment after 80 years of age, and treatment for other types of cancer. For each included survivor, a randomly selected control was invited from the same PCP, from the same age (± one year), but without a history of cancer or cancer treatment (chemotherapy or radiotherapy). We excluded women with severe mental or physical illness from both groups when they were not able to come to the university hospital according to their PCP. Compliance with the inclusion and exclusion criteria was checked using the electronic patient records and checked with the PCP.
Box 1 Overview of data derived from the electronic patient files of primary care physicians
Assessments and procedures
For all women, we collected data based on the ICPC codes for cardiovascular (CV) risk factors and CV disease (CVD), and used the ATC prescription codes for CV medications (Box 1). Hospital charts from breast cancer survivors were reviewed for detailed information on breast cancer treatment, including administered chemotherapy regimens, cumulative dosages, anti-hormone treatments, and radiotherapy site. In general, radiotherapy in the Netherlands consisted of Linac based photon tangential fields up to a dose of 50 Gy with or without a boost.99
We performed the following procedures at a cross-sectional follow-up assessment. Echocardiography was performed by experienced UMCG staff, using a VIVID E9 ultrasound machine (GE, Horten, Norway) according to the guidelines of the European Association of Echocardiography100, 101. A prespecified imaging protocol was used and
images were digitally stored. We also performed electrocardiography (ECG) and obtained plasma in lithium-heparin stored at -80oC for batch analysis of N-terminal pro B-type natriuretic peptide (NT-proBNP). Finally, we assessed body mass index (BMI) by
ICPC codes comprising of the presence of CV risk factors x dyslipidaemia [ICPC: T93]
x hypertension [ICPC: K86 AND K87] x diabetes mellitus [ICPC: T90] ICPC codes comprising the presence of CVD
Heart failure
x acute and chronic congestive heart failure [ICPC: K77] Ischemic cardiac disease
x stable/unstable angina pectoris [ICPC: K74] x acute myocardial infarction [ICPC: K75] x coronary artery sclerosis [ICPC: K91) x transient ischemic attack [ICPC: K89] x cerebrovascular accident [ICPC: K90])
Atrial fibrillation
x atrial fibrillation [ICPC: K78] Other
x paroxysmal tachycardia [ICPC: K79] x non-rheumatic valve disease [ICPC: K83]
x Wolff–Parkinson–White syndrome, atrioventricular block, cardiomyopathy, and long QT-syndrome [ICPC: K84] Prescriptions of the following (ATC codes) CV medication
x ACE-inhibitors x beta-blockers x anti-platelets x diuretics x statins
3
Chapter 3
40
measuring weight and length, smoking status (self-reported), and responses to the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH) for all participants.102
Study endpoints
The primary outcomes were left ventricular (LV) systolic and diastolic dysfunction. LV systolic cardiac dysfunction was defined as a LV ejection fraction (LVEF) <54% according to the European Association for Cardio Vascular Imaging/American Society of Echocardiography (EACVI/ASE), measured by the biplane method of disks summation (modified Simpson’s rule).100 If image quality was too low to detect the endocardial
border reliably, an estimation of the LVEF was given. LV diastolic cardiac dysfunction was defined as e’ lateral or e’ septal at 2.5% below the normal range for each age group, according to the EACVI/ASE recommendations. When impaired relaxation was present ǁŝƚŚĂŶŝŶĐƌĞĂƐĞĚůĞĨƚĂƚƌŝĂůǀŽůƵŵĞŝŶĚĞdž;>s/͖ĚĞĨŝŶĞĚĂƐшϯϰŵ>ͬŵϮͿ͕>sĚŝĂƐƚŽůŝĐ dysfunction was considered severe.101
The main secondary outcomes were: clinically used LVEF cut-off points <45% and <50%, right ventricular systolic dysfunction, valve dysfunction (at least II/III insufficiency of any valve), any ECG abnormality, and increased NT-proBNP (>125 ng/ml)103. Right ventricular (RV) systolic function was measured through the tricuspid
annular plane systolic excursion (< 17 mm) and tricuspid lateral annular systolic velocity wave (<9.5 cm/s) by Doppler imaging.100 Other secondary outcomes were newly
diagnosed CVD and CV medication. Power analysis
In the primary comparison, breast cancer survivors were compared with controls. Based on an event rate of 25% for cardiac dysfunction104-106, a 5% type I error rate, a 20% type II error rate, and an anticipated difference of 6.25% (odds ratio [OR] 2.25) between survivors and controls in the proportion of cases with cardiac dysfunction, we calculated a sample size of 350 participants per group.
