Exercise intervention studies in hematological cancer patients during and after therapy have demonstrated safety and beneficial effects on physiological and psychological outcomes (26,36,37). The accumulating evidence about beneficial effects of exercise in cancer survivors has led the American College of Sports Medicine (ACSM) to develop exercise guidelines for cancer survivors; it is recommended to perform aerobic exercise for 150 min·wk−1 with moderate training or 75 min·wk−1 with vigorous intensity training (27). These guidelines were adapted from existing recommendations for exercise from the ACSM for healthy individuals (13) noting that exercise programs in cancer survivors may need to be modified considering health status and treatment received (27). Thus, the guidelines do not provide exact training intensities as a result of a lack of information in previous studies (4). However, prescription of adequate intensity is crucial for both adequate training stimulus and control for exercise-related risks; furthermore, appropriate prescriptions are essential in terms of exploring dose–response effects (35). ACSM guidelines for healthy individuals recommend intensities for moderate endurance training of 40%–59% HR reserve (HRR), 64%–76% maximal HR (HRmax), or 46%–63% maximal oxygen consumption (V˙O2max) (13). Most exercise studies in hematological cancer patients that used exercise intensity prescriptions relied on commonly used equations for age-predicted HRmax estimates (e.g., 220 − age in years) (17,19,34).
However, the relationship between HR and V˙O2 during exercise may be different in hematological cancer patients and might change over time. Allogeneic hematopoietic stem cell transplantation (allo-HCT) used in hematological cancers is a very intense treatment regimen, which is composed of high-dose chemotherapy, intake of immunosuppressants and high-dose corticosteroids, and in some cases, total body irradiation (7). A substantial amount of evidence has shown that cancer patients have a marked reduction in cardiorespiratory fitness as a result of the toxic effects of anticancer therapy and physical inactivity during and after treatment (18,20). The causes are often multifactorial and involve pulmonary limitations after chest radiation, cardiac limitations after anthracycline-containing chemotherapy or mediastinal radiation, low hemoglobin levels, or alterations in the skeletal muscle oxidative capacity (12,20). Furthermore, even before transplantation, patients’ physical performance is reduced (33) and a long period of drug intake after allo-HCT (e.g., immunosuppressants and corticosteroids) is known to cause muscle wasting (21), which also may influence the addressed relationship.
Therefore, our aim was to investigate whether the ACSM intensity classification for healthy people and the application of age-predicted HRmax estimates are appropriate for endurance training prescriptions in hematological cancer patients before and after allo-HCT, and to examine if the relationship between V˙O2 and HR changes after therapy. Therefore, age, gender, body mass index (BMI), hemoglobin level, and beta-blocker intake were considered as covariates.
METHODS
Design.
Data were obtained from the PETRA study. The PETRA study is a randomized controlled ongoing 1-yr exercise intervention study in allo-HCT patients. Patients assigned to the experimental group (EG) received an endurance and resistance training program, whereas patients in the control group received a relaxation program. Patients conducted maximal cardiopulmonary exercise tests (CPET) at three time points. In the present analysis, we included all patients who performed at least one maximal CPET at two different assessment time points, before allo-HCT and/or 180 d after, and completed a minimum of two exercise stages of the maximal CPET. The assessment time points were selected because they include the period of intensive treatment and appear to be a common time point for starting exercise in the context of a rehabilitation program. The study has been approved by the Ethics Committees of the University of Mannheim (number 2009-349 N-MA) and Heidelberg (number S-021/2011) and is registered at ClinicalTrials.gov (NCT01374399). Written informed consent was obtained from each participant before first assessment.
Subjects.
A total of 110 hematological cancer patients were included in the analysis. Exclusion criteria were premature exercise cessation due to medical reasons or lack of maximal effort (exhaustion criteria: RER >1.1 or HR >85% of age-predicted maximum [16,25]). The most frequent disease was acute myeloid leukemia (n = 28), followed by chronic myeloid leukemia (n = 22), lymphoma (n = 18), multiple myeloma (n = 12), acute lymphatic leukemia (n = 7), chronic lymphatic leukemia (n = 6), and others (n = 13). Forty-three percent (n = 46) patients were in complete remission before allo-HCT. Subjects’ detailed characteristics are presented in Table 1. Because of the following reasons, we could not collect data in 61 patients for the second measurement point (180 d after allo-HCT): assessment point was not yet reached (n = 21), patients died (n = 16), drop-outs (n = 6), medical reasons (n = 8), and others (n = 10). For four patients included in the second measurement point, we had no data for the first time point. At the second measurement point, 27 patients (55%) were in the EG.
