Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Apr 1.
Published in final edited form as: Breast Cancer Res Treat. 2013 Mar 17;138(3):909–916. doi: 10.1007/s10549-013-2478-1

The Influence of Adjuvant Therapy on Cardiorespiratory Fitness in Early-Stage Breast Cancer Seven Years After Diagnosis: The Cooper Center Longitudinal Study

Susan G Lakoski 1, Carolyn E Barlow 2, Graeme J Koelwyn 3, Whitney E Hornsby 4, Jesse Hernandez 2, Laura F DeFina 2, Nina B Radford 2, Samantha M Thomas 4, James E Herndon II 4, Jeffrey Peppercorn 4, Pamela S Douglas 4, Lee W Jones 4
PMCID: PMC3640334  NIHMSID: NIHMS456973  PMID: 23504137

Abstract

Background

We examined cardiorespiratory fitness (CRF) levels in early-stage breast cancer patients and determined whether CRF differs as a function of adjuvant therapy regimen.

Patients and methods

A total of 180 early breast cancer patients representing three treatment groups (surgery only, single-modality adjuvant therapy, and multi-modality adjuvant therapy) in the Cooper Center Longitudinal Study (CCLS) were studied. A non-cancer control group (n=180) matched by sex, age, and date of the CCLS visit were included. All subjects underwent an incremental exercise tolerance test to symptom limitation to assess CRF (i.e., peak METs and time to exhaustion).

Results

The mean time from breast cancer diagnosis to exercise tolerance testing was 7.4 ± 6.2 years. In adjusted analyses, time to exhaustion and peak METs were incrementally impaired with the addition of surgery, single-modality, and multi-modality adjuvant therapy compared to matched controls (p=0.006 and p=0.028, respectively). CRF was lowest in the multi-modality group compared to all other groups (all p’s <0.05).

Conclusions

Despite being seven years post diagnosis, asymptomatic early breast cancer survivors have marked reductions in CRF. Patients treated with multi-modal adjuvant therapy have the greatest impairment in CRF.

Keywords: cardiorespiratory fitness, cardiovascular risk, adjuvant therapy, breast cancer

INTRODUCTION

Significant improvements in early detection and adjuvant therapy have resulted in substantial reductions in cancer-specific mortality among women diagnosed with early breast cancer.[1] As a result, approximately 2.5 million women are alive today in the U.S. with a history breast cancer,[2] a number that is expected to double over the next two decades. However, women with early breast cancer, particularly those over 65 years of age, now have sufficient survival to be at risk for non-breast cancer-related (competing) mortality, primarily cardiovascular disease (CVD).[3] The precise etiology of therapy-related CVD late effects in early breast cancer patients remains to be fully elucidated. Women with early breast cancer are subjected to prolonged and aggressive adjuvant therapies (e.g., surgery, radiation, systemic therapy) which are proposed to cause ‘direct’ insults to components of the cardiovascular system.[4] Direct insults in conjunction with ‘indirect’ lifestyle changes (e.g., weight gain, physical inactivity) collectively lead to marked reductions in cardiovascular function (reserve capacity). We have termed this phenomenon the ‘multiple-hit’ hypothesis.[3] As such, the accurate quantification of cardiovascular function is likely to become increasingly important in the management and long-term surveillance of women with early-stage breast cancer.[5]

In current oncology practice, evaluation of cardiovascular function is commonly determined via resting determination of left ventricular ejection fraction (LVEF); usually prior to the initiation of therapy and before administration of agents with known cardiotoxicity.[6] Global cardiovascular function is not routinely evaluated after the completion of adjuvant therapy, and is only repeated if patients exhibit signs or symptoms of heart failure or in patients receiving trastuzumab therapy. In addition, resting LVEF does not capture global cardiovascular function, which is determined by the integrative capacity of multiple organ systems working in concert to maintain whole-body homeostatic regulation under a variety of physiologic conditions.[7]. Taken together, global cardiovascular function of women following the completion of primary adjuvant therapy for early breast cancer is poorly characterized.

