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Maximal Exercise Testing of Men with Prostate Cancer Being Treated with Androgen Deprivation Therapy ˜ O2, NAEEM FATEHEE2, DENNIS R. TAAFFE2,3,4, NIGEL SPRY2,5,6, BRADLEY A. WALL1,2, DANIEL A. GALVA 2,5,6 , and ROBERT U. NEWTON2 DAVID JOSEPH 1
School of Psychology and Exercise Science, Murdoch University, Murdoch, Western Australia, AUSTRALIA; 2Edith Cowan University Health and Wellness Institute, Edith Cowan University, Joondalup, Western Australia, AUSTRALIA; 3School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, AUSTRALIA; 4School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA; 5Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, AUSTRALIA; and 6Faculty of Medicine, University of Western Australia, Nedlands, Western Australia, AUSTRALIA ABSTRACT ˜ O, N. FATEHEE, D. R. TAAFFE, N. SPRY, D. JOSEPH, and R. U. NEWTON. Maximal Exercise WALL, B. A., D. A. GALVA Testing of Men with Prostate Cancer Being Treated with Androgen Deprivation Therapy. Med. Sci. Sports Exerc., Vol. 46, No. 12, pp. 2210–2215, 2014. Exercise is being increasingly established as a key adjuvant therapy in clinical oncology. As research has demonstrated the beneficial effect of exercise for cancer management, a growing number of patients with cancer are undertaking structured exercise programs. Purpose: This study aimed to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool and for exercise prescription purposes. Methods: One hundred and twelve patients with prostate cancer undergoing androgen deprivation therapy (ADT) took part in a physician-supervised multistage maximal stress test (Bruce protocol). Sixty patients had been on ADT for G3 months (acute), whereas 52 had been on ADT for 93 months (chronic). Results: Of ˙ O2max, whereas three positive tests (3.2%) were observed. The three these men, 85% were able to meet the criteria for the attainment of V participants who recorded a positive stress test underwent further medical examination and were subsequently cleared of clinically significant ˙ O2max (24.7 T 6.0 mLIkgj1Iminj1, 10th–15th percentile), compared with normative cardiovascular disease. Apart from the relatively low V data in healthy age-matched controls, the cardiovascular response to exercise was similar in this cancer population. Moreover, treatment duration did not seem to influence cardiovascular responses to exercise. This early evidence suggests that risk of adverse events during maximal exercise testing is relatively low in this population and certainly no higher than that in ages-matched, apparently healthy individuals. ˙ O2max. The relatively low Conclusions: Maximal exercise testing was demonstrated to be feasible and safe, providing a direct assessment of V number of positive tests in this study suggests that the risk of adverse events is relatively low in this population and certainly no higher than that in age-matched, apparently healthy individuals. Key Words: ONCOLOGY, SCREENING, CARDIORESPIRATORY CAPACITY, CARDIOPULMONARY TESTING
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cancer are older (40), combined with the potential adverse cardiovascular effects of certain cancer treatments (1), the risk of cardiovascular disease is often elevated in these populations (1,25), highlighting the need for thorough screening before commencing an exercise program. Preexercise screening will often include a series of questions designed to identify individuals with signs or symptoms of an underlying disease. These questionnaires may be used in addition to detailed medical history and physical examination (4). Further screening often involves cardiopulmonary exercise testing, which provides an objective determination of an individual’s cardiorespiratory fitness and baseline parameters for training intensities as well as accurate screening for cardiac, pulmonary, and physical limitations (4). When cardiopulmonary testing is used during incremental exercise with continuous gas exchange, it provides the only way of assessing maximal oxygen consumption directly and is considered the gold standard in assessing cardiopulmonary fitness and exercise capacity (14). Although assessment of peak exercise during a graded exercise test may be subjective because of the motivation of the patient, collection of
xercise is being increasingly established as a key adjuvant therapy in clinical oncology, with a growing body of literature providing strong evidence that exercise is well tolerated, safe, and can mitigate several common treatment-related side effects (22). Because a growing number of patients with cancer begin to undertake structured exercise programs (6,22), it is necessary to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool for cardiovascular risk and for guiding the subsequent exercise prescription (24). Given that many patients with
Address for correspondence: Bradley A. Wall, Ph.D., School of Psychology and Exercise Science, Murdoch University, 90 South Street, Murdoch, Western Australia 6150, Australia; E-mail: [email protected]. Submitted for publication December 2013. Accepted for publication March 2014. 0195-9131/14/4612-2210/0 MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ Copyright Ó 2014 by the American College of Sports Medicine DOI: 10.1249/MSS.0000000000000353
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METHODS Subjects were recruited by invitation of their attending specialist physician. One hundred and twelve patients (age, 42–89 yr) with localized prostate cancer receiving ADT (mean duration, 4.3 months) underwent a physiciansupervised multistage maximal stress test using the Bruce protocol (7) on a motorized treadmill. Participant exclusion criteria included bone metastatic disease and the presence of
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an acute illness or any musculoskeletal, cardiovascular, or neurological disorder that could inhibit exercise response or adaptation or put the participant at risk from exercising. All participants obtained medical clearance from their general practitioner and completed a detailed health history questionnaire. This study protocol was approved by the university human research ethics committee, and all participants signed a written informed consent documentation before any data collection. Participants were continuously monitored with a 12-lead ECG system (CardioDirect 12S; Irvine, CA) at rest, during the maximal exercise test, and during recovery. During the maximal exercise test, the subject’s expired gases were collected (Parvo Metabolic Measuring System; Parvo Medics, ˙ O2max). Sandy, UT) to measure their maximal oxygen uptake (V All subjects were instructed to exercise until volitional exhaustion or they experienced signs or symptoms necessitating the termination of the test, which included the following: 1) chest pain, 2) ischemic ECG changes, or 3) an abnormal blood pressure response. A plateau in oxygen consumption was ˙ O2max. In the absence of used as qualification for achieving V a plateau, a secondary criterion was RER 91.1. If the subject was unable to achieve a plateau or RER values 91.1, their data were excluded from the presentation of maximal values. ˙ O2max is presented as an absolute value and relative to body V mass as well as MET of tasks, where 1 MET is equivalent to 3.5 mLIkgj1Iminj1. The duration of the maximal exercise test is presented as minutes:seconds. Systolic and diastolic blood pressure were assessed via manual auscultation using a mercury column sphygmomanometer and appropriate-sized cuff pretest while in the standing position on the treadmill, during the last minute of each stage, and 3 min after cessation of exercise. Positive test criteria. A positive (abnormal) test was defined as follows: 1) any significant ECG change indicative of ischemia during exercise or recovery or 2) development of exercise-induced bundle branch block. A significant ECG change was defined as Q0.1 mV of horizontal or downsloping ST segment depression Q80 ms after the J-point (as compared with the level of the PQ interval) (19). ST segment changes toward the isoelectric line were not considered positive regardless of the magnitude of change. If the baseline ECG revealed a J–ST segment depression of 90.05 mV, then ‘‘double criteria’’ (additional 0.2 mV) of ST depression was required with the appropriate horizontal or downsloping morphology to qualify as a positive test (24). All cases were interpreted by the same supervising physician. For further analysis, participants were stratified into two groups: 1) patients receiving ADT G3 months (acute ADT) or 2) patients receiving ADT Q3 months (chronic ADT) to determine whether additional ADT exposure influences the physiological responses to maximal exercise. Several studies have reported negative metabolic changes after short-term (3 months) ADT (12,34,36), suggesting that an acute exposure to ADT may be sufficient to elicit an adverse cardiovascular profile and hence alter the physiological response to exercise.
