Abstract
Exercise has been found to improve function, mitigate disability, enhance the anticancer immune system response, and improve quality of life for patients with osteosarcoma and its survivors. Of late, exercise has additionally been implemented as an adjuvant to standard therapies. These products of exercise, along with the benefits of physical activity in pre- and postoperative rehabilitation, were summarized in the recently published book chapter Exercise and Physical Activity in Patients with Osteosarcoma and Survivors. This commentary is intended to share its findings, provide new information since its publication, give an example of how this work is being programmatically implemented, and provide an update to exercise guidelines for patients undergoing cancer treatment and cancer survivors.
Keywords
Exercise, Physical activity, Osteosarcoma, Bone sarcoma, Cancer treatment, Survivors
Exercise and Physical Activity of Survivors of Osteosarcoma
Nearly 70% of children and adolescent young adult patients diagnosed with osteosarcoma will survive into adulthood [35]. Regrettably, these survivors are 5 times more likely than their siblings to report severe and chronic conditions, including ischemic heart disease, obesity, dyslipidemia, hypertension, and depression with 95.5% of survivors suffering from a serious or disabling chronic health condition by age 45 [36]. These conditions have fortunately been shown to be improved by exercise in the general population [37-39] and could be mitigated in the lives of survivors with similar application. The greatest obstacle may in fact be initiating a change in lifestyle as reportedly nearly 30% of childhood osteosarcoma survivors are completely sedentary and an additional 30% perform less than 150 minutes of moderate physical activity per week [40]. Understandably, in survivors who suffer from treatment- or cancer-related disability, engaging in routine exercise or vigorous physical activity can be daunting [41]. Thus, specific and individualized guidance will be essential for compliance, comfort, and self-empowerment to exercise regularly. While safety and efficacy of exercise have been shown in sarcoma survivors who have undergone amputation and developed subclinical cardiomyopathy due to anthracycline exposure [42], an exercise prescription tailored to an individual survivor's needs would be optimal. Tapered supervision is necessary until survivors gain comfort and resolve. Subsequent regular check-ins in person and/or virtually with a physical therapist or trainer experienced in exercise for survivors of cancer would allow for continued intensity adjustment and strength gains as well as ensure safety and accountability.
Introduction
Exercise has been found to be not only feasible in patients with cancer but potentially tumor-reducing. The study of the benefits of exercise in the treatment of cancer and hindrance of tumor growth can be traced as far back as 1938 in animal models and later in human clinical trials starting in the 1980s [1]. Studies demonstrating benefits to quality of life and the immune system followed, and exercise as an adjuvant to cancer therapy began to gain acceptance. Patients undertake exercise regimens as part of their cancer therapy as a necessary means of rehabilitation but have also found them overall doable, satisfying, and a way to build endurance and fitness while improving their mental and social well-being. In Exercise and Physical Activity in Patients with Osteosarcoma and Survivors [2], the feasibility, benefits, and barriers to exercise and physical activity in patients and survivors of osteosarcoma are described (Table 1). This work will briefly share and comment on these findings, provide new information since its publication, give an example of how this work is being programmatically implemented, and provide an update to exercise guidelines for patients undergoing cancer treatment and cancer survivors.