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TABLE 1: Subject characteristics before and 180 d after allo-HCT.
Data collection.
All maximal CPET were performed on an electronically braked cycle ergometer (Ergoselect 100; Ergoline, Bitz, Germany) and were monitored by a physician. The test protocol was a graded procedure of 2-min stages starting at 50 W and increasing by 25 W until voluntary exhaustion or medical reasons for premature exercise cessation. Cadence was kept constant between 60 and 70 rpm. A 12-lead ECG was recorded continuously, and blood pressure was measured every 2 min. Gas exchange measurements were performed continuously using a breath-by-breath system (Ergostik; Geratherm Respiratory, Bad Kissingen, Germany). The metabolic device was calibrated before each test according to the instructions provided by the manufacturer. Gas exchange data and HR were stationary time averaged over 30 s. V˙O2max and HRmax were considered the highest 30-s average value during or immediately postexercise. Maximal RER (RERmax) was considered the highest 30-s average value during exercise.
Data extraction and statistical analysis.
HR and V˙O2 were assessed at the end of each exercise stage and at maximum. Ventilatory threshold (VT) was determined according to the V-slope method (2). To calculate HRR and V˙O2R, resting data were obtained from the resting period before the start of the exercise test in a sitting position on the cycle ergometer (V˙O2) and in laying position during resting ECG (HR). HRR and V˙O2R were calculated by subtracting the resting value from the maximum value. Values of each exercise stage were expressed in %V˙O2max, %HRmax, %V˙O2R, %HRR, percentage of maximal power output (%Pmax), and %VT (the latter two are not part of the ACSM recommendations but are commonly used for training prescriptions [6,8]). After testing for normality, five linear regression analyses were calculated for each subject and test. We used %V˙O2R as the independent variable (reference to define exercise classes) and %V˙O2max, %HRmax, %HRR, %Pmax, or %VT as dependent variables, respectively. We selected V˙O2R as the reference because reserve values are superior to maximal values and V˙O2R represents the individual performance capacity (13). The resulting individual regression equations were used to calculate the %V˙O2max, %HRmax, %HRR, %Pmax, and %VT values that correspond to 30%, 40%, 60%, and 90 % V˙O2R, corresponding to the lower limit of light, moderate, vigorous, and near maximal intensity by ACSM. In addition, we estimated HRmax and HRR with the equation 220 − age (in years), as previously used in exercise studies. One-sample t-tests were used to compare the resulting values with the ACSM’s expected values. To compare differences between the two time points, paired t-tests were used. Furthermore, multiple regression models were applied to determine influence of beta-blocker intake (BB), age, gender, BMI, and hemoglobin level (Hb) on measured and calculated values. The probability of making a type I error was set at P < 0.05. Statistical analyses were performed using SAS 9.3.
RESULTS
Comparison with ACSM values.
Table 2a displays the results before transplantation. All %HRR, %HRmax, and %V˙O2max means, corresponding to 30%, 40%, 60%, and 90% V˙O2R, were significantly different from the ACSM’s recommended values. Although the %HRR values of the patients were significantly lower than ACSM recommendations, %HRmax and %V˙O2max values were significantly higher (except 90% HRmax). In addition, VT was located at 40% of V˙O2R. Figure 1 shows the regression lines for our patients in comparison with the ACSM values.
TABLE 2a: Calculated exercise intensities before allo-HCT (n = 106) in comparison with ACSM values.
FIGURE 1: Observed and expected linear regression lines for V˙O2R versus HRR, V˙O2R versus V˙O2max, and V˙O2R versus HRmax before allo-HCT (n = 106).
Table 2b displays the results 180 d after transplantation. Here, similar results for %HRmax and %V˙O2max were observed as for the measurement time point before transplantation. For %HRR, there was no significant difference between ACSM recommendations and patients’ values (except 90% HRR, where patients’ values were still significantly lower).
TABLE 2b: Calculated exercise intensities 180 d after allo-HCT (n = 49) in comparison with ACSM values.
Group assignment (exercise vs relaxation control) had no effect on regression lines 180 d after transplantation, and paired t-tests showed no significant changes in %HRR, %HRmax, and %V˙O2max values over time (all P > 0.05). Table 3a, b shows exercise intensity classes for patients before and 180 d after allo-HCT derived from our sample.
TABLE 3a: Exercise intensity classes in cancer patients before allo-HCT (n = 106).
TABLE 3b: Exercise intensity classes in cancer patients 180 d after allo-HCT (n = 49).
Comparison with predicted values from standard equation.
%HRR values calculated with the equation 220 − age were significantly lower than the observed values at both time points (all P < 0.01). %HRmax values were significantly higher than observed values at both time points (all P < 0.01, see Table 4a, b).
