Breast cancer is the most commonly diagnosed female cancer, with more than 1.6 million women diagnosed each year (1). Advances in detection and treatment over the past 25 yr have contributed to a 5-yr survival rate close to 90% (2). As a consequence of this excellent survival, long-term health outcomes are predominantly defined by comorbidities and latent adverse effects of cancer treatment (3). It has been demonstrated that early stage breast cancer patients are more likely to die of cardiovascular disease than breast cancer (4,5), thereby emphasizing the need to identify cardiovascular side effects of cancer therapies at their earliest stage and to define efficacious preventative strategies.
Anthracycline chemotherapy (AC) is a critical component of adjuvant and neoadjuvant therapy for women with higher risk early stage breast cancer (6). However, although being a highly effective treatment, its use is limited by dose-dependent and cumulative cardiac injury, which typically presents as left ventricular (LV) dysfunction and congestive heart failure (7). Clinical decision making related to LV dysfunction in this setting is typically quantified by the resting echocardiographic assessment of LV ejection fraction (LVEF) and global longitudinal strain (GLS) (8,9). However, the ability of this approach to detect early stages of cardiac dysfunction is limited by the modest reproducibility of LVEF (10) and theoretical limitations that relate to the assessment of cardiac function in the resting state (11). Indeed, cardiac function can appear preserved at rest because of the compensatory mechanisms from the remaining myocardium (12), which would suggest that the heart has already lost a substantial amount of its reserve capacity by the time dysfunction is apparent at rest. This introduces the concept of cardiac reserve (defined as the ability to augment cardiac output [Q˙] during exercise), whereby subtle cardiac impairment can be unmasked by quantifying the heart’s response to exercise (13,14). Thus, we hypothesized that the assessment of cardiac reserve may be a more sensitive and holistic marker for identifying cardiac impairment earlier in the disease trajectory after AC.
Cardiopulmonary fitness, measured objectively as oxygen uptake during peak exercise (V˙O2peak), has been recently endorsed by the American Heart Association as an important outcome for individuals with cardiovascular disease (15), as it is a holistic measure of functional capacity that is strongly associated with cardiac reserve, heart failure incidence, and prognosis in both healthy individuals and heart failure patients (16–18). There is growing evidence that AC can induce marked reductions in V˙O2peak, ranging between 6.5% and 10% over the course of chemotherapy (19,20). Furthermore, evidence from a large cross-sectional study of 248 breast cancer survivors demonstrated that 32% of patients had a V˙O2peak ≤ 18.0 mL·kg−1⋅min−1 (21). Notably, this threshold corresponds with significant impairment in functional capacity (22) (termed “functional disability”) alongside substantial increased risk of incident heart failure (17,23). Exercise training (ET) performed concurrently with chemotherapy can effectively blunt declines in V˙O2peak (19,20). There is also preclinical data suggesting that exercise can also protect the heart against cardiac injury induced by cancer treatment (and cancer itself) (24,25). However, the long-term effects of AC (and concurrent exercise) on V˙O2peak, and the implications for cardiac function and heart failure risk are yet to be determined in human subjects.
Therefore, the primary aim of this study is to assess whether reductions in V˙O2peak seen with AC are transient or sustained. A secondary aim was to assess whether changes in cardiac function progressed in time after AC as a potential explanation for the long-term incidence of heart failure. To address these aims, subjects who had participated in a previous nonrandomized controlled trial investigating the effects of ET during AC on V˙O2peak and cardiac function (26) were asked to return for an additional evaluation 12 months after the completion of AC. As part of this original study (26), we observed a significant reduction in V˙O2peak shortly after the completion of AC that was attenuated by 12 wk of supervised ET. We hypothesize that the acute reductions in V˙O2peak associated with AC persist beyond therapy, and that this coincides with evolving impairment in cardiac function.