|
Benefit |
Study population |
|
Improved function |
Sarcoma patients [16] |
|
Improved fitness, strength, balance, endurance |
Sarcoma patients [54.55] Multiple diagnoses [21] |
|
Improved post-operative rehabilitation |
Sarcoma patients after limb salvage surgery |
|
Enhanced immune system |
Pre-clinical mouse models of multiple tumor models [28-34] |
|
Reduced tumor burden/improved chemotherapy efficacy |
Pre-clinical mouse and rat models of multiple tumor models [25-27] |
|
Improved chemotherapy completion rate due to reduced side effects |
Multiple diagnoses (systematic review) [24] |
|
Improved fatigue |
Solid tumor patients undergoing chemotherapy [14,23] Multiple diagnoses (systematic review) [56] |
|
Improved cognition and memory |
Breast cancer survivors [57] Pediatric leukemia & brain tumor survivors [58,59] Multiple diagnoses, patients over 80 [60] |
|
Improved quality of life |
Multiple diagnoses during cancer treatment (Meta-analysis) [61] |
|
Reduced risk of co-morbidities |
Sarcoma survivors [62,63] |
Exercise and Physical Activity
The words exercise and physical activity appear frequently throughout the chapter. Outside of the clinical setting these words are often used interchangeably; however, clinically and throughout the book chapter, they are used to define two different forms of movement. Physical activity requires energy and is movement performed by skeletal muscles. Exercise too requires energy, is movement carried out by skeletal muscle, and additionally, it is meant to define structured, repetitive, and intentional movement to improve or maintain physical fitness [3]. Physical activity contributes to health, well-being, and function, but exercise additionally improves fitness of body systems including but not limited to cardiorespiratory, immune, and musculoskeletal [3,4]. Both exercise and physical activity have been linked to decreasing risk of certain cancers [4].
Exercise and Physical Activity During the Treatment of Osteosarcoma
Importantly, before exercise regimens can be prescribed to improve patient physical activity, quality of life, or as treatment, it must first be established that it is both feasible and safe. Exercise feasibility and safety for patients with osteosarcoma undergoing active treatment have been demonstrated by qualitative measures, such as patient ability to complete assigned exercise and improvement in fatigue and strength without adverse effects, as well as patient compliance and overall satisfaction [5,6] Physical activity levels of cancer patients is lower than that of non-cancer patients. Some of this can be attributed to tumor burden hindering activity and fitness. Patient physical activity levels improve as time following tumor resection or surgery increases during active therapy [7]. Even so, for physical gains to be maintained, patients should continue with their exercise programs beyond cancer therapy [8].
To further promote feasibility and compliance, exercise should not be limited to traditional aerobic activity, e.g. brisk walking and upper extremity ergometry or weight-based strength training. Benefits on function, endurance, and quality of life can also be gained from gentle yoga, qigong, or tai chi [9-11]. at home or in community-based settings [7,12-15]. Additionally, the importance of a multidisciplinary team is highlighted for a successful incorporation of exercise into the treatment regimen of osteosarcoma patients [16-20]. Without full support of a patient's medical and psychosocial teams, this economical and physically and emotionally rewarding adjuvant therapy may be easily neglected [21-23]. The positive effects exercise has on quality of life, including improved physical fitness and emotional health, are well-accepted.
Furthermore, exercise as a true adjuvant and treatment intervention in cancer therapy is gaining more support, which is likely to increase the commitment of care providers to supporting exercise for patients. One of the most convincing reasons to exercise during cancer therapy may be its impact on treatment efficacy. Newly emerging evidence suggests that physical activity or exercise improves chemotherapy full-dose completion rates [24], while preclinical studies demonstrate decreased tumor burden in exercised subjects [25-27], both effectively translating to improved efficacy. Exercise-induced modulation of the immune system may be one way that exercise could inhibit tumor progression. Exercise is known to change immune cells in both innate and adaptive immunity in healthy individuals which may thus hinder further tumorigenesis in patients with cancer [28]. Preclinical studies for example have demonstrated an improved innate immunity through altering macrophage, neutrophil, and NK cell infiltration in tumors of mice with solid tumors [29-32]. Pre-clinical and patient models have also shown an alteration of adaptive cell immunity in exercised mice and patients with an increase in dendritic cells and intra-tumoral T-cell composition [33,34].
Chronic Health Conditions in Survivors of Osteosarcoma and the Role of Exercise
To further elucidate the impact that treatment of bone sarcomas has on long term health, the St. Jude’s Lifetime Cohort Study recently reported on the cumulative burden of chronic health conditions in adult survivors of childhood osteosarcoma and Ewing sarcoma [43]. They found that survivors demonstrated an increased prevalence for cardiomyopathy and hypertension compared to controls and were impaired in their physical abilities including the 6-minute walk test, walking efficiency, mobility, strength, and endurance [43]. Not previously reported, they also found a deficit in survivor executive function and attention [43]. This study is shared here as there is potential for early exercise intervention to ameliorate the risk or detriment of these co-morbidities in osteosarcoma survivors. Exercise in cancer survivors has been found to improve blood pressure and cardiovascular health [44], as well as improve muscle strength and balance [45]. Emotional improvement of anxiety, depression, or stress in exercising survivors compared to non-exercising controls has also been reported [46]. More recently, the effect of exercise in patients with cancer has shown positive effect on cognitive function and brain measures [47].
Exercise in Practice for Patients and Survivors of Osteosarcoma
Not mentioned in Exercise and Physical Activity in Patients with Osteosarcoma and Survivors is the American College of Sports Medicine’s (ACSM) Moving Through Cancer initiative and mission “to assure that all people living with cancer and beyond are assessed, advised, and referred to and engaged in appropriate exercise and rehabilitation programing as standard of care” [48]. The ACSM believes that “exercise is medicine” and have developed an exercise program registry designed to assist patients, families, and providers find hospital- and community-based exercise programs [48]. The ACSM’s Exercise is Medicine website (https://www.exerciseismedicine.org/) also provides resources for patients, families, and providers regarding exercise prescriptions and updated cancer exercise guidelines [48]. Following the writing of the chapter in discussion, guidelines updating exercise recommendations for cancer patients and survivors were updated. These were published in Medicine & Science in Sports & Exercise and CA: A Cancer Journal for Clinicians [49-51]. Prior to these updated publications, the only organized exercise guidelines available were primarily for cancer survivors, not including active patients, from the ACSM, published in 2010, and the American Cancer Society, published in 2012 [52,53] Both the ACSM and American Cancer Society recommended 150 minutes of exercise per week for cancer survivors, similar to recommendations for the general public [52,53]. The new guidelines reflect recent evidence that both cancer survivors and patients receiving active treatment can derive benefits from exercise, and with less time than previously endorsed [1]. Based on current literature, the new guidelines recommend an exercise program that includes moderate-intensity aerobic training at least 3 times per week for 30 minutes per session and the addition of resistance training at least 2 times per week [49].
Conclusion
Exercise is indeed an important component of a multidisciplinary approach to cancer treatment and survivorship. Osteosarcoma patients will benefit in all aspects of health-physical function, cognitive, psychosocial-when adhering regularly to its prescription. With time, clinical studies may further support the use of exercise as treatment based on preclinical findings of improvement in immune or chemotherapeutic efficacy.
Conflicts of Interest
Authors have no conflicts of interest to declare.
References
2. Garcia MB, Ness KK, Schadler KL. Exercise and Physical Activity in Patients with Osteosarcoma and Survivors. InCurrent Advances in Osteosarcoma 2020 (pp. 193-207). Springer, Cham.
3. Gummelt D. Physical activity vs. exercise: What’s the difference. ACE. 2015.
4. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report. Physical activity and the risk of cancer. Available at dietandcancerreport.org
5. Cave J, Paschalis A, Huang CY, West M, Copson E, Jack S, et al. A systematic review of the safety and efficacy of aerobic exercise during cytotoxic chemotherapy treatment. Supportive Care in Cancer. 2018 Oct 1;26(10):3337-51.
6. Morri M, Raffa D, Barbieri M, Ferrari S, Mariani E, Vigna D. Compliance and satisfaction with intensive physiotherapy treatment during chemotherapy in patients with bone tumours and evaluation of related prognostic factors: An observational study. European Journal of Cancer Care. 2018 Nov;27(6):e12916.
7. Esbenshade AJ, Friedman DL, Smith WA, Jeha S, Pui CH, Robison LL, et al. Feasibility and initial effectiveness of home exercise during maintenance therapy for childhood acute lymphoblastic leukemia. Pediatric physical therapy: the official publication of the Section on Pediatrics of the American Physical Therapy Association. 2014;26(3):301.