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expired gas can provide an objective measure of maximal exercise capacity (9). The inclusion of ECG can be applied as both a diagnostic and screening tool (37). Although traditional exercise stress tests are primarily concerned with ST segment changes from ECG indicative of myocardial ischemia, the addition of exercise capacity, HR, and blood pressure responses all enhance the diagnostic and prognostic value of the exercise test (33). Androgen deprivation therapy (ADT) has become one of the important advances in the treatment of prostate cancer (28) and may be delivered in various forms, all with the aim to block the predominant androgen, testosterone (32). ADT is the most widely used systemic treatment for prostate cancer, with almost 50% of men diagnosed with prostate cancer expected to receive ADT at some point during treatment (25). Although ADT may improve prostate cancer survival, this widely used treatment option is also associated with numerous adverse effects relating to treatment toxicities (8,26). The risks of comorbidity-related conditions are increased in this group of patients with cancer, with side effects including reduced bone and lean mass, loss of muscle strength, negative change in lipid profiles, vasomotor flushing, fatigue, and increased risk of cardiovascular disease as well as numerous metabolic complications, all of which can act to compromise physical function and quality of life (5,16,20,26,31,35). Exercise is becoming increasingly recognized as an effective therapy to mitigate many of these negative side effects, with positive alterations seen in muscular strength and endurance, lipid profile, aerobic fitness, physical function, and quality of life (17,30). Given that ADT has been associated with an increased risk of cardiovascular disease (25,26,29), a comprehensive cardiovascular screening battery, including clinical exercise testing, may be necessary before the commencement of an exercise program, particularly if the patient is sedentary or has identified risk factors. To date, no study has investigated the safety and feasibility of maximal exercise testing, including ECG, expired gas, HR, and blood pressure responses in men undergoing ADT for the treatment of prostate cancer. As such, the purpose of this study was to determine the feasibility and safety of maximal exercise testing in patients with prostate cancer. Moreover, we examined whether ADTtreated patients with prostate cancer respond differently to maximal exercise when compared with normative data available from healthy age-matched controls and whether exposure duration to ADT, acute or chronic, has influence.
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Body weight was measured to the nearest 0.1 kg using a digital scale (AND TB: 200), and height was measured to the nearest millimeter using a wall-mounted stadiometer (SECA 700; Seca, Brooklyn, NY). Body mass index (kgImj2) was calculated as body mass (kg) divided by height (m) squared. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA) (Hologic Discovery A; Hologic, Waltham, MA). Statistical analysis. Data analyses were performed using the Statistical Package for Social Sciences version 18.0 software (PASW; SPSS Inc., Chicago, IL). Standard descriptive statistics were used to describe subject charac˙ O2max were examteristics. Differences between groups’ V ined using Student’s independent t-test, whereas blood pressure and HR responses were examined using 2 4 mixed-model ANOVA procedures. A chi-square test was used to examine potential differences between acute and chronic ADT groups in previous adjuvant therapies. All tests were two tailed, and an alpha level of 0.05 was applied as the criterion for statistical significance. Data were assessed for normality using the Kolmogorov–Smirnov test. Results are reported as mean T SD.
RESULTS Subject characteristics. One hundred and twelve participants were tested for the purposes of this study. Of the 112 ˙ O2max. participants, 95 (85%) met the criteria for attainment of V The characteristics for the 112 participants are presented in Table 1. There were no significant differences between acute and chronic ADT groups for any descriptive characteristics, except for a borderline difference (P = 0.053) in body fat percentage. Mean ADT duration was 2 T 0 months and 7.1 T 6.2 months for the acute and chronic groups, respectively. Adverse events and abnormal ECG responses. Of ˙ O2max, three positive tests the 95 participants who achieved V (3.2%) and 92 negative tests (96.8%) were observed. Two positive tests were due to ST segment depression, whereas the remaining positive test was due to right bundle branch block. There were no positive events in the 17 participants who failed
