Patti Antonino1, Paoli Antonio2, Bianco Antonino1, Palma Antonio1
1Sport and Exercise Sciences Research Unit, University of Palermo, Italy
2Departement of Biomedical Sciences, University of Padova, Padova, Italy
In the world today, there are roughly 25 million cancer survivors. Progress in treatments have greatly improved cure rates, with 5-year survival now approaching 80%, but are associated with numerous negative physical and psychological side-effects and a deterioration in the quality of future life. Cancer survivors are at increased risk for second cancers, other forms of comorbidity (e.g., cardiovascular disease, diabetes, osteoporosis), and functional decline. Lifestyle factors, such as a healthy diet, regular exercise, and smoking cessation may prevent these conditions and improve survivors' quality of life. Observational research has shown that the physical activity levels of survivors of hematological cancer are low, with deleterious health consequences. The aim of this systematic review was to understand and evaluate if and how much a program of physical activity improves the quality of life in children survivors of acute lymphoblastic leukemia (ALL). A systematic literature search was carried out in the MEDLINE/PubMed database (1993-2013) and has been analyzed 40 studies. Completing the analysis it seems that no one exercise-related risks in children was identified in these studies. Though more trials are needed, a growing literature supports the notion that regular physical activity has potential benefits for pediatric hematological cancer survivors.
Keywords: Physical activity, Health, Cancer, Leukemia
The attention of many researchers towards physical activity as a means for the primary prevention of cancer is increasing as the evidence for a protective effect is accumulating, but today, the physical activity is a candidate as an effective tool, in chemotherapy period and in the post-chemotherapy period, to improve the quality of life of survivors. Progress in treatments for childhood cancer have greatly improved cure rates, with 5-year survival now approaching 80% (Smith et al., 2010) , but improving survival rates, however, does not come without consequences, impaired physical fitness has been reported during and after childhood cancer treatment (Aznar et al., 2006, Jenney et al., 1995, San Juan et al., 2008a, van Brussel et al., 2005) . Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancer cases. Using modern treatment regimens, the 5-year survival rate of ALL has improved from virtually zero (in the 1950's) to approximately 80% (Silverman et al., 2001) . As the population of ALL survivors increases, the adverse effects of their treatment become apparent. Numerous endocrine/metabolic adverse effects such as deficient secretion of growth hormone, gonadotropins and thyroid hormones and metabolic syndrome have been demonstrated in survivors(Davies, 1993, Gleeson and Shalet, 2001, Trimis et al., 2007, Reisi et al., 2009) . A pediatric exercise's program has the potential to improve cardiopulmonary and musculoskeletal function, perhaps preventing long-term deﬁcits in physical fitness if incorporated during or soon after treatment in children with cancer diagnoses (San Juan et al., 2011, San Juan et al., 2007b, San Juan et al., 2008b, Marchese et al., 2004, Okada et al., 2012) . Furthermore, the perception of fatigue of these subjects is certainly greater, and this have a negative impact on physical activity and on psychosocial well-being. I.M. Johannsdottir et al showed that the prevalence of cancer-related fatigue was over three times higher in long-term survivors of childhood cancer when compared to the general population (Johannsdottir et al., 2012) . Some studies have shown that fatigue is a very good predictor of quality of life (Meeske et al., 2007) and given that physical activity can reduce the perception of fatigue in survivors of adult cancer, such interventions may have a similar effect in the pediatric population (Cox et al., 2009) . However, in literature, there aren't many exercise interventions undertaken in the pediatric cancer, the modality , the intensity, timing, and duration of the intervention are difficult to determine (the components of aerobic training, resistance, and flexibility exercises are implemented with differing intensity, timing, and duration) and in addition the sample sizes are small making it difficult to draw firm conclusions.
