Time-Dependent Effect Of Anthracycline-Based Chemotherapy On Central Arterial Stiffness: A Systematic Review And Meta-Analysis

Abstract

Background and Aims

Anthracycline-based chemotherapy (Anth-bc) has been proposed to increase arterial stiffness, however, the time-dependency of these effects remain unclear. This systematic review and meta-analysis aimed to investigate the time-dependent effect of Anth-bc on markers of central aortic stiffness, namely aortic distensibility (AD) and pulse-wave-velocity (PWV) in cancer patients.

Methods

An extensive literature search without language restrictions was performed to identify all studies presenting longitudinal data on the effect of Anth-bc on either AD and/or central PWV in cancer patients of all ages. An inverse-variance weighted random-effect model was performed with differences from before to after chemotherapy, as well as for short vs. mid-term effects.

Results

Of 1811 articles identified, 6 observational studies with a total of 282 patients (median age 51±11; 70% women) were included, of which four studies measured AD and five PWV. Short-term (3-4 months), there was a clinically meaningful increase in arterial stiffness, namely an increase in PWV of 4.21 m/s (95%CI -0.19; 8.61) and a decrease in AD of -1.49 mmHg-1 (-3.25; 0.27) but a much smaller effect was observed mid-term (6-12 months) for PWV of 1.05 m/s (-1.45; 3.55) and AD of -0.37 mmHg-1 (-1.13; 0.39). There was considerable heterogeneity among the studies.

Conclusions

Results from this analysis suggest that in the short-term, Anth-bc increases arterial stiffness, but that these changes may partly be reversible after therapy termination. Future studies need to elucidate the long-term consequences of Anth-bc on arterial stiffness, by performing repeated follow-up measurements after Anth-bc termination.

Introduction

Heart disease and cancer are the leading causes of mortality worldwide [1]. Due to remarkable improvements in screening, diagnosis, and treatment of many cancers, the number of cancer survivors is steadily increasing [2]. However, cancer survivors have an increased risk for cardiovascular disease (CVD), either as a result from shared cardiovascular risk factors and suboptimal lifestyle choices or from toxicities of cancer treatment [3–5]. A retrospective cohort study has shown that 10 years after cancer diagnosis the risk for death from CVD exceeds the risk of death from cancer [3].

Anthracyclines are very effective chemotherapeutic agents used for treatment of solid tumors and haematologic malignancies. However, due to their dose-dependent cardiotoxic effects, such as systolic and/or diastolic left ventricular (LV) dysfunction and heart failure [6–10]. their repetitive administration is limited. Hence, monitoring of LV function by echocardiography before and after treatment is recommended [11, 12]. Additionally, many anticancer drugs also have adverse effects on the vascular endothelium,[13, 14] It has been proposed that anthracycline-based chemotherapy (Anth-bc) may increase arterial stiffness[15] via generating reactive oxygen species and promoting oxidative stress [16, 17]. This in turn leads to structural changes within the vascular matrix and thus interferes with the regulation of vascular smooth muscle tone [14]. Both, in vitro and in vivo studies found that Anth-bc also causes apoptosis of vascular endothelial cells, which may impair vasodilatory and contractile responses and lead to endothelial dysfunction [18, 19].

The most established non-invasive methods to assess central arterial stiffness are central pulse wave velocity (PWV)[20] and aortic distensibility (AD) by cardiac magnetic resonance (CMR) or echocardiography.[20, 21] Both methods have been shown to predict CV events and CV mortality in various populations [22, 23].