˙ O2max. The three participants who to meet the criteria for V recorded a positive stress test underwent further examination. All three participants were cleared of any cardiovascular disease that would have precluded them from participating in an exercise intervention. One participant had their maximal exercise test postponed because of poorly controlled blood pressure (9200 mm Hg systolic and 110 mm Hg diastolic) but returned at a later date to safely complete the test. Cardiorespiratory fitness. The cardiorespiratory fitness data are presented in Table 2. The combined relative ˙ O2max for the 95 participants was 24.7 T 6.0 mLIkgj1Iminj1 V (range, 13.7–45.2 mLIkgj1Iminj1). There was a significant difference in cardiorespiratory fitness between the acute and chronic groups, with a significantly higher value in the acute group relative to body mass (P = 0.020), as an absolute value (P = 0.035) or in corresponding METs (P = 0.020). Although not statistically significant (P = 0.080), the acute group was able to complete an additional 59 s of the exercise stress test. HR and blood pressure responses to exercise. HR increased significantly (P G 0.001) from baseline (93 T 13 bpm) to the end of stage 1 (119 T 17 bpm), stage 2 (136 T ˙ O2max (155 T 18 bpm). There was no time– 18 bpm), and V group interaction (P = 0.378) between acute and chronic groups during the test, with acute and chronic groups increasing HR by 76 T 17 and 73 T 12 bpm, respectively. There were also no significant differences observed between the acute and chronic groups for HR recovery after 3 min of low-intensity active recovery, with values of 46 T 13 and 43 T 19 bpm, respectively. Systolic blood pressure increased significantly (P G 0.001) from baseline (145 T 18 mm Hg) to the end of stage 1 (188 T 28 mm Hg) and stage 2 (205 T 28 mm Hg). There was no time–group interaction (P = 0.941) between acute and chronic groups during the test, with acute and chronic groups increasing systolic blood pressure by 62 T 24 and 63 T 27 mm Hg, respectively. Combined diastolic blood pressure did not increase significantly (P = 0.857) from baseline during the graded exercise test, nor did mean arterial pressure (P = 0.344). Furthermore, there was no time–group interaction (P = 0.492)
TABLE 1. Subject characteristics (n = 112). Mean T SD
Variable Age (yr) Testosterone (mM) Prostate-specific antigen Gleason score No. of comorbiditiesa No. of medications Previous radiation, n (%)b Previous surgery, n (%)b Height (cm) Body mass (kg) Body mass index (kgImj2) % body fat
68.8 1.4 1.2 7.6 1.0 2.4 29 21 172.4 84.0 28.0 27.3
T 9.3 T 2.6 T 2.2 T 1.1 T 1.0 T 2.2 (26) (19) T 6.5 T 13.6 T 3.9 T 5.2
Acute ADT, Mean T SD (n = 60) 67.6 1.3T 1.2 7.6 1.0 2.0 14 13 172.1 84.3 28.2 26.4
T 9.0 1.5 T 1.7 T 0.8 T 1.0 T 1.9 (23) (22) T 6.6 T 13.2 T 3.8 T 5.1
Chronic ADT, Mean T SD (n = 52) 69.9 1.5 1.4 7.7 1.1 2.9 15 8 172.9 83.7 27.8 28.3
T 9.6 T 3.4 T 2.6 T 1.4 T 1.0 T 2.4 (29) (15) T 6.4 T 14.2 T 4.0 T 5.2
Mean Difference (95% CI) j2.3 j0.2 j0.2 j0.1 j0.1 j0.9
j0.8 0.7 0.4 j1.9
(j6.1 to 1.6) (j1.2 to 0.8) (j1.1 to 0.7) (j0.6 to 0.6) (j0.5 to 0.3) (j1.8 to 0.1) n/a n/a (j3.7 to 2.1) (j5.1 to 6.4) (j1.4 to 2.1) (j4.0, 0.1)
P Value 0.254 0.651 0.659 0.985 0.714 0.053 0.512 0.472 0.589 0.822 0.678 0.053
a
Cardiovascular disease, hypertension, diabetes, osteoporosis, and dislipidemia. Chi-square analysis. N/a, not applicable. b
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TABLE 2. Maximal exercise testing data.
Resting data HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Submaximal data Stage 1 HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Stage 2 HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Maximal data HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP(mm Hg) RER V˙O2max (mLIkgj1Iminj1) V˙O2max (LIminj1) V˙O2max (METs) Maximal test duration (min:s) Recovery data (3 min after) HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP(mm Hg)
Acute ADT, Mean T SD (n = 60)
Chronic ADT, Mean T SD (n = 52)
Mean Difference between Groups (95% CI)
P Value
83 145 87 106
T T T T
13 18 10 11
82 144 86 105
T T T T
11 19 10 11
84 146 85 105
T T T T
16 16 11 12
j2 j2 1 0
(j8 (j9 (j3 (j5
119 188 87 120
T T T T
17 28 11 14
118 188 86 118
T T T T
17 28 11 22
121 188 86 118
T T T T
16 30 14 25
j3 0 0 0
(j11 to 3) (12–12) (j5 to 5) (j10 to 10)
0.873 0.991 0.974 0.967
136 205 89 127
T T T T
18 28 12 15
135 205 87 123
T T T T
18 29 11 25
137 205 90 128
T T T T
19 29 13 17
2 0 j4 j5
(j11 to 6) (14–14) (j9 to 2) (j15 to 5)
0.869 0.999 0.226 0.302
155 208 88 128 1.18 24.7 2.1 7.1 8:06
T T T T T T T T T
18 30 12 15 0.09 6.0 0.9 1.7 2:43
157 206 87 126 1.17 26.1 2.3 7.5 8:33
T T T T T T T T T
17 30 11 14 0.09 6.0 1.1 1.7 2:46
152 209 90 129 1.19 23.2 1.9 6.6 7:34
T T T T T T T T T
18 30 13 17 0.07 5.8 0.6 1.6 2:36
(j2 to 13) (j15 to 10) (j8 to 2) (j9 to 4) (j0.06 to 0.01) (0.5–5.3) (0.1–0.7) (0.1–1.5) (j0:07 to 2:05)
0.158 0.684 0.214 0.377 0.131 0.020 0.035 0.020 0.080
111 178 83 114
T T T T
17 31 11 16
113 177 81 113
T T T T
18 31 11 15
108 179 84 116
T T T T
17 32 14 18
(j4 to 13) (16–12) (j9 to 2) (j10 to 4)
0.303 0.785 0.218 0.415
5 j3 j3 j3 j0.02 2.9 0.4 0.8 0:59 5 j2 j3 j3
to to to to
3) 5) 6) 5)
0.819 0.609 0.547 0.940
DBP, diastolic blood pressure; SBP, systolic blood pressure; MAP, mean arterial pressure.
between acute and chronic groups for either diastolic blood pressure or mean arterial pressure during the test.
