Time-restricted eating: A novel and simple dietary intervention for primary and secondary prevention of breast cancer and cardiovascular disease

Review Paper
Christensen RAG, Kirkham AA
Nutrients 2021;13(10), 3476

There is substantial overlap in risk factors for the pathogenesis and progression of breast cancer (BC) and cardiovascular disease (CVD), including obesity, metabolic disturbances, and chronic inflammation. These unifying features remain prevalent after a BC diagnosis and are exacerbated by BC treatment, resulting in elevated CVD risk among survivors. Thus, therapies that target these risk factors or mechanisms are likely to be effective for the prevention or progression of both conditions. In this narrative review, we propose time-restricted eating (TRE) as a simple lifestyle therapy to address many upstream causative factors associated with both BC and CVD. TRE is simple dietary strategy that typically involves the consumption of ad libitum energy intake within 8 h, followed by a 16-h fast. We describe the feasibility and safety of TRE and the available evidence for the impact of TRE on metabolic, cardiovascular, and cancer-specific health benefits. We also highlight potential solutions for overcoming barriers to adoption and adherence and areas requiring future research. In composite, we make the case for the use of TRE as a novel, safe, and feasible intervention for primary and secondary BC prevention, as well as tertiary prevention as it relates to CVD in BC survivors.

The Canadian Women’s Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women - Chapter 4: Sex- and gender-unique disparities: CVD across the lifespan of a woman

Review Paper
Mulvagh SL, Green CR, Levinsson ALE, Kirkham AA, Ahmed SB, Dhukai AR, Hart D, Pacheco C, Harvey PJ, Parry M, Hardy M, Foulds HJA, Dumanski SM, Grewal J, Nerenberg KA, Smith G, Mullen KA, Norris CM
Canadian Journal of Cardiology Open 2021; DOI:https://doi.org/10.1016/j.cjco.2021.09.013

Women have unique sex- and gender-related risk factors for cardiovascular disease (CVD) that can present or evolve over their lifespan. Pregnancy-associated conditions, polycystic ovarian syndrome, and menopause can increase a female’s risk of CVD. Women are at greater risk for autoimmune rheumatic disorders, which play a role in the predisposition and pathogenesis of CVD. The influence of traditional CVD risk factors (e.g., smoking, hypertension, diabetes, obesity, physical inactivity, depression, anxiety, and family history) is greater in women than men. Finally, there are sex differences in the response to treatments for CVD risk and comorbid disease processes. This Atlas chapter reviews sex- and gender-unique CVD risk factors that can occur across a woman’s lifespan, aiming to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment.

Rationale and design of the Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM) Study: A 2-arm parallel-group phase II randomized control trial of a short-term, calorie-restricted, and ketogenic diet plus exercise during intravenous chemotherapy versus usual care

Protocol Paper
Kirkham AA, King K, Joy AA, Pelletier AB, Mackey JR, Zhu X, Meza-Junco J, Young K, Basi S, Price-Hiller J, Brkin T, Michalowski B, Pituskin E, Paterson DI, Courneya KS, Thompson RB, Prado CM
BMC Cancer 2021, 21;Article number: 1093


An underlying cause of solid tumor resistance to chemotherapy treatment is diminished tumor blood supply, which leads to a hypoxic microenvironment, dependence on anaerobic energy metabolism, and impaired delivery of intravenous treatments. Preclinical data suggest that dietary strategies of caloric restriction and low-carbohydrate intake can inhibit glycolysis, while acute exercise can transiently enhance blood flow to the tumor and reduce hypoxia. The Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM) study will compare the effects of a short-term, 50% calorie-restricted and ketogenic diet combined with aerobic exercise performed during intravenous chemotherapy treatment to usual care on changes in tumor burden, treatment side effects, and quality of life.


Fifty patients with measurable metastases and primary breast cancer starting a new line of intravenous chemotherapy will be randomly assigned to usual care or the combined diet and exercise intervention. Participants assigned to the intervention group will be provided with food consisting of 50% of measured calorie needs with 80% of calories from fat and ≤ 10% from carbohydrates for 48–72 h prior to each chemotherapy treatment and will perform 30–60 min of moderate-intensity cycle ergometer exercise during each chemotherapy infusion, for up to six treatment cycles. The diet and exercise durations will be adapted for each chemotherapy protocol. Tumor burden will be assessed by change in target lesion size using axial computed tomography (primary outcome) and magnetic resonance imaging (MRI)-derived apparent diffusion coefficient (secondary outcome) after up to six treatments. Tertiary outcomes will include quantitative MRI markers of treatment toxicity to the heart, thigh skeletal muscle, and liver, and patient-reported symptoms and quality of life. Exploratory outcome measures include progression-free and overall survival.


The DREAM study will test a novel, short-term diet and exercise intervention that is targeted to mechanisms of tumor resistance to chemotherapy. A reduction in lesion size is likely to translate to improved cancer outcomes including disease progression and overall survival. Furthermore, a lifestyle intervention may empower patients with metastatic breast cancer by actively engaging them to play a key role in their treatment.

Trial registration

ClinicalTrials.gov, NCT03795493, registered 7 January, 2019.

Exercise-based multimodal programming: A treatment gap for older adults with advanced cancer

Small SD, Bland KA, Rickard JN, Kirkham AA
Oncologist 2021; in press

Evaluation of the structure and health impacts of exercise-based cardiac and pulmonary rehabilitation and prehabilitation for individuals with cancer: A Systematic review and meta-analysis

Original Research Paper
Rickard JN, Eswaran A, Gipson SD, Bonsignore A, Prakosh M, Oh, P, Kirkham AA
Frontiers in Cardiovascular Medicine 2021; DOI: 10.3389/fcvm.2021.739473

Exercise-based, multimodal rehabilitation programming similar to that used in the existing models of cardiac or pulmonary rehabilitation or prehabilitation is a holistic potential solution to address the range of physical, psychological, and existential (e.g., as their diagnosis relates to potential death) stressors associated with a cancer diagnosis and subsequent treatment. The purpose of this study was to systematically evaluate the structure and format of any type of exercise-based, multimodal rehabilitation programs used in individuals with cancer and the evidence base for their real-world effectiveness on metrics of physical (e.g., cardiorespiratory fitness, blood pressure) and psychological (e.g., health-related quality of life) health. Very few of the 33 included exercise-based, multimodal rehabilitation programs employed intervention components, education topics, and program support staff that were multi-disciplinary or cancer-specific. In particular, a greater emphasis on nutrition care, and the evaluation and management of psychosocial distress and CVD risk factors, with cancer-specific adaptations, would broaden and maximize the holistic health benefits of exercise-based rehabilitation. Despite these opportunities for improvement, exercise-based, multimodal rehabilitation programs utilized under real-world settings in individuals with cancer produced clinically meaningful and large effect sizes for cardiorespiratory fitness (VO2peak, ±2.9 mL/kg/min, 95% CI = 2.6 to 3.3) and 6-minute walk distance (+47 meters, 95% CI = 23 to 71), and medium effect sizes for various measures of cancer-specific, health-related quality of life. However, there were no changes to blood pressure, body mass index, or lung function. Overall, these findings suggest that exercise-based, multimodal rehabilitation is a real-world therapy that improves physical and psychological health among individuals with cancer, but the holistic health benefits of this intervention would likely be enhanced by addressing nutrition, psychosocial concerns, and risk factor management through education and counselling with consideration of the needs of an individual with cancer.

Effects of exercise on cancer treatment efficacy: A systematic review of preclinical and clinical studies

Review Paper
Yang L, Morielli A, Heer E, Kirkham AA, Cheung WY, Usmani N, Friedenreich CM, Courneya KS
Cancer Research 2021; DOI: 10.1158/0008-5472.CAN-21-1258

We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.

Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer

Original Research Paper
Kirkham AA, Haykowsky MJ, Beaudry RI, Grenier JG, Mackey JR, Pituskin E, Paterson DI, Thompson RB
Scientific Reports 2021; 11:article14005

This study aimed to characterize peak exercise cardiac function and thigh muscle fatty infiltration and their relationships with VO2peak among anthracycline-treated breast cancer survivors (BCS). BCS who received anthracycline chemotherapy ~ 1 year earlier (n = 16) and matched controls (matched-CON, n = 16) were enrolled. Resting and peak exercise cardiac function, myocardial T1 mapping (marker of fibrosis), and thigh muscle fat infiltration were assessed by magnetic resonance imaging, and VO2peak by cycle test. Compared to matched-CON, BCS had lower peak SV (64 ± 9 vs 57 ± 10 mL/m2, p = 0.038), GLS (− 30.4 ± 2.2 vs − 28.0 ± 2.5%, p = 0.008), and arteriovenous oxygen difference (16.4 ± 3.6 vs 15.2 ± 3.9 mL/100 mL, p = 0.054). Mediation analysis showed: (1) greater myocardial T1 time (fibrosis) is inversely related to cardiac output and end-systolic volume exercise reserve; (2) greater thigh muscle fatty infiltration is inversely related to arteriovenous oxygen difference; both of which negatively influence VO2peak. Peak SV (R2 = 65%) and thigh muscle fat fraction (R2 = 68%) were similarly strong independent predictors of VO2peak in BCS and matched-CON combined. Post-anthracyclines, myocardial fibrosis is associated with impaired cardiac reserve, and thigh muscle fatty infiltration is associated with impaired oxygen extraction, which both contribute to VO2peak.

Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial

Original Research Paper
Kirkham AA, Pituskin E, Thompson RB, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, Pagano JJ, Chow K, Tsui AK, Ezekowitz JA, Oudit GY, Paterson DI
European Heart Journal Cardiovascular Pharmacology 2021 Feb 19; doi: 10.1093/ehjcvp/pvab016

An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy.

Methods and results

This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (−0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (−2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively).


Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.

The effect of caloric restriction on blood pressure and cardiovascular function: A systematic review and meta-analysis of randomized controlled trials

Original Research Paper
Kirkham AA, Beka V, Prado CM
Clinical Nutrition; in press

Background & aims

Preclinical evidence suggests that caloric restriction is an effective therapy for a number of cardiovascular insults. Whether caloric restriction has cardio-protective effects in humans is not well understood. The aim was to systematically review and meta-analyze human randomized control trials (RCTs) testing the effect of caloric restriction on blood pressure (BP) and cardiovascular function.


A systematic review was performed using Medline, EMBASE, CINAHL (up to June 2017) to search for RCTs of adults receiving a calorie-restricted intervention versus a control/standard diet. Random-effect meta-analyses were performed to calculate weighted mean difference and 95% CI.


Thirty-two RCTs with 1722 participants assessing BP (n = 29 studies), heart rate (n = 10), VO2peak (n = 8), muscle sympathetic nerve activity (MSNA, n = 4), and endothelial function (n = 4) were included. Calorie-restricted interventions lasting 1–4 weeks had the largest effect on systolic (−5.5 mmHg, p < 0.001, 95% CI: −3.8, −7.1) and diastolic (−2.9 mmHg, p = 0.005, 95% CI: −5.0, −0.9) BP, but no effect on HR. Interventions lasting 1.5–6 months had similar effects on BP, and reduced HR (−4.4 beats/minute, p < 0.001, 95% CI: −6.1,-2.8). Relative VO2peak improved (1.8 mL/kg/min, p < 0.001, 95% CI: 1.3, 2.2). There were also potential positive effects on MSNA and endothelial function.


The effect of 1–4 weeks of calorie restriction on BP was similar to that expected with medications, and larger than that reported for other lifestyle interventions or supplements. Cardiovascular risk could be further reduced by caloric restriction lasting up to six months to lower heart rate and improve VO2peak.

Supervised, multi-modal exercise: the chemotherapy supportive therapy that almost does it all

Kirkham, AA
The Oncologist;2020;25(1):3-5

This commentary describes and places the results into context for the recent OptiTrain trial, a three‐arm randomized trial of two different exercise interventions versus usual care on rates of chemotherapy completion, hospitalization, and hematological toxicity.

State of the science in women's cardiovascular disease: a Canadian perspective on the influence of sex and gender

Review Paper
Norris C, Yip C, Nerenberg K, Clavel MA, Pacheco C, Foulds H, Hardy M, Gonsalves C, Jaffer S, Parry M, Colella TJF, Dhukai A, Grewal J, Price J, Levinsson A, Hart D, Harvey P, Van Spall H, Sarfi H, Sedlak T, Ahmed S, Baer C, Coutinho T, Edwards J, Green C, Kirkham AA, Srivaratharajah K, Dumanski S, Keeping-Burke L, Lappa N, Reid R, Robert H, Smith G, Martin-Rhee M, Mulvagh S
Journal of the American Heart Association. 2020;9(4):e015634.

Cardiovascular disease (CVD) is the leading cause of premature death for women in Canada. Although it has long been recognized that estrogen impacts vascular responses in women, there is emerging evidence that physiologic and pathophysiologic cardiovascular responses are uniquely affected across the spectrum of a woman’s life. Despite a global understanding that manifestations and outcomes of CVD are known to differ between men and women, uptake of the recognition of sex and gender influences on the clinical care of women has been slow or absent.

To highlight the need for better research, diagnosis, treatment, awareness, and support of women with CVD in Canada, the Canadian Women’s Heart Health Alliance (CWHHA), supported by the University of Ottawa Heart Institute, and in collaboration with the Heart and Stroke Foundation of Canada (HSFC), undertook a comprehensive review of the evidence on sex‐ and gender‐specific differences in comorbidities, risk factors, disease awareness, presentation, diagnosis, and treatment across the entire spectrum of CVD. The intent of this review was not to directly compare women and men on epidemiological and outcome measures of CVD, but to synthesize the state of the evidence for CVD in women and identify significant knowledge gaps that hinder the transformation to clinical practice and care that is truly tailored for women, a significant health challenge that has only been recognized in Canada relatively recently. This review highlights the scarcity of Canadian data on CVD in women as part of the ongoing struggle to increase awareness of and improve outcomes for women with CVD. Because of a paucity of published Canada‐specific evidence, the purpose of this review is to provide an infrastructure to summarize world‐wide published evidence, including knowledge gaps that must be understood to then make effective recommendations to alleviate the glaring “unders” of CVD for women in Canada: under‐aware, under‐diagnosed and under‐treated, under‐researched, and under‐support.

Rising to the challenge: Designing, implementing, and reporting exercise oncology trials in understudied populations

Larhart IM, Weller SK, Kirkham AA
British Journal of Cancer 2020 May 21. doi: 10.1038/s41416-020-0868-9

Exercise can improve cancer-related fatigue, quality of life and physical fitness, but is understudied in less common cancers such as multiple myeloma. Studying less common cancers and the adoption of novel study designs and open-science practices would improve the generalisability, transparency, rigour, credibility and reproducibility of exercise oncology research.

Rehabilitation needs in anti-cancer treatment-related cardiotoxicity

Review Paper
Pituskin E, Kirkham AA, Cox-Kennett N, Dimitry R, Dimitry J, Paterson DI, Gyenes G
Seminars in Oncology Nursing 2020;36(1):doi.org/10.1016/j.soncn.2020.150986

Objectives: To examine and summarize current international guidelines regarding cardiovascular risk reduction before and during cancer therapy, and to discuss the emerging role of cardio-oncology as a subspecialty in cancer care and the role of cardio-oncology rehabilitation.

Data sources: Published articles and guidelines.

Conclusion: With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number of individuals now survive a cancer diagnosis. However, for some the cost is high – many survivors are now at higher risk of death from cardiovascular disease than from recurrent cancer. Cardiovascular morbidity and mortality are common and associated with common cancer therapies serially administered in adult oncology care.

Implications for nursing practice: Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and support the patient within the family and community.

Physician referrals to a lifestyle intervention program for breast cancer patients: The experiences of patients and oncologists

Original Research Paper
Balneaves LG, Truant T, Van Patten CL, Kirkham AA, Waters E, Campbell KL
Journal of Clinical Medicine 2020;9(9):2815

This study explored the perspectives and experiences of breast cancer patients and medical oncologists with regards to participation in a lifestyle intervention at a tertiary cancer treatment center. A thematic approach was used to understand the context within which a lifestyle intervention was recommended and experienced, to inform future lifestyle programming and promote uptake. Twelve women with breast cancer receiving adjuvant chemotherapy and eight medical oncologists completed interviews. Findings suggest receiving a prescription for a lifestyle intervention from a trusted health professional was influential to women with breast cancer. The intervention offered physical, psychological, emotional, social, and informational benefits to the women and oncologists perceived both physiological and relational benefit to prescribing the intervention. Challenges focused on program access and tailored interventions. Lifestyle prescriptions are perceived by women with breast cancer to have numerous benefits and may promote lifestyle interventions and build rapport between oncologists and women. Oncology healthcare professionals play a pivotal role in motivating women’s participation in lifestyle interventions during breast cancer treatment. Maintenance programs that transition patients into community settings and provide on-going information and follow-up are needed.