Previous studies on the vasculotoxic effects of chemotherapies have mainly focused on anti-angiogenic drugs and some of the newer anticancer signaling inhibitors [24, 25]. A recent review and meta-analysis has summarized effects of various vasculotoxic chemotherapies, including anthracyclines, on arterial stiffness from longitudinal and cross-sectional studies.[26] Due to often various successive treatments in cancer patients, these cross-sectional studies do not allow the identification of the vasculotoxic effect of isolated Anth-bc. Anth-bc–induced vasculotoxicity may further be aggravated by the individual CV risk factor profile (i.e. current smoking, obesity, etc.), which are difficult to fully control for in cross-sectional studies. To date, several small longitudinal studies have assessed arterial stiffness before and after Anth-bc, but the vascular effects of Anth-bc over time remain unclear. An evidence synthesis is important because long-term vascular dysfunction may increase the risk for cardiovascular events and mortality [22, 27–29]. Therefore, we have conducted a systematic review to appraise the literature regarding the time-dependent effect of Anth-bc on markers of central aortic stiffness, namely PWV and AD measured before and after Anth-bc in cancer patients.

Methods

2.1 Study Design

The search was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations. The original study protocol was registered prospectively in PROSPERO (CRD42019141837).

2.2 Study Eligibility

Studies were eligible if they met all of the following criteria: a) experimental or observational studies (prospective or retrospective); b) reporting on the effect of Anth-bc on either AD and/or central (carotid-femoral (cf)/aortic arch/ carotid artery) PWV in cancer patients of all ages; c) longitudinal assessment with baseline measurement before administration of anthracyclines and at least one measurement during or after Anth-bc; d) based on human data. We did not include studies which provided PWV from peripheral arteries or derived from pulse wave analysis, due to the fact that PWV is not directly measured in pulse wave analysis but calculated based on the estimated distance of assumed reflection sites [30].

2.3 Database Search

The MEDLINE, Embase, Web of Science and the Cochrane Library databases were searched for eligible studies from database inception to February 18, 2021. The search strategy was built based on the PICO strategy. A combination of free textwords and MeSH subheadings were used, including the terms cardiotoxicity, aortic distensibility, central pulse wave velocity, anthracycline, doxorubicin, daunorubicin, adriamycin, idarubicin, epirubicin, appropriately linked with the Boolean operators AND or OR. Case reports, comments, and editorials were excluded. No language restrictions were applied. The full search algorithm for each database can be found in the eAppendix (Supplementary Table 1).

2.4 Study Selection and Data Extraction

Upon removal of duplicate publications, the title and abstract of the selected studies were screened by 3 independent reviewers (C.S., P.E. N.G.). For each potentially eligible study, two reviewers (C.S., P.E.) independently assessed the full manuscripts. In cases of disagreement, a decision was made by consensus or the third reviewer was consulted. The reference lists of selected publications were also manually searched to identify additional eligible studies. For data extraction, a template was used including information on study size and design, baseline population, location, age at baseline, anthracycline-dose, duration of follow-up, type of outcome assessment, type and numbers of outcomes, concomitant treatment, comorbidities of population and the reported degree of adjustment.

2.5 Risk of Bias Assessment

Risk of bias was assessed using the validated National Institute of Health (NIH) assessment tool for Before-After (Pre-Post) studies without control group [31].

2.6 Statistical analysis

Mean differences were calculated from the differences between group means at different time points. Standard deviations (SD) of the mean differences (MD) were derived by using reported p-values from repeated measure analyses using the following formula SD = MD * √(n)/t,[32] with n being the number of patients, and t the t-value for the given p-value and degrees of freedom according to the table on critical values of the Student's t distribution.

Measurement units were converted where appropriate. An inverse variance weighted random-effect model was used to obtain the pooled mean difference with 95% CI for the change in outcome from before to after Anth-bc treatment, separated by time-point of assessment into short-term (2–4 months) and mid-term effects (6–12 months).

We constructed forest plots, and assessed heterogeneity using the I² statistic, with I² ≤ 25% considered low, 25% < I² < 75% moderate, and I² ≥ 75% high [33].