DISCUSSION We examined the feasibility and safety of maximal treadmill exercise in patients with prostate cancer undergoing ADT and their cardiorespiratory responses. This study demonstrated that 85% of the participants were able to meet ˙ O2max. In the criteria established for the achievement of V terms of participant safety, three positive tests (3.2%) were observed whereas one test was postponed because of poorly controlled blood pressure. Although three positive tests were observed, further examination revealed no underlying issues that would preclude the individuals from commencing an exercise program. The test postponed because of poorly controlled blood pressure was conducted at a later date without any adverse event. This demonstrates that maximal exercise testing in this population seems to be a relatively safe and feasible assessment tool to be used for both screening and exercise prescription purposes. In our study, men with prostate cancer being treated ˙ O2max of 24.7 T 6.0 mLIkgj1Iminj1, with ADT exhibited a V which fell within the 10th–15th percentile for age-matched (60–69 yr) men according to the American College of Sports Medicine’s Guidelines for Exercise Testing and Prescription (39); however, the peak blood pressure response of 208 T 30/ 88 T 12 mm Hg closely corresponded to the age- and sexpredicted maximal mean blood pressure response of 197 T 24/
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84 T 12 mm Hg reported in a previous descriptive study using the Bruce treadmill protocol (11). The HRmax value of 155 T 18 bpm falls between the two most common HRmax formulas of 220 j age (151 bpm) (15) and 208 j 0.7 age (159 bpm) ˙ O2max (38). This suggests that aside from the relatively low V values recorded in this study (10th–15th percentile), the cardiovascular response to exercise is similar in this cancer population to that of healthy age-matched individuals. Physical function has been reported to decline in patients undergoing ADT (2) largely because of reduced muscular strength and endurance (18), whereas reduced levels of physical activity and increased levels of fatigue are also commonly reported in this population (16). These previously mentioned side effects are likely to have contributed to the relatively low ˙ O2max values reported in this study. V Acute versus chronic ADT exposure. When comparing acute and chronically suppressed ADT participants’ ˙ O2max physiological responses to the maximal exercise test, V was the only variable significantly differentiating the groups, with a mean difference of 0.4 LIminj1 (95% confidence in˙ O2max remained terval (CI), 0.1–0.7). The difference in V significant even when reporting relative to body mass, with a mean difference of 2.9 mLIkgj1Iminj1 (95% CI, 0.5–5.3). It is not precisely known why these differences occurred between the two groups, but one possible reason may be the reduction of physical activity levels after cancer diagnosis. Although not measured in the present study, physical activity has been shown to decline from prediagnosis levels in patients with cancer (10,21) and could result in a reduction of
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All Participants (n = 112)
Variable
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cardiac output and oxidative capacity (23,37) in addition to the previously established loss in muscle mass and increased fatigue (16). Both HR and blood pressure responded similarly before, during, and after the test regardless of the duration of ADT exposure, as did HR recovery. With regard to the ECG responses, all three positive tests were in the acute ADT exposure group; however, because of the small number of positive tests, no conclusion can be drawn as to the likelihood of a positive test being related to duration of ADT exposure. In a recent review, Steins Bisschop et al. (37) examined the safety and feasibility of cardiopulmonary exercise testing in patients with cancer, which included one prostate cancer study (121 patients). Twenty studies describing 1158 patients were deemed to meet the review eligibility criteria, and of the 20 studies, only 11 reported whether adverse events occurred. Of the 11 studies, it was reported that adverse events only occurred in 1% of all tests; however, the low incidence may be due to the fact that only 55% of the studies reviewed used ECG monitoring procedures. The relatively low rate of positive tests in the current study is also similar to previous work in clinical noncancer populations (3). In an extensive review conducted by Fletcher et al. (13), the risk of death and life-threatening complications during maximal exercise testing was reported to be 0.5 per 100,000 tests in healthy individuals, whereas in patients with cardiovascular disease, this rate rises to 2–5 per 100,000 tests. As a result of these findings, it seems that the risk of an adverse event in maximal exercise testing is dependent upon the type and extent of underlying disease (24). Several limitations need to be considered when interpreting the results of this study. The sample size of this study is relatively low, making it difficult to detect group differences in acute and chronic ADT responses. Selection bias does exist in this study because of the nature of recruitment. All participants who underwent the maximal exercise test were recruited for participation in a randomized controlled trial investigating the effects of an exercise intervention on reducing treatmentrelated side effects in men receiving therapy for prostate cancer (27). As such, the exclusion criteria applied to the intervention study were required to be met to complete the maximal exercise test. However, this does represent not only patients who have been recommended by their physician to undertake exercise but also those who are willing and able to engage in exercise. Although maximal exercise testing has been shown to be safe and feasible, it was not possible from the analysis to report whether there are any side effects or change in blood
parameters in this study. Finally, the small amount of positive tests observed, although promising from a safety aspect, does make it difficult to detect group differences.
CONCLUSIONS Maximal treadmill exercise testing in patients with prostate cancer undergoing ADT was demonstrated to be feasible and safe, with 85% of participants able to achieve the ˙ O2max and only criteria established for achievement of V 3.2% of participants recording a positive test. ADT-treated patients with prostate cancer responded similarly to a maximal graded exercise test regardless of ADT time exposure. Given that ADT has been associated with an increased risk of cardiovascular disease (25,26,29), it is recommended that patients with prostate cancer undergo a thorough screening process before commencing an exercise intervention. Furthermore, maximal exercise testing with gas exchange provides an objective measure of maximal aerobic capacity, which can form the basis of aerobic exercise prescription and accurately assess the effectiveness of the exercise intervention. Given the relatively low number of positive tests and subsequent clearance of any serious cardiac complications in this study, this early evidence suggests that risk of adverse events is relatively low in this population and certainly no higher than age-matched, apparently healthy individuals. Because the priority is to get more men with prostate cancer to exercise, it is important to not create barriers to participation with the requirement of expensive equipment and personnel to conduct the testing. Our results suggest that an exercise stress test, although strongly recommended, should not be a requirement for men with prostate cancer undergoing ADT before commencing an exercise program because the risks of morbidity and mortality resulting from maintaining a sedentary lifestyle seem far higher. Studies with larger sample size in this patient population are required to confirm and expand our findings. This study was funded by the National Health and Medical Research Council (ID, 534409). D. A. G. was funded by the Movember New Directions Development Award obtained through the Prostate Cancer Foundation of Australia’s Research Program. This study was a phase III clinical trial of exercise modalities on treatment side effects in men receiving therapy for prostate cancer (ACTRN12609000200280). The authors declare no conflicts of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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5. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106(3):581–8. 6. Baumann FT, Zopf EM, Bloch W. Clinical exercise interventions in prostate cancer patients—a systematic review of randomized controlled trials. Support Care Cancer. 2012;20(2):221–33. 7. Bruce RA. Exercise testing of patients with coronary heart disease. Principles and normal standards for evaluation. Ann Clin Res. 1971;3(6):323–32. 8. Chen AC, Petrylak DP. Complications of androgen-deprivation therapy in men with prostate cancer. Curr Urol Rep. 2005;6(3):210–6. 9. Cohn JN. Exercise tolerance as a guide to therapeutic efficacy for heart failure: the potential for angiotensin receptor blockers. Circulation. 1999;100(22):2208–9. 10. Courneya KS, Friedenreich CM. Relationship between exercise pattern across the cancer experience and current quality of life in colorectal cancer survivors. J Altern Complement Med. 2007;3(3): 215–26. 11. Daida H, Allison TG, Squires RW, Miller TD, Gau GT. Peak exercise blood pressure stratified by age and gender in apparently healthy subjects. Mayo Clin Proc. 1996;71(5):445–52. 12. Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond). 2003;104(2):195–201. 13. Fletcher GF, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards. A statement for healthcare professionals from the American Heart Association. Writing Group. Circulation. 1995;91(2):580–615. 14. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: A statement for healthcare professionals from the American Heart Association. Circulation. 2001;104(14):1694–740. 15. Fox SM 3rd, Naughton JP, Haskell WL. Physical activity and the prevention of coronary heart disease. Ann Clin Res. 1971;3(6): 404–32. 16. Galva˜o DA, Spry NA, Taaffe DR, et al. Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer. BJU Int. 2008;102(1):44–7. 17. Galva˜o DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol. 2010;28(2):340–7. 18. Galva˜o DA, Taaffe DR, Spry N, Joseph D, Turner D, Newton RU. Reduced muscle strength and functional performance in men with prostate cancer undergoing androgen suppression: a comprehensive cross-sectional investigation. Prostate Cancer Prostatic Dis. 2009;12(2):198–203. 19. Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation. 1997;96:345–54. 20. Greenspan SL, Coates P, Sereika SM, Nelson JB, Trump DL, Resnick NM. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab. 2005;90(12):6410–7. 21. Irwin ML, Crumley D, McTiernan A, et al. Physical activity levels before and after a diagnosis of breast carcinoma: the Health, Eating, Activity, and Lifestyle (HEAL) study. Cancer. 2003;97(7):1746–57.