Impact of exercise on chemotherapy tolerance and survival in early stage breast cancer: A Nonrandomized Controlled Trial

Original Research Paper
Kirkham AA, Gelmon KA, Van Patten CL, Bland KA, Wollmann H, McKenzie DC, Landry T, Campbell KL
Journal of the National Comprehensive Cancer Network; in press

Exercise training affects hemodynamics not cardiac function during chemotherapy

Original Research Paper
Kirkham AA, Virani SA, Bland KA, McKenzie DC, Gelmon KA, Warburton DER, Campbell KL
Breast Cancer Research and Treatment; in press


Preclinical data demonstrate the potential for exercise training to protect against anthracycline-related cardiotoxicity, but this remains to be shown in humans.


To assess whether exercise training during anthracycline-based chemotherapy for treatment of breast cancer affects resting cardiac function and hemodynamics.


In this prospective, non-randomized controlled study, 26 women who participated in aerobic and resistance training 3×/wk during chemotherapy were compared to 11 women receiving usual care. Two-dimensional echocardiography was performed before and 7–14 days after completion of anthracycline-based chemotherapy. Pre- and post-anthracycline cardiac function and hemodynamic variables were compared within each group with paired t-tests; the change was compared between groups using ANCOVA with adjustment for baseline values.


Left ventricular longitudinal strain, volumes, ejection fraction, E/A ratio, and mass did not change in either group. Hemoglobin, hematocrit, and mean arterial pressure decreased significantly from baseline in both groups (all p < 0.05) with no differences between groups. Cardiac output increased in the usual care group only (+ 0.27 ± 0.24 L/min/m2p < 0.01), which differed significantly from the exercise group (p = 0.03). Systemic vascular resistance (SVR) decreased in both groups (usual care: − 444, p < 0.01; exercise: − 265, dynes/s/cm5p = 0.01). However, the reduction in SVR was significantly attenuated in the exercise group (p = 0.03) perhaps due to a compensatory decrease in estimated vessel lumen radius.


Exercise training during anthracycline chemotherapy treatment had no effect on resting cardiac function but appeared to modify hemodynamic responses. Specifically, exercise training attenuated the drop in SVR in response to chemotherapy-related reductions in hematocrit potentially by increasing vessel lumen radius.

Cardiovascular risk factors are at age-dependent increased odds among cancer survivors: CLSA cohort

Original Research Paper
Kirkham AA, Pituskin E, Neil-Sztramko SE
Current Oncology; 2020; 27(4): e368–e376

Background: This study compared the odds of self-reported and objectively measured cardiovascular (cv) risk factors in a sample of Canadian cancer survivors and individuals without cancer.

Methods: A nationally representative sample of 45- to 85-year-old cancer survivors (n = 6288) in the Canadian Longitudinal Study on Aging were compared with individuals without cancer (n = 44,051).

Results: The most prevalent risk factors in cancer survivors were all self-reported or easily measured in clinic: overweight or obesity (68.0%), former smoking (62.9%), fewer than 5 daily servings of fruits and vegetables (59.8%), hypertension (43.7%), and high waist circumference (47.0%). After adjustment for sex and education, the odds ratios of several cv risk factors varied by age in cancer survivors and the non-cancer controls. At ages 50 and 60, cancer survivors have increased odds of overweight or obesity, former smoking, hypertension, high waist circumference and truncal fat, diabetes, lung disease, and heart rate greater than 80 bpm compared with non-cancer controls. At age 70, odds did not differ for many risk factors; at age 80, no differences were evident. Without modification by age, low physical activity was more prevalent in cancer survivors (odds ratio: 1.27; 95% confidence interval: 1.17 to 1.39). There were no differences in the odds of cv risk factors measured by specialized equipment, including electrocardiography, carotid ultrasonography, spirometry, and dual-energy X-ray absorptiometry.

Conclusions: The odds of several easy-to-assess cv disease risk factors are higher among middle-aged, but not older, cancer survivors relative to the general Canadian population. Initial assessment of cv risk for middle-aged adults in the survivorship setting could be quickly and inexpensively performed using self-reported and easily measured metrics.

Aerobic fitness is related to myocardial fibrosis post-anthracycline therapy

Original Research Paper
Kirkham AA, Paterson DI, Haykowsky MJ, Beaudry R, Mackey JR, Pituskin E, Grenier JG, Thompson RB
Medicine & Science in Sports & Exercise; in press

Adjuvant anthracycline chemotherapy for breast cancer is associated with cardiotoxicity and reduced cardiorespiratory fitness (VO2peak).


We evaluated the impact of anthracyclines on left ventricular (LV) function and tissue characteristics using cardiovascular magnetic resonance imaging (CMR) to determine their relationship with VO2peak.


Women with breast cancer who had not yet received treatment (No-AT, n=16) and had received anthracycline treatment ~one year earlier (Post-AT, n=16), and controls without cancer (CON, n=16) performed a maximal exercise test and a comprehensive 3T CMR examination including native myocardial T1 mapping, where elevated T1 times are indicative of myocardial fibrosis. ANOVA and linear regression were used to compare CMR variables between groups and to determine associations with VO2peak. Sub-group analysis was performed by categorizing participants as ‘fit’ or ‘unfit’ based on whether their VO2peak value was greater or less than 100% of reference value for age and body size, respectively.


LV end-diastolic volume, ejection fraction, and mass were similar between groups. Post-AT, T1 times were elevated (1534±32 vs 1503±28ms, p<0.01) and VO2peak (23.1±7.5 vs 29.5±7.7mL/kg/min, p=0.02) was reduced compared to CON. In No-AT, T1 times and VO2peak were similar to CON. In the Post-AT group, T1 time was associated with VO2peak (R2=64%), whereas in the absence of anthracyclines (i.e., No-AT and CON groups), T1 time was not associated with VO2peak. Regardless of group, all fit women had similar T1 times; while unfit women Post-AT had higher T1 than unfit CON (1546±22 vs 1500±33ms, p<0.01).


Following anthracycline chemotherapy, an elevated T1 time suggesting greater extent of myocardial fibrosis was associated with lower VO2peak. However, those who were fit did not have evidence of myocardial fibrosis following anthracycline treatment.

‘Chemotherapy-periodized’ exercise to accommodate for cyclical variation in symptoms

Original Research Paper
Kirkham AA, Bland KA, Zucker DS, Bovard J, Shenkier T, McKenzie DC, Davis MK, Gelmon KA, Campbell KL
Medicine & Science in Sports & Exercise 2020;52(2):278-286


The purpose of this study was to provide a rationale for ‘chemotherapy-periodized’ exercise by characterizing cyclical variations in fatigue and exercise response across a chemotherapy cycle and comparing exercise adherence during chemotherapy between a prescription that is periodized according to chemotherapy cycle length and a standard linearly progressed prescription.


Women with breast cancer who were prescribed taxane-based chemotherapy were randomly assigned to a supervised aerobic and resistance exercise program following a chemotherapy-periodized exercise prescription (n=12) or to usual care during chemotherapy (n=15). Fatigue and steady state exercise responses were assessed in both groups prior to the first taxane treatment and across the third treatment (i.e., 0-3 days prior and 3-5 days after the third treatment, and 0-3 days prior to the fourth treatment) to assess cyclical variations. Adherence to the chemotherapy-periodized exercise prescription was compared to adherence to a standard linear prescription from a prior study in a similar population (n=51).


Fatigue increased from baseline (marginal mean±standard error: 3.2±0.4) to prior to the third treatment (4.1±0.4, p=0.025), then peaked at 3-5 days after the third treatment (5.1±0.4, p=0.001), before recovering prior to the next treatment (4.3±0.5, p=0.021). The peak in fatigue at 3-5 days post-third treatment corresponded to a decrease in steady state exercise oxygen consumption (VO2) (p=0.013). Compared to a standard linear exercise prescription during chemotherapy, a chemotherapy-periodized exercise prescription resulted in higher attendance during the week after chemotherapy (57±30% vs 77±28%, p=0.04) and overall attendance (63+25% vs 78±23%, p=0.05).


Fatigue and exercise VO2 vary across a chemotherapy cycle. A chemotherapy-periodized exercise prescription that accommodates cyclical variations in fatigue may increase adherence to supervised exercise.


Measurement and correction of the bulk magnetic susceptibly effects of fat: application in venous oxygen saturation imaging

Original Research Paper
Yang E, Kirkham AA, Grenier JG, Thompson RB
Magnetic Resonance in Medicine 2019;81(5):3124-37

To develop a correction method for the effects of the magnetic susceptibility of fat (χFat ) on the calculation of venous oxygen saturation (SvO2 ).

