Peak oxygen consumption (V˙O2peak) or cardiorespiratory fitness represents the integrative ability of the heart to deliver oxygen to skeletal muscle and vital organs. Numerous epidemiological studies have demonstrated that V˙O2peak is a powerful, independent predictor of cardiovascular disease and survival. Moreover, V˙O2peak is emerging as an important risk marker and tool to assess cardiac risk in breast cancer patients (9). A recent meta-analysis has shown that V˙O2peak is lower in breast cancer survivors compared with healthy, sedentary controls (11). The reason for this V˙O2peak decline in breast cancer is multifactorial. Breast cancer therapies, such as anthracyclines and radiotherapy, can adversely impact cardiac function and components of the cascade to reduce V˙O2peak. In addition, molecularly targeted therapies such as trastuzumab, used in approximately 20% of breast cancer patients with an amplification of the human epidermal growth factor rector type 2 (14), is also associated with cardiac dysfunction (13). Lastly, breast cancer and subsequent treatment can have significant side effects, such as fatigue (3) that can influence an individual’s ability and desire to perform physical activities, which, in turn, may impact cardiac performance and V˙O2peak.
Several clinical trials of breast cancer patients have shown that exercise training, during chemotherapy, attenuates the decline in V˙O2peak that results from reductions in physical activity (4–6). It is important to note that studies measuring V˙O2peak in breast cancer patients have not focused on highly trained aerobic athletes. Consequently, little is known about baseline values or the trajectory of V˙O2peak for athletes exposed to radiation and cardiotoxic chemotherapy. Furthermore, there has been little study of how exercise training may mitigate the declines in V˙O2peak and cardiac function during treatment. To this end, we present the case of an aerobically trained, multisport, female athlete diagnosed with locally advanced breast cancer and focus on change in V˙O2peak and cardiac function as well as her exercise training regimen through the course of her therapy and recovery.
The individual (A.L.) is an otherwise very healthy 39-yr-old female. Her prior medical history was notable only for a diagnosis of hypothyroidism for which she was treated with Armour Thyroid. She is an extremely active recreational athlete participating in year-round activities, including primarily mountain biking and skate-style cross-country skiing.
Her presenting breast cancer symptom was a palpable lump in her left breast that she was aware of for approximately 1 yr. Eventually, A.L. experienced discomfort radiating to her shoulders and clavicle area. She underwent testing that included mammography and ultrasound imaging, which showed an area of hypoechoic breast tissue with enlarged intramammary nodes. Imaging was followed by a biopsy of the breast and intramammary node revealing invasive ductal cancer, nuclear grade 3, estrogen and progesterone receptors negative, and human epidermal growth factor receptor 2 positive by immunohistochemistry. The breast cancer was clinical staging IIIc, and a second opinion regarding diagnosis was confirmatory. She underwent staging computed tomography scanning, which was negative for distant metastasis.
A chest port was placed, and 4 cycles of neoadjuvant chemotherapy (doxorubicin [Adriamycin], cyclophosphamide) (A/C) with Neulasta support (within 24 h) was given over the course of 8 wk. Paclitaxel and trastuzumab were administered weekly for 12 wk after completion of A/C. Trastuzumab, alone, was then continued every 3 wk for 1 yr.
Chemotherapy was followed by bilateral mastectomies, left axillary dissection, and bilateral expander placement. Approximately 3 months after surgery, external beam radiation therapy was provided to the left chest and axilla. Radiation therapy for a total dose of 5.4 Gy in 28 fractions was delivered over the course of 37 d. Nearly 4 months after completing radiation therapy, A.L. experienced tight “cording” of the left-sided upper extremity and severe lymphedema, which necessitated postponing her implant exchange and breast reconstruction surgery. Treatment included physical therapy, focusing on stretching and range of motion exercises, 3 to 4 d·wk−1 for 4 wk. In addition, lymphatic drainage procedures were used, and wrapping and compression garments were used. A.L. underwent breast reconstruction surgery, followed 2 months later by lymph node transfer surgery.