Maximal Exercise Testing of Men with Prostate Cancer Being Treated with Androgen Deprivation Therapy ˜ O2, NAEEM FATEHEE2, DENNIS R. TAAFFE2,3,4, NIGEL SPRY2,5,6, BRADLEY A. WALL1,2, DANIEL A. GALVA 2,5,6 , and ROBERT U. NEWTON2 DAVID JOSEPH 1
School of Psychology and Exercise Science, Murdoch University, Murdoch, Western Australia, AUSTRALIA; 2Edith Cowan University Health and Wellness Institute, Edith Cowan University, Joondalup, Western Australia, AUSTRALIA; 3School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, AUSTRALIA; 4School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA; 5Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, AUSTRALIA; and 6Faculty of Medicine, University of Western Australia, Nedlands, Western Australia, AUSTRALIA ABSTRACT ˜ O, N. FATEHEE, D. R. TAAFFE, N. SPRY, D. JOSEPH, and R. U. NEWTON. Maximal Exercise WALL, B. A., D. A. GALVA Testing of Men with Prostate Cancer Being Treated with Androgen Deprivation Therapy. Med. Sci. Sports Exerc., Vol. 46, No. 12, pp. 2210–2215, 2014. Exercise is being increasingly established as a key adjuvant therapy in clinical oncology. As research has demonstrated the beneficial effect of exercise for cancer management, a growing number of patients with cancer are undertaking structured exercise programs. Purpose: This study aimed to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool and for exercise prescription purposes. Methods: One hundred and twelve patients with prostate cancer undergoing androgen deprivation therapy (ADT) took part in a physician-supervised multistage maximal stress test (Bruce protocol). Sixty patients had been on ADT for G3 months (acute), whereas 52 had been on ADT for 93 months (chronic). Results: Of ˙ O2max, whereas three positive tests (3.2%) were observed. The three these men, 85% were able to meet the criteria for the attainment of V participants who recorded a positive stress test underwent further medical examination and were subsequently cleared of clinically significant ˙ O2max (24.7 T 6.0 mLIkgj1Iminj1, 10th–15th percentile), compared with normative cardiovascular disease. Apart from the relatively low V data in healthy age-matched controls, the cardiovascular response to exercise was similar in this cancer population. Moreover, treatment duration did not seem to influence cardiovascular responses to exercise. This early evidence suggests that risk of adverse events during maximal exercise testing is relatively low in this population and certainly no higher than that in ages-matched, apparently healthy individuals. ˙ O2max. The relatively low Conclusions: Maximal exercise testing was demonstrated to be feasible and safe, providing a direct assessment of V number of positive tests in this study suggests that the risk of adverse events is relatively low in this population and certainly no higher than that in age-matched, apparently healthy individuals. Key Words: ONCOLOGY, SCREENING, CARDIORESPIRATORY CAPACITY, CARDIOPULMONARY TESTING
E
cancer are older (40), combined with the potential adverse cardiovascular effects of certain cancer treatments (1), the risk of cardiovascular disease is often elevated in these populations (1,25), highlighting the need for thorough screening before commencing an exercise program. Preexercise screening will often include a series of questions designed to identify individuals with signs or symptoms of an underlying disease. These questionnaires may be used in addition to detailed medical history and physical examination (4). Further screening often involves cardiopulmonary exercise testing, which provides an objective determination of an individual’s cardiorespiratory fitness and baseline parameters for training intensities as well as accurate screening for cardiac, pulmonary, and physical limitations (4). When cardiopulmonary testing is used during incremental exercise with continuous gas exchange, it provides the only way of assessing maximal oxygen consumption directly and is considered the gold standard in assessing cardiopulmonary fitness and exercise capacity (14). Although assessment of peak exercise during a graded exercise test may be subjective because of the motivation of the patient, collection of
xercise is being increasingly established as a key adjuvant therapy in clinical oncology, with a growing body of literature providing strong evidence that exercise is well tolerated, safe, and can mitigate several common treatment-related side effects (22). Because a growing number of patients with cancer begin to undertake structured exercise programs (6,22), it is necessary to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool for cardiovascular risk and for guiding the subsequent exercise prescription (24). Given that many patients with
Address for correspondence: Bradley A. Wall, Ph.D., School of Psychology and Exercise Science, Murdoch University, 90 South Street, Murdoch, Western Australia 6150, Australia; E-mail: [email protected]. Submitted for publication December 2013. Accepted for publication March 2014. 0195-9131/14/4612-2210/0 MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ Copyright Ó 2014 by the American College of Sports Medicine DOI: 10.1249/MSS.0000000000000353
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METHODS Subjects were recruited by invitation of their attending specialist physician. One hundred and twelve patients (age, 42–89 yr) with localized prostate cancer receiving ADT (mean duration, 4.3 months) underwent a physiciansupervised multistage maximal stress test using the Bruce protocol (7) on a motorized treadmill. Participant exclusion criteria included bone metastatic disease and the presence of
