Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design

CONCLI-00894; No of Pages 10 Contemporary Clinical Trials xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Contemporary Clinical Trials

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Luisa Soares-Miranda a,⁎,1, Carmen Fiuza-Luces b,1, Alvaro Lassaletta c, Elena Santana b, Julio R. Padilla b, Lucía Fernández-Casanova c, Rosalía Lorenzo-González c, Luis M. López-Mojares b, Margarita Pérez b, Antonio Pérez-Martínez c,2, Alejandro Lucía b,d,2 a b c d

Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal Universidad Europea de Madrid, Madrid, Spain Hospital Infantil Universitario Niño Jesús, Madrid, Spain Instituto de Investigación i+12, Madrid, Spain

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Article history: Received 28 January 2013 Received in revised form 23 May 2013 Accepted 29 May 2013 Available online xxxx

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America (12.2%) among children aged 1 to 14 years, surpassed only by accidents (34.5%) [1]. The most common pediatric solid tumors include brain tumors (25%), lymphomas (10%), neuroblastoma (8%), Wilm's tumor (6%), and bone tumors (5%). Children are not simply small adults, and their cancers are not just a variation of adult cancers [2]. Pediatric cancers typically respond better to current therapies than adult cancers [2,3]. In general, the cure rate of childhood cancer is about 75%, which is much higher than for adult cancers [3]. The better cure rates of pediatric cancers can be explained by the different biology of pediatric and adult tumors [3]. Adult

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Keywords: Randomized controlled trial In-hospital exercise Children Cancer

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1. Introduction

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The 2010 report by the American Cancer Society has identified cancer as the second leading cause of death in North

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Background: This randomized controlled trial on Physical Activity in Pediatric Cancer (PAPEC) was designed to assess the impact of an exercise program on pediatric cancer patients undergoing chemotherapy for solid tumors. Methods and design: 60 pediatric patients of both sexes, aged 4 to 18 years and undergoing treatment for extracranial primary solid tumors will be recruited for this trial. Each participant will be randomly assigned (with blocking on sex) to either an intervention or control (normal care) group. The intervention group will participate in combined inpatient physical training (aerobic + strength) for the duration of neoadjuvant chemotherapy. The intervention will include 3 weekly 60–70 min exercise sessions in the child's room or in a pediatric gym at the hospital, depending on the child's health state. In both groups, determination of several primary (cardio-respiratory fitness, muscle strength, functional capacity, physical activity levels, body weight and quality of life) and secondary outcomes [immune function and inflammatory profile (blood levels of 47 cytokines)] will be made at the following time points: (i) before the exercise intervention (immediately after diagnosis and before treatment onset); (ii) after the exercise intervention (upon termination of neoadjuvant chemotherapy); and (iii) after a detraining period (2 months after the intervention). Discussion: The PAPEC trial will provide relevant new information on biological mechanisms and inform on the potential clinical use of exercise during pediatric cancer treatment as a simple way to prevent future long-term treatment effects and improve the general health state of pediatric cancer patients. © 2013 Published by Elsevier Inc.

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Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design☆

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journal homepage: www.elsevier.com/locate/conclintrial

☆ Trial Registration: ClinicalTrials.gov ID: NCT01645436. ⁎ Corresponding author at: Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Rua Dr Placido Costa 91, Porto 4200-450, Portugal. Tel.: + 351962591421 E-mail address: [email protected] (L. Soares-Miranda). 1 First two authors contributed equally. 2 Antonio Pérez-Martínez and Alejandro Lucia share senior authorship. 1551-7144/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cct.2013.05.012

Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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The aim of this RCT on Physical Activity in Pediatric Cancer (PAPEC) is to determine the possible benefits of regular, supervised exercise in pediatric cancer patients with solid tumors. Such benefits will be assessed in terms of impacts on cardio-respiratory capacity, muscle strength, functional capacity, PA levels and quality of life as well as immune function and inflammatory profiles. PAPEC trial will investigate the effects of a supervised in-hospital combined exercise-training program (aerobic and strength) in pediatric cancer patients with solid tumors undergoing chemotherapy. The effect of the exercise training program intervention will be assessed by comparing the intervention group to a (control) group receiving normal hospital care. The specific aims of this trial will be:

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1. To assess the effects of a supervised exercise program performed in-hospital during the course of neoadjuvant

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2.2. Study design

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2.1. Aims

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2. To determine possible changes after the exercise program in baseline levels of (i) immune cell subpopulations [leukocytes, monocytes and lymphocytes (NK cells, NK cell subsets, T cells, T cell subsets, NKT cells, dendritic cells and B cells) and immune function (NK cell cytotoxicity)], and (ii) markers of inflammation (blood profiles of 47 cytokines, pro-action or anti-inflammatory, or modulating the immune system at the local or systemic level) (secondary outcome measures). 3. To establish gains in the above mentioned outcomes due to the exercise program after a period of detraining (2 months).