Informed written consent for testing was obtained from the subject, and A.L. agreed to the use of her clinical data for this case study. A symptom-limited cardiopulmonary exercise tolerance test (CPET) was performed to determine V˙O2peak at multiple time points during and after cancer treatment (Fig. 1). We used the Bruce treadmill protocol (1), and expired gas was measured by indirect calorimetry continuously with a Medgraphic Ultima CPX™ metabolic stress testing system (Saint Paul, MN). The highest average 15-s value for V˙O2 was defined as V˙O2peak. RER was determined, and HR was monitored by electrocardiogram. A CPET was performed at five different time points: 1) at diagnosis of breast cancer and before initiating chemotherapy, 2) after completion of chemotherapy (5 months postdiagnosis), 3) 2.5 months after bilateral mastectomy surgery (9 months postdiagnosis), 4) immediately after radiation therapy (11 months postdiagnosis), and 5) recovery (32 months postdiagnosis) (Fig. 1). Guidance regarding exercise prescription (i.e., intensity, duration, and frequency) vis-à-vis oncologic therapies was provided after each of the stress tests.
Rest measures of left ventricular ejection fraction (LVEF) were obtained from clinical echocardiography at the following three time points: 1) before initiating chemotherapy, 2) after completing chemotherapy, and 3) after completing radiation therapy. Hemoglobin values were recorded at each of the time points that cardiac function was measured in addition to after mastectomy surgery.
Exercise training data were extracted from the subject’s daily training log. A.L. recorded the mode and total duration of physical activity. The subject wore a SIGMA SPORT® USA HR monitor (St. Charles, IL) during her exercise sessions, and average HR was recorded. For a particular exercise session, training intensity was calculated by dividing HRpeak achieved on the exercise tolerance test by average exercise training HR. The compendium of physical activities (https://sites.google.com/site/compendiumofphysicalactivities/) was accessed to determine the MET for the different types of exercise performed. MET-minutes per day was calculated by multiplying the time engaged in an activity with the assigned MET value. Thus, a 5-MET activity performed for 30 min would be calculated as follows: 5 MET × 30 min = 150 MET·min.
In the month before her diagnosis, A.L. was exercising (i.e., mountain biking) four to five times per week at a mean intensity of 76% of HRpeak and an estimated mean MET level of 14. The mean MET-minutes per day was 1768 (Fig. 2) (mean MET·min·wk−1 = 7445). At the time of diagnosis of breast cancer and before initiating chemotherapy, V˙O2peak and HR peak were determined to be 50.1 mL O2·min−1·kg−1 and 190 bpm, respectively (Table 1). Her resting LVEF was measured to be 60% to 65%, and her hemoglobin value was on low end of normal at 12.2 g·dL−1. Her LVEF remained 60% to 65% at each subsequent exam. Her hemoglobin remained relatively stable through the study period. In addition, A.L.’s baseline weight was 56.8 kg (body mass index = 25) and remained unchanged throughout the course of treatment and recovery. After the “baseline” CPET, the patient was instructed to exercise at light to moderate intensity and to avoid high-intensity activity (<80% of HRpeak measured at baseline CPET) during AC + T (doxorubicin [Adriamycin], cyclophosphamide, Taxol (paclitaxel)) chemotherapy because of the use cardiotoxic agent, Adriamycin. She was counseled that she could continue but not exceed her usual exercise training volume, as tolerated.