Incremental exercise tolerance testing to symptom-limitation evaluates the ability of the cardiovascular, hematological and musculoskeletal systems to transport and utilize oxygen (O2) for ATP resynthesis.[8] The efficiency of O2 transport and utilization determines an individual’s cardiorespiratory fitness (CRF); CRF, as assessed by exercise tolerance testing, is inversely correlated with cardiovascular and all-cause mortality in a broad range of adult populations.[9, 10] Thus, exercise tolerance testing provides an accurate assessment of global cardiovascular function that may, in turn, not only complement current methods used in the oncology setting (prior to the initiation of therapy), but also to evaluate cardiovascular reserve capacity after the completion of therapy. Such information may help to identify those patients requiring close or further monitoring and/or therapeutic intervention.

Few studies have examined the clinical utility of exercise tolerance testing to evaluate cardiovascular function in early breast cancer patients following the completion of primary adjuvant therapy and/or evaluated the additive contribution of different component of adjuvant therapy on CRF. Accordingly, we utilized the Cooper Center Longitudinal Study (CCLS) database(1971–2007) [11] to examine CRF levels in early breast cancer patients on average 7 years after primary adjuvant therapy, and determined whether CRF differed as a function of the type of prior local or systemic adjuvant therapy. We hypothesized that breast cancer patients would have significant impairments in CRF compared to matched control women without a history of breast cancer. We further hypothesized that patients treated with multi-modal adjuvant therapy would have the greatest impairment in CRF.

METHODS

Participants and Procedures

The CCLS is a prospective observational cohort study of participants undergoing a preventive health examination including exercise tolerance testing to symptom limitation or volitional exhaustion at the Cooper Clinic in Dallas, Texas. Patients enrolled in CCLS signed an informed consent and the Cooper Institute’s Institutional Review Board approved this study.

An overview of the methods and procedures of CCLS has been described previously.[11–13] In the present study, the CCLS database was queried for individuals reporting a history of non-skin related cancer. A detailed medical chart review was then conducted to confirm a diagnosis of breast cancer (between 1971 and 2007) as well as to ascertain date of cancer diagnosis and type of local and/or systemic therapy. Among the cases, time from diagnosis to CRF testing were as follows: 18% (0–2 years), 26% (>2 to 4 years), 13% (>4 to 6 years), 19% (>6 to 10 years), and 24% (>10 years). A total of 180 participants with a history of early breast cancer were categorized into one of three treatment groups: (i) surgery only (n=67), (ii) surgery plus radiotherapy or chemotherapy (n=71) (herein referred to as the single-modality adjuvant therapy group), and (iii) surgery plus chemotherapy and radiation (n=42) (herein referred to as the multi-modality adjuvant therapy group). Within the single-modality adjuvant therapy group, 55% received radiation+ surgery and 45% received chemotherapy+ surgery. A non-cancer control group (n=180) individually-matched to breast cancer patients by sex, age, and date of the CCLS preventive medical exam was included for comparison purposes.

Cardiorespiratory Fitness

Cardiorespiratory fitness was evaluated by a maximal treadmill exercise tolerance test using a modified-Balke protocol. Women who reached 85% of their maximal predicted heart rate were included. Treadmill speed was initially set at 3.3 mph. In the first minute, the grade was set at 0% followed by a 2% increase in the second minute and a 1% increase for every minute thereafter. After 25 minutes, the grade remained unchanged but the speed was increased 0.3 mph (5.4 m/min) for each additional minute until test termination. The test was terminated by volitional exhaustion reported by the participant or by the physician for medical reasons. Time to exhaustion utilizing this protocol correlates with direct measurement of VO2peak (r=0.92).[14] Furthermore, using well-characterized regression equations, time to exhaustion from the modified-Balke protocol permits estimation of CRF level in peak metabolic equivalents (METs) (1 MET = 3.5 mL·kg·−1min−1).[15] Continuous electrocardiography (ECG) and heart rate monitoring were performed during exercise and for ten minutes following peak stress (recovery).[16] Abnormal resting and exercise ECG findings were broadly categorized as rhythm and conduction disturbances and ischemic ST-T wave abnormalities as described elsewhere.[17]

Other Cardiovascular Disease Risk Factors

Information about age, gender, and health habits were obtained by questionnaires and were physician verified. Body mass index (BMI) was calculated from measured weight and height. Blood pressure was measured with standard auscultatory methods after the participant had been seated for 5 minutes. Systolic and diastolic blood pressure was recorded as the first and fifth Korotkof sounds, respectively. Physical activity was assessed by self-report and was used to calculate metabolic equivalents (MET) minutes/wk.[18] A 12-hour fasting antecubital venous blood sample was obtained and plasma concentrations of glucose and lipids were determined with automated bioassays in the Cooper Clinic laboratory, which meets quality control standards of the CDC Lipid Standardization Program.