Sensitivity analyses were performed to assess the impact of age (</≥50 years), cumulative Anth-bc dose (</≥200 mg/m²), and assessment method (CMR vs. echocardiography for AD and CMR vs. Doppler echography for PWV) on vasculotoxicity. Results of all studies (AD and PWV data) were collated by expressing the mean change relative to mean baseline. Dose-response relationship was assessed by linear regression between arterial stiffness ratio relative to baseline and cumulative mean dose (if only range of dose was indicated, the central value was used). Statistical analyses were performed using Rev Manager (Version 5.3, The Cochrane Collaboration, 2014).

Results

3.1 Study Selection and Characteristics

Of the 2029 studies identified, 8 studies met the inclusion criteria for this review (Fig. 1), with clinical characteristics shown in Table 1.

All studies were published between 2010 and 2020 and included patients with solid tumors, such as breast cancer or sarcoma,[34–38] or hematologic malignancies, such as lymphoma and leukemia,[34, 35, 38–41] or a combination thereof [34, 35, 38]. All studies were prospective with data provided from before treatment as well as after a follow-up period between 1 to 14 months (Fig. 2). Three studies included a control group consisting of healthy, age-matched volunteers,[34, 37] or a cancer group without Anth-bc [38]. Studies were based on 10 to 110 patients, with mean age 51 (SD 11) years, and 64% women. Concomitant treatments mostly included cyclophosphamide, trastuzumab, taxanes and/or radiotherapy. Based on available data, we decided to perform meta-analyses on short-term effects at 2–4 months, which coincided with conclusion of Anth-bc in breast cancer and some lymphoma patients, and at 6–12 months, at which time point also all lymphoma patients had concluded their treatment,[42, 43] while some patients were likely to have terminated Anth-bc several months previously. Mean cumulative dose of Doxorubicin delivered was 310 mg/m² (range 215–436 mg/m²) (range for individual patients 50–436 mg/m²). Other anthracyclines included were Daunorubicin and Epirubicin, which have comparable or lower cardiotoxic effects compared to Doxorubicin [12, 44].

Four studies provided data on AD and five on PWV (AD and PWV were concomitantly reported in two studies, Graphical abstract). Three studies measured AD by cardiovascular magnetic resonance imaging (CMR)[34, 37, 38] and one by echocardiography [36, 39]. PWV was assessed using CMR[34, 35, 37], echocardiography[36, 40] or SphygmoCor [41] and was reported in m/s by all studies.

Table 1: Description of the included studies

ACE= angiotensin-converting–enzyme; AD = aortic distensibility; Anth-bc = anthracycline-based chemotherapy; ARBs = angiotensin-receptor blockers; CAD = coronary artery disease; CV = cardiovascular PC-CMR = phase-contrast cardiovascular magnetic resonance; PWV = pulse- wave- velocity; TZM = Trastuzumab

3.2 Risk of bias analysis and quality of evidence

Risk of bias was generally low in most included studies (Table 2) for the following items: delivery of intervention and outcome assessment. Only four studies provided sufficient information on eligibility criteria [36, 37, 39]. None of the six included studies provided a study flow. Most studies provided the mean administered anthracycline-dose, however, two studies[37, 39] reported only the range of administered doses. 

Table 2: Quality Assessment of Included Studies using the NIH. Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group.

3.3 Aortic Distensibility

Meta-analyses for short- and mid-term reporting on AD are summarized in Figure 3. AD was reported in mmHg^-1 in all except one study,[39] which we converted as 1 dyne/cm² = 0.00075 mmHg. 

Short-term analysis of studies assessing AD after 3 or 4 months, coinciding with termination of Anth-bc in breast cancer and lymphoma patients who had 4 and 6 chemotherapy cycles, showed an effect of -1.49 mmHg^-1 (95%CI -3.25; 0.27). There was considerable heterogeneity amongst these studies (Chi²= 29.03, df=2, p<0.00001, I² =93%, Figure 3a). In the subgroup analysis for measuring method, heterogeneity disappeared in the CMR studies where AD was reduced significantly by -2.28 mmHg^-1 (95%CI -3.06; -1.49, I² =0%) (Supplement Figure 1a). This sub-group analysis corresponded to the sensitivity analysis for age and anthracycline dose since the study which used echocardiography was also the study with younger mean age (44±19 years) and lower anthracycline dose (<200mg/m²) [39].  

