1134 Clinical Sciences
Demonstration of the Need for Cardiovascular and Pulmonary Normative Data for Cancer Survivors
Affiliations
Key words ▶ cancer rehabilitation ● ▶ population-specific ● normative values ▶ exercise ● ▶ cancer treatment side ● effects
C. M. Schneider1, C. P. Repka1, J. M. Brown1, T. L. Lalonde2, K. T. Dallow3, C. E. Barlow4, R. Hayward1 1
Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, United States Department of Applied Statistics and Research Methods, University of Northern Colorado, Greeley, United States 3 Family Medicine, North Colorado Medical Center, Greeley, United States 4 Research Department, The Cooper Institute, Dallas, United States 2
Abstract
▼
Despite evidence that cancer and its treatments severely reduce cardiorespiratory fitness (CRF), normative data for cancer survivors do not exist. The present study identifies age and genderspecific CRF distributions in a cancer population. The use of cancer-specific normative CRF data may help stratify initial fitness status and assess improvements in response to exercise interventions in cancer survivors. Data from 703 cancer survivors were analyzed for this study. Quintiles were compiled for peak oxygen consumption (VO2peak), forced vital capacity (FVC), and forced expiratory volume (FEV1) for males and females in 5 age groups (19–39, 40–49, 50–59,
Introdution
▼ accepted after revision April 14, 2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375691 Published online: July 4, 2014 Int J Sports Med 2014; 35: 1134–1137 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0172-4622 Correspondence Chris P. Repka Rocky Mountain Cancer Rehabilitation Institute University of Northern Colorado Campus Box 6 Greeley United States 80639 Tel.: + 1/908/419 2767 Fax: + 1/970/351 1720 [email protected]
Cancer mortality rates have decreased in recent years, resulting in more cancer survivors living with detrimental treatment-associated side effects. The cytotoxic effects of cancer treatments can damage healthy tissues within the heart, lung, skeletal muscle, circulatory system and nervous system [13, 14]. These physiological alterations can lead to reduced functional capacity [6], cardiac dysfunction [7, 9], pulmonary dysfunction [12], peripheral neuropathy [18], muscular weakness [15] and postural instability [22]. These alterations can result in a drastic decrease in cardiorespiratory function [11]. Reduced cardiorespiratory fitness (CRF) following cancer therapy is the result of damage to systems supporting aerobic capacity. For example, chemotherapy treatment with anthracyclines such as doxorubicin are characterized by a dose dependent cardiotoxicity [16], resulting in altered cardiac myosin heavy chain expression, along with reductions in left ventricular mass, relative wall thickness, fractional shortening and maximal cardiac flow velocities [9, 10]. Such treatments have also
Schneider CM et al. Demonstration of the Need … Int J Sports Med 2014; 35: 1134–1137
60–69, and ≥ 70 years of age). VO2peak values for the cancer population were significantly lower than the general US population. The cancer population average in each age group fell within the “very poor” classification of VO2peak values for the general population. FVC values in the cancer population were similar to the general population. Cancer survivors had very low age group-specific VO2peak values compared to the apparently healthy general US population. Previously, CRF values of cancer survivors were compared to normative values for the apparently healthy general population, which yielded imprecise classifications of initial fitness and changes in fitness, resulting in patient discouragement.
been shown to inactivate important mitochondrial enzymes, such as myocardial cytochrome c oxidase [3]. Other treatment-associated side effects, including mitochondrial and cardiac pathologies, cachexia, anemia, and pulmonary and endothelial dysfunction are well established in clinical oncology and cancer rehabilitation literature [1, 5, 13, 14, 23]. Furthermore, the majority of cancer survivors experience fatigue following cancer treatment [17], which often results in reduced physical activity and subsequent deconditioning. Despite evidence that cancer treatment can severely reduce CRF, normative CRF data for cancer survivors do not exist to date. For cancer survivors, classification of fitness using norms for the apparently healthy population is not only inappropriate, but may also be discouraging as perception of CRF has been shown to influence psychological well-being in the cancer population, regardless of true physiological capacity [21]. The ability to evaluate individuals within the cancer population allows cancer exercise specialists to more precisely assess cancer population-specific initial fitness status and identify
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
Clinical Sciences 1135
Methods
▼
Study population Data from 703 cancer survivors ranging in age from 19 to 90 years were compiled to evaluate CRF data for the cancer population. Study participants were referred by their oncologists to a cancer rehabilitation program in northern Colorado for an exercise intervention. Upon acceptance to the program, assessments of aerobic capacity and pulmonary function were performed. ▶ Table 1. Using a Detailed subject characteristics are found in ● multifactor ANCOVA that controls for age, no significant differences were found in CRF across cancer type (p = 0.0598), cancer stage (p = 0.2115), treatment status (p = 0.5526), chemotherapy treatment (p = 0.0946), surgery (p = 0.9546), or radiation treatment (p = 0.1515). All cancer survivors were therefore analyzed as one group for the normative data tables. Physical activity questionnaires were given to cancer survivors prior to fitness assessments, and it was determined that 46.4 % of participants exercise on a regular basis. This compares favorably to data from the 2011 National Health Interview Survey (NHIS) which indicate that 48.4 % of the US population meet the aerobic exercise recommendations established by the 2008 Physical Activity Guidelines for Americans [2].