Materials and methods
Publications were selected based on a literature search from 1993 until 2013 using the Medline/Pubmed database. This paper summarizes exercise intervention studies among children with cancer and is limited to studies that tested or described exercise intervention in children diagnosed with a primary pediatric cancer. Search terms: ‘pediatric exercise leukemia’, ‘physical ﬁtness’, ‘exercise testing’, ‘exercise’, ‘exercise capacity’, ‘exercise tolerance’, ‘child’, ‘survivors’, and ‘leukemia’ were used. References of the selected papers were tracked to ﬁnd additional publications on this subject. The search of the Pubmed database initially resulted in a total of 40 records; only 20 articles were identified, according to our searching criteria. The systematic review of Huang and Ness was adopted as starting point (Huang and Ness, 2011). Tables 1 is showing all articles identified for a total of 467 subjects including children, adolescent and young adult. The table shows the study design: randomized or non randomized study, if study included a control group or control intervention, etc. The exercise interventions consisted in programs of aerobic, resistance, and flexibility training with or without home-based exercises. The majority of the interventions included only patients with acute lymphoblastic leukemia (ALL) diagnoses; 61 were children and adolescents with ALL during maintenance chemotherapy and 194 were the survivors of childhood cancer with mixed diagnoses or children who had undergone hematopoietic stem cell transplant (HCT) after hematologic oncologic diseases.
Effects of Physical Exercise on Immune Suppression
Concerns about the eﬀects of physical exercise (PE) on immune function involves the possibility that PE may tax an already compromised immune system and either may a delay of recovery and/or cause additional damage to the physiological functions. Ladha et al (Ladha et al., 2006) not found deleterious eﬀects of PE intervention on immune function and their data are supported by Chamorro-Vina et al (Chamorro-Vina et al., 2012, Chamorro-Vina et al., 2010) . Furthermore, Battaglini et al. (Battaglini et al., 2009) didn't observed significant changes in inflammation after an exposure to a PE program.
Effects of Physical Exercise on Cardiopulmonary System
Cardiopulmonary fitness (CPF) is impaired in children during treatment and among survivors of childhood cancer (San Juan et al., 2008a, van Brussel et al., 2005) . The results obtained from exercise programs addressed to improve or maintain CPF, are controversial. Likely, controversial can be caused by the aerobic training programs that, many times, are boring and or too intense. Marchese et al. following a four-month intervention, not found cardiopulmonary response to the exercise protocol, assessed through a nine minute run-walk test (Marchese et al., 2004). Mileur Moyer et al. and San Juan et al. have reported an improvement of CPF after training programs (Moyer-Mileur et al., 2009, San Juan et al., 2007b, San Juan et al., 2008a) . Moreover the Sharkey's study (Sharkey et al., 1993) reported an increase of 13 percent (%) in exercise time during cardiopulmonary test, after 12-week of aerobic training program, among childhood cancer survivors. Tanir et al. (Tanir and Kuguoglu, 2013), in 20 surviving children, after a cardio-respiratory fitness program, has reported significant improvements of CPF, strength and coordination.
Effects of Physical Exercise on the Musculoskeletal System
Loss of muscle mass, and reduced muscle strength are reported in children with cancer , unfortunately this is side effect of chemotherapy (Ness et al., 2007) ; the results of studies in the literature to compensate this deficit, are very promising. Marchese et al. reported that after stretching and resistance training the ankle range of motion and the knee extension strength are significantly improved, respectively (Marchese et al., 2006, Marchese et al., 2004) . These results were largely confirmed by subsequent studies by other authors (San Juan et al., 2008a, Hartman et al., 2009, Hartman et al., 2013, Keats and Culos-Reed, 2008) .