METHODS
Participant Population and Study Design
This study was a longitudinal observational study of subjects who had participated in a larger nonrandomized controlled trial investigating the diagnostic and therapeutic utility of exercise for anthracycline-induced cardiac injury in women with early stage breast cancer scheduled for AC (26). Participants were excluded from the study if they had known structural heart disease, sustained arrhythmias, or contraindications to cardiac magnetic resonance (CMR) imaging. Thirty women were recruited into the parent study between November 2015 and March 2017; however, two withdrew from the study before completing baseline testing because of personal reasons. This left 28 participants who had completed an evaluation of their cardiopulmonary fitness and cardiac function before AC and 3 wk after their last cycle of AC (4 months after their pre-AC assessment). After the completion of their baseline evaluation, participants self-selected to participate in supervised ET (n = 14) or usual care (UC, n = 14) during AC using a nonrandomized approach. For the current observational substudy, participants who completed both the pre-AC and the post-AC evaluations (n = 28) from the original study were contacted via telephone and invited to undergo a repeat evaluation of the same measures 12 months after the completion of AC (additional consent was sought at the time of testing). Participant flow through the study is shown in Supplemental Figure 1 (see Figure, Supplemental Digital Content 1, Overview of participant flow through the study, https://links.lww.com/MSS/B560). The experimental procedures were explained to all participants, with informed consent obtained as approved by the institutional review board of the Alfred Health Research Ethics Committee (Study no. 269/15). All procedures conformed to the standards set by the Declaration of Helsinki.
Intervention
Exercise intervention
A detailed description of the exercise intervention has been outlined previously (26). In brief, participants who opted for the exercise program underwent a 12-wk, periodized ET program incorporating aerobic and resistance exercise that was designed to synchronize with their AC schedule. Participants performed two supervised exercise sessions per week (each of 30 min of moderate- to vigorous-intensity aerobic interval training using a cycle ergometer and 30 min of resistance training). Participants were also prescribed one unsupervised 30–60 min of home-based aerobic exercise session per week of continuous moderate-intensity exercise. The aerobic exercise program was individually prescribed, based on the maximum watts achieved on baseline maximal exercise test and regular submaximal incremental cycle tests performed in weeks 4 and 8 of the intervention. This periodization plan followed a modified version of the 2:1 step paradigm (2 wk of loading, 1 wk unloading), which is similar to an athletic-style mesocycle. Importantly, this model accounted for fatigue accumulation with the inclusion of an unloading week, which corresponded to the week after chemotherapy treatment. The decision to continue with ET after the completion of AC was left to each participant’s volition.
UC group
The UC group received standard medical care throughout the trial. These participants were not provided any specific exercise recommendations but were not precluded from exercising independently of the study.
Measurements
All participants underwent a battery of testing, detailed below, before commencing AC (pre-AC), 3 wk after completing AC (4 months), and 12 months after the completion of AC (16 months).
Exercise capacity
Exercise tests were performed on an electronically braked cycle ergometer (Lode, Gronigen, The Netherlands) for the measurement of V˙O2peak. Briefly, all participants performed an incremental ramp protocol, which began at 10–25 W and progressively increased at 10–30 W·min−1 until volitional exhaustion. Respiratory gas analysis was measured continuously throughout the test using a calibrated metabolic cart (True One 2400; Parvomedics, Sandy, UT). Heart rate (HR) was measured continuously by 12-lead electrocardiograph (Norav Medical, Wiesbaden, Germany). V˙O2peak was defined as a 30-s rolling average of the six highest 5-s oxygen uptake values.
Echocardiography
A comprehensive resting echocardiography study was performed (Vivid E95; General Electric Medical Systems, Milwaukee, WI), and images were saved in a digital format for offline analysis (Echopac v13.0.00, GE, Norway). A full-volume three-dimensional data set was acquired. LV end-diastolic and end-systolic volumes were measured according to standard recommendations (27). Two-dimensional global LV strain was quantified from three apical views at a temporal resolution of 60–90 frames per second. The average negative value on the strain curve was reported as GLS. LV inflow was assessed by pulsed-wave Doppler from the apical four-chamber view with the sample volume located between the tips of mitral leaflets and included peak early (E) and late diastolic flow velocity (A), and deceleration time of the E-wave. Pulsed-wave tissue Doppler was used to measure peak early diastolic tissue velocity (e′) at the septal and lateral portions of the mitral annulus. The ratio of early diastolic mitral inflow to mitral annular velocity (E/e′) and the ratio of early diastolic inflow to late diastolic inflow (E/A) were used as measures of diastolic function.