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2. Material and methods

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The study described is a RCT (ClinicalTrials.gov ID: NCT01645436) designed to comply with the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) statement [12]. The RCT will be conducted over 3 years at the children's hospital, Hospital Infantil Universitario Niño Jesús (Madrid, Spain).

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chemotherapy on pediatric patients with extracranial primary solid tumors on the following variables: cardiorespiratory fitness, muscle strength, functional capacity, body weight, PA levels and quality of life (primary outcome measures).

2.3. Participants

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tumors are usually carcinomas arising from highly differentiated epithelial tissues, whereas pediatric tumors are largely of embryonic origin and normally arise from non-ectodermal embryonic tissues [3]. This accordingly suggests different causal mechanisms underlying pediatric and adult cancers [4]. In pediatric cancer the capacity of tumors to avoid the immune system is seen as an important feature for tumor survival and metastasis [4]. The relative high survival in pediatric cancers has had the consequence that more attention is now paid to minimize the short and long term adverse effects of chemo- and radiotherapy in survivors, even preventing the development of second malignancies [2] and future health conditions. Although the survival rate of children and adolescents diagnosed with cancer is 75%, about 60% of these survivors will suffer chronic treatment-related health problems for years or decades after completing therapy [5]. Thus, besides survival, efforts are now being directed toward improving the quality of life of cancer survivors [6]. With this goal in mind, interest in physical activity (PA) has primarily focused on its potential to ameliorate the short and long term side effects of treatments [7]. PA has beneficial effects on a broad range of physiological systems and functions, including the central nervous and cardio-respiratory systems, skeletal muscle, immune system, inflammation and oxidative pathways. PA programs are starting to emerge as beneficial during and after pediatric cancer treatment. Current evidence suggests that the bed rest traditionally recommended for pediatric cancer patients could aggravate some of the side effects of treatments, particularly loss of physical function and muscle strength. To the best of our knowledge, only 4 randomized controlled trials (RCTs) have been conducted in pediatric cancer patients [8–11]. Of those 3 were conducted in children with hematological malignancies and one was conducted in a mix group of pediatric cancer patients (which included 25 with solid tumors and 4 with acute myeloid leukemia). So, evidence is lacking in pediatric cancer patients, particularly in children with solid tumors undergoing more aggressive treatments. With this in mind, the aim of this RCT is to determine the possible benefits of regular, supervised exercise in pediatric cancer patients with solid tumors.

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Pediatric patients of both sexes will be recruited for this trial if meeting each of the following inclusion criteria: aged 4 to 18 years; new diagnosis of an extracranial solid tumor; receiving treatment at the above mentioned hospital; being Madrid province residents; not having received previously therapy, and having a good performance status (i.e. for patients aged 12 + years, score ≤ 2 in the Eastern Cooperative Oncology Group scale, and for patients aged ≤ 12 years, score ≥ 50% in the Lansky scale). Approximately 30 children meeting all the aforementioned criteria are treated in this hospital every year and thus we will have a total number of 90 potentially eligible participants. Based on our previous experience, we expect that at least 80% of the children will enter the trial, which should ensure having a total sample size of 60 patients, which will allow us to detect clinically relevant improvements (even under 20%) with a statistical power of 0.80 and an effect size (Cohen's f) of 0.56 [13,14]. Each participant will be randomly assigned (with blocking on sex) to either an intervention or control group. Patients in the control group will undertake no scheduled training and those in the intervention group will take part in an inpatient physical training program (aerobic + strength) (Fig. 1). The parents/guardians of the children identified as possible candidates for the PAPEC trial will be provided with sufficient information for their written informed consent for participation. The study will be performed over the period of September 2012 to September 2015. The study protocol adheres to the ethics guidelines of the Declaration of Helsinki, last modified in 2011.