Statistical Methods

Descriptive statistics were used to assess patient demographic and clinical parameters. Analysis of covariance (ANCOVA) was used to assess differences in measures of cardiorespiratory fitness (i.e., time to exhaustion and peak METs) between the overall cohort of breast cancer patients and matched controls with adjustment for age, physical activity, years since breast cancer diagnosis, and cardiovascular risk factors (total cholesterol, glucose, systolic and diastolic blood pressure). To examine differences in cardiorespiratory fitness between the three patient treatment groups and matched controls, we conducted an overall F-test with posthoc (Tukey-Kramer) analysis, as appropriate to control for varying sample sizes between groups. These analyses were also adjusted for the aforementioned covariates. A two-sided significance level of 0.05 was used for all statistical tests. All statistical analyses were conducted using SAS version 9.2 (SAS Institute, Cary, NC).

RESULTS

Participant Characteristics

Participant characteristics are described in Table 1. The mean and median time from breast cancer diagnosis to CRF assessment was 7.4 ± 6.2 years. Breast cancer patients and matched controls mean age and body mass index (BMI) were 55 ± 9 years and 25 ± 5 kg/m2 and 55 ± 10 years and 24 ± 5 kg/m2, respectively (both p=NS). There were no significant between group differences in any cardiovascular risk factors including the proportion of subjects presenting with ECG abnormalities (all p’s <0.05). All patients underwent surgical resection, while 22%, 18%, and 23% received adjuvant radiotherapy, chemotherapy, or both, respectively. No participants had evidence of recurrent or metastatic disease and all were asymptomatic at the time of examination.

Table 1.

Characteristics of the Participants

Variable Breast Cancer
Patients (n=180)		 Controls
(n=180)		 P
Medical Characteristics
  Age, yr 55 ± 10 55 ± 10
    Range 34 – 85 35 – 83
  BMI, kg/m2 25 ± 5 24.5 ± 4.8 0.346
    Range 15.3 – 41.8 17.8 – 41.5
  Physical activity, MET min/week 1135 ± 1408 1050 ± 1113 0.557
    Range 0 – 10936 0 – 5475
  Time since diagnosis, years 7.4 ± 6.2
    Range 5 – 39
  Prior adjuvant therapy – no. (%)
    Surgery only 67 (36)
    Single modality adjuvant therapy 71 (39)
    Multi-modality adjuvant therapy 42 (23)
Cardiovascular risk factors
  Total cholesterol, mg/dL 210 ± 38.6 206.1 ± 38.5 0.397
  Fasting glucose, mg/dL 96.4 ± 18.3 96.5 ± 23.3 0.977
  Systolic blood pressure, mmHg 119 ± 18 118 ± 16 0.618
  Diastolic blood pressure, mmHg 78 ± 10 78 ± 9 0.711
  Waist girth, cm 78.3 ± 12.7 75.9 ± 16.2 0.174
  Resting ECG abnormalities, no. (%) 12 (7) 8 (4) 0.575
Open in a new tab

Data presented as mean ± (SD) for continuous data and n (%) for categorical data.

Single modality adjuvant therapy (surgery plus radiotherapy or chemotherapy); multi-modality adjuvant therapy (surgery plus radiation and chemotherapy)

Abbreviations: BMI, body mass index; ECG, electrocardiogram

Differences between the Overall Breast Cancer Patients and Matched Controls

Differences in CRF are presented in Table 2. Adjusted analyses indicated that measures of CRF were lower in breast cancer patients compared to matched controls but these differences did not reach statistical significance. Specifically, mean time to exhaustion was 723 ± 259 secs (range: 150 – 1587 secs) in patients compared to 781 ± 287 secs (range: 77 – 1710 secs) in matched controls (mean difference 51 secs, p=0.136; Fig 1A). Mean peak METs was 8.9 ± 2.1 (range: 4 – 15) in patients compared to 9.3 ± 2.4 (range: 4 – 18) in controls (mean difference 0.4, p=0.114; Fig 1B). Results were similar to the overall results when stratifying on median time from diagnosis and testing (5 years). For example, women >5 years from diagnosis has a mean peak METs of 8.8 (2.2) compared to women <5 years from diagnosis [9.0 METs(1.9)] and controls [9.3 METs (2.4)] (p=0.06). Peak heart rate was 165 ± 18 beats·min−1 and 167 ± 18 beats·min−1 in patients and controls, respectively (p=0.915). There were no between group differences in heart rate recovery (ptrend = 0.365).