Exercise CMR imaging
The real-time CMR protocol used in this study has been described in detail previously and validated against invasive measures (28). In brief, imaging was performed with a Siemens MAGNETOM Prisma 3.0T CMR with a five-element phased array coil. Ungated real-time steady-state free-precision cine imaging was performed without cardiac or respiratory gating. Forty to 75 consecutive frames were acquired every 36 to 38 ms at each of the 13 to 18 contiguous 8-mm slices in the short axis plane, and 50 consecutive frames were acquired at approximately the same temporal resolution for 11 to 15 contiguous 8-mm slices in the horizontal long axis plane. Using this technique, our group has demonstrated excellent interobserver (R = 0.98 and R = 0.97 for LV and RV stroke volume (SV), respectively) and interstudy reproducibility (R = 0.98 for Q˙).
After resting images were obtained, subjects cycled on an MRI-compatible ergometer (MR Ergometer Pedal, Lode) at an intensity equal to 20%, 40%, and 60% of maximal power output obtained during the upright incremental cycle exercise test. These workloads will subsequently be referred to as rest and low, moderate, and high intensity. We have previously determined that 66% of the maximal power during upright cycling approximates maximal exercise capacity in a supine position (28). Each stage of exercise was maintained for up to 3 min; the first 30 s was taken to achieve a physiological steady state, whereas approximately 1.5 to 2.5 min was required for image acquisition.
Images were analyzed on a software program developed in-house (RightVol; Right Volume Leuven, Leuven, Belgium), in which the physiological data (respiratory movement and ECG) were synchronized to the images so that contouring could be performed at the same point in the respiratory cycle thereby greatly minimizing cardiac translation error. LV and RV endocardial contours were then manually traced on the short axis image, and the points of transection with the horizontal long axis plane were indicated, thus enabling constant referencing of the atrioventricular valve plane. Trabeculations and papillary muscle were considered part of the ventricular blood pools, and volumes were calculated by a summation of disks. SV was measured as the difference between end-diastolic volume and end-systolic volumes, whereas Q˙ was calculated as (RVSV + LVSV/2) × HR. Cardiac reserve was defined as the ability to augment Q˙ during exercise (peak Q˙ − resting Q˙). Peripheral muscle arteriovenous oxygen extraction (a-vO2 difference) was calculated indirectly according to the Fick principle (29), using V˙O2peak from the cardiopulmonary exercise test and peak Q˙ measured by exercise CMR.
Biochemistry
Nonfasted peripheral venous blood samples were collected as part of routine clinical care to measure hemoglobin, B-type natriuretic peptide (BNP), and troponin I.
Definition of cardiotoxicity and functional disability
Cardiotoxicity was defined as an absolute reduction in LVEF by >10 percentage points to an LVEF <50% in line with contemporary guidelines (9). Functional disability was quantified by the number of participants who fell below the V˙O2peak cut point designated as that required for functional independence (i.e., ≤18 mL·kg−1⋅min−1) at the 16-month follow-up visit (15).
Self-reported physical activity
Participants completed the Active Australia physical activity survey to estimate their self-reported duration (min) of moderate- and vigorous-intensity physical activity over the previous 7 d (30). Participants were classified as sufficiently active if they exceeded 150 min of moderate- and/or 75 min of vigorous-intensity activity (duration of vigorous-intensity activity was scaled by a factor of 2). This questionnaire was performed at the 16-month follow-up visit only.
Statistical analysis
Continuous variables are expressed as mean ± SD or mean (95% confidence interval), and categorical variables are expressed as n (%). Differences in participant characteristics were compared by independent t-tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. The primary analysis included all participants who completed follow-up testing at 16 months. The effect of ET on continuous variables was compared by ANCOVA adjusting for age and baseline values. Where there was no effect of ET, results for UC and ET groups were pooled, and continuous variables were analyzed using repeated-measures ANOVA analysis with post hoc analysis conducted using Bonferroni correction. The repeated-measures models included a repeated factor for study visits and an interaction term for time–exercise response for exercise CMR parameters. Differences at 16 months in cardiac function and cardiac biomarkers between those with and without functional disability were assessed by independent t-tests. Pearson correlations were used to test for associations between V˙O2peak and measures of cardiac function and cardiac biomarkers at 16 months. A two-sided P value of <0.05 was considered statistically significant.