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an acute illness or any musculoskeletal, cardiovascular, or neurological disorder that could inhibit exercise response or adaptation or put the participant at risk from exercising. All participants obtained medical clearance from their general practitioner and completed a detailed health history questionnaire. This study protocol was approved by the university human research ethics committee, and all participants signed a written informed consent documentation before any data collection. Participants were continuously monitored with a 12-lead ECG system (CardioDirect 12S; Irvine, CA) at rest, during the maximal exercise test, and during recovery. During the maximal exercise test, the subject’s expired gases were collected (Parvo Metabolic Measuring System; Parvo Medics, ˙ O2max). Sandy, UT) to measure their maximal oxygen uptake (V All subjects were instructed to exercise until volitional exhaustion or they experienced signs or symptoms necessitating the termination of the test, which included the following: 1) chest pain, 2) ischemic ECG changes, or 3) an abnormal blood pressure response. A plateau in oxygen consumption was ˙ O2max. In the absence of used as qualification for achieving V a plateau, a secondary criterion was RER 91.1. If the subject was unable to achieve a plateau or RER values 91.1, their data were excluded from the presentation of maximal values. ˙ O2max is presented as an absolute value and relative to body V mass as well as MET of tasks, where 1 MET is equivalent to 3.5 mLIkgj1Iminj1. The duration of the maximal exercise test is presented as minutes:seconds. Systolic and diastolic blood pressure were assessed via manual auscultation using a mercury column sphygmomanometer and appropriate-sized cuff pretest while in the standing position on the treadmill, during the last minute of each stage, and 3 min after cessation of exercise. Positive test criteria. A positive (abnormal) test was defined as follows: 1) any significant ECG change indicative of ischemia during exercise or recovery or 2) development of exercise-induced bundle branch block. A significant ECG change was defined as Q0.1 mV of horizontal or downsloping ST segment depression Q80 ms after the J-point (as compared with the level of the PQ interval) (19). ST segment changes toward the isoelectric line were not considered positive regardless of the magnitude of change. If the baseline ECG revealed a J–ST segment depression of 90.05 mV, then ‘‘double criteria’’ (additional 0.2 mV) of ST depression was required with the appropriate horizontal or downsloping morphology to qualify as a positive test (24). All cases were interpreted by the same supervising physician. For further analysis, participants were stratified into two groups: 1) patients receiving ADT G3 months (acute ADT) or 2) patients receiving ADT Q3 months (chronic ADT) to determine whether additional ADT exposure influences the physiological responses to maximal exercise. Several studies have reported negative metabolic changes after short-term (3 months) ADT (12,34,36), suggesting that an acute exposure to ADT may be sufficient to elicit an adverse cardiovascular profile and hence alter the physiological response to exercise.
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expired gas can provide an objective measure of maximal exercise capacity (9). The inclusion of ECG can be applied as both a diagnostic and screening tool (37). Although traditional exercise stress tests are primarily concerned with ST segment changes from ECG indicative of myocardial ischemia, the addition of exercise capacity, HR, and blood pressure responses all enhance the diagnostic and prognostic value of the exercise test (33). Androgen deprivation therapy (ADT) has become one of the important advances in the treatment of prostate cancer (28) and may be delivered in various forms, all with the aim to block the predominant androgen, testosterone (32). ADT is the most widely used systemic treatment for prostate cancer, with almost 50% of men diagnosed with prostate cancer expected to receive ADT at some point during treatment (25). Although ADT may improve prostate cancer survival, this widely used treatment option is also associated with numerous adverse effects relating to treatment toxicities (8,26). The risks of comorbidity-related conditions are increased in this group of patients with cancer, with side effects including reduced bone and lean mass, loss of muscle strength, negative change in lipid profiles, vasomotor flushing, fatigue, and increased risk of cardiovascular disease as well as numerous metabolic complications, all of which can act to compromise physical function and quality of life (5,16,20,26,31,35). Exercise is becoming increasingly recognized as an effective therapy to mitigate many of these negative side effects, with positive alterations seen in muscular strength and endurance, lipid profile, aerobic fitness, physical function, and quality of life (17,30). Given that ADT has been associated with an increased risk of cardiovascular disease (25,26,29), a comprehensive cardiovascular screening battery, including clinical exercise testing, may be necessary before the commencement of an exercise program, particularly if the patient is sedentary or has identified risk factors. To date, no study has investigated the safety and feasibility of maximal exercise testing, including ECG, expired gas, HR, and blood pressure responses in men undergoing ADT for the treatment of prostate cancer. As such, the purpose of this study was to determine the feasibility and safety of maximal exercise testing in patients with prostate cancer. Moreover, we examined whether ADTtreated patients with prostate cancer respond differently to maximal exercise when compared with normative data available from healthy age-matched controls and whether exposure duration to ADT, acute or chronic, has influence.
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Body weight was measured to the nearest 0.1 kg using a digital scale (AND TB: 200), and height was measured to the nearest millimeter using a wall-mounted stadiometer (SECA 700; Seca, Brooklyn, NY). Body mass index (kgImj2) was calculated as body mass (kg) divided by height (m) squared. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA) (Hologic Discovery A; Hologic, Waltham, MA). Statistical analysis. Data analyses were performed using the Statistical Package for Social Sciences version 18.0 software (PASW; SPSS Inc., Chicago, IL). Standard descriptive statistics were used to describe subject charac˙ O2max were examteristics. Differences between groups’ V ined using Student’s independent t-test, whereas blood pressure and HR responses were examined using 2 4 mixed-model ANOVA procedures. A chi-square test was used to examine potential differences between acute and chronic ADT groups in previous adjuvant therapies. All tests were two tailed, and an alpha level of 0.05 was applied as the criterion for statistical significance. Data were assessed for normality using the Kolmogorov–Smirnov test. Results are reported as mean T SD.