Table 2.

Differences in Cardiorespiratory Fitness between the Overall Breast Cancer Patients and Matched Controls

Variable Breast Cancer Patients
(n=180)		 Controls
(n=180)		 Adjusted
p-value*
Time to exhaustion, secs 723 ± 260 781 ± 287 0.136
  Range 150 – 1587 77 – 1710
Peak METs 8.9 ± 2 9.3 ± 2.4 0.114
  Range 4.4 – 15.4 4.4 – 17.6
Resting heart rate, beats·min−1 66 ± 11 64 ± 10 0.274
Peak heart rate, beats·min−1 165 ± 18 167 ± 17 0.915
Peak ECG abnormalities, no. (%) 14 (8) 24 (13) 0.086
Open in a new tab

Data presented as mean ± (SD) for continuous data and n (%) for categorical data.

*

Adjusted for age, physical activity, time since diagnosis, total cholesterol, glucose, and resting systolic and diastolic blood pressure.

Abbreviations: METs, metabolic equivalents; ECG, electrocardiograph

Figure 1.

Figure 1

Open in a new tab

Differences in cardiorespiratory fitness between the overall cohort of breast cancer patients (n=180) and age-matched controls (n=180) for: (A) time to exhaustion and (B) peak METs. Statistical Tests: *p<0.05

Differences between Breast Cancer Patients by Prior Adjuvant Therapy and Matched Controls

In comparison to matched controls, time to exhaustion and peak METs were incrementally lower with the addition of surgery, single-modality adjuvant therapy, and multi-modality adjuvant therapy in patients (ptrend=0.006 and ptrend=0.028, respectively)(Table 3). Specifically, time to exhaustion was 758 ± 301 secs in the surgery only (mean difference from controls: 23 secs), 737 ± 228 secs in the single-modality adjuvant therapy group (mean difference from controls: 44 secs), and 645 ± 226 secs in the multi-modality adjuvant therapy group (mean difference from controls: 136 secs) (ptrend=0.006; Fig 2A). Post-hoc analysis indicated that time to exhaustion was lowest in the multi-modality adjuvant therapy group compared to all other groups (all p’s <0.05).

Table 3.

Cardiopulmonary Data Across the Breast Cancer Continuum

Breast Cancer Patients
Variable Controls
(n=180)		 Surgery Only
(n=67)		 Single Modality
Adjuvant Therapy
(n=71)		 Multi-Modality
Adjuvant Therapy
(n=42)		 Overall Adjusted
p-value*
No. (%) 180 (100) 67 (37) 71 (39) 42 (23)
Time to exhaustion, secs 781 ± 287 758 ± 301 737 ± 228 645 ± 226 0.006
  Range 77 – 1710 164 – 1587 167 – 1212 150 – 1211
Peak METs 9.3 ± 2.4 9.2 ± 2.3 9 ± 1.8 8.3 ± 1.9ŧ 0.028
  Range 4 – 18 4 – 15 7 – 13 4 – 13
Resting heart rate, beats·min−1 64 ± 10 64 ± 13 67 ± 10 68 ± 10 0.474
Peak heart rate, beats·min−1 167 ± 17 162 ± 19 166 ± 18 169 ± 17 0.990
Peak ECG abnormalities, no. (%) 24 (13) 4 (6) 4 (6) 6 (14) 0.197
Open in a new tab

Data presented as mean ± (SD) for continuous data and n (%) for categorical data.

Single modality adjuvant therapy (surgery plus radiotherapy or chemotherapy); multi-modality adjuvant therapy (surgery plus radiation and chemotherapy)

Abbreviations: METs, metabolic equivalent; ECG, electrocardiograph

*

Adjusted for age, physical activity, time since diagnosis, total cholesterol, glucose, and resting systolic and diastolic blood pressure. Significantly different from all other groups

ŧ

Significantly different from matched controls only

Figure 2.