The magnetic field shifts associated with the magnetic susceptibility of deoxyhemoglobin can be used to estimate SvO2 , a measure of oxygen extraction and metabolism. However, the distinct magnetic susceptibility of fat surrounding targeted veins will give rise to magnetic field perturbations that will extend into the vein and surrounding tissues, potentially confounding the calculation of SvO2 .

Multi-echo modified Dixon fat-water separated imaging was used to quantify fat-water distributions around the superficial femoral vein (venous return from the lower leg). Fat fraction images were used to generate χFat images, to calculate and remove the associated fat-susceptibility-induced magnetic field shifts before the estimation of SvO2 . This approach was evaluated at rest and with plantar flexion exercise to evaluate calf muscle oxygen extraction in 10 healthy subjects.

The presence of fat around the vein resulted in complex magnetic field shifts and errors in estimated SvO2 . Corrected resting SvO2 values were significantly larger than those measured with conventional methods, at rest (72.6 ± 11.0% vs. 65.2 ± 12.2%, P < 0.05) and post-exercise (37.4 ± 12.3% vs. 31.7 ± 12.7%, P < 0.05), with larger errors in individuals and/or regions with increased fat volumes. Estimation and removal of the field-effects from χFat enabled the use of fat tissues for the measurement and removal of the background magnetic field.

The magnetic susceptibility effects of fat can confound SvO2 estimation, but the susceptibility field effects can estimated and removed with the use of modified Dixon fat-water separated imaging.

Maintenance of fitness and quality of life benefits from supervised exercise offered as supportive care for breast cancer

Original Research Paper
Kirkham AA, Bland KA, Wollmann H, Bonsignore A, McKenzie DC, Gelmon KA, Van Patten CL, Campbell KL
Journal of the National Comprehensive Cancer Network;2019;17(6):695-702

Background: Overwhelming randomized controlled trial evidence demonstrates that exercise has positive health impacts during and after treatment for breast cancer. Yet, evidence generated by studies in which exercise programs are delivered outside a tightly controlled randomized trial setting is limited. The purpose of this study was to assess the effectiveness of an evidence-based exercise program with real-world implementation on physical fitness and quality of life (QoL).

Patients and Methods: Oncologists referred women with early-stage breast cancer who were scheduled to receive adjuvant chemotherapy. The program consisted of supervised aerobic and resistance exercise of moderate to vigorous intensity 3 times per week until the end of treatment (chemotherapy ± radiotherapy), then twice per week for 10 weeks, followed by once per week for 10 weeks. Health-related physical fitness and QoL were assessed at baseline, end of treatment, end of program, and 1-year follow-up.

Results: A total of 73 women were enrolled. Estimated peak VO2 (VO2peak), QoL, and body weight were maintained between baseline and end of treatment, whereas muscular strength improved (P<.01). By the end of the program, VO2peak, heart rate recovery, waist circumference, and some aspects of QoL were improved (all P<.01) relative to baseline. One year later, VO2peak, QoL, and waist circumference were maintained relative to end of program, whereas the improvements in strength and heart rate recovery had dissipated (all P<.01).

Conclusions: Evidence-based exercise programming delivered with real-world implementation maintained VO2peak, strength, and QoL during adjuvant treatment and improved these measures after treatment completion among women with breast cancer. Continued guidance and support may be required for long-term maintenance of strength improvements in this population.

Impaired exercise tolerance in anthracycline-treated breast cancer survivors: The role of skeletal muscle bioenergetics, oxygenation, and composition

Original Research Paper
Beaudry RI, Kirkham AA (co-first author), Thompson RB, Grenier JG, Mackey JR, Haykowsky MJ
The Oncologist 2020;25(5):e852-e860

Background: Peak oxygen consumption (VO2) is reduced in women with a history of breast cancer (BC). We measured leg blood flow, oxygenation, bioenergetics, and muscle composition in women with BC treated with anthracycline chemotherapy (n=16, mean age: 56) and age- and body mass index-matched controls (n=16).

Methods: Whole-body peak VO2 was measured during cycle exercise. 31Phospohous magnetic resonance (MR) spectroscopy was used to measure muscle bioenergetics during and after incremental to maximal plantar flexion exercise (PFE). MR imaging was used to measure lower leg blood flow, venous saturation (SvO2) and VO2 during submaximal PFE, and abdominal, thigh and lower leg intermuscular fat (IMF) and skeletal muscle (SM).

Results: Whole-body peak VO2 was significantly lower in BC survivors vs. controls (23.1±7.5 vs. 29.5±7.7 ml/kg/min). Muscle bioenergetics and mitochondrial oxidative capacity were not different between groups. No group differences were found during submaximal PFE for lower leg blood flow, SvO2 or VO2. The IMF:SM ratio was higher in the thigh and lower leg in BC survivors (0.36±0.19 vs 0.22±0.07, p=0.01; 0.10±0.06 vs 0.06±0.02, p=0.03, respectively) and were inversely related to whole-body peak VO2 (r= -0.71, p=0.002; r=-0.68, p=0.003, respectively). In the lower leg, IMF:SM ratio was inversely related to VO2 and O2 extraction during PFE.

Conclusion: SM bioenergetics and oxidative capacity in response to PFE are not impaired following anthracycline treatment. Abnormal SM composition (increased thigh and lower leg IMF:SM ratio) may be an important contributor to reduced peak VO2 during whole-body exercise among anthracycline-treated BC survivors.

Effect of exercise on taxane chemotherapy-induced peripheral neuropathy in women with breast cancer: A randomized control trial

Original Research Paper
Bland KA, Kirkham AA, Bovard J, Shenkier T, Zucker D, McKenzie DC, Davis MK, Gelmon KA, Campbell KL
Clin Breast Cancer. 2019 Dec;19(6):411-422


Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse effect of taxanes. We sought to evaluate the effect of exercise on taxane CIPN in women with breast cancer.

Patients and Methods

Women (n = 27) were randomized to immediate exercise (IE, during taxane chemotherapy) or delayed exercise (DE, after chemotherapy). Supervised aerobic, resistance, and balance training was offered 3 days a week for 8-12 weeks. CIPN symptoms and quality of life were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and CIPN20 (scored from 0 to 100). The percentage of participants reporting moderate to severe sensory symptoms (‘3/4’ or ‘4/4’ for CIPN20 sensory items) was also evaluated, along with clinical sensory testing at the lower limb (vibration sense and pinprick). Taxane treatment adherence, including relative dose intensity, was extracted from patient medical records. Assessments occurred at: baseline (before taxane chemotherapy), pre-cycle 4 (before the final taxane cycle), the end of chemotherapy, and follow-up (10-15 weeks after chemotherapy).


No differences in the EORTC QLQ CIPN20 symptom scores were detected between groups at any time point. At pre-cycle 4, there was a significant difference between groups in patient-reported moderate to severe numbness in the toes or feet (IE: n = 1, 9%, DE: n = 7, 50%, P = .04) and impaired vibration sense in the feet (IE: n = 2, 18%, DE: n = 10, 83%, P < .01). Overall global health status/quality of life was higher in IE compared to DE at the end of chemotherapy (P = .05), yet both groups had worse CIPN20 sensory (Δ24.3 ± 4.6, P < .01) and motor symptom scores (Δ10.5 ± 1.9, P < .01) relative to baseline. By the end of chemotherapy, no differences between groups were found for moderate to severe numbness in the toes or feet (P = 1.0) or impaired vibration sense in the feet (P = .71). More IE participants received ≥ 85% relative dose intensity (IE: n = 12, 100%, DE: n = 10, 67%, P < .05).


Exercise may attenuate CIPN over the course of taxane chemotherapy and possibly improve taxane adherence in women with breast cancer. These findings, as well as whether exercise can attenuate CIPN by the end of taxane chemotherapy, should be confirmed in larger trials.

Curing breast cancer and killing the heart: A novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer

Review Paper
Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ
Progress in Cardiovascular Diseases 2019;62(2):116-26

Due to advances in prevention, early detection and treatment, early breast cancer mortality has decreased by nearly 40% during the last four decades. Yet, the risk of cardiovascular disease (CVD) mortality is significantly elevated following a breast cancer diagnosis, and it is a leading cause of death in this population. This review will discuss the most recent evidence for risks, pathology, mechanisms, and prevention of CVD morbidity and mortality in women with breast cancer. This evidence will be synthesized into a new model ‘the compounding risk and protection model.’ This model proposes that the balance between risk factors (i.e., older age, pre-existing traditional CVD risk factors and shared biologic pathways for CVD and cancer such as inflammation, as well as treatment-related and lifestyle toxicity) and potential protection factors (i.e., lifelong non-smoking, regular physical activity, a healthy diet rich in fruits and vegetables, and management of body weight and stress, heart failure therapy) determine the individual risk of CVD morbidity and mortality after diagnosis of early breast cancer.