TABLE 4a: Exercise intensities calculated by equation 220 − age before allo-HCT (n = 106).
TABLE 4b: Exercise intensities calculated by equation 220 − age 180 d after allo-HCT (n = 49).
Effects of potential biasing factors.
Regression analysis revealed that the relationship between V˙O2R and HRmax was not affected by beta-blocker intake, age, gender, BMI, or hemoglobin level at all intensities (all P > 0.05). The V˙O2R–HRR relationship was significantly influenced by age (R2, 11.7%–12.6%, model: P < 0.026; age: all P < 0.001) in all models (except for 90%V˙O2R), and the V˙O2R–V˙O2max relationship was significantly influenced by hemoglobin level (R2, 10.4%; model: P < 0.049; Hb: all P = 0.019) in all models. Because no influence of beta-blocker intake on calculated regressions was observed, we included all patients in the analysis.
DISCUSSION
To our knowledge, this is the first study evaluating ACSM’s exercise intensity classification in cancer patients. Before allo-HCT, the %HRR values of our patients related to light, moderate, or vigorous exercise (specified by %V˙O2R) were significantly lower than ACSM recommendations, whereas %HRmax and %V˙O2max values were significantly higher (except for 90% HRmax). Similar results were observed 180 d after allo-HCT for %HRmax and %V˙O2max. In contrast, for %HRR, the patient values did not differ significantly from ACSM recommendations (except 90% HRR). Our results indicate that the ACSM guidelines concerning endurance exercise intensity are not applicable before allo-HCT because they did not meet the targeted intensity class. One hundred eighty days after transplantation, only 30%, 40%, and 60% HRR were comparable with ACSM recommendations. Furthermore, when calculating HRmax with the equation 220 − age, values for %HRR and %HRmax significantly differed from measured values before and 180 d after transplantation.
In healthy people, a dose–response relationship between exercise intensity and favorable effects occurs. Therefore, exercise prescription should ensure a sufficient training stimulus, a reasonable control during exercise sessions, but also avoid overexertion (10). Thus, in cancer patients, it is recommended to tailor exercise intensity to individual cardiopulmonary fitness levels. However, light to moderate intensity is recommended without any further definition (4,27,30). The Australian Association for Exercise and Sport Science published in their guidelines for cancer patient values of 50%–75% V˙O2max or HRR and 60%–80% HRmax for moderate intensity, but it remains unclear if the data were derived from a cancer population (15). In comparison with these guidelines, percentages of HRR in our patients were considerably below the recommended percentages (50%–75% HRR vs 35%–54% HRR before and 38%–57% HRR 180 d after) for moderate intensity. The application of these guidelines would have led to a prescription of higher exercise intensity than targeted. Therefore, we provide tables with exercise intensities for endurance training prescription that were derived from a sample of hematological cancer patients. These tables can be used to determine exercise intensity before and 180 d after allo-HCT and should be of major clinical interest.
Some studies investigated the relationship between HR and V˙O2 proposed by ACSM in various populations. Swain and Leutholtz (32) demonstrated that in low-fit subjects, the relationship was significantly different from the ACSM values, whereas Lounana et al. (22) concluded that in highly trained subjects, the ACSM values were not applicable. Furthermore, in patients with heart disease (3,24) and chronic obstructive pulmonary disease (29) and obese individuals (5), the proposed percent values from the ACSM significantly differed from the calculated percent values in the different studies. Moreover, most of the studies as well as the ACSM used pooled group data to establish the intensity categories, but it is more appropriate to perform a linear regression for each subject and then calculate the mean regression equation (31). In our analyses, we used the aforementioned approach and calculated individual linear regression equations accordingly.
Furthermore, the precise reporting of exercise intensity is critical to allow exact comparisons between training studies. In hematological cancer patients during and after HCT, most studies that used CPET applied submaximal ergometer or treadmill tests (1,17,34); very few small studies applied maximal tests (6,14). For training intensity prescription, percentages of HRmax and HRR were widely used and the intensity varied between 40% and 90% HRmax (11,14,19,28,34). However, most studies used formulas for age-predicted HRmax estimates for defining exercise intensities. For example, one exercise program beginning 180 d after HCT started at 50%–60% HRmax and increased intensity up to 70%–80% HRmax (19). By categorizing these intensities based on our results, 50%–60% HRmax represents a very light intensity (light intensity started at 65%), whereas 70%–80% HRmax falls in the vigorous intensity classification. Another study, examining endurance training during chemotherapy, used 70% HRmax as an intensity target. This intensity was carried out five times in an interval training pattern with 3-min interval (11). In comparison with our data, this would correspond to a moderate-to-vigorous intensity. Thus, our tables can be used to compare the intensities of different exercise studies.