8. Winter CC, Müller C, Hardes J, Gosheger G, Boos J, Rosenbaum D. The effect of individualized exercise interventions during treatment in pediatric patients with a malignant bone tumor. Supportive Care in Cancer. 2013 Jun 1;21(6):1629-36.
9. Bower JE, Woolery A, Sternlieb B, Garet D. Yoga for cancer patients and survivors. Cancer Control. 2005 Jul;12(3):165-71.
10. Wurz A, Chamorro-Vina C, Guilcher GM, Schulte F, Culos-Reed SN. The feasibility and benefits of a 12-week yoga intervention for pediatric cancer out-patients. Pediatric Blood & Cancer. 2014 Oct;61(10):1828-34.
11. Zeng Y, Luo T, Xie H, Huang M, Cheng AS. Health benefits of qigong or tai chi for cancer patients: a systematic review and meta-analyses. Complementary Therapies in Medicine. 2014 Feb 1;22(1):173-86.
12. Haas BK, Kimmel G, Hermanns M, Deal B. Community-based FitSTEPS for life exercise program for persons with cancer: 5-year evaluation. Journal of Oncology Practice. 2012 Nov;8(6):320-4.
13. Kolden GG, Strauman TJ, Ward A, Kuta J, Woods TE, Schneider KL, et al. A pilot study of group exercise training (GET) for women with primary breast cancer: feasibility and health benefits. Psycho-Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer. 2002 Sep;11(5):447-56.
14. Cheville AL, Kollasch J, Vandenberg J, Shen T, Grothey A, Gamble G, et al. A home-based exercise program to improve function, fatigue, and sleep quality in patients with Stage IV lung and colorectal cancer: a randomized controlled trial. Journal of Pain and Symptom Management. 2013 May 1;45(5):811-21.
15. Nyrop KA, Deal AM, Choi SK, Wagoner CW, Lee JT, Wood A, et al. Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer. Breast Cancer Research and Treatment. 2018 Feb 1;168(1):43-55.
16. Punzalan M, Hyden G. The role of physical therapy and occupational therapy in the rehabilitation of pediatric and adolescent patients with osteosarcoma. In Pediatric and adolescent osteosarcoma 2009 (pp. 367-384). Springer, Boston, MA.
17. Götte M, Kesting S, Winter C, Rosenbaum D, Boos J. Experience of barriers and motivations for physical activities and exercise during treatment of pediatric patients with cancer. Pediatric Blood & Cancer. 2014 Sep;61(9):1632-7.
18. Yelton L, Forbis S. Influences and barriers on physical activity in pediatric oncology patients. Frontiers in Pediatrics. 2016 Dec 19;4:131.
19. Dishman RK, Sallis JF, Orenstein DR. The determinants of physical activity and exercise. Public Health Reports. 1985 Mar;100(2):158.
20. Shropshire J, Carroll B. Family variables and children's physical activity: Influence of parental exercise and socio-economic status. Sport, Education and Society. 1997 Mar 1;2(1):95-116.
21. Sweegers MG, Altenburg TM, Brug J, May AM, Van Vulpen JK, Aaronson NK, et al. Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: a meta-analysis of individual patient data. British Journal of Sports Medicine. 2019 Jul 1;53(13):812-.
22. Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database of Systematic Reviews. 2012(8).
23. Lipsett A, Barrett S, Haruna F, Mustian K, O'Donovan A. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: A systematic review and meta-analysis. The breast. 2017 Apr 1;32:144-55.
24. Bland KA, Zadravec K, Landry T, Weller S, Meyers L, Campbell KL. Impact of exercise on chemotherapy completion rate: A systematic review of the evidence and recommendations for future exercise oncology research. Critical reviews in Oncology/Hematology. 2019 Apr 1;136:79-85.
25. Schadler KL, Thomas NJ, Galie PA, Bhang DH, Roby KC, Addai P, et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget. 2016 Oct 4;7(40):65429.