Figure 2: Compounding risk and protection model

The effect of an aerobic exercise session 24 h prior to each doxorubicin treatment for breast cancer on markers of cardiotoxicity and treatment symptoms: a RCT

Original Research Paper
Kirkham AA, Eves ND, Shave RE, Bland KA, Bovard J, Gelmon KA, Virani SA, McKenzie DC, Stöhr EJ, Warburton DER, Campbell KL
Breast Cancer Research and Treatment 2018;167(3):719-29

In rodents, a single exercise bout performed 24 h prior to a single doxorubicin treatment provides cardio-protection. This study investigated whether performing this intervention prior to every doxorubicin treatment for breast cancer reduced subclinical cardiotoxicity and treatment symptoms.

Twenty-four women with early stage breast cancer were randomly assigned to perform a 30-min, vigorous-intensity treadmill bout 24 h prior to each of four doxorubicin-containing chemotherapy treatments or to usual care. Established echocardiographic and circulating biomarkers of subclinical cardiotoxicity, as well as blood pressure and body weight were measured before the first and 7–14 days after the last treatment. The Rotterdam symptom checklist was used to assess patient-reported symptoms.

The exercise and usual care groups did not differ in the doxorubicin-related change in longitudinal strain, twist, or cardiac troponin. However, the four total exercise bouts prevented changes in hemodynamics (increased cardiac output, resting heart rate, decreased systemic vascular resistance, p < 0.01) and reduced body weight gain, prevalence of depressed mood, sore muscles, and low back pain after the last treatment (p < 0.05) relative to the usual care group. No adverse events occurred. Conclusions An exercise bout performed 24 h prior to every doxorubicin treatment did not have an effect on markers of subclinical cardiotoxicity, but had a positive systemic effect on hemodynamics, musculoskeletal symptoms, mood, and body weight in women with breast cancer. A single exercise bout prior to chemotherapy treatments may be a simple clinical modality to reduce symptoms and weight gain among women with breast cancer.

Rationale and Design of the Caloric Restriction and Exercise protection from Anthracycline Toxic Effects (CREATE) Study: A 3-arm Parallel Group Phase II Randomized Controlled Trial in Early Breast Cancer

Protocol Paper
1. Kirkham AA, Paterson DI, Prado CM, Mackey JM, Courneya KS, Pituskin E, Thompson RB
BMC Cancer, in press

Background: Anthracycline chemotherapy agents are commonly used to treat breast cancer, but also result in cardiac injury, and potentially detrimental effects to vascular and skeletal muscle. Preclinical evidence demonstrates that exercise and caloric restriction can independently reduce anthracycline-related injury to the heart as well as cancer progression, and may be promising short-term strategies prior to treatment administration. For women with breast cancer, a short-term strategy may be more feasible and appealing, as maintaining regular exercise training or a diet throughout chemotherapy can be challenging due to treatment symptoms and psychosocial distress.
Methods: The Caloric Restriction and Exercise protection from Anthracycline Toxic Effects (CREATE) study will determine whether acute application of these interventions shortly prior to receipt of each treatment can reduce anthracycline-related toxicity to the heart, aorta, and skeletal muscle. Fifty-six women with early stage breast cancer scheduled to receive anthracycline treatment will be randomly assigned to one of three groups who will: 1) perform a single, 30-minute, vigorous-intensity, aerobic exercise session 24 hours prior to each anthracycline treatment; 2) consume a prepared diet reduced to 50% of caloric needs for 48 hours prior to each anthracycline treatment; or 3) receive usual cancer care. The primary outcome is magnetic resonance imaging (MRI) derived left ventricular ejection fraction reserve (peak exercise LVEF – resting LVEF) at the end of anthracycline treatment. Secondary outcomes include MRI-derived measures of cardiac, aortic and skeletal muscle structure and function, circulating NT-proBNP, cardiorespiratory fitness and treatment symptoms. Exploratory outcomes include quality of life, fatigue, tumor size (only in neoadjuvant patients), oxidative stress and antioxidants, as well as clinical cardiac or cancer outcomes. MRI, exercise tests, and questionnaires will be administered before, 2-3 weeks after the last anthracycline treatment, and one-year follow-up.
Discussion: The proposed lifestyle interventions are accessible, low cost, drug-free potential methods for mitigating anthracycline-related toxicity. Reduced toxic effects on the heart, aorta and muscle are very likely to translate to short and long-term cardiovascular health benefits, including enhanced resilience to the effects of subsequent cancer treatment (e.g., radiation, trastuzumab) aging, and infection.
Trial registration: ClinicalTrials.gov NCT03131024; 4/21/18.

Predictors of attendance to an oncologist-referred exercise program for women with breast cancer

Original Research Paper
Bland KA, Neil-Sztramko SE, Kirkham AA, Bonsignore A, Van Patten CL, McKenzie DC, Gelmon KA, Campbell KL
Supportive Care in Cancer 2018;26(9):3297-3306

While exercise is associated with numerous benefits in women with breast cancer, adherence to exercise training concurrent to cancer treatment is challenging. We aimed to identify predictors of attendance to an oncologist-referred exercise program offered during and after adjuvant breast cancer treatment.

Women with early-stage breast cancer receiving chemotherapy (n = 68) enrolled in the Nutrition and Exercise During Adjuvant Treatment (NExT) study. Supervised aerobic and resistance exercise was prescribed three times per week during treatment, then one to two times per week for 20 additional weeks. Predictors of attendance were identified using multivariate linear regression for three phases of the intervention, including during (1) adjuvant chemotherapy, (2) radiation, and (3) 20-weeks post-treatment.

Higher baseline quality of life (QoL) predicted higher attendance during chemotherapy (β = 0.51%, 95 CI: 0.09, 0.93) and radiation (β = 0.85%, 95 CI: 0.28, 1.41), and higher QoL, measured at the end of treatment, predicted higher attendance post-treatment (β = 0.81%, 95 CI: 0.34, 1.28). Being employed pre-treatment (β = 34.08%, 95 CI: 5.71, 62.45) and a personal annual income > $80,000 (β = 32.70%, 95 CI: 0.85, 64.55) predicted higher attendance during radiation. Being divorced, separated or widowed (β = - 34.62%, 95 CI: - 56.33, - 12.90), or single (β = - 25.38%, 95 CI: - 40.64, - 10.13), relative to being married/common-law, and undergoing a second surgery (β = - 21.37%, 95 CI: - 33.10, - 9.65) predicted lower attendance post-treatment.

Demographic variables, QoL, and receipt of a second surgery significantly predicted attendance throughout the NExT supervised exercise program. These results may help identify individuals with exercise adherence challenges and improve the design of future interventions, including optimizing the timing of program delivery.

Adjuvant chemotherapy; Breast neoplasm; Exercise training; Radiation; Resistance training

Exercise Prescription and Adherence for Breast Cancer: One Size Does Not FITT All

Original Research Paper
Amy A. Kirkham, Alis Bonsignore, Kelcey A. Bland, Donald C. McKenzie, Karen A Gelmon, Cheri L Van Patten, Kristin L Campbell
Medicine & Science in Sports & Exercise, in press, DOI: 10.1249/MSS.0000000000001446

Purpose: To prospectively assess adherence to oncologist-referred, exercise programming consistent with current recommendations for cancer survivors among women with early breast cancer across the trajectory of adjuvant treatment.

Methods: Sixty-eight women participated in supervised, hour-long, moderate-intensity, aerobic and resistance exercise 3x/week during adjuvant chemotherapy ± radiation, with a step-down in frequency for 20 additional weeks. Adherence to exercise frequency (i.e. attendance), intensity, and time/duration, and barriers to adherence were tracked and compared during chemotherapy versus radiation, and during treatment (chemotherapy plus radiation, if received) versus after treatment.