Figure 2

Open in a new tab

Differences in cardiorespiratory fitness between breast cancer patients by prior adjuvant therapy for: (A) time to exhaustion (*significantly different from controls, surgery only, single modality adjuvant therapy, and multi-modal adjuvant therapy) and (B) peak METs (*significantly different from matched controls). Statistical Tests: *p<0.05

Similarly, peak METs was 9.2 ± 2.3 secs in the surgery only group (mean difference from controls: 0.1), 9.0 ± 1.8 secs in the single-modality adjuvant therapy group (mean difference from controls: 0.3), and 8.3 ± 1.9 secs in the multi-modality adjuvant therapy group (mean difference: 1.0) (ptrend=0.028; Fig 2B). Posthoc analysis indicated that peak METs was lowest in the multi-modality adjuvant therapy group compared to matched controls (p=0.021). There were no between group differences in resting or peak heart rate, the proportion of ECG abnormalities at peak exercise, or heart rate recovery (ptrend=0.944).

DISCUSSION

The principal finding of this study was that patients treated with multi-modality adjuvant therapy had a significant impairment in CRF compared to women of similar age without a history of breast cancer. To our knowledge, this is the first study to evaluate the additive contribution of different components of adjuvant therapy (i.e., surgery, chemotherapy, radiation) on CRF in early breast cancer survivors. Furthermore, the additive nature of the observed impairment is consistent with the tenets of the ‘multiple-hit’ hypothesis.[3] Finally, our findings demonstrate the feasibility and safety of maximal exercise tolerance testing in the post therapy breast cancer survivorship setting. From a clinical perspective, our findings provide support for exercise tolerance testing as an assessment tool that could identify a sub-group of patients with diminished CRF, and hence high-risk of therapy-induced cardiovascular late-effects, that likely requires close monitoring, further evaluation, and therapeutic intervention.

In the present data (for the overall cohort), patients’ mean CRF was 8.9 METs or an estimated VO2peak of 31.1 mL·kg·−1min−1, the equivalent to ~5% below matched women without a history of breast cancer. The level of CRF impairment in the present study is lower than that observed in our prior work. Specifically, we previously found that despite ‘normal’ resting cardiac function (i.e., LVEF ≥50%), CRF, as measured by peak oxygen consumption (VO2peak) was, on average, 18.4 mL·kg·−1min−1, the equivalent to 22% below that of age-matched sedentary women a mean of 27 months following the completion of primary adjuvant therapy.[19] Several important study methodological differences may explain these divergent findings including: (1) measurement of CRF (maximal ‘stress’ test vs. direct measurement of VO2peak, which may have resulted in over-estimation of CRF in the present study[20, 21]), (2) exercise test modality (treadmill vs. cycle ergometer; CRF is typically 5–10% higher on a treadmill,[22] and (3) timing of CRF assessment following cancer diagnosis (~3 years in prior work vs. ~7 years in the current study).

The CCLS data provided a unique opportunity to investigate the additive contribution of adjuvant therapies on CRF impairment. As hypothesized, CRF levels became increasingly impaired with the addition of single or multi-modal adjuvant therapy to surgery, with multi-modality adjuvant therapy conferring the greatest impairment in CRF. These data provide further support for the major tenets of the ‘multiple hit’ hypothesis, contending that as a patient progresses through diagnosis and adjuvant therapy they are subjected to a series of sequential or concurrent direct perturbations in one or more organs that govern O2 transport and utilization, which collectively deplete cardiovascular reserve capacity.[3] Indeed, compared to matched controls, the impact of surgery alone was associated with a ~3% reduction in CRF; the addition of radiation or chemotherapy to surgery was associated with a further 3% reduction; whereas the addition of both radiation and chemotherapy was associated with a further 15% reduction in CRF (a total CRF reduction of 21%). The mean CRF in the multi-modality adjuvant therapy group was 8.3 METs (equivalent to a VO2peak of ~29.0 mL·kg·−1min−1), the equivalent to ~12.4% (3.5 mL·kg·−1min−1) below matched controls, and ~9% to ~12% (2.5 to 3.0 mL·kg·−1min−1) below that of the other breast cancer treatment groups. The magnitude of CRF impairment in the multi-modality adjuvant therapy, compared with matched controls, is similar to that observed in our prior work (−18.4% vs. −22%).[19]