26. Morrell MB, Alvarez-Florez C, Zhang A, Kleinerman ES, Savage H, Marmonti E, et al. Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma. Pediatric Blood & Cancer. 2019 Sep;66(9):e27835.
27. Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM, Devi GR, et al. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. JNCI: Journal of the National Cancer Institute. 2015 May 1;107(5).
28. Koelwyn GJ, Wennerberg E, Demaria S, Jones LW. Exercise in regulation of inflammation-immune axis function in cancer initiation and progression. Oncology (Williston Park, NY). 2015 Dec;29(12).
29. Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH,et al. Voluntary running suppresses tumor growth through epinephrine-and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism. 2016 Mar 8;23(3):554-62.
30. McClellan JL, Steiner JL, Day SD, Enos RT, Davis MJ, Singh UP, Murphy EA. Exercise effects on polyp burden and immune markers in the ApcMin/+ mouse model of intestinal tumorigenesis. International Journal of Oncology. 2014 Aug 1;45(2):861-8.
31. Almeida PW, Gomes-Filho A, Ferreira AJ, Rodrigues CE, Dias-Peixoto MF, Russo RC, et al. Swim training suppresses tumor growth in mice. Journal of Applied Physiology. 2009 Jul;107(1):261-5.
32. Zielinski MR, Muenchow M, Wallig MA, Horn PL, Woods JA. Exercise delays allogeneic tumor growth and reduces intratumoral inflammation and vascularization. Journal of Applied Physiology. 2004 Jun;96(6):2249-56.
33. Liao HF, Chiang LM, Yen CC, Chen YY. Effect of a periodized exercise training and active recovery program on antitumor activity and development of dendritic cells. Journal of Sports Medicine and Physical Fitness. 2006 Jun 1;46(2):307.
34. Kruijsen-Jaarsma M, Révész D, Bierings MB, Buffart LM, Takken T. Effects of exercise on immune function in patients with cancer: a systematic review. Exercise Immunology Review. 2013 Jan 1;19.
35. Howlader N et al, editors (2012). SEER Cancer Statistics Review, 1975-2008. Bethesda, MD: National Cancer Institute.
36. Armstrong GT, Kawashima T, Leisenring W, Stratton K, Stovall M, Hudson MM, et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. Journal of Clinical Oncology. 2014 Apr 20;32(12):1218.
37. Ostman C, Smart NA, Morcos D, Duller A, Ridley W, Jewiss D. The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis. Cardiovascular Diabetology. 2017 Dec 1;16(1):110.
38. Rao S, Pandey A, Garg S, Park B, Mayo H, Després JP, et al. Effect of exercise and pharmacological interventions on visceral adiposity: a systematic review and meta-analysis of long-term randomized controlled trials. InMayo Clinic Proceedings 2019 Feb 1 (Vol. 94, No. 2, pp. 211-224). Elsevier.
39. Sharman JE, La Gerche A, Coombes JS. Exercise and cardiovascular risk in patients with hypertension. American Journal of Hypertension. 2015 Feb 1;28(2):147-58.
40. Scott JM, Li N, Liu Q, Yasui Y, Leisenring W, Nathan PC, et al. Association of exercise with mortality in adult survivors of childhood cancer. JAMA Oncology. 2018 Oct 1;4(10):1352-8.
41. Lansing RW, Gracely RH, Banzett RB. The multiple dimensions of dyspnea: review and hypotheses. Respiratory Physiology & Neurobiology. 2009 May 30;167(1):53-60.
42. Smith WA, Ness KK, Joshi V, Hudson MM, Robison LL, Green DM. Exercise training in childhood cancer survivors with subclinical cardiomyopathy who were treated with anthracyclines. Pediatric Blood & Cancer. 2014 May;61(5):942-5.
43. Bishop MW, Ness KK, Li C, Liu W, Srivastava DK, Chemaitilly W, et al. Cumulative Burden of Chronic Health Conditions in Adult Survivors of Osteosarcoma and Ewing Sarcoma: A Report from the St. Jude Lifetime Cohort Study. Cancer Epidemiology and Prevention Biomarkers. 2020 Jan 1.