RESULTS
Participant characteristics
Of the original 28 women who completed the initial study, 17 consented to participate in the additional follow-up evaluation (UC, n = 8; ET, n = 9), which was completed 11.6 ± 1.1 months after completion of AC. Reasons participants did not consent for the 16-month follow-up evaluation are reported in Supplemental Figure 1 (see Figure, Supplemental Digital Content 1, Overview of participant flow through the study, https://links.lww.com/MSS/B560), but these were most commonly due to geographical constraints (patients relocating overseas or more than 3 h of travel from the study site). There were no differences in age, fitness, or cardiac function between those who did and did not return for the 16-month evaluation (see Table, Supplemental Digital Content 2, Comparison of the baseline characteristics for participants who did and did not return for the evaluation at 16 months, https://links.lww.com/MSS/B561). Characteristics for the participants who returned for follow-up evaluation are summarized in Table 1. The UC group was older and tended to be heavier and has lower baseline fitness than the exercise group. Otherwise, both groups were similar in terms of breast cancer diagnosis and adjuvant treatment. The majority of participants went on to receive taxane-based chemotherapy and radiation therapy after completion of AC, with seven participants also undergoing trastuzumab treatment during this period (Table 1). The most common form of AC was doxorubicin-based chemotherapy (15 of 17 participants, 88%), with a mean ± SD cumulative dose of 256 ± 41 mg·m−2; the remaining two participants underwent epirubicin-based chemotherapy (cumulative dose of 301 mg·m−2 for both). The average adherence to the supervised exercise sessions was 76% (range 38%–88%). There was no significant difference between groups in self-reported weekly duration of moderate- to vigorous-intensity physical activity at 16 months (Table 1). Less than half of the total cohort (41%) were sufficiently physically active at the 16-month evaluation, with a similar proportion of the UC (38%) and ET groups (44%).
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TABLE 1: Participant characteristics.
Exercise capacity
Changes in exercise capacity over the course of the study are summarized in Figure 1, Supplemental Table 2 (see Table, Supplemental Digital Content 3, Changes in peak exercise parameters in the ET and UC groups, https://links.lww.com/MSS/B562), and Supplemental Table 3 (see Table, Supplemental Digital Content 4, Pooled changes for ET and UC groups in peak exercise parameters across the evaluation period, https://links.lww.com/MSS/B563). As can be seen in Figure 1, there was a significant reduction in V˙O2peak at 4 months in both the UC (−4.0 ± 2.3 mL·kg−1⋅min−1; 18% reduction) and the ET groups (−1.6 ± 2.4 mL·kg−1⋅min−1; 6% reduction) that persisted at 16 months (UC, −16%; ET, −7% vs pre-AC). V˙O2peak was significantly higher in the exercise group throughout the study (group, P = 0.015); however, there was no effect of ET on the reduction in V˙O2peak (group–time interaction P = 0.10, adjusted for age and baseline V˙O2peak; Supplemental Digital Content 3, https://links.lww.com/MSS/B562). Pooled results for ET and UC groups for peak exercise parameters (Supplemental Digital Content 4, https://links.lww.com/MSS/B563) demonstrate that despite marked reductions in V˙O2peak, there were minimal changes in peak workload or maximal HR.
FIGURE 1: Changes in V˙O2peak after AC with or without ET. V˙O2peak is significantly reduced with chemotherapy in both the ET and the UC groups, and these reductions persist at 16 months. The persistent effect of chemotherapy on V˙O2peak was not altered by 12 wk of ET during chemotherapy. Values are presented as mean ± SD. *P < 0.05 vs pre-AC.