Gupta and colleagues[9] reported that a single assessment of CRF significantly improved the discrimination and reclassification of all-cause and cardiovascular mortality risk prediction at 10 and 25 years, even after controlling for traditional cardiovascular risk factors (e.g., systolic blood pressure, diabetes mellitus) in 66,371 asymptomatic individuals participating in the CCLS. Given emerging data indicating that early breast cancer patients have heightened risk for therapy-induced CVD late effects,[23] [24] tools such as exercise tolerance testing that improve CVD mortality risk prediction may also have utility in the oncology setting. Furthermore, exercise tolerance testing can facilitate the design of intervention strategies to prevent and/or mitigate therapy-induced fitness impairments. Further work evaluating the clinical importance of CRF impairments in post-therapy breast cancer as well as other cancer populations appears warranted.

As in non-cancer clinical populations, the mechanisms underlying impaired CRF in breast cancer patients are likely multifactorial with pulmonary, cardiovascular, and/or musculoskeletal limitations playing central roles.[25] Clearly, in cancer patients, normal, age-related mechanisms of exercise limitation are dramatically compounded by the adverse effects of conventional and modern anti-cancer therapies. Most adjuvant therapies used in the treatment of breast cancer are associated with unique and varying degrees of injury to the different organ components that govern the transport and utilization of oxygen that collectively determine CRF (i.e., pulmonary, cardiac, blood-vascular, and skeletal muscle function).[25] The acute effects of radiation, chemotherapy, and other anti-cancer therapies used in the management of early breast cancer (i.e., endocrine therapy, HER-2 directed therapy) on components of the cardiovascular system, particularly cardiac function, have been described previously.[26–28] It is important to note that we were unable to obtain information on use of adjuvant endocrine therapy or adjuvant trastuzumab therapy, which are also hypothesized to also potentially impair global cardiovascular function. Similarly, information on molecular or clinical breast cancer subtypes was unavailable. While tumor subtype is not likely to impact fitness per se, it may correlate with selection of therapy. Clearly, understanding the mechanisms of injury as well as the contribution of each component of adjuvant therapy to the observed impairments in CRF is an important goal of future research. Nevertheless, and of equal importance, varying degrees of cardiovascular impairment appears to persist for years following the completion of primary adjuvant therapy. The establishment of large cohort studies is required to elucidate the physiological mechanisms of therapy-induced cardiovascular late-effects in women with early breast cancer. This approach would parallel studies being conducted in adult survivors of childhood cancers.[29] Such studies will dramatically improve our understanding of the prevalence, incidence, severity, and mechanisms of therapy-induced impaired CRF as well as related cardiovascular toxicities / symptoms in cancer survivors.

The strengths and limitations of this study require consideration. Lack of data on use of other adjuvant therapies (e.g., endocrine therapy, trastuzumab), type of chemotherapy prescribed and therapy dose, as well as the cross-sectional study design is an important limitation. Prospective studies evaluating the trajectory of change in CRF across patient cohorts receiving different adjuvant therapy regimens are required to fully elucidate the relative contribution and potential synergistic or additive effects of modern adjuvant therapies, including endocrine and HER2 targeted agents on CRF. Data were obtained on women attending a private preventive health visit and thus are more likely to be following healthy lifestyle recommendations and experiencing less treatment-related complications. In addition, data pertaining to specific treatment-related characteristics including type and length / dose of adjuvant therapy were not available. As such, the generalizability of our findings to the larger cohort of population of breast cancer patients receiving adjuvant chemotherapy is limited. A major strength of our study was that breast cancer patients and controls were matched on age and date of preventive health visit. In our prior work, the ‘healthy’ control comparison data was obtained from population-based normative data as opposed to investigator-derived data.[19] Here, CRF testing in both patients and controls was conducted using the identical procedures and equipment, at the same institute, with groups comparable in CVD risk factor profile.

In conclusion, the addition of each form of adjuvant therapy to surgical resection is associated with step-wise reductions in CRF in women with early breast cancer. Women treated with multi-modal adjuvant therapy have the greatest impairment in CRF. Although the prognostic and clinical importance or these findings remains to be determined, breast cancer patients have marked reductions in CRF that persists years after the completion of therapy.