44. Sabiston CM, Brunet J. Reviewing the benefits of physical activity during cancer survivorship. American Journal of Lifestyle Medicine. 2012 Mar;6(2):167-77.
45. Visovsky C. Muscle strength, body composition, and physical activity in women receiving chemotherapy for breast cancer. Integrative Cancer Therapies. 2006 Sep;5(3):183-91.
46. Cormie P, Zopf EM, Zhang X, Schmitz KH. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Epidemiologic Reviews. 2017 Jan 1;39(1):71-92.
47. Witlox L, Schagen SB, De Ruiter MB, Geerlings MI, Peeters PH, Koevoets EW, et al. Effect of physical exercise on cognitive function and brain measures after chemotherapy in patients with breast cancer (PAM study): protocol of a randomised controlled trial. BMJ Open. 2019 Jun 1;9(6):e028117.
48. American College of Sports Medicine (2020). Exercise is Medicine. Moving Through Cancer. Available at https://www.exerciseismedicine.org/support_page.php/moving-through-cancer/.
49. Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Medicine & Science in Sports & Exercise. 2019 Nov 1;51(11):2375-90.
50. Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, et al. American College of Sports Medicine roundtable report on physical activity, sedentary behavior, and cancer prevention and control. Medicine & Science in Sports & Exercise. 2019 Nov 1;51(11):2391-402.
51. Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS, et al. Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA: A Cancer Journal for Clinicians. 2019 Nov;69(6):468-84.
52. Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvão DA, Pinto BM, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine & Science in Sports & Exercise. 2010 Jul 1;42(7):1409-26.
53. Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA: A Cancer Journal for Clinicians. 2012 Jul;62(4):242-74.
54. Agarwal S, Cicone C, Pipia PA, Maheshwari AV (2017). In: Henshaw RM ed. Sarcoma: A Multidisciplinary Approach to Treatment. Cham: Springer International Publishing; 295-311
55. Shehadeh A, El Dahleh M, Salem A, Sarhan Y, Sultan I, Henshaw RM, et al. Standardization of rehabilitation after limb salvage surgery for sarcomas improves patients’ outcome. Hematology/Oncology and Stem Cell Therapy. 2013 Sep 1;6(3-4):105-11.
56. Meneses-Echavez JF, Gonzalez-Jimenez E, Ramirez-Velez R. Supervised exercise reduces cancer-related fatigue: a systematic review. Journal of Physiotherapy. 2015 Jan 1;61(1):3-9.
57. Salerno EA, Rowland K, Kramer AF, McAuley E. Acute aerobic exercise effects on cognitive function in breast cancer survivors: a randomized crossover trial. BMC Cancer. 2019 Dec;19(1):1-9.
58. Kesler SR, Lacayo NJ, Jo B. A pilot study of an online cognitive rehabilitation program for executive function skills in children with cancer-related brain injury. Brain Injury. 2011 Jan 1;25(1):101-12.
59. Cox E, Bells S, Timmons BW, Laughlin S, Bouffet E, de Medeiros C, et al. A controlled clinical crossover trial of exercise training to improve cognition and neural communication in pediatric brain tumor survivors. Clinical Neurophysiology. 2020 Jul 1;131(7):1533-47.
60. Sprod LK, Mohile SG, Demark-Wahnefried W, Janelsins MC, Peppone LJ, Morrow GR, et al. Exercise and cancer treatment symptoms in 408 newly diagnosed older cancer patients. Journal of Geriatric Oncology. 2012 Apr 1;3(2):90-7.
61. Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database of Systematic Reviews. 2012(8).
62. Nagarajan R, Kamruzzaman A, Ness KK, Marchese VG, Sklar C, Mertens A, et al. Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study. Cancer. 2011 Feb 1;117(3):625-34.
63. Nicholson HS, Mulvihill JJ, Byrne J. Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma. Medical and Pediatric Oncology. 1992;20(1):6-12.