Assessment of fitness All study procedures were approved by the University Institutional Review Board and complied with the ethical standards of this journal [8]. Informed consent was obtained before participation in the study. Cancer survivors exercised to volitional fatigue using the Bruce treadmill protocol or, in the case of subjects with low functional capacity, an internally validated protocol with approximately 0.5 MET increments every minute. Oxygen consumption was determined by ACSM prediction equations [20]. To evaluate test reliability and objectivity, a subset of 15 participants was reassessed by a different cancer exercise specialist and utilizing the alternate treadmill protocol one week apart, yielding a reliability coefficient of r = 0.92. Expired gas analysis was utilized during these assessments to validate VO2peak values derived from the ACSM equations. Pulmonary function assessment was conducted on 632 individuals and included forced vital capacity (FVC) and forced expiratory volume (FEV1), both of which were measured using a Spiromentrics Flowmate Plus dry spirometer (Auburn ME, USA). Pulmonary function was expressed as percent of age, gender and heightpredicted values, and classified as low (< 75 %), low limit of normal (75–80 %), within normal limits (81–94 %) or excellent (95 %).
Development of normative categories Participants were assigned to the same 10 age and sex groups used by ACSM (19–39, 40–49, 50–59, 60–69, and ≥ 70 years of age) for classification of VO2peak values. CRF values were compiled into quintiles for each group, establishing a set of cancerspecific CRF distributions. The quintiles were identified in terms that are intended to be easily distinguished from disease status:
Table 1 Subject characteristics. N females ( %) age (years) cancer type ( %) breast male urological malignancies (including prostate) hematological colon gynecological glandular and epithelial neoplasms lung melanoma and squamous cell carcinoma sarcoma brain cancer treatments ( %) surgery alone chemotherapy alone radiation alone surgery and chemotherapy surgery and radiation surgery, chemotherapy, and radiation still in treatment ( %) months out of treatment (excluding patients in treatment) cancer Stage a ( %) 1 2 3 4 body fat percentage VO2peak (mL · kg − 1 · min − 1) physically active prior to cancer diagnosis ( %) prior exercise frequency ( % of previously active) 1–2 days/week 3–4 days/week 5 + days/week prior exercise duration ( % of previously active) < 30 min 30–60 min > 60 min prior intensity exercise ( % of previously active) mild/low moderate vigorous a
703 78 57.4 ± 11.2 51 10 10 7 6 5 5 3 2 1 25 7 2 47 6 12 23 7.5 ± 9.8 28 22 23 27 30.8 ± 7.7 21.7 ± 6.9 46 16 43 41 27 46 28 51 45 3
Only includes diagnoses staged using the 1–4 TNM scale
low, below average, average, above average and excellent. The cutoff values for these quintiles, equating the 20th, 40th, 60th, and 80th percentiles of the cancer population, were contrasted with the same percentiles of the general United States (US) population [20]. For the purposes of this analysis, summary data was provided directly by the Cooper Institute. The distributions of scores obtained for VO2peak, FVC, and FEV1 from the cancer population were characterized using means and standard deviations, medians, skewness, and kurtosis and compared to the Cooper Institute reference population. Cancer population median values were compared to the centers of the reference data using the Wilcoxon signed-ranks test for each of the 10 cross-classifications and again for the whole data set. Standard deviations for the cancer population were compared to those of the reference data using chi-square tests of variation for each of the 10 cross-classifications and again for the whole data set. A Bonferroni correction was applied to the standard significance level of 0.05, producing a significance level of 0.017 for each of the 3 tests for center, variation, and normality.
Schneider CM et al. Demonstration of the Need … Int J Sports Med 2014; 35: 1134–1137
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
clinically significant improvements following an exercise intervention. Accordingly, cancer survivors’ psychological status may be enhanced by providing a greater sense of self efficacy at the time of reassessment [4]. The purpose of this study was to therefore demonstrate the need to establish normative CRF data for cancer survivors.