ACKNOWLEDGEMENTS

LWJ is supported in part by research grants from the National Cancer Institute (CA143254, CA142566, CA138634, CA133895, CA164751).

ABBREVIATIONS

CVD

Cardiovascular disease

CCLS

Cooper Center Longitudinal Study

METs

Metabolic equivalents

LVEF

Left ventricular ejection fraction

CRF

Cardiorespiratory fitness

ECG

Electrocardiogram

ANCOVA

Analysis of covariance

Footnotes

CONFLICT OF INTEREST

The authors declare no conflicts of interest

REFERENCES

  • 1.Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a cancer journal for clinicians. 2012;62(1):10–29. doi: 10.3322/caac.20138. [DOI] [PubMed] [Google Scholar]
  • 2.Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006. CA: a cancer journal for clinicians. 2006;56(2):106–130. doi: 10.3322/canjclin.56.2.106. [DOI] [PubMed] [Google Scholar]
  • 3.Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. Journal of the American College of Cardiology. 2007;50(15):1435–1441. doi: 10.1016/j.jacc.2007.06.037. [DOI] [PubMed] [Google Scholar]
  • 4.Lakoski SG, Eves ND, Douglas PS, Jones LW. Exercise rehabilitation in patients with cancer. Nat Rev Clin Oncol. 2012;9(5):288–296. doi: 10.1038/nrclinonc.2012.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(13):2900–2902. doi: 10.1200/JCO.2005.05.827. [DOI] [PubMed] [Google Scholar]
  • 6.Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. The Annals of pharmacotherapy. 2008;42(1):99–104. doi: 10.1345/aph.1K359. [DOI] [PubMed] [Google Scholar]
  • 7.Hsia CC, Ramanathan M, Estrera AS. Recruitment of diffusing capacity with exercise in patients after pneumonectomy. The American review of respiratory disease. 1992;145(4 Pt 1):811–816. doi: 10.1164/ajrccm/145.4_Pt_1.811. [DOI] [PubMed] [Google Scholar]
  • 8.Jones LW, Eves ND, Haykowsky M, Joy AA, Douglas PS. Cardiorespiratory exercise testing in clinical oncology research: systematic review and practice recommendations. The lancet oncology. 2008;9(8):757–765. doi: 10.1016/S1470-2045(08)70195-5. [DOI] [PubMed] [Google Scholar]
  • 9.Gupta S, Rohatgi A, Ayers CR, Willis BL, Haskell WL, Khera A, Drazner MH, de Lemos JA, Berry JD. Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality. Circulation. 2011;123(13):1377–1383. doi: 10.1161/CIRCULATIONAHA.110.003236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. The New England journal of medicine. 2002;346(11):793–801. doi: 10.1056/NEJMoa011858. [DOI] [PubMed] [Google Scholar]
  • 11.Blair SN, Kohl HW, 3rd, Paffenbarger RS, Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA. 1989;262(17):2395–2401. doi: 10.1001/jama.262.17.2395. [DOI] [PubMed] [Google Scholar]
  • 12.Blair SN, Kohl HW, 3rd, Barlow CE, Paffenbarger RS, Jr, Gibbons LW, Macera CA. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA. 1995;273(14):1093–1098. [PubMed] [Google Scholar]
  • 13.Lakoski SG, Barlow CE, Farrell SW, Berry JD, Morrow JR, Jr, Haskell WL. Impact of body mass index, physical activity, and other clinical factors on cardiorespiratory fitness (from the Cooper Center longitudinal study) The American journal of cardiology. 2011;108(1):34–39. doi: 10.1016/j.amjcard.2011.02.338. [DOI] [PubMed] [Google Scholar]
  • 14.Pollock ML, Foster C, Schmidt D, Hellman C, Linnerud AC, Ward A. Comparative analysis of physiologic responses to three different maximal graded exercise test protocols in healthy women. Am Heart J. 1982;103(3):363–373. doi: 10.1016/0002-8703(82)90275-7. [DOI] [PubMed] [Google Scholar]
  • 15.Pollock ML, Bohannon RL, Cooper KH, Ayres JJ, Ward A, White SR, Linnerud AC. A comparative analysis of four protocols for maximal treadmill stress testing. Am Heart J. 1976;92(1):39–46. doi: 10.1016/s0002-8703(76)80401-2. [DOI] [PubMed] [Google Scholar]