The second CPET was performed after completing chemotherapy (AC + T) and while on trastuzumab. Between the first and the second CPET, A.L. exercised at a much lower intensity than before initiating chemotherapy. This was evidenced by a mean exercise HR of 55% of HRpeak and a mean MET level of 5.6. The mean MET-minutes per day was 590 (mean MET·min·wk−1 = 3047). Activities performed during this time consisted of walking, biking, and yoga. The subject achieved a V˙O2peak of 43 mL O2·min−1·kg−1, which represented a decline of 14% from baseline and was the lowest value obtained during the study period. After the second CPET, exercise training restrictions were removed, and she was allowed to return to normal activity as tolerated. We did not limit exercise intensity during her exposure to trastuzumab, given she had no drop in LVEF during molecularly targeted therapy, and the mechanism for cardiac dysfunction with trastuzumab differs from anthracyclines (7). Future research, however, will be necessary to support this clinical decision.
Between completion of chemotherapy and surgery (bilateral mastectomies with an axillary dissection and expander placement), A.L. exercised at a mean training intensity of 65% of HRpeak and at a mean MET level of 8.3. The mean MET-minutes per day during this period was 654 (mean MET·min·wk−1 = 3529). Activities performed during this period include skate-style cross-country skiing and indoor (spinning-style) cycle ergometer. The subject’s V˙O2peak after surgery was 47 mL O2·min−1·kg−1, which represented a 9% increase over the value obtained at the completion of chemotherapy.
To prevent fatigue, it was recommended that A.L. avoid high-intensity activities and to exercise at a moderate intensity as tolerated during postoperative radiation therapy. Her mean exercise training intensity was 64% of HRpeak, and her mean MET level was 7.9 during radiation therapy. The mean MET-minutes per day was 719 (mean MET·min·wk−1 = 2847). Exercise training during this period consisted primarily of mountain biking and walking. V˙O2peak was 45 mL O2·min−1·kg−1 after completing radiation therapy, which represented a decrease of 2 mL O2·min−1·kg−1 from the measure obtained before radiation therapy.
The time interval between completion of radiation therapy and the final CPET was approximately 21 months. During this time, she underwent lymph node transfer surgery, which necessitated severe activity restrictions for 6 wk with an incremental, gradual return to activity. After the activity restrictions were lifted, she was allowed to resume low level activities of daily living and exercise at a decreased intensity, and volume was allowed after about a month. Approximately 3 months after resuming low-level activity, she was allowed to return to normal exercise duration but at a low intensity. Finally, after approximately 1 month of low-intensity exercise A.L. was allowed to return to her normal exercise duration and intensity. The duration of time from lymph node transfer surgery to when activity restrictions were completely removed was approximately 8 months. In the 5 wk immediately preceding the final CPET, A.L. exercised (primarily skate-style cross-country skiing) at a mean intensity of 79.6% of HRpeak and a mean MET level of 12.6. The mean MET-minutes per day was 1505 (mean MET·min·wk−1 = 5959). The final V˙O2peak measure was 49.2 mL O2·min−1·kg−1, which was a less than 2% decline as compared with baseline or pretreatment values.
To our knowledge, this is the first study to obtain measures of V˙O2peak at the time of diagnosis, through the course of breast cancer therapy and recovery. The most precipitous decline in V˙O2peak, approximately 14%, was observed from initial diagnosis through the completion of chemotherapy. The subject was able to regain 9% of her fitness after chemotherapy, despite an intervening mastectomy. Radiation therapy was associated with an approximately 4% decline in fitness from her postmastectomy surgery. Ultimately, 32 months after diagnosis and 22 months beyond completion of radiation therapy, A.L. regained her pretreatment aerobic fitness levels. The results of this case study suggest that a superiorly fit individual can withstand the rigors of breast cancer therapy and ultimately retain to her pretreatment aerobic capacity.