Effects of Physical Exercise on Fatigue
Common functional late effects that significantly impact quality of life include neuro-cognitive impairment and fatigue. Survivors of childhood cancer are at increased risk for neuro-cognitive impairment, as either a direct or indirect result of central nervous system (CNS) treatment. Fatigue is a common symptom in children during and following cancer treatment. Reduced sleep quality and fatigue are also reported to impact neuro-cognitive functioning. Specifically, fatigue is associated with impairments in processing speed, attention, and memory functions (Kahol et al., 2008) . In studies that have focused on manual tasks, deterioration has been reported in psychomotor and, to a lesser extent, cognitive skills (Denisco et al., 1987). Among adults diagnosed with chronic fatigue syndrome, slow processing speed, impaired working memory, and poor memory and learning of new information have been reported (Michiels and Cluydts, 2001, Majer et al., 2008) . The exercise interventions show some eﬃcacy in the management of fatigue during and after cancer chemotherapy in children (Blaauwbroek et al., 2009, Keats and Culos-Reed, 2008) . However, the reduction of the perception of fatigue seems to be linked to training response (Yeh et al., 2011, Blaauwbroek et al., 2009, Keats and Culos-Reed, 2008, Rosenhagen et al., 2011) . Would seem that in studies, where the exercise response was null, so was the fatigue reduction response (Takken et al., 2009).
Effects of Physical Exercise on General Physical Functioning
Childhood cancer and treatments associated to it, can cause to decreased levels of physical fitness and functional deficits; this, as literature suggests, predisposes children survived to develop neuromuscular and musculoskeletal complications. Recent literature has demonstrated the usefulness and effectiveness of PE programs to improve overall physical functioning and mobility in order to prevent a decline in physical fitness level in survivors of pediatric cancer. San Juan et al. in their studies confirms the benefits that a personalized training program among young children with ALL or in children following HCT, these positive results were confirmed by Gohar et al (Gohar et al., 2011) and recently by Soares-Miranda et al (Soares-Miranda et al., 2013) in subject with solid tumors. After 16-week home-based aerobic exercise program (exercise intensity: 40% - 60% of HRR) and a PT program (weekly strengthening and stretching exercise), in seventeen children survivors of childhood acute lymphoblastic leukemia , Jarvela et al. (Jarvela et al., 2012) reported improved gross motor function. However, we want to highlight that in the Takken's study (Takken et al., 2009) , after twelve-week of supervised intervention, there weren't training effect and no impact on functional mobility.
Effects of Physical Exercise on Health-Related Quality of Life
Gohar et al. and Speyer et al. have reported overall improvement in health-related quality of life outcome in response to PE intervention among children during acute phases of treatment (Gohar et al., 2011, Speyer et al., 2010) ; these results are confirmed by Rosenhagen et al. and Tanir et al. (Rosenhagen et al., 2011, Tanir and Kuguoglu, 2013) . Other studies report positive results, but the absence of a control population or a pre-and post-test trial, making it difficult to attribute the outcomes to the intervention.
Treatments for pediatric cancer have been linked to a wide range of early and late side effects including: impaired growth and development, cognitive dysfunction, diminished neurological function, cardiopulmonary compromise, musculoskeletal complications and secondary malignancy (Huang and Ness, 2011). Oeffinger et al. (Oeffinger et al., 2006) reported that 30 years after cancer diagnosis in childhood, 73% of survivors had numerous negative physical and psychological side-effects and a deterioration in the quality of future. Thus, efforts are now being directed toward improving the quality of this survival. From the studies collected in this review, we can certainly assert that the exercise has beneficial effects in children with hematologic cancer on a broad range of physiological systems and functions. Fatigue and general physical function are enhanced if the intervention generates cardiopulmonary training effects. Thus, regular exercise increases in patient capacity to blackberries easily and effectively deals with the physical demands of daily life. Further, inactive children are likely to become inactive adults. However, the studies analyzed show that there isn't still a single protocol to program the exercise, this may clear or resize the possible positive results. However, the inconsistencies in exercise type, intensity, frequency, duration and outcome measurement cannot guide an individual clinician to prescribe exercise in practice. If in one side the chemotherapy pharmacological protocol is identical or very similar in all parts of the world, on the other side it is not possible to standardize the physical activity, but guidelines and/or evidences are needed with the intention of improve the collaboration between professionals like Physicians, Sport Scientists and Personal Trainers. In the future, certainly, the physical exercise will have an important role on the quality of life of the survivors.
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