RESULTS Subject characteristics. One hundred and twelve participants were tested for the purposes of this study. Of the 112 ˙ O2max. participants, 95 (85%) met the criteria for attainment of V The characteristics for the 112 participants are presented in Table 1. There were no significant differences between acute and chronic ADT groups for any descriptive characteristics, except for a borderline difference (P = 0.053) in body fat percentage. Mean ADT duration was 2 T 0 months and 7.1 T 6.2 months for the acute and chronic groups, respectively. Adverse events and abnormal ECG responses. Of ˙ O2max, three positive tests the 95 participants who achieved V (3.2%) and 92 negative tests (96.8%) were observed. Two positive tests were due to ST segment depression, whereas the remaining positive test was due to right bundle branch block. There were no positive events in the 17 participants who failed
˙ O2max. The three participants who to meet the criteria for V recorded a positive stress test underwent further examination. All three participants were cleared of any cardiovascular disease that would have precluded them from participating in an exercise intervention. One participant had their maximal exercise test postponed because of poorly controlled blood pressure (9200 mm Hg systolic and 110 mm Hg diastolic) but returned at a later date to safely complete the test. Cardiorespiratory fitness. The cardiorespiratory fitness data are presented in Table 2. The combined relative ˙ O2max for the 95 participants was 24.7 T 6.0 mLIkgj1Iminj1 V (range, 13.7–45.2 mLIkgj1Iminj1). There was a significant difference in cardiorespiratory fitness between the acute and chronic groups, with a significantly higher value in the acute group relative to body mass (P = 0.020), as an absolute value (P = 0.035) or in corresponding METs (P = 0.020). Although not statistically significant (P = 0.080), the acute group was able to complete an additional 59 s of the exercise stress test. HR and blood pressure responses to exercise. HR increased significantly (P G 0.001) from baseline (93 T 13 bpm) to the end of stage 1 (119 T 17 bpm), stage 2 (136 T ˙ O2max (155 T 18 bpm). There was no time– 18 bpm), and V group interaction (P = 0.378) between acute and chronic groups during the test, with acute and chronic groups increasing HR by 76 T 17 and 73 T 12 bpm, respectively. There were also no significant differences observed between the acute and chronic groups for HR recovery after 3 min of low-intensity active recovery, with values of 46 T 13 and 43 T 19 bpm, respectively. Systolic blood pressure increased significantly (P G 0.001) from baseline (145 T 18 mm Hg) to the end of stage 1 (188 T 28 mm Hg) and stage 2 (205 T 28 mm Hg). There was no time–group interaction (P = 0.941) between acute and chronic groups during the test, with acute and chronic groups increasing systolic blood pressure by 62 T 24 and 63 T 27 mm Hg, respectively. Combined diastolic blood pressure did not increase significantly (P = 0.857) from baseline during the graded exercise test, nor did mean arterial pressure (P = 0.344). Furthermore, there was no time–group interaction (P = 0.492)
TABLE 1. Subject characteristics (n = 112). Mean T SD
Variable Age (yr) Testosterone (mM) Prostate-specific antigen Gleason score No. of comorbiditiesa No. of medications Previous radiation, n (%)b Previous surgery, n (%)b Height (cm) Body mass (kg) Body mass index (kgImj2) % body fat
68.8 1.4 1.2 7.6 1.0 2.4 29 21 172.4 84.0 28.0 27.3
T 9.3 T 2.6 T 2.2 T 1.1 T 1.0 T 2.2 (26) (19) T 6.5 T 13.6 T 3.9 T 5.2
Acute ADT, Mean T SD (n = 60) 67.6 1.3T 1.2 7.6 1.0 2.0 14 13 172.1 84.3 28.2 26.4
T 9.0 1.5 T 1.7 T 0.8 T 1.0 T 1.9 (23) (22) T 6.6 T 13.2 T 3.8 T 5.1
Chronic ADT, Mean T SD (n = 52) 69.9 1.5 1.4 7.7 1.1 2.9 15 8 172.9 83.7 27.8 28.3
T 9.6 T 3.4 T 2.6 T 1.4 T 1.0 T 2.4 (29) (15) T 6.4 T 14.2 T 4.0 T 5.2
Mean Difference (95% CI) j2.3 j0.2 j0.2 j0.1 j0.1 j0.9
j0.8 0.7 0.4 j1.9
(j6.1 to 1.6) (j1.2 to 0.8) (j1.1 to 0.7) (j0.6 to 0.6) (j0.5 to 0.3) (j1.8 to 0.1) n/a n/a (j3.7 to 2.1) (j5.1 to 6.4) (j1.4 to 2.1) (j4.0, 0.1)
P Value 0.254 0.651 0.659 0.985 0.714 0.053 0.512 0.472 0.589 0.822 0.678 0.053
a
Cardiovascular disease, hypertension, diabetes, osteoporosis, and dislipidemia. Chi-square analysis. N/a, not applicable. b
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TABLE 2. Maximal exercise testing data.
Resting data HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Submaximal data Stage 1 HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Stage 2 HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) Maximal data HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP(mm Hg) RER V˙O2max (mLIkgj1Iminj1) V˙O2max (LIminj1) V˙O2max (METs) Maximal test duration (min:s) Recovery data (3 min after) HR (bpm) SBP (mm Hg) DBP (mm Hg) MAP(mm Hg)
Acute ADT, Mean T SD (n = 60)
Chronic ADT, Mean T SD (n = 52)
Mean Difference between Groups (95% CI)
P Value
83 145 87 106
T T T T
13 18 10 11
82 144 86 105
T T T T
11 19 10 11
84 146 85 105
T T T T
16 16 11 12
j2 j2 1 0
(j8 (j9 (j3 (j5
119 188 87 120
T T T T
17 28 11 14
118 188 86 118
T T T T
17 28 11 22
121 188 86 118
T T T T
16 30 14 25
j3 0 0 0
(j11 to 3) (12–12) (j5 to 5) (j10 to 10)
0.873 0.991 0.974 0.967
136 205 89 127
T T T T
18 28 12 15
135 205 87 123
T T T T
18 29 11 25
137 205 90 128
T T T T
19 29 13 17
2 0 j4 j5
(j11 to 6) (14–14) (j9 to 2) (j15 to 5)
0.869 0.999 0.226 0.302
155 208 88 128 1.18 24.7 2.1 7.1 8:06
T T T T T T T T T
18 30 12 15 0.09 6.0 0.9 1.7 2:43
157 206 87 126 1.17 26.1 2.3 7.5 8:33
T T T T T T T T T
17 30 11 14 0.09 6.0 1.1 1.7 2:46
152 209 90 129 1.19 23.2 1.9 6.6 7:34
T T T T T T T T T
18 30 13 17 0.07 5.8 0.6 1.6 2:36
(j2 to 13) (j15 to 10) (j8 to 2) (j9 to 4) (j0.06 to 0.01) (0.5–5.3) (0.1–0.7) (0.1–1.5) (j0:07 to 2:05)
0.158 0.684 0.214 0.377 0.131 0.020 0.035 0.020 0.080
111 178 83 114
T T T T
17 31 11 16
113 177 81 113
T T T T
18 31 11 15
108 179 84 116
T T T T
17 32 14 18
(j4 to 13) (16–12) (j9 to 2) (j10 to 4)
0.303 0.785 0.218 0.415
5 j3 j3 j3 j0.02 2.9 0.4 0.8 0:59 5 j2 j3 j3
to to to to
3) 5) 6) 5)
0.819 0.609 0.547 0.940
DBP, diastolic blood pressure; SBP, systolic blood pressure; MAP, mean arterial pressure.
between acute and chronic groups for either diastolic blood pressure or mean arterial pressure during the test.