1136 Clinical Sciences
Age
N
Low
Below
Average
average VO2 peak (mL · kg − 1 · min − 1) Females 19–39 47 ≤ 20.7 20.8–23.7 40–49 114 ≤ 18.0 18.1–21.7 50–59 189 ≤ 17.6 17.7–21.3 60–69 132 ≤ 15.2 15.3–17.5 ≥ 70 64 ≤ 12.1 12.2–15.9 Males 19–39 12 ≤ 24.5 24.6–24.9 40–49 15 ≤ 22.1 22.2–24.5 50–59 25 ≤ 16.6 16.7–19.5 60–69 41 ≤ 14.2 14.3–17.3 ≥ 70 64 ≤ 13.0 13.1–15.8
Above
Excel-
average
lent
Table 4 Cancer population aerobic capacity vs. general US population (Cooper Institute values) (N = 703). Age
N
Cancer
Median
Mean (SD) 23.8–26.7 21.8–24.5 21.4–23.4 17.6–20.9 16.0–18.0
26.8–31.5 24.6–29.1 23.5–26.8 21.0–25.3 18.1–22.8
≥ 31.6 ≥ 29.2 ≥ 26.9 ≥ 25.4 ≥ 22.9
25.0–27.6 24.6–30.3 19.6–22.6 17.4–22.9 15.9–21.2
27.7–34.9 30.4–34.3 22.7–29.1 23.0–28.4 21.3–24.8
≥ 35.0 ≥ 34.4 ≥ 29.2 ≥ 28.5 ≥ 24.9
VO2 peak (mL · kg − 1 · min − 1) Females 19–39 47 26.10 (7.42) 40–49 114 23.42 (6.87) 50–59 189 22.26 (5.74) 60–69 132 19.84 (6.10) ≥ 70 64 17.82 (6.13) Males 19–39 12 26.80 (7.70) 40–49 15 27.46 (7.63) 50–59 25 21.79 (7.16) 60–69 41 20.55 (7.46) ≥ 70 64 19.16 (6.34)
US
p-value
mean
ACSM classification
25.25 23.34 22.74 18.36 17.05
36.07 33.76 30.33 27.52 25.59
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
very poor very poor very poor very poor very poor
26.52 28.50 20.68 19.10 19.45
43.29 40.82 37.03 33.09 29.96
0.0005 < 0.0001 < 0.0001 < 0.0001 < 0.0001
very poor very poor very poor very poor very poor
Table 3 Pulmonary function norms for cancer survivors (N = 632). Age
Low
Below
Average
average
Above
Excellent
average
a
FVC ( % of predicted) Females 19–39 ≤ 92 93–100 40–49 ≤ 83 84–96 50–59 ≤ 85 86–96 60–69 ≤ 80 81–92 ≥ 70 ≤ 74 75–86 Males 19–39 ≤ 61 62–88 40–49 ≤ 71 72–88 50–59 ≤ 81 82–90 60–69 ≤ 78 79–85 ≥ 70 ≤ 86 87–99 FEV1 ( % of predicted)b Females 19–39 ≤ 78 79–95 40–49 ≤ 77 78–92 50–59 ≤ 78 79–90 60–69 ≤ 71 72–88 ≥ 70 ≤ 64 65–78 Males 19–39 ≤ 54 55–75 40–49 ≤ 80 81–88 50–59 ≤ 71 72–90 60–69 ≤ 72 73–77 ≥ 70 ≤ 76 77–91 a
101–111 97–105 97–103 93–102 87–99
112–121 106–113 104–115 103–116 100–111
≥ 122 ≥ 114 ≥ 116 ≥ 117 ≥ 112
89–97 89–104 91–100 86–94 100–106
98–105 105–113 101–114 95–110 107–112
≥ 106 ≥ 114 ≥ 115 ≥ 111 ≥ 113
96–102 93–100 91–101 89–96 79–90
103–122 101–110 102–115 97–111 91–105
≥ 123 ≥ 111 ≥ 116 ≥ 112 ≥ 106
76–92 89–103 91–105 78–90 92–103
93–105 104–111 106–115 91–101 104–110
≥ 106 ≥ 112 ≥ 116 ≥ 102 ≥ 111
FVC = forced vital capacity; b FEV1 = forced expiratory volume in 1 s
Results
▼
Cancer-specific VO2peak normative values for females and males ▶ Table 2. Reliability and objectivity testing indiare found in ● cated no significant difference between method of VO2peak quantification (p = 0.72) or treadmill protocol used (p = ▶ Table 3 contains cancer-specific FVC and FEV distribu0.86). ● 1 tions for female and male cancer survivors. Statistics describing the distributions of VO2peak for subgroups of the cancer population, along with comparisons to Cooper Institute reference val▶ Table 4. For each age group, ues and classifications are found in ● the cancer population shows clear evidence of a difference from the general population in VO2peak, as all p-values for the Wilcoxon signed-ranks test show significance at our corrected level
of 0.017. Based on chi-square tests of variation, there is no evidence that the variation in VO2peak differs for the cancer population. Overall, VO2peak values are significantly different for the entire cancer population compared to the general population, as there is clear evidence of a difference between the median VO2peak and the 50th percentile of the reference values. ▶ Table 5, are simFVC values in the cancer population, found in ● ilar to the general population for all groups. The male subgroups of the cancer population exhibit normal distributions, while all female groups do not. The discrepancies from normality in females seem to be caused by positive skewness (unexpected proportions of high observations, with skew ranging from 1.32 to 2.04) and by positive kurtosis (a tightly clustered distribution, with kurtosis values ranging from 2.12 to 6.69). FEV1 values were clearly lower in the older female and lung cancer subgroups. There is no evidence of non-normality of FEV1 values for males, but there is evidence of non-normality of FEV1 values for all female groups. The non-normality is characterized by negative skewness (unexpected proportions of low observations, with skew ranging from − 0.84 to − 1.48) and by positive kurtosis (with kurtosis values ranging from 0.57 to 3.53). Overall, there is evidence that FEV1 values for the cancer population showed non-normality for the female subgroups due to negative skewness and positive kurtosis.
Discussion
▼
We propose that normative data from an apparently healthy general population is inappropriate for cancer survivors. Furthermore, we assert that cancer survivors represent a distinct population that mandates cancer population-specific normative data. The cancer population average in each age group fell within the “very poor” classification for VO2peak values using general population normative data. Age-specific VO2peak was strikingly lower in all cancer age groups, ranging from 27 to 31 % lower for females and 33 to 41 % lower for males. FVC for cancer survivors appears to be similar to the general population, as values fell within the “excellent” to “within normal limits” classifications even for lung cancer patients. Alternately, 35 % of the cancer population and all LC patients had “lower limit of normal” values for FEV1. Other studies indicate that neither FVC nor FEV1 change significantly in breast cancer patients following local or regional radiotherapy alone [12] or in conjunction with chemotherapy [19].
Schneider CM et al. Demonstration of the Need … Int J Sports Med 2014; 35: 1134–1137
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Table 2 Aerobic capacity norms for cancer survivors (N = 703).
Clinical Sciences 1137 Conflict of interest: The authors have no conflict of interest to declare.
Age
N
FVC ( % of predicted) a Females 19–39 52 40–49 103 50–59 159 60–69 121 ≥ 70 68 21 LCc Males 19–39 12 40–49 15 50–59 33 60–69 33 ≥ 70 36 LC 12 FEV1 ( % of predicted) d Females 19–39 51 40–49 109 50–59 162 60–69 122 ≥ 70 68 LC 21 Males 19–39 13 40–49 15 50–59 32 60–69 33 ≥ 70 36 LC 12
Cancer mean (SD)
ACSM classification
104.5 (16.50) 99.8 (16.44) 100.0 (17.90) 97.0 (21.20) 91.8 (22.90) 86.6 (22.00)
excellent excellent excellent excellent WNL b WNL
88.9 (21.70) 99.8 (17.22) 98.0 (20.10) 92.1 (23.60) 102.4 (18.70) 83.6 (25.00)
WNL excellent excellent WNL excellent WNL
91.1 (32.46) 90.6 (24.85) 88.6 (28.51) 79.2 (32.49) 79.1 (29.37) 80.1 (24.80)
WNL WNL WNL LLN e LLN LLN
86.2 (21.73) 90.5 (33.07) 92.5 (30.29) 85.6 (24.60) 90.6 (32.38) 76.7 (20.50)
WNL WNL WNL WNL WNL LLN
a
FVC = forced vital capacity; b WNL = within normal limits c LC = lung cancer;
d
FEV1 = forced expiratory volume in 1 s; e LLN = lower limits of normal
Currently, there are no published normative CRF data specific to cancer survivors. The cancer-specific VO2peak distributions from the current study are substantially lower than the general population for all age and sex groups. It would therefore be practical to use these values to classify cancer survivors within their own population to more appropriately evaluate their fitness and more precisely detect improvements in population-specific fitness classification following an exercise intervention. Pulmonary function was not drastically altered in the cancer population as a whole, but FEV1 were lower than the US population in some subgroups. While a meta-analysis of VO2peak data derived from expired gas analyses would be required to establish a definitive normative dataset for the cancer population, we propose that the VO2peak distributions presented here be used in addition to reference data from the general US population during the assessment and evaluation of cancer populations both before and after engaging in exercise interventions.
Acknowledgements
▼
Funding received for this work from the Department of Health & Human Services, Susan G. Komen Foundation, Caring for Colorado Foundation, Cleveland Foundation, North Colorado Medical Center and the University of Northern Colorado Faculty Research & Publications Board. The authors declare that they have no conflict of interest or financial disclosures.
References 1 Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, Hagerty KL, Somerfield MR, Vaughn DJ. ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991–4008 2 Centers for Disease Control and Prevention. Adult participation in aerobic and muscle-strengthening physical activities – United States, 2011. MMWR Morb Mortal Wkly Rep 2013; 62: 326–330 3 Chandran K, Aggarwal D, Migrino RQ, Joseph J, McAllister D, Konorev EA, Antholine WE, Zielonka J, Srinivasan S, Avadhani NG, Kalyanaraman B. Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys J 2009; 96: 1388–1398 4 Cunningham AJ, Lockwood GA, Cunningham JA. A relationship between perceived self-efficacy and quality of life in cancer patients. Patient Ednc Couns 1991; 17: 71–78 5 DeVita V, Hellman S, Rosenberg S (ed.). Cancer: Principles and Practice of Oncology. 7th ed. Philadephia: Lippincott Williams & Wilkins, 2005 6 Dimeo F, Fetscher S, Lange W, Mertelsmann R, Keul J. Effects of aerobic exercise on the physical performance and incidence of treatmentrelated complications after high-dose chemotherapy. Blood 1997; 90: 3390–3394 7 Ewer MS, Swain SM, Cardinale D, Fadol A, Suter TM. Cardiac dysfunction after cancer treatment. Texas Heart Inst J 2011; 38: 248–252 8 Harriss DJ, Atkinson G. Ethical standards in sports and exercise science research: 2014 update. Int J Sports Med 2013; 34: 1025–1028 9 Hayward R, Hydock DS. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci 2007; 46: 20–32 10 Hydock DS, Lien CY, Hayward R. Anandamide preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model. J Cardiovasc Pharmacol Ther 2009; 14: 59–67 11 Jones LW, Eves ND, Mackey JR, Peddle CJ, Haykowsky M, Joy AA, Courneya KS, Tankel K, Spratlin J, Reiman T. Safety and feasibility of cardiopulmonary exercise testing in patients with advanced cancer. Lung cancer 2007; 55: 225–232 12 Lind PA, Rosfors S, Wennberg B, Glas U , Bevergård S , Fornander T. Pulmonary function following adjuvant chemotherapy and radiotherapy for breast cancer and the issue of three-dimensional treatment planning. Radiother Oncol 1998; 49: 245–254 13 Makker V, Spriggs D. Principles of Chemotherapy. In: Stubblefield MD, O'Dell MW (eds.). Cancer Rehabilitation: Principles and Practice. New York: Demos Medical Publishing, 2009; 23–52 14 Schneider CM, Dennehy CA, Carter SD. Exercise and Cancer Recovery. Champaign: Human Kinetics, 2003 15 Schneider CM, Hsieh CC, Sprod LK, Carter SD, Hayward R. Cancer treatment-induced alterations in muscular fitness and quality of life: the role of exercise training. Ann Oncol 2007; 18: 1957–1962 16 Simunek T, Sterba M, Popelova O, Adamcova M, Hrdina R, Gersl V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep: PR 2009; 61: 154–171 17 Smets EM, Garssen B, Schuster-Uitterhoeve AL, de Haes JC. Fatigue in cancer patients. Br J Cancer 1993; 68: 220–224 18 Starkweather A. Increased interleukin-6 activity associated with painful chemotherapy-induced peripheral neuropathy in women after breast cancer treatment. Nurs Res Pract 2010; 2010: 281531 19 Theuws JC, Muller SH, Seppenwoolde Y, Kwa SL, Boersma LJ, Hart GA, Baas P, Lebesque JV. Effect of radiotherapy and chemotherapy on pulmonary function after treatment for breast cancer and lymphoma: A follow-up study. J Clin Oncol 1999; 17: 3091–3100 20 Thomson WR, Gordon NF, Pescatello L. ACSM’s Guidelines for Exericse Testing and Prescription. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2010 21 Thorsen L, Nystad W, Stigum H, Hjermstad M, Oldervoll L, Martinsen EW, Hornslien K, Strømme SB, Dahl AA, Fosså SD. Cardiorespiratory fitness in relation to self-reported physical function in cancer patients after chemotherapy. The J Sports Med Phys Fitness 2006; 46: 122–127 22 Wampler MA, Topp KS, Miaskowski C, Byl NN, Rugo HS, Hamel K. Quantitative and clinical description of postural instability in women with breast cancer treated with taxane chemotherapy. Arch Phys Med Rehabil 2007; 88: 1002–1008 23 Wauters I, Vansteenkiste J. Darbepoetin alfa in the treatment of anemia in cancer patients undergoing chemotherapy. Expert Rev Anticancer Ther 2012; 12: 1383–1390
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Table 5 Cancer population pulmonary function vs. ACSM classifications (N = 632).
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Demonstration of the Need for Cardiovascular and Pulmonary Normative Data for Cancer Survivors
Affiliations
Key words ▶ cancer rehabilitation ● ▶ population-specific ● normative values ▶ exercise ● ▶ cancer treatment side ● effects
C. M. Schneider1, C. P. Repka1, J. M. Brown1, T. L. Lalonde2, K. T. Dallow3, C. E. Barlow4, R. Hayward1 1
Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, United States Department of Applied Statistics and Research Methods, University of Northern Colorado, Greeley, United States 3 Family Medicine, North Colorado Medical Center, Greeley, United States 4 Research Department, The Cooper Institute, Dallas, United States 2
Abstract
▼
Despite evidence that cancer and its treatments severely reduce cardiorespiratory fitness (CRF), normative data for cancer survivors do not exist. The present study identifies age and genderspecific CRF distributions in a cancer population. The use of cancer-specific normative CRF data may help stratify initial fitness status and assess improvements in response to exercise interventions in cancer survivors. Data from 703 cancer survivors were analyzed for this study. Quintiles were compiled for peak oxygen consumption (VO2peak), forced vital capacity (FVC), and forced expiratory volume (FEV1) for males and females in 5 age groups (19–39, 40–49, 50–59,
Introdution
▼ accepted after revision April 14, 2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375691 Published online: July 4, 2014 Int J Sports Med 2014; 35: 1134–1137 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0172-4622 Correspondence Chris P. Repka Rocky Mountain Cancer Rehabilitation Institute University of Northern Colorado Campus Box 6 Greeley United States 80639 Tel.: + 1/908/419 2767 Fax: + 1/970/351 1720 [email protected]
Cancer mortality rates have decreased in recent years, resulting in more cancer survivors living with detrimental treatment-associated side effects. The cytotoxic effects of cancer treatments can damage healthy tissues within the heart, lung, skeletal muscle, circulatory system and nervous system [13, 14]. These physiological alterations can lead to reduced functional capacity [6], cardiac dysfunction [7, 9], pulmonary dysfunction [12], peripheral neuropathy [18], muscular weakness [15] and postural instability [22]. These alterations can result in a drastic decrease in cardiorespiratory function [11]. Reduced cardiorespiratory fitness (CRF) following cancer therapy is the result of damage to systems supporting aerobic capacity. For example, chemotherapy treatment with anthracyclines such as doxorubicin are characterized by a dose dependent cardiotoxicity [16], resulting in altered cardiac myosin heavy chain expression, along with reductions in left ventricular mass, relative wall thickness, fractional shortening and maximal cardiac flow velocities [9, 10]. Such treatments have also
Schneider CM et al. Demonstration of the Need … Int J Sports Med 2014; 35: 1134–1137
60–69, and ≥ 70 years of age). VO2peak values for the cancer population were significantly lower than the general US population. The cancer population average in each age group fell within the “very poor” classification of VO2peak values for the general population. FVC values in the cancer population were similar to the general population. Cancer survivors had very low age group-specific VO2peak values compared to the apparently healthy general US population. Previously, CRF values of cancer survivors were compared to normative values for the apparently healthy general population, which yielded imprecise classifications of initial fitness and changes in fitness, resulting in patient discouragement.