Resting cardiac function and morphology, and biochemical markers
Results for standard of care measures of resting cardiac function and cardiotoxicity are summarized in Table 2. There was no significant effect of the exercise intervention on the trajectory of these measures (group–time interaction P > 0.05 for all measures; see Table, Supplemental Digit Content 5, Changes in resting echocardiographic measures of cardiac function and biochemical markers for the ET and UC groups, https://links.lww.com/MSS/B564). The small reductions seen in resting LVEF measured at 4 months were maintained at 16 months (P = 0.020 vs pre-AC). There was also a significant reduction in GLS over the 16-month period (time P = 0.015). There were no significant changes in any of the resting echocardiographic measures of cardiac structure or diastolic function. BNP did not change at any time point, whereas there was a transient reduction in hemoglobin post-AC. There was an increase in troponin at 4 months that recovered at 16 months but remained slightly elevated compared with pre-AC values (P = 0.004 vs pre-AC).
TABLE 2: Pooled results for UC and ET groups for resting echocardiographic measures of cardiac function and biochemical measures.
Cardiac reserve
Results related to the central hemodynamic response to supine exercise are presented in Figure 2A–C and Figure 3A–B. Every subject completed the full exCMR protocol at each time point. There was no effect of ET on measures of cardiac reserve throughout the follow-up period (Supplemental Digital Content 3, https://links.lww.com/MSS/B562), and so pooled data for both groups are presented. Although the cardiac response to exercise was preserved at 4 months (Fig. 2A), this was impaired at 16 months. There was a significant reduction in Q˙ during exercise at 16 months compared with pre-AC and 4 months (time P < 0.05), resulting in peak Q˙ being 13% lower than pre-AC values. The reduction in Q˙ at 16 months appears to be driven by a reduction in SV (time P < 0.01) and a blunted augmentation of SV during exercise (Fig. 2B; exercise response–time interaction P = 0.032; peak SV 14% lower). HR did not contribute to reductions in Q˙, as the HR response was largely similar across the study period (Fig. 2C). Both exercise LVEF and RVEF were lower at 16 months relative to both pre-AC and 4 months (Fig. 3A–B), which was primarily due to a reduction in LV end-systolic volume and an increase in RV end-diastolic volume, respectively (see Table, Supplemental Digital Content 6, Pooled changes for ET and UC groups in the bivolumetric response to exercise, https://links.lww.com/MSS/B565). Furthermore, the increase in LVEF in response to exercise was now impaired at 16 months relative to responses at pre-AC and 4 months (pre-AC: +7.7% ± 3.9%; 4 months: +7.0% ± 6.5%; 16 months: +3.5% ± 4.2%; exercise response–time interaction P = 0.042). There was also a transient reduction in estimated a-vO2 difference measured at 4 months (−1.3; 95% confidence interval = −2.3 to 0.3) that returned to baseline values at 16 months (0.4; 95% confidence interval = −0.8 to 1.6; Supplemental Digital Content 4, https://links.lww.com/MSS/B563).
FIGURE 2: Pooled results for UC and ET groups documenting changes in cardiac hemodynamic response to exercise after AC. Q˙ was reduced 12 months after chemotherapy (A). SV was also lower and had a blunted augmentation from rest to peak exercise (B), whereas the HR response was similar at all three time points (C). Values are presented as mean ± SD. a P < 0.05 for time effect vs pre-AC. b P < 0.05 for time effect vs 4 months.
FIGURE 3: Effect of AC on LVEF and RVEF during exercise. Both LVEF (A) and RVEF (B) were significantly lower throughout exercise, and there was a blunted increase in the LVEF response to exercise. Values are presented as mean ± SD. a P < 0.05 for time effect vs pre-AC. b P < 0.05 for time effect vs 4 months.
Incidence of cardiotoxicity and their relationship with functional disability
Two participants from the UC group were independently diagnosed with cardiotoxicity by their treating hospital between the 4- and the 16-month evaluations. In both cases, this was due to an asymptomatic absolute reduction in LVEF from baseline by >10 percentage points while undergoing trastuzumab. In one of these cases, the reduction in LVEF coincided with a relative reduction in GLS by >15%. No other participants met the criteria for cardiotoxicity based on standard criteria (9). In comparison, two participants (12% of total cohort) had a V˙O2peak below the functional disability threshold before starting chemotherapy. This increased to four participants (24% of total cohort) at 4 months and five participants (29% of total cohort) at 16 months, all of whom were from the UC group (UC, 5 of 8 [63%]; ET, 0 of 9 [0%]; P < 0.01]. When the study group was differentiated into those with and without functional disability at 16 months, there was no significant difference in resting LVEF (58.6% ± 7.3% vs 59.3% ± 5.7%, P = 0.83), GLS (−18.6 ± 1.43 vs −17.2 ± 2.4, P = 0.19), troponin (6.5 ± 3.7 vs 4.6 ± 1.1 ng·L−1, P = 0.28), or BNP (31.4 ± 26.2 vs 19.5 ± 16.7 ng·L−1, P = 0.37) measured at 16 months. By contrast, those who were functionally disabled had significantly lower augmentation of cardiac index (CI) from rest to peak exercise (CI reserve: +2.83 ± 0.42 vs +3.94 ± 0.96 L·min−1·m−2, P = 0.028) and a significantly lower a-vO2 difference at peak exercise (9.3% ± 1.4% vs 11.8% ± 2.0%). Similarly, of these variables, V˙O2peak was significantly associated with CI reserve and a-vO2 difference at 16 months, whereas standing measures of cardiotoxicity were not (Table 3).
TABLE 3: Correlations between V˙O2peak and cardiac measures at 16 months.
DISCUSSION
This study is the first to prospectively demonstrate that a marked impairment in V˙O2peak observed after AC does not recover. Specifically, measures of V˙O2peak at 16 months were similar to those immediately after chemotherapy, and as a result, patients who undertook ET were protected from short- and long-term functional disability. Importantly, we have shown that the sustained reduction in V˙O2peak observed at 16 months is associated with an evolving impairment in cardiac function that is most evident using exercise measures of cardiac function.
Reductions in cardiopulmonary fitness are a normal aspect of the aging process, with longitudinal studies suggesting that V˙O2peak declines between approximately 8% and 23% per decade (31,32). In the current study, the entire cohort had a mean reduction in V˙O2peak of 8% from baseline to 16 months, and this was particularly marked in those in the UC group, who had a nearly 20% of their baseline fitness over this period. This approximates the amount of cardiovascular aging that would normally be expected in one or two decades occurring over 12–16 wk of AC treatment. We demonstrate for the first time that these substantial reductions in V˙O2peak persist at 12 months after the completion of chemotherapy (despite the recovery of other factors such as hemoglobin). This is particularly important given the wealth of evidence, albeit in noncancer populations, supporting the strong prognostic relationship between low levels of V˙O2peak and increased risk of incident heart failure (17,23), cardiovascular morbidity, and mortality (18). Of particular note is that a substantial proportion (over one quarter) of this cohort fell below the threshold defining functional disability at 16 months. This threshold holds important functional and prognostic significance given it has been associated with a significant increased likelihood of requiring assistance with basic daily tasks (22), while also being shown to predict an almost sevenfold increased risk of incident heart failure (17,23) and, intriguingly, a twofold increased risk of all-cause mortality in patients with metastatic breast cancer (21). Our results highlight that a reduction in fitness or functional capacity after AC may be an important marker to identify patients in need of early intervention and close monitoring to prevent future cardiovascular morbidity.
The assessment of the cardiac function during exercise can be used to identify subtle cardiovascular injury when resting measures are unchanged (14,33). In applying similar state-of-the-art exercise imaging techniques in the current study, we have been able to demonstrate a key component in the evolution of cardiac impairment in breast cancer patients exposed to AC. We found that Q˙ was significantly lower during exercise, and this was primarily due to a reduction in the SV response to exercise. This is consistent with two previous cross-sectional reports demonstrating reduced augmentation in cardiac function during exercise in breast cancer patients treated with chemotherapy as compared with age-matched control subjects (34,35). However, our study is the first to comprehensively document how this process evolves over the months after AC and, importantly, how this relates to other measures of cardiac function. This is noteworthy, as although we also saw marked reductions in exercise-based measures of cardiac function, we saw only small changes in standard of care measures of resting cardiac function. Furthermore, resting measures were not associated with functional capacity, whereas there was a strong correlation between exercise cardiac reserve and V˙O2peak. This suggests that reductions in cardiac function measured during exercise may be an early marker of the cardiac impairment that predisposes patients to an increased risk of heart failure years after treatment.