DISCUSSION We examined the feasibility and safety of maximal treadmill exercise in patients with prostate cancer undergoing ADT and their cardiorespiratory responses. This study demonstrated that 85% of the participants were able to meet ˙ O2max. In the criteria established for the achievement of V terms of participant safety, three positive tests (3.2%) were observed whereas one test was postponed because of poorly controlled blood pressure. Although three positive tests were observed, further examination revealed no underlying issues that would preclude the individuals from commencing an exercise program. The test postponed because of poorly controlled blood pressure was conducted at a later date without any adverse event. This demonstrates that maximal exercise testing in this population seems to be a relatively safe and feasible assessment tool to be used for both screening and exercise prescription purposes. In our study, men with prostate cancer being treated ˙ O2max of 24.7 T 6.0 mLIkgj1Iminj1, with ADT exhibited a V which fell within the 10th–15th percentile for age-matched (60–69 yr) men according to the American College of Sports Medicine’s Guidelines for Exercise Testing and Prescription (39); however, the peak blood pressure response of 208 T 30/ 88 T 12 mm Hg closely corresponded to the age- and sexpredicted maximal mean blood pressure response of 197 T 24/
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84 T 12 mm Hg reported in a previous descriptive study using the Bruce treadmill protocol (11). The HRmax value of 155 T 18 bpm falls between the two most common HRmax formulas of 220 j age (151 bpm) (15) and 208 j 0.7 age (159 bpm) ˙ O2max (38). This suggests that aside from the relatively low V values recorded in this study (10th–15th percentile), the cardiovascular response to exercise is similar in this cancer population to that of healthy age-matched individuals. Physical function has been reported to decline in patients undergoing ADT (2) largely because of reduced muscular strength and endurance (18), whereas reduced levels of physical activity and increased levels of fatigue are also commonly reported in this population (16). These previously mentioned side effects are likely to have contributed to the relatively low ˙ O2max values reported in this study. V Acute versus chronic ADT exposure. When comparing acute and chronically suppressed ADT participants’ ˙ O2max physiological responses to the maximal exercise test, V was the only variable significantly differentiating the groups, with a mean difference of 0.4 LIminj1 (95% confidence in˙ O2max remained terval (CI), 0.1–0.7). The difference in V significant even when reporting relative to body mass, with a mean difference of 2.9 mLIkgj1Iminj1 (95% CI, 0.5–5.3). It is not precisely known why these differences occurred between the two groups, but one possible reason may be the reduction of physical activity levels after cancer diagnosis. Although not measured in the present study, physical activity has been shown to decline from prediagnosis levels in patients with cancer (10,21) and could result in a reduction of
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All Participants (n = 112)
Variable
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cardiac output and oxidative capacity (23,37) in addition to the previously established loss in muscle mass and increased fatigue (16). Both HR and blood pressure responded similarly before, during, and after the test regardless of the duration of ADT exposure, as did HR recovery. With regard to the ECG responses, all three positive tests were in the acute ADT exposure group; however, because of the small number of positive tests, no conclusion can be drawn as to the likelihood of a positive test being related to duration of ADT exposure. In a recent review, Steins Bisschop et al. (37) examined the safety and feasibility of cardiopulmonary exercise testing in patients with cancer, which included one prostate cancer study (121 patients). Twenty studies describing 1158 patients were deemed to meet the review eligibility criteria, and of the 20 studies, only 11 reported whether adverse events occurred. Of the 11 studies, it was reported that adverse events only occurred in 1% of all tests; however, the low incidence may be due to the fact that only 55% of the studies reviewed used ECG monitoring procedures. The relatively low rate of positive tests in the current study is also similar to previous work in clinical noncancer populations (3). In an extensive review conducted by Fletcher et al. (13), the risk of death and life-threatening complications during maximal exercise testing was reported to be 0.5 per 100,000 tests in healthy individuals, whereas in patients with cardiovascular disease, this rate rises to 2–5 per 100,000 tests. As a result of these findings, it seems that the risk of an adverse event in maximal exercise testing is dependent upon the type and extent of underlying disease (24). Several limitations need to be considered when interpreting the results of this study. The sample size of this study is relatively low, making it difficult to detect group differences in acute and chronic ADT responses. Selection bias does exist in this study because of the nature of recruitment. All participants who underwent the maximal exercise test were recruited for participation in a randomized controlled trial investigating the effects of an exercise intervention on reducing treatmentrelated side effects in men receiving therapy for prostate cancer (27). As such, the exclusion criteria applied to the intervention study were required to be met to complete the maximal exercise test. However, this does represent not only patients who have been recommended by their physician to undertake exercise but also those who are willing and able to engage in exercise. Although maximal exercise testing has been shown to be safe and feasible, it was not possible from the analysis to report whether there are any side effects or change in blood
parameters in this study. Finally, the small amount of positive tests observed, although promising from a safety aspect, does make it difficult to detect group differences.
CONCLUSIONS Maximal treadmill exercise testing in patients with prostate cancer undergoing ADT was demonstrated to be feasible and safe, with 85% of participants able to achieve the ˙ O2max and only criteria established for achievement of V 3.2% of participants recording a positive test. ADT-treated patients with prostate cancer responded similarly to a maximal graded exercise test regardless of ADT time exposure. Given that ADT has been associated with an increased risk of cardiovascular disease (25,26,29), it is recommended that patients with prostate cancer undergo a thorough screening process before commencing an exercise intervention. Furthermore, maximal exercise testing with gas exchange provides an objective measure of maximal aerobic capacity, which can form the basis of aerobic exercise prescription and accurately assess the effectiveness of the exercise intervention. Given the relatively low number of positive tests and subsequent clearance of any serious cardiac complications in this study, this early evidence suggests that risk of adverse events is relatively low in this population and certainly no higher than age-matched, apparently healthy individuals. Because the priority is to get more men with prostate cancer to exercise, it is important to not create barriers to participation with the requirement of expensive equipment and personnel to conduct the testing. Our results suggest that an exercise stress test, although strongly recommended, should not be a requirement for men with prostate cancer undergoing ADT before commencing an exercise program because the risks of morbidity and mortality resulting from maintaining a sedentary lifestyle seem far higher. Studies with larger sample size in this patient population are required to confirm and expand our findings. This study was funded by the National Health and Medical Research Council (ID, 534409). D. A. G. was funded by the Movember New Directions Development Award obtained through the Prostate Cancer Foundation of Australia’s Research Program. This study was a phase III clinical trial of exercise modalities on treatment side effects in men receiving therapy for prostate cancer (ACTRN12609000200280). The authors declare no conflicts of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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3. American Thoracic Society, American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003;167(2):211–77. 4. Balady GJ, Chaitman B, Driscoll D, et al. Recommendations for cardiovascular screening, staffing, and emergency policies at health/fitness facilities. Circulation. 1998;97(22): 2283–93.
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