been shown to inactivate important mitochondrial enzymes, such as myocardial cytochrome c oxidase [3]. Other treatment-associated side effects, including mitochondrial and cardiac pathologies, cachexia, anemia, and pulmonary and endothelial dysfunction are well established in clinical oncology and cancer rehabilitation literature [1, 5, 13, 14, 23]. Furthermore, the majority of cancer survivors experience fatigue following cancer treatment [17], which often results in reduced physical activity and subsequent deconditioning. Despite evidence that cancer treatment can severely reduce CRF, normative CRF data for cancer survivors do not exist to date. For cancer survivors, classification of fitness using norms for the apparently healthy population is not only inappropriate, but may also be discouraging as perception of CRF has been shown to influence psychological well-being in the cancer population, regardless of true physiological capacity [21]. The ability to evaluate individuals within the cancer population allows cancer exercise specialists to more precisely assess cancer population-specific initial fitness status and identify
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
Clinical Sciences 1135
Methods
▼
Study population Data from 703 cancer survivors ranging in age from 19 to 90 years were compiled to evaluate CRF data for the cancer population. Study participants were referred by their oncologists to a cancer rehabilitation program in northern Colorado for an exercise intervention. Upon acceptance to the program, assessments of aerobic capacity and pulmonary function were performed. ▶ Table 1. Using a Detailed subject characteristics are found in ● multifactor ANCOVA that controls for age, no significant differences were found in CRF across cancer type (p = 0.0598), cancer stage (p = 0.2115), treatment status (p = 0.5526), chemotherapy treatment (p = 0.0946), surgery (p = 0.9546), or radiation treatment (p = 0.1515). All cancer survivors were therefore analyzed as one group for the normative data tables. Physical activity questionnaires were given to cancer survivors prior to fitness assessments, and it was determined that 46.4 % of participants exercise on a regular basis. This compares favorably to data from the 2011 National Health Interview Survey (NHIS) which indicate that 48.4 % of the US population meet the aerobic exercise recommendations established by the 2008 Physical Activity Guidelines for Americans [2].
Assessment of fitness All study procedures were approved by the University Institutional Review Board and complied with the ethical standards of this journal [8]. Informed consent was obtained before participation in the study. Cancer survivors exercised to volitional fatigue using the Bruce treadmill protocol or, in the case of subjects with low functional capacity, an internally validated protocol with approximately 0.5 MET increments every minute. Oxygen consumption was determined by ACSM prediction equations [20]. To evaluate test reliability and objectivity, a subset of 15 participants was reassessed by a different cancer exercise specialist and utilizing the alternate treadmill protocol one week apart, yielding a reliability coefficient of r = 0.92. Expired gas analysis was utilized during these assessments to validate VO2peak values derived from the ACSM equations. Pulmonary function assessment was conducted on 632 individuals and included forced vital capacity (FVC) and forced expiratory volume (FEV1), both of which were measured using a Spiromentrics Flowmate Plus dry spirometer (Auburn ME, USA). Pulmonary function was expressed as percent of age, gender and heightpredicted values, and classified as low (< 75 %), low limit of normal (75–80 %), within normal limits (81–94 %) or excellent (95 %).
Development of normative categories Participants were assigned to the same 10 age and sex groups used by ACSM (19–39, 40–49, 50–59, 60–69, and ≥ 70 years of age) for classification of VO2peak values. CRF values were compiled into quintiles for each group, establishing a set of cancerspecific CRF distributions. The quintiles were identified in terms that are intended to be easily distinguished from disease status:
Table 1 Subject characteristics. N females ( %) age (years) cancer type ( %) breast male urological malignancies (including prostate) hematological colon gynecological glandular and epithelial neoplasms lung melanoma and squamous cell carcinoma sarcoma brain cancer treatments ( %) surgery alone chemotherapy alone radiation alone surgery and chemotherapy surgery and radiation surgery, chemotherapy, and radiation still in treatment ( %) months out of treatment (excluding patients in treatment) cancer Stage a ( %) 1 2 3 4 body fat percentage VO2peak (mL · kg − 1 · min − 1) physically active prior to cancer diagnosis ( %) prior exercise frequency ( % of previously active) 1–2 days/week 3–4 days/week 5 + days/week prior exercise duration ( % of previously active) < 30 min 30–60 min > 60 min prior intensity exercise ( % of previously active) mild/low moderate vigorous a
703 78 57.4 ± 11.2 51 10 10 7 6 5 5 3 2 1 25 7 2 47 6 12 23 7.5 ± 9.8 28 22 23 27 30.8 ± 7.7 21.7 ± 6.9 46 16 43 41 27 46 28 51 45 3
Only includes diagnoses staged using the 1–4 TNM scale
low, below average, average, above average and excellent. The cutoff values for these quintiles, equating the 20th, 40th, 60th, and 80th percentiles of the cancer population, were contrasted with the same percentiles of the general United States (US) population [20]. For the purposes of this analysis, summary data was provided directly by the Cooper Institute. The distributions of scores obtained for VO2peak, FVC, and FEV1 from the cancer population were characterized using means and standard deviations, medians, skewness, and kurtosis and compared to the Cooper Institute reference population. Cancer population median values were compared to the centers of the reference data using the Wilcoxon signed-ranks test for each of the 10 cross-classifications and again for the whole data set. Standard deviations for the cancer population were compared to those of the reference data using chi-square tests of variation for each of the 10 cross-classifications and again for the whole data set. A Bonferroni correction was applied to the standard significance level of 0.05, producing a significance level of 0.017 for each of the 3 tests for center, variation, and normality.