The mean weighted change in AD for the studies with follow-up at 6-12 months was -0.37 mmHg^-1 (95% CI -1.13; 0.39, I²= 82%, Figure 3b). Heterogeneity persisted in the subgroup analysis for assessment method in CMR studies (95%CI -0.95; -3.59; 1.69, I² =91%, Supplement Figure 1b).

3.4 Pulse Wave Velocity

The five studies reporting on PWV presented means with standard deviations (SD) at each time point, as well as p-values of paired tests (Table1). Since the study by Turan et al. (2020) reported the median (range) instead of the mean (SD), it was included in the systematic review only. One study did not provide an exact p-value for PWV change but only indicated that it was non-significant [36]. Since the SD of the change could not be calculated for this study, it was approximated by taking the mean SD of the other three studies who provided exact p-values. The other study stated that p was <0.05. Using a conservative estimation, we calculate the SD of the mean change based on p = 0.049.[40] In a third study, PWV data at 4 months was only provided in a graph from which data was estimated visually [35].

Meta-analysis of the four  studies who provided data at 2-4 months showed an increase in PWV of 2.48 m/s (95%CI -0.52; 4.45) from before to after Anth-bc (Figure 4a) with considerable heterogeneity among the studies (Chi² = 21.89, df = 3, p < 0.0001, I² = 86%). Subgroup analysis for CMR-studies only showed an increase in PWV of 3.34 m/s (95%CI 1.10; 5.58, Supplement Figure 2a) with considerable heterogeneity amongst the studies (Chi² = 7.22, df = 2, p = 0.03, I² = 72%).

For studies with follow-up at 6-12 months, mean weighted change in PWV was 1.09 m/s (95%CI -0.38; 2.56, I² = 68%, Figure 4b). Subgroup analysis for assessment method showed a significant effect of 2.16 m/s (95%CI 0.26; 4.07) in CMR studies with reduced heterogeneity (I² =53%, Supplement Figure 2b).

3.5 Assessment of publication bias

For studies who assessed AD, studies including a greater number of patients [38, 39] showed smaller effects than those with smaller sample sizes [34, 36, 37].

Discussion

This systematic review summarized the current evidence of the time-dependent effect of Anth-bc on central aortic stiffness, assessed as AD or central PWV. Results from this meta-analysis suggest that in the short term (at termination of Anth-bc), moderate dose Anth-bc has a clinically meaningful effect on increasing arterial stiffness, with an increase in PWV and a decrease in AD, herewith confirming the results of a recent meta-analysis on this topic [26]. However, we observed smaller effects when measurements were performed at 6-12 months (Figure 2). The risk of bias of the included studies was moderate to high. The quality of the studies included in this review was limited mainly by study design and methodology.  

Comparison with other studies

Over the past 10-15 years, an extensive body of literature has been published identifying increased arterial stiffness as a predictor of cardiovascular events and mortality [22, 23, 45]. AD has been found a sensitive parameter of arterial stiffness in patients younger than 50 years, while PWV is the more sensitive parameter after the age of 50 [21]. According to a meta-analysis of general population studies, a 1 m/s increase in PWV, as found in our study, corresponds to an age-, sex-, and risk factor-adjusted risk increase of approximately 14% in total CV events, CV mortality, and all-cause mortality [22]. According to a study by Redheuil et al. who assessed the predictive value of AD for mortality, hard CV events and HF events in 3675 patients without clinical CVD (mean age 61± 10 years),[23] patients included in our meta-analysis had either a not elevated[34, 38] to two-fold increased risk[37, 39] for CV events. 