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2.4. Intervention

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The totality of the training program will be performed 171 in-hospital, usually after school hours (i.e. after the children 172

Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

L. Soares-Miranda et al. / Contemporary Clinical Trials xxx (2013) xxx–xxx

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Recruiting participants with primary solid tumors, aged between 4 an 18 years. Excluding central nervous system tumors.

Checking eligibility criteria

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Baseline measurements

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Detraining measurements (2 months after the end of the Intervention).

outpatients). The training program will last from the start to 176 the end of the neoadjuvant chemotherapy. This chemother- 177 apy duration depends on the tumor type and ranges from 178

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have attended school classes inside the hospital while they are inpatients, or after school classes usually taught at home by teachers of the Spanish public system while they are

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Fig. 1. General design of the PAPEC trial.

Fig. 2. Gymnasium at the children's teaching hospital, Hospital Infantil Universitario Niño Jesús (Madrid, Spain).

Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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2.5.1. Primary outcomes Cardio-respiratory fitness ([peak oxygen uptake (VO2 peak)]) will be assessed using a metabolic cart ‘breath by breath’ (Vmax 29C, Sensormedics, California, USA) and pediatric masks during arm-ergometer (see below) or treadmill exercise testing. After a session in which the children will be able to practice on the treadmill (Technogym Run Race 1400HC; Gambettola, Italy), a special protocol designed for children will be carried out. This involves an initial treadmill speed of 1.5 km·h−1 (for the smaller children, height b120 cm) or 2.5 km·h−1 (if the child's height is > 120 cm) at a 0.5% slope. Thereafter, both treadmill speed and inclination will be increased (by 0.1 km·h−1 and 0.5%, respectively) every 15 s until volitional exhaustion [18]. For those children missing a lower limb and who are thus unable to perform treadmill testing, the latter will be substituted by a test with a crank arm-ergometer (Monark Rehab Trainer model 881E, Monark, Varberg, Sweeden).

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2.5. Outcome measures

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exercise [16,17] with a rest period of 1 to 2 min between sets. Participants randomly assigned to the control group will receive normal hospital care, which includes some physiotherapy as needed as well as recommendation to families to follow a healthy lifestyle that comprises playing sports, playing in the park with other children as well as in the school playground and walking around 30 min per day.

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4 weeks (Wilm's tumor) to 21–24 weeks (rhabdomyosarcoma). The intervention will include a thrice per week exercise session at the hospital lasting ~ 60–70 min. Exercise plans will be individualized according to guidelines for aerobic [15] and strength training in children/adolescents [16,17]. Depending on the physician's recommendations, exercise sessions will be held in the child's room or in the hospital gymnasium appropriately equipped for this purpose (Figs. 2 & 3). Training will be supervised and individualized for each subject (1 supervisor per patient) by experienced professionals (Science of Physical Activity and Sport graduates). Additionally, exercise intervention will be standardized and will follow the same scheme and guidelines for every patient. Each session will include a conditioning period of approximately 30 min of aerobic exercise (cycle-ergometer pedaling, running, aerobic games). The training load will be gradually increased depending on the age, capacity and health state of each child. Exercise intensity (60–70% maximum heart rate for each child) will be monitored continuously by measuring heart rate using portable telemeters (‘heart rate monitors’). Aerobic exercise will be followed by approximately 30 min of strength training. This additional work will include 11 exercises performed against resistance (with dumbbells or special machines for children, Fig. 2) involving a wide range of joint movements: shoulder, chest and leg presses, side-arm rowing extension and flexion, knee extension and flexion, and abdominal, lumbar and shoulder adduction. Participants will perform 2 to 3 sets (8–15 repetitions) per

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Fig. 3. Exercise training at the Hospital Infantil Universitario Niño Jesús (Madrid, Spain).

Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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A blinded assessor will ascertain adverse events related to the testing sessions in both groups and to training sessions in the intervention group, including muscle pain, fatigue, and general aches and pains according to self-report (or parents' reports for the younger patients). On the other hand, special consideration will be given for those children whose tumor prevents them from performing a given type of exercise during training sessions or testing, e.g. children with leg bone tumors with high fracture risk, or children requiring limb amputation. In these cases, obviously treadmill or leg strength testing might not be feasible and only some data (i.e. upper body strength) will be available for statistical analyses. In any case, for ethical reasons we will facilitate all children benefit from training advantages and enjoy the program whatever their specific disease condition is, e.g. treadmill training will be substituted by arm-crank training (with the same ergometer used for testing — see above) or ‘normal’ cycle-ergometer training will be substituted by one-leg pedaling.

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4. Statistical analysis

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To assess training effects on the study variables, we will analyze the data according to the intention-to-treat principle [32], i.e. in those cases of missing data at post- or detraining we will use baseline scores. We will use a two-factor (group and time) analysis of covariance (ANCOVA) with repeated measures. As covariates we will use the baseline values of the study variables, as well as the length of the training intervention (since the duration of the coadjuvant chemotherapy varies depending on each type of tumor). For each outcome variable, the level of significance corresponding to the main group (between-subjects), time (within-subjects) and interaction (group × time) effects will be reported. To minimize statistical type I errors, post hoc comparisons will be conducted within each group only when a significant group ∗ time effect is observed. We will apply the Bonferroni correction to set the level of significance (α), i.e. for primary outcomes, α = 0.008, which is the result of diving 0.05 by 6 (number of primary outcomes) while for secondary outcomes α = 0.015 (=0.05 divided by 3).

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3. Potential adverse effects and special considerations

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2.5.2. Secondary outcomes Immune cell subpopulations, immune function and cytokine levels in peripheral (venous) blood will be determined as detailed in Table 1. All the aforementioned variables (primary and secondary outcome measures) will be determined in the intervention and control groups at the following time points: (i) before the exercise intervention (immediately after diagnosis and before treatment onset); (ii) after the exercise intervention (upon termination of neoadjuvant chemotherapy); and (iii) after a detraining period (2 months after the intervention).

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Illness Profile-Child Edition” (CHIP-CE/CRF), Adolescent Edi- 294 tion (CHP-PE/AE) and Parents Report Form (CHP-CE/PRF) 295 [29–31]. 296

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Starting at 5 W, the load will be increased in a ramp-like fashion, i.e. by 5 W every 20 s, while cadence is kept constant at 50 rpm. It should be noted that: a reduced VO2 has been linked to a higher risk of cardiovascular disease in young children [19] and that resistance training can improve the cardiovascular risk profile and motor skills of young children [17]. Muscle strength will be measured after three sessions of comprehensive familiarization with the equipment. A test of 6 repetition maximum (6RM) leg and chest (bench) presses and lateral rowing [20] on pediatric weight machines will be performed (Strive Inc., PA, USA). Tests to evaluate the child's ability to perform daily living activities will also be administered. After the familiarization sessions, the following test validated for children [20,21] will be performed: ladder test (‘Timed Up and Down Stairs test’, TUDS), out of a chair test and 3 and 10 meter walk test (‘3 m and 10 m Timed Up and Go test’, abbreviated TUG3 and TUG10 respectively). Body weight will be determined to the nearest 0.05 kg using a balance scale (Ano Sayol S.L., Barcelona, Spain) with patients in their underwear. PA levels will be estimated using a uni-axial accelerometer (Actigraph MTI, model GT1M, Manufacturing Technology Inc., Fort Walton Beach, FL, USA). Details on this methodology are provided elsewhere [22]. In the presence of the parents, all children will be instructed to wear the monitor attached with an elastic belt to the iliac crest of the right hip for 7 days (Monday–Sunday). They should remove it for sleep and for any activity that could damage the monitor such as swimming or bathing. Verbal and written instructions for the care and placement of the monitor will be given to both the children and their parents. GT1M is a small (4.5 × 3.5 × 1.0 cm), lightweight (27 g), single plane (vertical) accelerometer. Movement in a vertical plane is detected as a combined function of the frequency and intensity of the movement, while an electronic filter rejects motion outside the range of normal human movement. Validation studies have indicated that this accelerometer is valid and reliable for measuring PA in children. The instrument shows significant correlation (r = 0.86) with energy expenditure as assessed by indirect calorimetry, and good inter-instrument reliability [22–26]. PA will be monitored for up to 7 consecutive days. A minimum of 4 days' monitoring including a weekend day, and a minimum of 10 h of data are considered necessary for adequate assessment of PA [27]. Data will be analyzed using Kinesoft software, developed specifically for Actical and Actigraph accelerometers. Outcome variables will be expressed as average intensity (counts/minute). We will calculate mean counts per minute by dividing the sum of total counts per epoch (15 s) for a valid day by the number of minutes of wear time in that day across all valid days. We will exclude from the analysis bouts of 20 continuous minutes of activity with intensity counts of 0, considering these periods to be nonwearing time [28]. Counts will be transformed to average minutes per day engaged in low, light, moderate, vigorous and very vigorous PA using the cut-offs published elsewhere [22,23]. Daily time spent undertaking moderate-to-vigorous physical activity (MVPA) will be calculated. To assess quality of life, all children and their parents/guardians will be administered the validated version of the Spanish “Child Report Form of the Child's Health and