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clinically significant improvements following an exercise intervention. Accordingly, cancer survivors’ psychological status may be enhanced by providing a greater sense of self efficacy at the time of reassessment [4]. The purpose of this study was to therefore demonstrate the need to establish normative CRF data for cancer survivors.
1136 Clinical Sciences
Age
N
Low
Below
Average
average VO2 peak (mL · kg − 1 · min − 1) Females 19–39 47 ≤ 20.7 20.8–23.7 40–49 114 ≤ 18.0 18.1–21.7 50–59 189 ≤ 17.6 17.7–21.3 60–69 132 ≤ 15.2 15.3–17.5 ≥ 70 64 ≤ 12.1 12.2–15.9 Males 19–39 12 ≤ 24.5 24.6–24.9 40–49 15 ≤ 22.1 22.2–24.5 50–59 25 ≤ 16.6 16.7–19.5 60–69 41 ≤ 14.2 14.3–17.3 ≥ 70 64 ≤ 13.0 13.1–15.8
Above
Excel-
average
lent
Table 4 Cancer population aerobic capacity vs. general US population (Cooper Institute values) (N = 703). Age
N
Cancer
Median
Mean (SD) 23.8–26.7 21.8–24.5 21.4–23.4 17.6–20.9 16.0–18.0
26.8–31.5 24.6–29.1 23.5–26.8 21.0–25.3 18.1–22.8
≥ 31.6 ≥ 29.2 ≥ 26.9 ≥ 25.4 ≥ 22.9
25.0–27.6 24.6–30.3 19.6–22.6 17.4–22.9 15.9–21.2
27.7–34.9 30.4–34.3 22.7–29.1 23.0–28.4 21.3–24.8
≥ 35.0 ≥ 34.4 ≥ 29.2 ≥ 28.5 ≥ 24.9
VO2 peak (mL · kg − 1 · min − 1) Females 19–39 47 26.10 (7.42) 40–49 114 23.42 (6.87) 50–59 189 22.26 (5.74) 60–69 132 19.84 (6.10) ≥ 70 64 17.82 (6.13) Males 19–39 12 26.80 (7.70) 40–49 15 27.46 (7.63) 50–59 25 21.79 (7.16) 60–69 41 20.55 (7.46) ≥ 70 64 19.16 (6.34)
US
p-value
mean
ACSM classification
25.25 23.34 22.74 18.36 17.05
36.07 33.76 30.33 27.52 25.59
< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001
very poor very poor very poor very poor very poor
26.52 28.50 20.68 19.10 19.45
43.29 40.82 37.03 33.09 29.96
0.0005 < 0.0001 < 0.0001 < 0.0001 < 0.0001
very poor very poor very poor very poor very poor
Table 3 Pulmonary function norms for cancer survivors (N = 632). Age
Low
Below
Average
average
Above
Excellent
average
a
FVC ( % of predicted) Females 19–39 ≤ 92 93–100 40–49 ≤ 83 84–96 50–59 ≤ 85 86–96 60–69 ≤ 80 81–92 ≥ 70 ≤ 74 75–86 Males 19–39 ≤ 61 62–88 40–49 ≤ 71 72–88 50–59 ≤ 81 82–90 60–69 ≤ 78 79–85 ≥ 70 ≤ 86 87–99 FEV1 ( % of predicted)b Females 19–39 ≤ 78 79–95 40–49 ≤ 77 78–92 50–59 ≤ 78 79–90 60–69 ≤ 71 72–88 ≥ 70 ≤ 64 65–78 Males 19–39 ≤ 54 55–75 40–49 ≤ 80 81–88 50–59 ≤ 71 72–90 60–69 ≤ 72 73–77 ≥ 70 ≤ 76 77–91 a
101–111 97–105 97–103 93–102 87–99
112–121 106–113 104–115 103–116 100–111
≥ 122 ≥ 114 ≥ 116 ≥ 117 ≥ 112
89–97 89–104 91–100 86–94 100–106
98–105 105–113 101–114 95–110 107–112
≥ 106 ≥ 114 ≥ 115 ≥ 111 ≥ 113
96–102 93–100 91–101 89–96 79–90
103–122 101–110 102–115 97–111 91–105
≥ 123 ≥ 111 ≥ 116 ≥ 112 ≥ 106
76–92 89–103 91–105 78–90 92–103
93–105 104–111 106–115 91–101 104–110
≥ 106 ≥ 112 ≥ 116 ≥ 102 ≥ 111
FVC = forced vital capacity; b FEV1 = forced expiratory volume in 1 s
Results
▼
Cancer-specific VO2peak normative values for females and males ▶ Table 2. Reliability and objectivity testing indiare found in ● cated no significant difference between method of VO2peak quantification (p = 0.72) or treadmill protocol used (p = ▶ Table 3 contains cancer-specific FVC and FEV distribu0.86). ● 1 tions for female and male cancer survivors. Statistics describing the distributions of VO2peak for subgroups of the cancer population, along with comparisons to Cooper Institute reference val▶ Table 4. For each age group, ues and classifications are found in ● the cancer population shows clear evidence of a difference from the general population in VO2peak, as all p-values for the Wilcoxon signed-ranks test show significance at our corrected level
of 0.017. Based on chi-square tests of variation, there is no evidence that the variation in VO2peak differs for the cancer population. Overall, VO2peak values are significantly different for the entire cancer population compared to the general population, as there is clear evidence of a difference between the median VO2peak and the 50th percentile of the reference values. ▶ Table 5, are simFVC values in the cancer population, found in ● ilar to the general population for all groups. The male subgroups of the cancer population exhibit normal distributions, while all female groups do not. The discrepancies from normality in females seem to be caused by positive skewness (unexpected proportions of high observations, with skew ranging from 1.32 to 2.04) and by positive kurtosis (a tightly clustered distribution, with kurtosis values ranging from 2.12 to 6.69). FEV1 values were clearly lower in the older female and lung cancer subgroups. There is no evidence of non-normality of FEV1 values for males, but there is evidence of non-normality of FEV1 values for all female groups. The non-normality is characterized by negative skewness (unexpected proportions of low observations, with skew ranging from − 0.84 to − 1.48) and by positive kurtosis (with kurtosis values ranging from 0.57 to 3.53). Overall, there is evidence that FEV1 values for the cancer population showed non-normality for the female subgroups due to negative skewness and positive kurtosis.