Our meta-analysis suggests that adverse effects of Anth-bc on arterial stiffness may partially be reversible after Anth-bc termination. However, the greater short- comparted to long-term effect is mainly based on the large adverse effect found on AD and PWV in the study by Chaosuwannakit [34], and the slightly positive changes measured at 6 months by Jordan et al. and at 9-12 months   by Mizia-Stec et al. Of the four studies that performed two follow-up measurements, one at 3 months (end of Anth-bC) and one at 6 months [35, 39, 40] or 12 months [37], three studies found a further worsening [35, 39, 40], while only the study by Grover and colleagues found an improvement (Figure 2). However, even if partial recovery after the acute adverse effect on arterial stiffness at Anth-bC treatment conclusion was found in some patients, this may not mean that long-term vasculotoxic effects are not be present. Nevertheless, at 5 or 10 years after treatment termination it will be difficult to ascribe increased arterial stiffness to certain chemotherapies, as other treatments, advanced age, cancer itself, or cardiovascular risk factors are known to also play a role. The hypothesis of partial recovery of adverse effects over time will need to be confirmed in longitudinal studies which measure both at completion of Anth-bc and at a later follow-up time. Further, it is clinically important to assess whether partial recovery may be due to cardioprotective treatment of diagnosed cardiotoxic side-effects following cancer therapy.

In our meta-analysis, baseline AD values of three studies were within the range of 1.7±1.3 to 4.1±1.6 mmHg^-1,[34, 38, 39] and in the range of reference values in the literature for age-matched, healthy individuals (3.1±1.8 to 4.0±1.6 mmHg^-1)[46]. However, baseline AD in the study by Grover et al. was markedly higher (8.1 ± 3.6 mmHg^-1). Similarly, values for baseline PWV from the study by Mizia-Stec and colleagues, who measured cfPWV by Doppler echography were noticeably higher (16.7±11.8 m/s) compared to those assessed in the other studies (6.7±0.5 to 6.9±2.3 m/s), which measured aortic arch PWV by CMR [34, 35, 37]. Surface cfPWV has been found to overestimate true aortic PWV by 2-3 m/s,[21] however, this methodological difference cannot explain the almost 10 m/s higher values. However, the unusually high SD of 11 m/s in the study by Mizia-Stec and colleagues raises some doubt about the reliability of their PWV data.

Sources of heterogeneity

Overall, we found high heterogeneity amongst the studies included in the random-effect analyses for AD and PWV that persisted when performing sensitivity and subgroup analyses. Possible reason for the observed heterogeneity could be the clinical diversity of the study populations with various degrees of cardiovascular risk, bias from patient drop-out, or lack of blinding. None of the studies could be found in a trial registry for verification of reported results with study protocol, and none presented a patient flow. In addition, publication bias may be present. 

Potential modulators of vasculotoxicity

Vasculotoxicity is likely to be modulated by age, the effect of cumulative Anth-bc dose, the individual cardiovascular risk factor profile, additional chemo- and radiotherapies, and cardioprotective medication. Two of the included studies in this analysis excluded patients with CV comorbidities and coronary artery disease (CAD)[36, 39] with one of them including patients with younger mean age compared to the other studies (44 vs 51 years) [39]. Both studies showed smaller effects of Anth-bc on AD and PWV, suggesting that, similar to cardiotoxicity, vascular toxicity may be more pronounced in older patients with preexisting CV risk factors or CV disease. It is well established that cumulative Anth-bc dose plays an important role in the development of cardiotoxicity [12]. While Chaosuwannakit et al. found an association between cumulative Anth-bc dose and worsening of AD (r= 0.34, p= 0.02), Drafts et al. could not confirm these findings (p=0.6). In this meta-analysis, studies with moderate Anth-bc-dose (between 200-450mg/m²) show either a much (ratio of 2.2) or somewhat increased arterial stiffness (ratio of 1.1-1.4) or a decrease (ratio of 0.8-1.0, see Figure 2) leading to non-significant regression (r= 0.07, p= 0.0612). However, this may not be interpreted as a non-existing dose-response relationship but rather be a consequence of the large heterogeneity between the included studies. 