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Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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Table 1 Secondary outcomes.

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Outcome

Specific variables within each outcome

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Immune cell subpopulations in peripheral (venous) blood

Total leukocyte and monocyte count

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Lymphocyte subpopulations

Immune function

Cytotoxicityof NK cells

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Additional specifications for each variable

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Additional specifications (continuation)

Natural Killer (NK) lymphocytes NK subsets NK dim NK bright T lymphocytes NKT lymphocytes B lymphocytes Dendritic cells (DC) DC subsets DC1 (myeloid) DC2 (lymphoid) DC1 − DC2−

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CD3−, CD56+ Moderate expression of CD56 and CD16 on NK cells High expression of CD56 and absence of CD16 on NK cells CD3+ CD56− CD3+ CD56+ CD19+ CD20+ lineage (Lin) − HLA-DR + lineage − HLADR+ CD11c+ Lin − HLA-DR + CD11c − BDCA4 Lin − HLA-DR + CD11c − BDCA4−

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Blood analyzer (Advia 120 Hematology System, Bayer Corporation, Tarrytown, NY, USA) Subpopulations phenotyped in fresh samples of peripheral blood, after Ficoll gradient separation by multiparametric flow cytometry (Becton Dickinson, FACS Canto II, Madrid, Spain). Fluorochrome-labeled antibodies against human antigens: CD3 PE-Cy7, CD20-PE CD45-FITC, Lineage-FITC, HLADR-APC-Cy7, CD11c-PECy5 (Becton Dickinson, Franklin Lakes, NJ, USA) CD19-PE, CD56-APC (Beckman Coulter, Fullerton, CA), and BDCA4-APC (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany).

No. of cells in each lymphocyte subpopulation = total No. of white blood cells × % of each subpopulation.

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2-hour europium-TDA release assay (Perkin-Elmer Wallac, Turku, Finland). K562 erythroleukemia cell line used as the target cell, with effector/target ratios of 8:1, 4:1, 2:1 and 1:1. Target cells are labeled with fluorescenceenhancing ligand (BATDA). Cytolysis, results in the release

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The following formulas will be used to calculate spontaneous and specific cytotoxicity: % specific release = (experimental release − spontaneous release) /( maximum release − spontaneous release) × 100. % spontaneous release = (spontaneous release − background) / (maximum release − background) × 100.

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Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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Cytokines in serum

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Beta nerve growth factor (beta-NGF) Cutaneous T cell-attracting chemokine Eotaxin Fibroblast growth factor Granulocyte colony-stimulating factor Granulocyte-macrophage colony-stimulating factor Growth-related oncogene α Hepatocyte growth factor Inter-cellular adhesion molecule (ICAM) 1 Interferon (IFN) α2 IFNγ IFN-inducible protein 10 Interleukins (IL) Leukemia inhibitory factor Macrophage colony stimulating factor Macrophage inflammatory protein 1(MIP1)α MIP1β Macrophage migration inhibitory factor Monocyte chemotactic protein (MCP) 1 MCP3 Monokine induced by IFNγ Platelet-derived growth factor bb Stem cell factor Stem cell growth factor β Stromal cell-derived factor 1α Tumor necrosis factor (TNF)-related apoptosis-inducing ligand TNFα TNFβ Vascular cell adhesion molecule 1 Vascular endothelial growth factor (VEGF)

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IL1α IL1β IL1ra IL2 IL2RA IL3 IL4 IL6 IL7 IL8 IL9 IL10 IL12 IL13 IL15 IL16 IL17 IL18