Statistics
Baseline characteristics were described at the date of diagnosis or at the corresponding index date for the matched controls. Age and follow-up period were reported as medians and interquartile ranges (IQR). Information on diagnosis and treatment was presented for survivors.
Besides comparing all survivors with all controls on all outcomes, we also specifically compared the chemotherapy ± radiotherapy group with the chemotherapy control group and the radiotherapy only group with the radiotherapy control group. Logistic regression analysis was used to compare the prevalence of long-term cardiac dysfunction and secondary outcomes between survivors and controls by estimating ORs and their 95% confidence intervals (95%CIs). To evaluate whether the association between breast cancer treatment and the prevalence of long-term cardiac dysfunction was confounded by risk factors, multivariable logistic regression was performed to give an adjusted OR for LV dysfunction, increased NT-proBNP, and the occurrence of CVD after breast cancer diagnosis. We adjusted for baseline characteristics (model 1) and for characteristics at the time of echocardiography (model 2). The effect of higher-dose anthracycline therapy (e.g., doxorubicin doseௗ>ௗ240 mg/m2 or epirubicin doseௗ>ௗ450
mg/m2) compared with low-dose therapy, and the effect of left-sided radiotherapy
compared with right-sided therapy, were also analysed. Finally, we compared the ages and CVD diagnoses of participants and non-participants from PCPs that contributed to data registries. To evaluate the impact of potential selection bias on the prevalence of diagnosed CVD, a sensitivity analysis was performed including all eligible women who were invited. All analyses were performed with IBM SPSS, Version 23.
Chapter 3
42 Results
Among 741 breast cancer survivors considered eligible by 80 participating PCPs, 668 were approached for inclusion (Figure 1). There were 22 women with a local/loco-regional recurrence in our sample. The median year of diagnosis was 2004 (IQR 2000-2007). Compared with non-participants from 58 PCPs, participating survivors tended to be four years younger (p<0.01), and participating controls tended to be two years younger (p<0.01). Participating survivors showed no differences with regards to the prevalence of diagnosed CVD, but fewer participating controls had CVD (OR 0.5 [95%CI 0.3-0.8]), probably based on ischemic CVD (OR 0.3 [95%CI 0.3-0.6]; Table 1). In the sensitivity analysis including all eligible women, we observed no difference in diagnosed CVD, except for atrial fibrillation, which was more frequent in survivors (Table 2).
Figure 1 Flow diagram of the selection of survivors of breast cancer and their matched controls
After exclusion by PCP
Breast cancer survivors (N=668) and controls (N=1365)
Chemo- ± radiotherapy Invited: N=249 Consenting: N=175 (70%)
Subjects identified and meeting in- and exclusion criteria
Breast cancer survivors (N=741) and controls (N=1524)
General practitioner (GP) (N=80)
Reasons for exclusion by GP
Physical: survivors (N=13) and controls (N=27)
Psychosocial: survivors (N=20) and controls (N=48)
Other: survivors (N=40) and controls (N=84)
Not invited
Survivors (N=143) and controls (N=636) Controls of chemo- ± radiotherapy Invited: N=372 Consenting: N=175 (47%) Controls of radiotherapy Only Invited: N=357 Consenting: N=175 (49%) Radiotherapy Only Invited: N=276 Consenting: N=175 (63%)