Results: Attendance decreased with cumulative chemotherapy dose (cycles 1-2 vs. cycles 3-8, cycle 3 vs. cycles 7-8, all P ≤ 0.05), and was lower during chemotherapy than radiation (64 ± 25 vs. 71 ± 32%, P = 0.02), and after treatment than during treatment (P < 0.01). Adherence to exercise intensity trended toward being higher during chemotherapy than radiation (69 ± 23 vs. 51 ± 38%, P = 0.06), and was higher during than after treatment (P = 0.01). Adherence to duration did not differ with treatment. Overall adherence to the resistance prescription was poor, but was higher during chemotherapy than radiation (57 ± 23 vs. 34 ± 39%, P < 0.01), and was not different during than after treatment. The most common barriers to attendance during treatment were cancer-related (e.g. symptoms, appointments), and after treatment were life-related (e.g. vacation, work).

Conclusion: Adherence to supervised exercise delivered in a real-world clinical setting varies among breast cancer patients and across the treatment trajectory. Behavioral strategies and individualization in exercise prescriptions to improve adherence are especially important for later chemotherapy cycles, after treatment, and for resistance exercise.

Does cancer affect cardiac function prior to cancer therapy exposure?

Kirkham AA, Pituskin E, Paterson DI.
Canadian Journal of Cardiology 2018; 34(3):234-5

A longitudinal study of the association of clinical indices of cardiovascular autonomic function with breast cancer treatment and exercise training

Original Research Paper
Kirkham AA, Lloyd MG, Claydon VE, Gelmon KA, McKenzie DC, Campbell KL
The Oncologist 2019;24(2):273-84

Background: Cardiovascular autonomic dysfunction is an early marker for cardiovascular disease. Anthracycline chemotherapy and left-sided radiation for breast cancer are associated with negative autonomic function changes. Study objectives were to characterize changes in, and the association of exercise training with clinical indices of cardiovascular autonomic function across the trajectory of breast cancer therapy. Patients and Methods: Seventy-three patients receiving adjuvant chemotherapy participated to varying degrees in supervised aerobic and resistance exercise during chemotherapy±radiation and for 20 weeks after. Resting heart rate (HRrest) and blood pressure were measured weekly during chemotherapy. HRrest, exercise heart rate recovery (HRrecovery) and aerobic fitness, were measured at enrolment, end of chemotherapy±radiation, 10 and 20 weeks post-treatment. Results: During chemotherapy, HRrest increased in a parabolic manner within a single treatment and with increasing treatment dose, while systolic and diastolic blood pressure decreased linearly across treatments. Tachycardia and hypotension were present in 32-51% of participants. Factors associated with weekly changes during chemotherapy included receiving anthracyclines or trastuzumab, days since last treatment, hematocrit, and exercise attendance. Receipt of anthracyclines, trastuzumab and left-sided radiation individually predicted impairments of HRrest and HRrecovery during chemotherapy±radiation, while aerobic fitness change and ≥twice weekly exercise attendance predicted improvement. By 10 weeks post-treatment, HRrest and blood pressure were not different from pre-chemotherapy. Conclusion: In this study, chemotherapy resulted in increased HRrest and tachycardia, as well as decreased blood pressure and hypotension. Anthracyclines, trastuzumab, and left-sided radiation were associated with HRrest elevations, and impairments of HRrecovery, while exercise training ≥twice/week appeared to mitigate these changes.

Protective effects of acute exercise prior to doxorubicin on cardiac function of breast cancer patients: A proof-of-concept RCT

Original Research Paper
Kirkham AA, Shave RE, Bland KA, Bovard JM, Eves ND, Gelmon KA, McKenzie DC, Virani SA, Stohr EJ, Warburton DER, Campbell KL
International Journal of Cardiology 2017; 245:263-70


Preclinical studies have reported that a single treadmill session performed 24 h prior to doxorubicin provides cardio-protection. We aimed to characterize the acute change in cardiac function following an initial doxorubicin treatment in humans and determine whether an exercise session performed 24 h prior to treatment changes this response.


Breast cancer patients were randomized to either 30 min of vigorous-intensity exercise 24 h prior to the first doxorubicin treatment (n = 13), or no vigorous exercise for 72 h prior to treatment (control, n = 11). Echocardiographically-derived left ventricular volumes, longitudinal strain, twist, E/A ratio, and circulating NT-proBNP, a marker of later cardiotoxicity, were measured before and 24–48 h after the treatment.


Following treatment in the control group, NT-proBNP, end-diastolic and stroke volumes, cardiac output, E/A ratio, strain, diastolic strain rate, twist, and untwist velocity significantly increased (all p ≤ 0.01). Whereas systemic vascular resistance (p < 0.01) decreased, and ejection fraction (p = 0.02) and systolic strain rate (p < 0.01) increased in the exercise group only. Relative to control, the exercise group had a significantly lower NT-proBNP (p < 0.01) and a 46% risk reduction of exceeding the cut-point used to exclude acute heart failure.


The first doxorubicin treatment is associated with acutely increased NT-proBNP, echocardiographic parameters of myocardial relaxation, left ventricular volume overload, and changes in longitudinal strain and twist opposite in direction to documented longer-term changes. An exercise session performed 24 h prior to treatment attenuated NT-proBNP release and increased systolic function. Future investigations should verify these findings in a larger cohort and across multiple courses of doxorubicin.

Effectiveness of oncologist-referred exercise and healthy eating programming as a part of supportive adjuvant care for early breast cancer

Original Research Paper
Kirkham AA, Van Patten C, Gelmon KA, McKenzie DC, Bonsignore A, Bland KA, Campbell KL
The Oncologist 2017;22:1–11

Background. Randomized trials have established efficacy of supervised exercise training during chemotherapy for breast cancer for numerous health outcomes. The pur- pose of this study was to assess reach, effectiveness, maintenance, and implementation of an evidence-based exercise and healthy eating program offered within an adjuvant care setting.

Subjects, Materials, and Methods. Women receiving adjuvant chemotherapy for breast cancer were given a prescription by their oncologist to participate in the Nutrition and Exercise dur- ing Adjuvant Treatment (NExT) program. The NExT program consisted of supervised, moderate-intensity, aerobic and resist- ance exercise three times a week during adjuvant therapy, fol- lowed by a step-down in supervised sessions per week for 20 additional weeks, plus one group-based healthy eating session. Usual moderate-to-vigorous physical activity (MVPA) and health-related quality of life (HRQoL) were assessed by

questionnaire at baseline, program completion, and one year later, along with measures of satisfaction and safety.
Results. Program reach encompassed referral of 53% of eligible patients, 78% uptake (n 5 73 enrolled), and 78% retention for the 45.0 6 8.3-week program. During the program, MVPA increased (116 6 14 to 154 6 14 minutes per week, p 5 .014) and HRQoL did not change. One year later, MVPA (171 6 24 minutes per week,p5.014)andHRQoL(4461to4961,p<.001)weresig- nificantly higher than baseline. Exercise adherence was 60% 6 26% to three sessions per week during treatment. No major adverse events occurred and injury prevalence did not change rel- ative to baseline. Participants were highly satisfied.

Conclusion. This oncologist-referred exercise and healthy eating supportive-care program for breast cancer patients receiving chemotherapy was safe, successful in reaching oncologists and patients, and effective for improving MVPA and maintaining HRQoL.

Implications for Practice: Despite evidence that exercise is both safe and efficacious at improving physical fitness, quality of life, and treatment side effects for individuals with cancer, lifestyle programming is not offered as standard of cancer care. This study describes an oncologist-referred, evidence-based exercise and healthy eating program offered in collaboration with a university as supportive care to women with breast cancer receiving chemotherapy. The program was well received by oncologists and patients, safe, and relatively inexpensive to operate. Importantly, there was a significant positive impact on physical activity levels and health-related quality of life lasting for 2 years after initiation of therapy.

Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT

Original Research Paper
Campbell KL, Kam JWY, Liu Ambrose T, Handy TC, Lim H, Hayden S, Hsu L, Neil-Sztramko SE, Kirkham AA, Gotay CC, McKenzie DC, Boyd LA
Psycho-Oncology, in press


Change in cognitive ability is a commonly reported side effect by breast cancer survivors (BCS). The underlying etiology of cognitive complaints is unclear and to date there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial (RCT) tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal BCS.


Women, age 40-65 years, postmenopausal, stage I-IIIA breast cancer, and who self-reported cognitive dysfunction following chemotherapy treatment were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (FACT-Cog), objective neuropsychological testing and functional magnetic resonance imaging (fMRI) at baseline and 24-weeks.