Discussion
▼
We propose that normative data from an apparently healthy general population is inappropriate for cancer survivors. Furthermore, we assert that cancer survivors represent a distinct population that mandates cancer population-specific normative data. The cancer population average in each age group fell within the “very poor” classification for VO2peak values using general population normative data. Age-specific VO2peak was strikingly lower in all cancer age groups, ranging from 27 to 31 % lower for females and 33 to 41 % lower for males. FVC for cancer survivors appears to be similar to the general population, as values fell within the “excellent” to “within normal limits” classifications even for lung cancer patients. Alternately, 35 % of the cancer population and all LC patients had “lower limit of normal” values for FEV1. Other studies indicate that neither FVC nor FEV1 change significantly in breast cancer patients following local or regional radiotherapy alone [12] or in conjunction with chemotherapy [19].
Schneider CM et al. Demonstration of the Need … Int J Sports Med 2014; 35: 1134–1137
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Table 2 Aerobic capacity norms for cancer survivors (N = 703).
Clinical Sciences 1137 Conflict of interest: The authors have no conflict of interest to declare.
Age
N
FVC ( % of predicted) a Females 19–39 52 40–49 103 50–59 159 60–69 121 ≥ 70 68 21 LCc Males 19–39 12 40–49 15 50–59 33 60–69 33 ≥ 70 36 LC 12 FEV1 ( % of predicted) d Females 19–39 51 40–49 109 50–59 162 60–69 122 ≥ 70 68 LC 21 Males 19–39 13 40–49 15 50–59 32 60–69 33 ≥ 70 36 LC 12
Cancer mean (SD)
ACSM classification
104.5 (16.50) 99.8 (16.44) 100.0 (17.90) 97.0 (21.20) 91.8 (22.90) 86.6 (22.00)
excellent excellent excellent excellent WNL b WNL
88.9 (21.70) 99.8 (17.22) 98.0 (20.10) 92.1 (23.60) 102.4 (18.70) 83.6 (25.00)
WNL excellent excellent WNL excellent WNL
91.1 (32.46) 90.6 (24.85) 88.6 (28.51) 79.2 (32.49) 79.1 (29.37) 80.1 (24.80)
WNL WNL WNL LLN e LLN LLN
86.2 (21.73) 90.5 (33.07) 92.5 (30.29) 85.6 (24.60) 90.6 (32.38) 76.7 (20.50)
WNL WNL WNL WNL WNL LLN
a
FVC = forced vital capacity; b WNL = within normal limits c LC = lung cancer;
d
FEV1 = forced expiratory volume in 1 s; e LLN = lower limits of normal
Currently, there are no published normative CRF data specific to cancer survivors. The cancer-specific VO2peak distributions from the current study are substantially lower than the general population for all age and sex groups. It would therefore be practical to use these values to classify cancer survivors within their own population to more appropriately evaluate their fitness and more precisely detect improvements in population-specific fitness classification following an exercise intervention. Pulmonary function was not drastically altered in the cancer population as a whole, but FEV1 were lower than the US population in some subgroups. While a meta-analysis of VO2peak data derived from expired gas analyses would be required to establish a definitive normative dataset for the cancer population, we propose that the VO2peak distributions presented here be used in addition to reference data from the general US population during the assessment and evaluation of cancer populations both before and after engaging in exercise interventions.
Acknowledgements
▼
Funding received for this work from the Department of Health & Human Services, Susan G. Komen Foundation, Caring for Colorado Foundation, Cleveland Foundation, North Colorado Medical Center and the University of Northern Colorado Faculty Research & Publications Board. The authors declare that they have no conflict of interest or financial disclosures.
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Table 5 Cancer population pulmonary function vs. ACSM classifications (N = 632).
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