  • 16.Ho JS, Fitzgerald SJ, Barlow CE, Cannaday JJ, Kohl HW, 3rd, Haskell WL, Cooper KH. Risk of mortality increases with increasing number of abnormal non-ST parameters recorded during exercise testing. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. 2010;17(4):462–468. doi: 10.1097/HJR.0b013e328336a10d. [DOI] [PubMed] [Google Scholar]
  • 17.Peel JB, Sui X, Adams SA, Hebert JR, Hardin JW, Blair SN. A prospective study of cardiorespiratory fitness and breast cancer mortality. Med Sci Sports Exerc. 2009;41(4):742–748. doi: 10.1249/MSS.0b013e31818edac7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O'Brien WL, Bassett DR, Jr, Schmitz KH, Emplaincourt PO, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc. 2000;32(9 Suppl):S498–S504. doi: 10.1097/00005768-200009001-00009. [DOI] [PubMed] [Google Scholar]
  • 19.Jones LW, Courneya KS, Mackey JR, Muss H, Pituskin EN, Scott JM, Hornsby WE, Coan AD, Herndon JE, 2nd, Douglas PS, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. Journal of Clinical Oncology. 2012 doi: 10.1200/JCO.2011.39.9014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pollock ML, Bohannon RL, Cooper KH, Ayres JJ, Ward A, White SR, Linnerud AC. A comparative analysis of four protocols for maximal treadmill stress testing. American heart journal. 1976;92(1):39–46. doi: 10.1016/s0002-8703(76)80401-2. [DOI] [PubMed] [Google Scholar]
  • 21.Froelicher VF, Jr, Thompson AJ, Jr, Davis G, Stewart AJ, Triebwasser JH. Prediction of maximal oxygen consumption. Comparison of the Bruce and Balke treadmill protocols. Chest. 1975;68(3):331–336. doi: 10.1378/chest.68.3.331. [DOI] [PubMed] [Google Scholar]
  • 22.Hermansen L, Saltin B. Oxygen uptake during maximal treadmill and bicycle exercise. J Appl Physiol. 1969;26(1):31–37. doi: 10.1152/jappl.1969.26.1.31. [DOI] [PubMed] [Google Scholar]
  • 23.York B, Mann B, Jones C, Orlowski JP. "Every organ, every time" attitude teamed up with SoftMD results in successful lung transplant from a 72-year-old donor. Prog Transplant. 2012;22(2):207–211. doi: 10.7182/pit2012265. [DOI] [PubMed] [Google Scholar]
  • 24.Siegel RL, Ward EM, Jemal A. Trends in colorectal cancer incidence rates in the United States by tumor location and stage, 1992–2008. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2012;21(3):411–416. doi: 10.1158/1055-9965.EPI-11-1020. [DOI] [PubMed] [Google Scholar]
  • 25.Lakoski SG, Eves ND, Douglas PS, Jones LW. Exercise rehabilitation in patients with cancer. Nature reviews Clinical oncology. 2012;9(5):288–296. doi: 10.1038/nrclinonc.2012.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Khakoo AY, Yeh ET. Therapy insight: Management of cardiovascular disease in patients with cancer and cardiac complications of cancer therapy. Nature clinical practice Oncology. 2008;5(11):655–667. doi: 10.1038/ncponc1225. [DOI] [PubMed] [Google Scholar]
  • 27.Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, Mabuchi K, Marks LB, Mettler FA, Pierce LJ, et al. Radiation-related heart disease: current knowledge and future prospects. International journal of radiation oncology, biology, physics. 2010;76(3):656–665. doi: 10.1016/j.ijrobp.2009.09.064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, Durand JB, Gibbs H, Zafarmand AA, Ewer MS. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122–3131. doi: 10.1161/01.CIR.0000133187.74800.B9. [DOI] [PubMed] [Google Scholar]
  • 29.Hudson MM, Ness KK, Nolan VG, Armstrong GT, Green DM, Morris EB, Spunt SL, Metzger ML, Krull KR, Klosky JL, et al. Prospective medical assessment of adults surviving childhood cancer: study design, cohort characteristics, and feasibility of the St. Jude Lifetime Cohort study. Pediatric blood & cancer. 2011;56(5):825–836. doi: 10.1002/pbc.22875. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES