INTRODUCTION AND PURPOSE
Cure rates for acute lymphoblastic leukemia (ALL), the most common type of childhood cancer, have now risen to more than 85%,1,2 resulting in a growing cohort of survivors who are at potential risk for long-term complications from ALL and its therapy. One of these complications is the development of components of the metabolic syndrome, which includes obesity, hypertension, dyslipidemia, and insulin resistance.3,4 Recent data have indicated that these metabolic changes manifest first while patients are still receiving therapy, particularly during maintenance, a 2- to 3-year time period that includes pulses of corticosteroid treatment.5–8 Thus, the period of maintenance therapy, when patients are also found to be deconditioned with decreased muscle strength,9,10 appears optimal to develop a preventive intervention. The aim of this pilot study was to determine the feasibility and initial efficacy of an aerobic and strengthening exercise intervention program conducted during maintenance therapy among children treated for ALL.
Participants for this pilot study were recruited from among children being treated for ALL. Eligible children were between 5 and 10 years old at enrollment, in first remission, and in the maintenance phase of chemotherapy with at least 6 months of treatment remaining. Each child approached had a modified Lansky score of at least 60 and medical clearance to participate. Parents/guardians provided written informed consent and participants 8 to 10 years old provided assent prior to enrollment.
All participants in this pilot study received an intervention that included 6 months of ability specific, progressive stretching, strengthening, and aerobic exercise. The exercise intervention was designed to address 7 common neuromusculoskeletal and fitness impairments seen during and following treatment for childhood ALL including (1) impaired ankle range of motion, (2) distal lower extremity weakness, (3) proximal lower extremity weakness, (4) distal upper extremity weakness, (5) poor balance, (6) poor general fitness/coordination, and (7) poor aerobic fitness.11
The exercise intervention included 5 main exercise components: flexibility, ankle strengthening, leg strengthening, balance, and general fitness (Appendices 1 and 2, Supplemental Digital Contents 1 and 2, http://links.lww.com/PPT/A66 and http://links.lww.com/PPT/A67, respectively). Participants were instructed to complete prescribed flexibility, strengthening, and balance exercises 3 days per week, and to complete prescribed general fitness activities on 3 other days per week. Each workout took 30 to 45 minutes to complete. Weekly phone calls from an exercise coach (exercise physiologist, physical therapist, or study nurse) were made to answer participant and/or parent questions and to assess and progress the intensity and duration of the intervention. An assessment and progression of the intervention was also made during each medical clinic visit, approximately monthly. Participants were provided with necessary equipment for the prescribed exercises, detailed written and graphic instructions (Appendices 1 and 2, Supplemental Digital Contents 1 and 2, http://links.lww.com/PPT/A66 and http://links.lww.com/PPT/A67, respectively), a videotape demonstrating each exercise (see Videos, Supplemental Digital Content 3, http://links.lww.com/PPT/A68), and a log book (Appendix 3, Supplemental Digital Content 4, http://links.lww.com/PPT/A69) to record the exercise. Parents were given a supply of stickers and small toys to reward their children at their discretion.
Feasibility was evaluated by determining the percentage of children enrolled among those who were eligible and approached, the percentage of children who remained in the study, and the percentage of prescribed sessions completed among children who remained in the study.
Preliminary effectiveness of this intervention was evaluated by having participants complete both baseline and follow-up physical performance testing including measures of flexibility, strength, cardiopulmonary fitness, and age-specific motor performance. Height and weight were recorded and then converted into body mass index (BMI) using the formula weight (kilograms)/height2 (meters). Percentiles for BMI were calculated using age- and gender-standardized growth population data (based on the Centers for Disease Control and Prevention's Year 2000 growth charts).12 A BMI > 85th percentile adjusted for age and sex was considered overweight and >95th percentile was considered obese.12
General flexibility was evaluated with the sit and reach test. A yardstick was placed on a firm flat surface and tape placed across it at a right angle to the 15-inch mark. The participant sat with the yardstick between the legs, which were extended at right angles to a line taped on the floor. The heels of the feet touched the edge of the line and were 10 to 12 inches apart. The participant reached forward with the hands in parallel as far as possible. The best value for 3 trials, in centimeters, at the most distant point of the fingertips was recorded and used for analysis.13–15
Ankle dorsiflexion passive range of motion was measured with a goniometer with the child sitting with the hips and knees in 90° of flexion using standard procedures.16,17 The maximum of 2 trials was used for analysis.
Isometric knee extension strength in newton-meters (Nm) was measured with the subject seated in an adjustable straight-back chair. The pelvis and contralateral thigh were fixed with adjustable straps and the knee being tested flexed at 45°. The participant was instructed to exert a maximal voluntary force until their contraction was “broken.” Resistance was applied by the examiner with a hand-held myometer (Chatillion-Ametek, Largo, Florida) held against the anterior surface of the leg, just above the medial malleoli.17 The contraction was repeated 3 times with each leg; the peak values from each leg were averaged for analysis. Handgrip strength in kilograms was measured using a hand-held dynamometer (Jamar, Sammons Preston Rolyan, Nottinghamshire, the United Kingdom). Participants were seated with the shoulder in 0 to 10° of flexion and the elbow in 90° of flexion. The forearm was positioned in neutral. Each participant completed 3 trials; the peak value from each hand was averaged for analysis.18,19
The Bruininks-Oseretsky Test of Motor Proficiency Version 2 (BOT-2) Short Form was used to evaluate motor function. This norm-referenced instrument was designed to test gross and fine motor function, balance, and strength in children and adolescents aged 4 to 21 years. Coefficients range from 0.95 to 0.96 for internal consistency reliability and from 0.77 to 0.82 for test-retest reliability. The R 2 value for interrater reliability is 0.98. Scores consistently increase with the increasing age. The items were administered and scored according to the standardized procedures in the manual. Standard scores were used for analysis and range from 20 to 80 with a mean of 50 and a standard deviation of 10.20
Cardiopulmonary fitness was evaluated with the modified 6-Minute Walk Test (6MWT).21 Children used a wheeled measuring device with an adjustable handle to motivate them to keep walking and to determine distance in meters. Children were instructed to walk as far as possible along a 20-meter course, without jogging or running, in 6 minutes. Stopping, slowing down, and resting against the wall during the test were allowed, but the distance covered at the end of 6 minutes was the measurement used. Encouragement was given at 1-minute intervals.
Among the 27 participants eligible and approached to participate in this study, 17 (63.0%) agreed to enroll and completed baseline testing. Among the 10 who declined participation, 4 reported being too busy, 3 were not interested in doing exercises, and 3 gave no reason. Children who declined participation were, on average, 6.0 ± 1.8 years of age and 8 (80.0%) were male. Participants were similar in age to the nonparticipants (7.4 ± 2.0) and 12 (70.6%) were male. Among the 17 enrolled participants, 12 (70.6%) completed the study. Of the 5 who did not complete the study, 3 withdrew because they were unable to incorporate the exercises into their daily routines, 1 did not return for the final appointment, and 1 had leukemia relapse. Children primarily enrolled in this study in the fall and winter months. Those who dropped out were equally distributed across enrollment seasons. The 12 participants who completed the study completed 81.7 ± 7.2% of their prescribed exercise sessions.
Physical performance measures before and after the 6-month intervention are provided in Table 1. Overall, changes in flexibility, strength, age-specific motor performance, and cardiopulmonary fitness were positive, with the biggest percent changes in flexibility (81.4% for passive ankle dorsiflexion and 42.2% for the sit and reach test). Average handgrip strength improved by 16.9% and average distance walked in 6 minutes improved by 16.0%. Improvements of 5% or greater occurred in 67% for knee strength, 75% for hand grip strength, 58% for performance on the sit and reach test, 83% for ankle range of motion, 75% for the 6MWT, and 33% for age- and sex-specific standard scores on the BOT-2 Short Form. Body mass index also decreased by a mean of 4.2 percentile points, and weight was maintained or reduced among 8 patients with weights above the 75th percentiles, with 4 achieving normal weight by the end of the intervention. Only 1 subject who was not overweight became overweight during the study. There were no associations between changes in BMI and strength parameters.
Family and Coach Responses
In addition to improvements in functional measures, children and parents generally reported that they enjoyed the exercise program and felt that it was beneficial. Often, the entire family participated in the general exercise activity to encourage the child. Families universally expressed that the exercises were challenging during the weeks when the child's chemotherapy included dexamethasone and vincristine. The exercise coaches at the 2 sites reported that the program was easy to administer because it was well received by most children and their families. Successful strategies for coaching included making the exercises a game and engaging siblings. Families who were the most engaged required the least amount of follow-up from the exercise coach.
Sustained exercise interventions in patients with ALL during maintenance can be difficult as they are often deconditioned and have not made exercise a priority. However more than 75% of the patients who enrolled in this pilot study were at least 70% compliant with a 6-month exercise plan indicating feasibility. Furthermore, our results suggest that such an intervention will result in improvement of overall fitness. Of the patients who completed the study, half showed a 5% or greater improvement in at least 6 of the 7 metrics that were measured.
Many trials have evaluated exercise interventions in children with ALL, with differing sample sizes, methodology, and measurement,11,22–37 which make it difficult to directly compare results. Among 14 recent trials, the exercise intervention was implemented at different stages in therapy including the first 6 months of therapy, maintenance therapy, throughout therapy, off therapy, and post–stem cell transplant. Duration of the interventions ranges from less than 1 week to 2 years, with only 3 of the interventions 6 months or longer, and some included adolescents older than 12 years. Enrollment rates ranged from 56% to 100% and completion rates from 25% to100%, similar to our rates of 63% and 71%, respectively.
The maintenance phase of ALL therapy has been shown to be a key time period that puts patients at risk for excessive weight gain.5,6,8 Previous studies were not able to show an improvement in BMI after an exercise intervention.24,25,29,31 In a study of 51 children with ALL randomized to a 2-year exercise program versus usual care, weight gain was similar in both groups during therapy, but those in the intervention group showed a more rapid decline in body fat 1 year off therapy.22 Our intervention resulted in an overall trend of weight maintenance or loss with many patients maintaining or losing weight. In contrast to previous studies,22,24,25,29,31 our exercise program was longer than most and included an exercise coach.
Among children with ALL receiving therapy, muscle strength capacity has been shown to be worse than that in matched healthy controls in 2 studies.10,33 In the current pilot study, leg strengthening exercises were specifically targeted, which resulted in clinically important improvement (>5%) in knee extension in 75% of subjects. Although upper body strengthening was only targeted indirectly through general fitness exercises, a mean 17% improvement in hand grip was achieved among all participants. Our results demonstrating increases in muscle strength, measured by knee extension and grip, confirm those in other studies of short-term interventions, measured by knee extension strength,33 seated bench press, seated tow, and seated leg press29 and isometric muscle strength by dynamometer.26 However, other small studies did not demonstrate improvements of muscle strength.24,25
To improve overall fitness, we focused on flexibility exercises. The participants had modest gains on the sit and reach test, with more than half of the subjects showing substantial improvements. The improvement in passive ankle dorsiflexion was even more impressive with a third improving by more than 100%. These data are in agreement with other small pilot studies demonstrating improvement in passive ankle dorsiflexion33 and flexibility.30 However, as found with muscle strength, results are not consistent across studies, with several showing no differences in flexibility24,29 or even worsening over a 2-year intervention period.22 In a study by San Juan et al, 29 although no difference was noted at the end of the 16-week intervention, improvement in passive ankle dorsiflexion was noted at a 20-week postintervention assessment.
To improve motor functioning, this study included several exercises to increase balance. However, the results were modest; only 1 patient had a large improvement (140%). Peripheral neuropathy is a well-described adverse effect of vincristine,38,39 a drug universally used during ALL therapy. Forty percent of patients in our pilot had documented neuropathy, which likely mitigated improvements in balance.
We sought to improve general fitness by a range of exercises such as jogging in place, 2-feet hopping, jumping jacks, jump and switch, hopscotch, and jump rope. In general fitness, as assessed by the distance covered in the 6MWT, subjects showed a mean improvement of 71 m, with 75% of subjects demonstrating substantial improvement. This supports findings of Marchese et al33 in their 16-week exercise intervention, although the differences between intervention and control subjects in their study did not reach statistical significance.
An important consideration in the design of any study is sustainability and an approach that is amenable to the broader target population. This study is significant in that it creates an exercise plan that can be completed at home without special equipment. The intervention includes the use of a trained exercise coach, familiar with oncology practice and the potential side effects of medications, so that program modifications can be incorporated into the plan when children are receiving chemotherapy agents that make exercise challenging. This was shown to be feasible with preliminary efficacy with a design that can be used across pediatric oncology centers. A larger prospective randomized efficacy study that includes a control group, thus taking into account improved fitness simply as a result of maturation or recovery from illness, is now warranted. Future research should include outcomes such as health-related quality of life and fatigue, which others have shown to be affected by exercise programs.27,29,30,33,35,36,40 Given the high prevalence of metabolic syndrome observed in childhood ALL survivors,4,5,41–52 preventive interventions focused on increased physical fitness and maintaining a healthy weight need to be a priority. Effective approaches, initiated during ALL therapy, have the potential to prevent and ameliorate long-term cardiovascular complications that ultimately limit quality and quantity of life in these long-term survivors.
The authors thank David Hughes and Chad Holland, videographers/editors, and Elizabeth Stevens, Graphic Artist, Biomedical Communications, for their expertise in creating the video and exercise graphics for this study. We also thank Kathy Laub for her administrative assistance during the preparation of the manuscript.
1. Howlader NNA, Krapcho M, Garshell J, et al., eds. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. http://seer.cancer.gov/csr/1975_2010/
. Accessed August 6, 2013.
2. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120(6):1165–1174.
3. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006;23(5):469–480.
4. Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013;309(22):2371–2381.
5. Chow EJ, Pihoker C, Hunt K, Wilkinson K, Friedman DL. Obesity and hypertension among children after treatment for acute lymphoblastic leukemia. Cancer. 2007;110(10):2313–2320.
6. Esbenshade AJ, Simmons JH, Koyama T, Koehler E, Whitlock JA, Friedman DL. Body mass index and blood pressure changes over the course of treatment of pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;56(3):372–378.
7. Esbenshade AJ, Simmons JH, Koyama T, Lindell RB, Friedman DL. Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy. Pediatr Blood Cancer. 2013;60(8):1287–1291.
8. Withycombe JS, Post-White JE, Meza JL, et al. Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer. 2009;53(7):1249–1254.
9. Gocha Marchese V, Chiarello LA, Lange BJ. Strength and functional mobility in children with acute lymphoblastic leukemia. Med Pediatr Oncol. 2003;40(4):230–232.
10. Muratt MD, Perondi MB, Greve JM, Roschel H, Pinto AL, Gualano B. Strength capacity in young patients who are receiving maintenance therapy for acute lymphoblastic leukemia: a case-control study. Clinics (Sao Paulo). 2011;66(7):1277–1281.
11. Huang TT, Ness KK. Exercise interventions in children with cancer: a review. Int J Pediatr. 2011;2011:461512.
12. Ogden CL, Kuczmarski RJ, Flegal KM, et al. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics. 2002;109(1):45–60.
13. Butterfeld SA, Lehnhard RA, Coladarci T. Age, sex, and body mass index in performance of selected locomotor and fitness tasks by children in grades K-2. Percept Mot Skills. 2002;94(1):80–86.
14. Mikkelsson L, Kaprio J, Kautiainen H, Kujala U, Mikkelsson M, Nupponen H. School fitness tests as predictors of adult health-related fitness. Am J Hum Biol. 2006;18(3):342–349.
15. Patterson P, Wiksten DL, Ray L, Flanders C, Sanphy D. The validity and reliability of the back saver sit-and-reach test in middle school girls and boys. Res Q Exerc Sport. 1996;67(4):448–451.
16. Brosseau L, Balmer S, Tousignant M, et al. Intra- and intertester reliability and criterion validity of the parallelogram and universal goniometers for measuring maximum active knee flexion and extension of patients with knee restrictions. Arch Phys Med Rehabil. 2001;82(3):396–402.
17. Edwards RH, Hyde S. Methods of measuring muscle strength and fatigue. Physiotherapy. 1977;63(2):51–55.
18. Hager-Ross C, Rosblad B. Norms for grip strength in children aged 4-16 years. Acta Paediatr. 2002;91:617–625.
19. Mathiowetz V, Wiemer DM, Federman SM. Grip and pinch strength: norms for 6- to 19-year-olds. Am J Occup Ther. 1986;40(10):705–711.
20. Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). Minneapolis, MN: NCS Pearson Inc; 2006.
21. Geiger R, Strasak A, Treml B, et al. Six-Minute Walk Test in children and adolescents. J Pediatrics. 2007;150:395–399.
22. Hartman A, te Winkel ML, van Beek RD, et al. A randomized trial investigating an exercise program to prevent reduction of bone mineral density and impairment of motor performance during treatment for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009;53(1):64–71.
23. Jarvela LS, Kemppainen J, Niinikoski H, et al. Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012;59(1):155–160.
24. Moyer-Mileur LJ, Ransdell L, Bruggers CS. Fitness of children with standard-risk acute lymphoblastic leukemia during maintenance therapy: response to a home-based exercise and nutrition program. J Pediatr Hematol Oncol. 2009;31(4):259–266.
25. Takken T, van der Torre P, Zwerink M, et al. Development, feasibility and efficacy of a community-based exercise training program in pediatric cancer survivors. Psychooncology. 2009;18(4):440–448.
26. Tanir MK, Kuguoglu S. Impact of exercise on lower activity levels in children with acute lymphoblastic leukemia: a randomized controlled trial from Turkey. Rehabil Nurs. 2013;38(1):48–59.
27. Yeh CH, Man Wai JP, Lin US, Chiang YC. A pilot study to examine the feasibility and effects of a home-based aerobic program on reducing fatigue in children with acute lymphoblastic leukemia. Cancer Nurs. 2011;34(1):3–12.
28. Ruiz JR, Fleck SJ, Vingren JL, et al. Preliminary findings of a 4-month intrahospital exercise training intervention on IGFs and IGFBPs in children with leukemia. J Strength Cond Res. 2010;24(5):1292–1297.
29. San Juan AF, Fleck SJ, Chamorro-Vina C, et al. Effects of an intrahospital exercise program intervention for children with leukemia. Med Sci Sports Exerc. 2007;39(1):13–21.
30. Keats MR, Culos-Reed SN. A community-based physical activity program for adolescents with cancer (project TREK): program feasibility and preliminary findings. J Pediatr Hematol Oncol. 2008;30(4):272–280.
31. Sharkey AM, Carey AB, Heise CT, Barber G. Cardiac rehabilitation after cancer therapy in children and young adults. Am J Cardiol. 1993;71(16):1488–1490.
32. Ladha AB, Courneya KS, Bell GJ, Field CJ, Grundy P. Effects of acute exercise on neutrophils in pediatric acute lymphoblastic leukemia survivors: a pilot study. J Pediatr Hematol Oncol. 2006;28(10):671–677.
33. Marchese VG, Chiarello LA, Lange BJ. Effects of physical therapy intervention for children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2004;42(2):127–133.
34. San Juan AF, Chamorro-Vina C, Moral S, et al. Benefits of intrahospital exercise training after pediatric bone marrow transplantation. Int J Sports Med. 2008;29(5):439–446.
35. Speyer E, Herbinet A, Vuillemin A, Briancon S, Chastagner P. Effect of adapted physical activity sessions in the hospital on health-related quality of life for children with cancer: a cross-over randomized trial. Pediatr Blood Cancer. 2010;55(6):1160–1166.
36. Gohar SF, Comito M, Price J, Marchese V. Feasibility and parent satisfaction of a physical therapy intervention program for children with acute lymphoblastic leukemia in the first 6 months of medical treatment. Pediatr Blood Cancer. 2011;56(5):799–804.
37. Chamorro-Vina C, Ruiz JR, Santana-Sosa E, et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc. 2010;42(6):1045–1053.
38. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nature Rev Neurol. 2010;6(12):657–666.
39. Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol. 1986;1(6):421–427.
40. Blaauwbroek R, Bouma MJ, Tuinier W, et al. The effect of exercise counselling with feedback from a pedometer on fatigue in adult survivors of childhood cancer: a pilot study. Support Care Cancer. 2009;17(8):1041–1048.
41. Armstrong GT, Sklar CA, Hudson MM, Robison LL. Long-term health status among survivors of childhood cancer: does sex matter? J Clin Oncol. 2007;25(28):4477–4489.
42. Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(5):619–625.
43. Garmey EG, Liu Q, Sklar CA, et al. Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2008;26(28):4639–4645.
44. Gurney JG, Ness KK, Sibley SD, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer. 2006;107(6):1303–1312.
45. Janiszewski PM, Oeffinger KC, Church TS, et al. Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab. 2007;92(10):3816–3821.
46. Kourti M, Tragiannidis A, Makedou A, Papageorgiou T, Rousso I, Athanassiadou F. Metabolic syndrome in children and adolescents with acute lymphoblastic leukemia after the completion of chemotherapy. J Pediatr Hematol Oncol. 2005;27(9):499–501.
47. Meacham LR, Chow EJ, Ness KK, et al. Cardiovascular risk factors in adult survivors of pediatric cancer—a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2010;19(1):170–181.
48. Oeffinger KC. Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer. 2008;50(2) (suppl):462–467; discussion 468.
49. Oeffinger KC, Mertens AC, Sklar CA, et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2003;21(7):1359–1365.
50. Razzouk BI, Rose SR, Hongeng S, et al. Obesity in survivors of childhood acute lymphoblastic leukemia and lymphoma. J Clin Oncol. 2007;25(10):1183–1189.
51. van Waas M, Neggers SJ, Pieters R, van den Heuvel-Eibrink MM. Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer. Ann Oncol. 2010;21(5):1121–1126.
52. Landier W, Armenian SH, Lee J, et al. Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol. 2012;30(35):4401–4408.