Compared to CON, EX had a reduced time to complete a processing speed test (Trail Making Task-A) (-14.2 seconds, p < 0.01; effect size [ES] 0.35). Compared to CON, there was no improvement in self-reported cognitive function and effect sizes were small Interestingly, lack of between-group differences in Stroop behavioral performance were accompanied by functional changes in several brain regions of interest in EX compared to CON at 24-weeks.


These findings provide preliminary proof-of-concept results for the potential of aerobic exercise to improve cancer-related cognitive impairment, and will serve to inform the development of future trials.

Fee-for-service cancer rehabilitation programs improve health-related quality of life

Original Research Paper
A.A. Kirkham, S.E. Neil-Sztramko, J. Morgan, S. Hodson, S. Weller, T. McRae, K.L. Campbell
Current Oncology, 2016;23(4):233-40.

Background Rigorously applied exercise interventions undertaken in a research setting result in improved health- related quality of life (HRQoL) in cancer survivors, but research to demonstrate effective translation of that research to practice is needed. The objective of the present study was to determine the effect of fee-for-service cancer rehabilitation programs in the community on HRQoL and on self-reported physical activity and its correlates.

Methods After enrolment and 17 ± 4 weeks later, new clients (n = 48) to two fee-for-service cancer rehabilitation programs completed the 36-Item Short Form Health Survey (RAND-36: RAND Corporation, Santa Monica, CA, U.S.A.), the Godin Leisure-Time Exercise Questionnaire, and questions about physical activity correlates. Normal fee-for-service operations were maintained, including a fitness assessment and individualized exercise programs supervised in a group or one-on-one setting, with no minimum attendance required. Fees were associated with the assessment and with each exercise session.

Results Of the 48 participants, 36 (75%) completed both questionnaires. Improvements in the physical functioning, role physical, pain, and energy/fatigue scales on the RAND-36 exceeded minimally important differences and were of a magnitude similar to improvements reported in structured, rigorously applied, and free research interventions. Self-reported levels of vigorous-intensity (p = 0.021), but not moderate-intensity (p = 0.831) physical activity increased. The number of perceived barriers to exercise (p = 0.035) and the prevalence of fatigue as a barrier (p = 0.003) decreased. Exercise self-efficacy improved only in participants who attended 11 or more sessions (p = 0.002). Exercise enjoyment did not change (p = 0.629).

Conclusions Enrolment in fee-for-service cancer rehabilitation programs results in meaningful improvements in HRQoL comparable to those reported by research interventions, among other benefits. The fee-for-service model could be an effective model for delivery of exercise to more cancer survivors.

Effective translation of research to practice: Hospital-based rehabilitation program improves health-related physical fitness and quality of life of cancer survivors

Original Research Paper
Kirkham AA, Klika RJ, Ballard TM, Downey P, Campbell KL
Journal of the National Comprehensive Cancer Network 2016;14(12):1555-62

Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors

Review Paper
Kirkham AA, Bland K, Sayyari S, Campbell KL, Davis M
Current Oncology Reports 2016;18(2):12

Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors.

Utility of equations to estimate peak oxygen uptake and work rate from a sixminute walk test in patients with COPD in a clinical setting.

Original Research PaperReview Paper
Kirkham AA, Pauhl KE, Elliot RM, Scott JA, Doria SC, Davidson HK, Campbell KL, Camp PG
Journal of Cardiopulmonary Rehabilitation and Prevention 2015;35(6):431-8.


To determine the utility of equations that use the 6-minute walk test (6MWT) results to estimate peak oxygen uptake ((Equation is included in full-text article.)o2) and peak work rate with chronic obstructive pulmonary disease (COPD) patients in a clinical setting.


This study included a systematic review to identify published equations estimating peak (Equation is included in full-text article.)o2 and peak work rate in watts in COPD patients and a retrospective chart review of data from a hospital-based pulmonary rehabilitation program. The following variables were abstracted from the records of 42 consecutively enrolled COPD patients: measured peak (Equation is included in full-text article.)o2 and peak work rate achieved during a cycle ergometer cardiopulmonary exercise test, 6MWT distance, age, sex, weight, height, forced expiratory volume in 1 second, forced vital capacity, and lung diffusion capacity. Estimated peak (Equation is included in full-text article.)o2 and peak work rate were estimated from 6MWT distance using published equations. The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work to prescribe aerobic exercise intensities of 60% and 80% was calculated.


Eleven equations from 6 studies were identified. Agreement between estimated and measured values was poor to moderate (intraclass correlation coefficients = 0.11-0.63). The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work rate to prescribe exercise intensities of 60% and 80% of measured values ranged from mean differences of 12 to 35 and 16 to 47 percentage points, respectively.


There is poor to moderate agreement between measured peak (Equation is included in full-text article.)o2 and peak work rate and estimations from equations that use 6MWT distance, and the use of the estimated values for prescription of aerobic exercise intensity would result in large error. Equations estimating peak (Equation is included in full-text article.)o2 and peak work rate are of low utility for prescribing exercise intensity in pulmonary rehabilitation programs.

The utility of cardiac stress testing for detection of cardiovascular disease in breast cancer survivors: A systematic review

Review Paper
Kirkham AA, Virani SA, Campbell KL
International Journal of Women’s Health 2015;7:127-140.



Heart function tests performed with myocardial stress, or “cardiac stress tests”, may be beneficial for detection of cardiovascular disease. Women who have been diagnosed with breast cancer are more likely to develop cardiovascular diseases than the general population, in part due to the direct toxic effects of cancer treatment on the cardiovascular system. The aim of this review was to determine the utility of cardiac stress tests for the detection of cardiovascular disease after cardiotoxic breast cancer treatment.


Systematic review.


Medline and Embase were searched for studies utilizing heart function tests in breast cancer survivors. Studies utilizing a cardiac stress test and a heart function test performed at rest were included to determine whether stress provided added benefit to identifying cardiac abnormalities that were undetected at rest within each study.


Fourteen studies were identified. Overall, there was a benefit to utilizing stress tests over tests at rest in identifying evidence of cardiovascular disease in five studies, a possible benefit in five studies, and no benefit in four studies. The most common type of stress test was myocardial perfusion imaging, where reversible perfusion defects were detected under stress in individuals who had no defects at rest, in five of seven studies of long-term follow-up. Two studies demonstrated the benefit of stress echocardiography over resting echocardiography for detecting left ventricular dysfunction in anthracycline-treated breast cancer survivors. There was no benefit of stress cardiac magnetic resonance imaging in one study. Two studies showed a potential benefit of stress electrocardiography, whereas three others did not.


The use of cardiac stress with myocardial perfusion imaging and echocardiography may provide added benefit to tests performed at rest for detection of cardiovascular disease in breast cancer survivors, and merits further research.

Assessment of health-related physical fitness in community-based cancer rehabilitation

Original Research Paper
Kirkham AA, Neil SE, Morgan J, Hodson S, McRae T, Campbell KL
Supportive Care in Cancer 2015; in press doi:10.1007/s00520-014-2599-z

ABSTRACT Assessment of physical fitness is important in order to set goals, appropriately prescribe exercise, and monitor change over time. This study aimed to determine the utility of a standardized physical fitness assessment for use in cancer-specific, community-based exercise programs.
Tests anticipated to be feasible and suitable for a community setting and a wide range of ages and physical function were chosen to measure body composition, aerobic fitness, strength, flexibility, and balance. Cancer Exercise Trainers/Specialists at cancer-specific, community-based exercise programs assessed new clients (n = 60) at enrollment, designed individualized exercise programs, and then performed a re-assessment 3-6 months later (n = 34).
Resting heart rate, blood pressure, body mass index, waist circumference, handgrip strength, chair stands, sit-and-reach, back scratch, single-leg standing, and timed up-and-go tests were considered suitable and feasible tests/measures, as they were performed in most (≥88 %) participants. The ability to capture change was also noted for resting blood pressure (-7/-5 mmHg, p = 0.02), chair stands (+4, p < 0.01), handgrip strength (+2 kg, p < 0.01), and sit-and-reach (+3 cm, p = 0.03). While the submaximal treadmill test captured a meaningful improvement in aerobic fitness (+62 s, p = 0.17), it was not completed in 33 % of participants. Change in mobility, using the timed up-and-go was nominal and was not performed in 27 %.
Submaximal treadmill testing, handgrip dynamometry, chair stands, and sit-and-reach tests were feasible, suitable, and provided meaningful physical fitness information in a cancer-specific, community-based, exercise program setting. However, a shorter treadmill protocol and more sensitive balance and upper body flexibility tests should be investigated.

Exercise prevention of cardiovascular disease in breast cancer survivors

Review Paper
Kirkham AA, Davis MK
Journal of Oncology special issue: “Cancer and Cardiovascular Disease: The Complex Labyrinth” 2015; Article ID 917606, in press

Thanks to increasingly effective treatment, breast cancer mortality rates have significantly declined over the past few decades. Following the increase in life expectancy of women diagnosed with breast cancer, it has been recognized that these women are at an elevated risk for cardiovascular disease due in part to the cardiotoxic side effects of treatment. This paper reviews evidence for the role of exercise in prevention of cardiovascular toxicity associated with chemotherapy used in breast cancer, and in modifying cardiovascular risk factors in breast cancer survivors. There is growing evidence indicating that the primary mechanism for this protective effect appears to be improved antioxidant capacity in the heart and vasculature and subsequent reduction of treatment-related oxidative stress in these structures. Further clinical research is needed to determine whether exercise is a feasible and effective nonpharmacological treatment to reduce cardiovascular morbidity and mortality in breast cancer survivors, to identify the cancer therapies for which it is effective, and to determine the optimal exercise dose. Safe and noninvasive measures that are sensitive to changes in cardiovascular function are required to answer these questions in patient populations. Cardiac strain, endothelial function, and cardiac biomarkers are suggested outcome measures for clinical research in this field.

Lateral trunk lean gait modification increases the energy cost of treadmill walking in those with knee osteoarthritis

Original Research Paper
• Takacs J, Kirkham AA, Brown J, Marriot E, Monkman D, Havey J, Hung S, Campbell KL, Hunt MH
Osteoarthritis and Cartilage 2014;22(2):203-9

Objective: To compare the energy expenditure of increased lateral trunk lean walking e a suggested method of reducing medial compartment knee joint load e compared to normal walking in a population of older adults with medial knee osteoarthritis (OA).
Method: Participants completed two randomly-presented treadmill walking conditions: 15 min of normal walking or walking with ten degrees of peak lateral trunk lean. Lateral trunk lean angle was displayed in front of the participant in real-time during treadmill conditions. Energy expenditure (VO2 and METs), heart rate (HR), peak lateral trunk lean angle, knee pain and perceived exertion were measured and differences between conditions were compared using paired t-tests.

Results: Twelve participants (five males, mean (standard deviation (SD)) age 64.1 (9.4) years, body mass index (BMI) 28.3 (4.9) kg/m2) participated. All measures were significantly elevated in the lateral trunk lean condition (P < 0.008), except for knee pain (P  0.22). Oxygen consumption (VO2) was, on average 9.5% (95% CI 4.2e14.7%) higher, and HR was on average 5.3 beats per minute (95% CI 1.7e9.0 bpm) higher during increased lateral trunk lean walking.

Conclusion: Increased lateral trunk lean walking on a treadmill resulted in significantly higher levels of steady-state energy expenditure, HR, and perceived exertion, but no difference in knee pain. While increased lateral trunk lean has been shown to reduce biomechanical measures of joint loading relevant to OA progression, it should be prescribed with caution given the potential increase in energy expen- diture experienced when it is employed.

Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer: A systematic review

Review Paper
• Neil SE, Kirkham AA, Hung SH, Niksirat N, Nishikawa K, Campbell KL
Journal of Physiotherapy 2014;60(4):189-200

Question: What are typical values of physical function for women diagnosed with breast cancer and how do these compare to normative data? Design: Systematic review with meta-analysis. Participants: Women diagnosed with breast cancer who were before, during or after treatment. Outcome measures: Physical function was divided into three categories: aerobic capacity, upper and lower extremity muscular fitness, and mobility. Measures of aerobic capacity included field tests (6-minute walk test, 12- minute walk tests, Rockport 1-mile test, and 2-km walk time) and submaximal/maximal exercise tests on a treadmill or cycle ergometer. Measures of upper and lower extremity muscular fitness included grip strength, one repetition maximum (bench, chest or leg press), muscle endurance tests, and chair stands. The only measure of mobility was the Timed Up and Go test. Results: Of the 1978 studies identified, 85 were eligible for inclusion. Wide ranges of values were reported, reflecting the range of ages, disease severity, treatment type and time since treatment of participants. Aerobic fitness values were generally below average, although 6-minute walk time was closer to population norms. Upper and lower extremity strength was lower than population norms for women who were currently receiving cancer treatment. Lower extremity strength was above population norms for women who had completed treatment. Conclusion: Aerobic capacity and upper extremity strength in women diagnosed with breast cancer are generally lower than population norms. Assessment of values for lower extremity strength is less conclusive. As more research is published, expected values for sub-groups by age, treatment, and co- morbidities should be developed.

Comparison of aerobic exercise intensity prescription methods in breast cancer

Original Research Paper
• Kirkham AA, Campbell KL, McKenzie DC
Medicine & Science in Sports & Exercise 2013;45(8):1443-50

Introduction: Exercise plays an important role in cancer rehabilitation, but a precise prescription of exercise intensity is required to maximize the benefits of this intervention. It is unknown whether different methods of prescribing aerobic exercise intensity achieve the same intensity. Breast cancer treatments may alter exercise response and thereby may affect the accuracy of these methods. Purpose: The purpose of this study was to compare the accuracy and achieved intensity of four common methods of prescribing exercise intensity within and between breast cancer patients recently finished chemotherapy (n = 10), survivors finished treatment (n = 10), and healthy controls (n = 10). Methods: The methods compared were as follows: the American College of Sports Medicine’s metabolic equation for treadmill walking (METW), heart rate reserve (HRR), direct heart rate (DIRECT HR), and RPE. The methods were used to prescribe 60% oxygen consumption reserve (V ̇ O2R) in four randomly assigned 10-min periods of treadmill walking with expired gas collection to evaluate 1) achieved intensity (measured % V ̇ O2R) and 2) accuracy (defined as: [60% V ̇ O2R–achieved intensity]). Results: The accuracy of the methods was not equivalent across groups (P = 0.04). HRR and METW did not differ across groups and were most accurate in patients. HRR, METW, and DIRECT HR were all more accurate than RPE in survivors (P e 0.01). RPE was the least accurate in all groups. The accuracy of DIRECT HR was much lower in patients than that in survivors and controls (P e 0.01). Conclusions: The four methods of exercise intensity prescription varied in accuracy in prescribing 60% V ̇O2R and did not achieve equivalent exercise intensities within breast cancer patients, survivors, and healthy controls. HRR and METW were the most accurate methods for exercise intensity prescription in breast cancer patients and survivors.

Feasibility of a lifestyle intervention on body weight and serum biomarkers in breast cancer survivors with overweight and obesity

Original Research Paper
• Campbell KL, Van Patten CL, Neil SE, Kirkham AA, Gotay CC, Gelmon KA, McKenzie DC
Journal of the Academy of Nutrition and Dietetics, 2012;112(4), 559-67.

Physical inactivity and being overweight or obese are lifestyle factors that put breast cancer survivors at a higher risk for a cancer recurrence and/or development of other chronic diseases. Despite this, there is limited research that has identified effective lifestyle interventions aimed specifically at weight loss in breast cancer survivors. This pilot study is a single-arm experimental pre–post test design, conducted from Novem- ber 2009 to July 2010, that tested the efficacy of a 24-week group-based lifestyle inter- vention modeled on the Diabetes Prevention Program in early stage breast cancer sur- vivors (N􏰁14). The intervention included 16 diet sessions led by a registered dietitian and 150 min/wk of moderate-to-vigorous exercise. Study outcome measures were com- pleted at baseline, 24, and 36 weeks (nonintervention follow-up). The primary outcome was change in body weight, and secondary outcomes were change in body composition, aerobic fitness, dietary intake, and blood biomarkers. Overall, participants were post- menopausal women aged 54.6􏰂8.3 years with obesity (body mass index 30.1􏰂3.6), and had completed adjuvant cancer treatment 2 years prior. Results showed an average weight loss of 3.8􏰂5.0 kg and a decrease in body mass index, percent body fat, and waist and hip circumferences at 24 weeks and an additional mean weight loss of 0.8􏰂1.2 kg at 36 weeks. In exploratory analysis, participants who lost 􏰃7% body weight were older and attended a greater percentage of diet and supervised exercise sessions. There were no significant changes in any of the blood biomarkers at 24 and 36 weeks; however, the results provide a measure of expected effect size for future research studies. This pilot study demonstrated the efficacy of a lifestyle intervention based on the Diabetes Pre- vention Program in early stage breast cancer survivors and represents an innovative clinical intervention for dietetics practitioners to address the unmet need for programs.