Most of our studies investigated the relation between blood pressure and vascular injury.[34-37, 39] Grover et al. found a higher increase in arterial stiffness in patients with higher systolic BP. A higher PWV at baseline and greater increase over time with higher systolic BP was also found by Drafts et al., and Daskalaki et al. found decreased AD to be associated with higher systolic BP. Contrarily, Mizia-Stec and colleagues did not find any relationship between the diagnosis of systemic hypertension and Anth-bc induced changes in PWV. However, none of the studies adjusted changes in arterial stiffness for changes in BP, which has a direct impact on PWV.[47] As blood pressure tends to be decreased with Anth-bc,[48] the increase in arterial stiffness measured by PWV found in this and the previous meta-analysis[26] may be underestimated [47].

None of our studies found a significant effect of additional chemotherapies,[34, 35] however, the small sample sizes may have precluded the detection of such associations. Future studies are warranted to gain more insight into the effect of age, cumulative Anth-bc dose, the presence of cardiovascular risk factors and the addition of co-medication on vascular function.  

Strengths and limitations

Subgroup analyses of different time points has allowed the detection of a potential (partial) reversibility of adverse effects by Anth-bc on arterial stiffness. Another strength of this meta-analysis is the inclusion of studies assessing central arterial stiffness only. This is important since central (i.e. aorta and carotid arteries) and peripheral (i.e. brachial or femoral) arteries differ in their passive and active contractile properties [49]. In contrast to a recent meta-analysis on the same topic, using p-values of repeat measure analyses provided us with a higher power to detect significant results due to a more efficient adjustment for confounders.

A limitation of our study was that all included studies were observational and expectedly did not include a truly comparable control group of cancer patients. This greatly limits the value of a meta-analysis [32]. Therefore, the effect of cancer itself, presence of CV risk factors or other confounding treatments and comorbidities could not be identified. Secondly, they were based on small numbers of participants, which explains the large CIs of some of the studies. It should further be noted, that due to the limited number of the included studies, short-term effects of Anth-bc are greatly driven by the study from Chaosuwannakit and colleagues and smaller effects were observed in sensitivity analyses when their study was removed, however heterogeneity persisted (Supplement Figure 3). Studies did not report Anth-bc duration, making it difficult to estimate the follow-up time after Anth-bc termination for the various cancer patients. Unfortunately, none of included studies were able to provide individual patient data. 

Clinical implications

The adverse effect of Anth-bc on arterial stiffness likely applies to the whole vasculature and expands beyond the myocardium. Several reviews highlighted the importance of arterial stiffness in the prediction of all-cause cardiovascular outcomes [22, 27-29]. Therefore, non-invasive assessment of arterial stiffness may be used for detection of early cardiovascular injury in asymptomatic patients at risk during treatment and effects of cardio-/vasculo-protective treatments. Further, prospective longitudinal studies should measure arterial stiffness before, immediately after treatment termination, as well as preferably at several follow-up times in order to assess long-term consequences of Anth-bc on arterial stiffness and potential alleviating effects of cardioprotective medication or spontaneous recovery.

Abbreviations

AD: aortic distensibility

ANTH-BC: Anthracycline-based chemotherapy

CFPWV: carotid-femoral pulse-wave velocity

CI: confidence interval

CMR: cardiac magnetic resonance

PR: phase- contrast

PWV: Pulse-wave-velocity

CVD: cardiovascular disease

CV: cardiovascular

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Competing interests

All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Funding

The study did not receive any funding.

Author contribution

CS, PE and MW were involved in the conception and design. CS, TM and PE performed the analysis and interpretation of this meta-analysis and drafted the manuscript. NGJ assisted with screening of potential studies and was further involved in the design of this analysis. AB was involved in the analysis and interpretation of data and revised the manuscript. KC and TS revised the manuscript critically to provide intellectual content.

Acknowledgements

Not applicable.

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