Changes in fitness mirrored the subject’s volume and intensity of exercise. Exercise training intensity was prescribed based on treatment exposure, specifically the use of anthracyclines. It was recommended that higher-intensity exercise training be avoided during the use of Adriamycin to minimize the risk of myocardial ischemia and, potentially, worsen LVEF. A.L. reported the highest training intensity and duration before her diagnosis. In the month preceding her diagnosis, the subject was mountain biking for up to 4 h·d−1 at a mean intensity of 76% of HRpeak. During chemotherapy, A.L. was advised to avoid high-intensity exercise (<80% HRpeak), although she could maintain exercise volume as tolerated. She reported a mean exercise HR of 55% of HRpeak. Consequently, her mean MET-minutes per day was reduced by two-thirds over base line values. A meta-analysis by Peel et al. (11) reported that V˙O2peak in the postadjuvant setting was 10% lower than pretreatment values. Although the 14% decline in V˙O2peak observed for A.L. was somewhat higher, her baseline value was more than twice that described in the meta-analysis (50.1 vs 24.6 mL O2·min−1·kg−1).
It has previously been shown in breast cancer patients that V˙O2peak is significantly impaired despite preservation of normal cardiac function (9). Certainly, some of the decline in V˙O2peak can be attributed to a decrease in exercise training intensity. Repeat echocardiographic measures revealed that A.L. maintained a normal resting LVEF throughout the course of her oncologic interventions. Her HRpeak values were essentially unchanged over the course of her multiple exercise tolerance tests. In addition, A.L.’s O2 carrying capacity, as reflected by her hemoglobin values, remained unchanged during treatment. This would suggest that declines in aerobic fitness were a result of another aspect the O2 transport system. Anthracyclines, independent of the central effects on the heart, increase the generation of reactive oxygen species resulting in endothelial injury and dysfunction, vascular remodeling, and arterial stiffness all of which could affect oxygen delivery (2). In addition, A.L. likely experienced skeletal muscle dysfunction, given V˙O2peak is a product of central [cardiac output (stroke volume × HR)] and peripheral [arterial − venous O2 difference], with the peripheral component predominately driven by skeletal muscle during exercise. Prior work has shown that anthracyclines impair mitochondrial function and increase reactive oxidative species, promoting a proinflammatory state in the skeletal muscle (10). This can be compounded by the use of steroids during chemotherapy, which can have an adverse effect on skeletal muscle (8).
Aerobically, A.L. was indeed exceptionally fit at the time of her diagnosis. A V˙O2peak of 50 mL O2·min−1·kg−1 would place her in the 95th percentile for aerobic fitness for age and sex (1). Her mean MET-minutes of exercise per day was 1912, which is remarkably high. Of note, A.L.’s activity levels were severely restricted for approximately 2.5 months after lymph node transfer surgery. Otherwise, A.L. was able to remain active during breast cancer therapies, albeit at reduced levels over prediagnosis values during chemotherapy. A.L. activity levels, even at a reduced volume, still far exceeded minimal recommendations. For context, the recommendation from the U.S. Department of Health and Human Services Physical Activity Guidelines for Americans (http://health.gov/paguidelines/guidelines/summary.aspx) is that we accumulate 500 to 1000 MET·min of exercise per week. Her activity levels not only helped maintain her fitness level throughout treatment but also likely aided in preventing the deleterious weight gain that has been reported among breast cancer patients (12). Importantly, A.L. was able to maintain her standard high-volume of activity, which was integral to her emotional and physical well-being and “athletic” self-image. This was not lost with a diagnosis of breast cancer. Furthermore, we were able to vary her training intensity, so not to interfere or cause “harm” to her cardiac function during exposure to cytotoxic agents (e.g., Adramycin).
The results of the case study describe the effects of undergoing multiple therapeutic interventions for breast cancer on measures of peak aerobic for a highly aerobically trained multisport athlete. In this case, exercise training reversed the decrement in measured V˙O2peak that occurred during cancer therapy. Further research is needed to confirm that the results of this case study are generally reproducible in other highly trained athletes undergoing breast cancer therapy.
Dr. Dittus was supported by the National Institutes of Health Center of Biomedical Research Excellence award P20GM103644 from the National Institute of General Medical Sciences.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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