Because we observed different values for %HRR between the two time points without change in V˙O2max and Pmax values, our results also indicate that the relationship between HR and V˙O2 may have changed after intensive treatment. Although the results of the paired t-tests did not reach significant levels, this change should be considered when prescribing exercise intensities.
Furthermore, we could not find an influence of beta-blockade on the %V˙O2R and %HRR, %HRmax, and %V˙O2max relationship; therefore, we pooled data from patients with and without beta-blocker intake. This is consistent with other studies in heart disease patients, which showed that the aforementioned relationships are not affected by beta-blockade (3,24). In addition, one study with healthy subjects showed that beta-blockade had no effect on V˙O2max or Pmax (39). This finding indicates that our intensity values can be applied to patients regardless of beta-blocker use, which is relevant because beta-blockers are frequently prescribed in cancer patients.
Despite having a large homogeneous sample, we observed a relatively large SD for %HRR, indicating that there is some heterogeneity in the data. Our regression models revealed influence of hemoglobin levels, gender, BMI, and age on the relationships; therefore, these parameters may also be important to consider when defining intensity prescriptions; when using values estimated from the equation 220 − age, the variation was even larger. However, recommendations on individual level, for example, using threshold concepts (e.g., VT and respiratory compensation point), might be more useful for identifying the appropriate exercise intensity for an individual patient. When this is not possible, our values provided in the tables can be used instead. In addition, we provide information about %Pmax and %VT because these parameters are also frequently used for prescribing exercise intensity in clinical practice. Our data show that %V˙O2max did not correspond to %Pmax, an important finding because both are frequently used interchangeably in practice. Notably, in our patients, VT occurred at 40% V˙O2max, which is lower than that in untrained healthy people (23). VT was already suggested as an indicator for functional capacity in diseased patients when maximal incremental tests are not possible (23). However, our maximal CPET protocol was not ideal for cancer patients (see below), and therefore, these results should be interpreted with caution. Further studies should focus on determining whether VT as a submaximal parameter can be used to give adequate endurance training prescriptions for these patients. In addition, prolonged exercise tests should be performed to further evaluate our recommended intensity values.
Our results are quite important from a clinical perspective because first studies in hematological cancer patients after HCT show a potential relationship between cardiorespiratory fitness and survival (40), underlying the high importance of adequate exercise programs that target an optimal effect on cardiopulmonary fitness. Furthermore, our results underscore the need of individualized exercise prescriptions in this patient group. This finding complements with other results from our group showing that the individual exercise training response depends on baseline fitness level in allo-HCT patients (38).
One strength of our analysis is the large patient population. All patients received allo-HCT, an aggressive and demanding treatment that is known to profoundly affect physical performance. Furthermore, we included two measurement points to see if the relationship between HR and V˙O2 changes over time. Moreover, we used single linear regressions to calculate intensity categories. However, a methodological limitation is that our maximal CPET protocol started at a relatively high intensity (50 W); therefore, the lowest intensity class might be imprecisely represented, especially in patients with low physical performance. The assessment of resting V˙O2 did not fulfill the criteria for resting measurement. However, Cunha et al. (9) did not find a significant effect of different resting measurement conditions on the regression equation between V˙O2R and HRR.
CONCLUSION
It becomes increasingly evident that maintaining cardiorespiratory fitness during cancer treatment and regaining fitness after treatment improves different outcomes, right up to survival. Despite a large body of evidence, accurate intensity recommendations regarding endurance training do not exist; instead, recommendations for healthy subjects are used. Our data show that this exercise intensity classification may not be valid in hematological cancer patients before and 180 d after allo-HCT because it may result in over- or underestimation of exercise intensity. We provide exercise intensity classifications that were derived from a large population of hematological cancer patients before and after allo-HCT. These classifications can be used to define more appropriate exercise prescriptions in hematological cancer patients and to compare intensities used in previous studies. Because of variability in the observed data, more research is needed to further evaluate optimal exercise intensities with respect to different treatment conditions in hematological cancer patients.
The authors thank the study participants who spend their time, Andrea Bondong, Linda Keilbach, and Kristin Zerfass from the case management in the allogeneic transplantation ambulance at the University Clinic Heidelberg for recruitment and coordination assistance, the MTAs of the department of Sports Medicine at the University Clinic Heidelberg for assistance in CPET, and Michael Paskow for critically reading the manuscript.
This study was funded by the German José Carreras Leukemia Foundation (project no. R10/42pf).
The authors declare no conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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