The causes of exercise intolerance measured across the breast cancer continuum have been a matter of ongoing debate (36). The finding that CI reserve was significantly associated with V˙O2peak measured at 16 months also provides an important link between the sustained reductions seen in V˙O2peak after AC and the impairments in cardiac function. Previous studies have suggested that severe impairment in resting measures is required before an association with functional impairment can be established (13,37). This suggests that the current standard of care is insensitive at identifying patients experiencing significant chemotherapy-induced cardiac injury. Although our exercise-based measure of cardiac function showed better discrimination, it was intriguing to note that the acute reductions in V˙O2peak measured at 4 months could not be explained by reductions in cardiac function, as peak Q˙ was largely preserved at this point. Accordingly, “noncardiac” peripheral factors that result in reduced O2 delivery to and/or utilization by the exercising muscles may be important determinants of the decline in V˙O2peak in breast cancer survivors (36). Indeed, we demonstrated that both cardiac reserve and a-vO2 difference were strongly associated with V˙O2peak at 16 months, and these were both significantly lower in patients who were functionally disabled after treatment. This may hold important relevance for breast cancer patients, as there are preclinical studies documenting AC induces significant vascular and skeletal muscle injury (38,39) that may also contribute to functional impairment. Therefore, if the goal of therapy is to have a meaningful effect on a patient’s symptoms and functional capacity, our findings should be interpreted to highlight the need for therapies capable of targeting both central and peripheral determinants of V˙O2peak.
ET has been proposed as an important therapy for preventing anthracycline-induced cardiovascular injury and functional impairment because of its ability to target the entire spectrum of the oxygen cascade (40). The patients in our study who underwent ET had higher functional capacity across the three time points, and none were functionally disabled at 16 months as compared with five of eight UC patients (P < 0.01 for comparison). We were unable to demonstrate a significant legacy effect of ET, and in the 12 months after chemotherapy, functional capacity remained unchanged in both groups to a similar extent. It should be noted that the nonrandomized nature of this study makes it difficult to interpret the true effect of ET. However, our study provides an important insight into clinical practice, whereby patients who choose to exercise are more likely to obtain better functional outcomes, reinforcing the importance of recommending exercise therapy during chemotherapy. Our findings also suggest that a continuation of structured exercise after chemotherapy may be necessary to facilitate a return to prechemotherapy levels of function. This point may be particularly important because as we noted in our study, cardiac impairment appeared during the months after the completion of AC. Therefore, the post-AC period may also be a critical time point for further intervention if this trajectory is to be altered in a meaningful way.
The primary limitation with this study is the small sample size. Only 61% of the original study cohort agreed to complete the follow-up testing at 16 months. The group who declined to participate demonstrated similar baseline characteristics as those who did choose to participate, suggesting that there was no inherent selection bias. The demonstration of significant differences in exercise capacity and cardiac function in these small cohorts would suggest that the effect size of AC on these measures is substantial. However, although not being the primary aim of this study, the small sample size may have limited our ability to investigate the long-term effects of the ET intervention. In addition, as physical activity was only recorded at the 16-month follow-up assessment, it cannot be determined how much of the cardiovascular impairment measured over this period reflects a detraining effect versus direct cardiovascular injury induced by breast cancer therapy. However, it is also important to note that physical inactivity is an important risk factor for cardiovascular disease and highlights the importance of using exercise-based measures, which can capture the multicomponent nature of cardiotoxicity.
CONCLUSION
In summary, anthracycline-based chemotherapy is associated with marked reductions in V˙O2peak that do not recover at 16 months. This coincides with a progressive impairment in measures of cardiac function that are most evident when measured during exercise. The strong correlation between exercise-induced cardiac dysfunction and functional impairment provide the strongest link to date between the acute effects of chemotherapy and the heightened long-term risk of heart failure.
This project was supported by a project grant from the Jack Brockhoff Foundation, Australia (JBF 4039). Andre La Gerche is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC 1089039) and a Future Leaders Fellowship from the National Heart Foundation (NHF 100409) of Australia. Stephen Foulkes is supported by an Australian Government Research Training Program Scholarship (RTP 4635089552). Professor Haykowsky is funded, in part, by the Moritz Chair in Geriatrics in the College of Nursing and Health Innovation at the University of Texas at Arlington.
The authors have no conflict of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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