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Assays performed according manufacturer's recommended procedure: premixed standards reconstituted in 0.5 ml of culture medium, generating a stock concentration of 50,000 pg·ml−1 for each molecule been measured. The standard stock will be serially diluted in the same culture medium to generate 8 points for the standard curve. The assay will be performed in a 96-well filtration plate supplied with the assay kit. Premixed beads (50 μl) coated with target capture antibodies will be transferred to each well of the filter plate (~5000 beads per well per cytokine) and washed twice with Bio-Plex wash buffer. Premixed standards or samples (50 μl) will be added to each well containing washed beads. The samples will be used directly without further dilution. The plate will be shaken for 30 s and then incubated at room temperature for 30 min with low-speed shaking (300 rpm). After incubation and washing, premixed detection antibodies (50 μl, final concentration of 2 μg·ml−1) will be added to each well. The incubation will be terminated after shaking for 10 min at room temperature. After 3 washes, the beads will be resuspended in 125 μl of Bio-Plex assay buffer. Beads will be read on the Bio-Plex suspension array system, and the data will be analyzed using Bio-Plex Manager™ software (v 3.0) with 5PL curve fitting. All samples will be run in duplicate to assess the coefficient of variation between samples.

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Please cite this article as: Soares-Miranda L, et al, Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): Trial rationale and design, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.05.012

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of the ligand and ultimately the ligand reacts with the europium to form a stable, fluorescing chelate, which is evaluated fluorometrically (Infinite F200 reader TECAN Group Ltd, Männedorf, Switzerland). Bio-Plex human cytokine immunoassay (Bio-Rad Laboratories Inc., Hercules, CA, USA) for simultaneous quantification of all the studied cytokines

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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 sequelae and secondary malignancy [6]. Oeffinger et al. [36] reported that 30 years after cancer diagnosis in childhood, ~73%

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6. Discussion

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We are currently conducting a preliminary, pilot trial with 11 children [enrolment rate relative to total number of potential eligible participants during this time = 87%; 9 boys, 2 girls, age range of 4 to 16 years; tumors: alveolar rhabdomyosarcoma (n = 2), embryonal rhabdomyosarcoma (n = 2), Hodgkin lymphoma (n = 3), osteosarcoma (n = 2), Burkitt's lymphoma (n = 1), lymphoblastic lymphoma (n = 1), and Wilm's tumor (n = 1)], six of whom were assigned to perform the aforementioned training program. Accelerometry data revealed that their PA levels were low, i.e. about 24 min/day of MVPA (corresponding to ~26 and ~20 min on week and weekend days respectively). These daily levels of MVPA are below those we previously reported in children with hematological cancer (acute lymphoblastic leukemia), i.e. ~49 and ~53 min per week and weekend days respectively of MVPA [33]. They are also clearly below current PA guidelines for health promotion, i.e. children should accumulate ≥60 min of MVPA every day [34]. These results indicate the need to promote PA in these children. Four of the pediatric patients have now completed the exercise intervention (total duration ranging from 3 to 5 months) with a mean adherence to the sessions >70% (and with no side effect attributable to exercise, other than the usual muscle soreness, especially at the start of the program). Three other children have completed the treatment protocol without exercise (control group). The mean VO2peak levels of the exercised children increased about 16% after the intervention (from 22.9 to 27.3 mL/kg/min), whereas their muscle strength levels increased by higher percentages, e.g. 19% and 36% improvement for leg and bench press respectively. In contrast, no such improvements were observed in their inactive peers-control group (average VO2peak decreased from 22.1 to 18.0 ml/kg/min, and leg and bench press slightly decreased, i.e. by −1% and −2% respectively). The latter data illustrate the negative effects of the disease itself and the treatment aggressiveness, in the children's cardio-respiratory and muscle systems. We also found improvements in the NK cell's cytotoxicity of the exercised children at the end of the intervention compared with the start of the training program (which increased by 21%, 17% and 6% at 4, 2 and 1 effector/target ratio respectively), as well as in the rate of T cells' recovery (52% increase). Such high improvements were not found in their inactive peers, in whom relative changes in NK cell's cytotoxicity during the same time period were 8%, 5% and 5% at 4, 2, 1 effector/target ratio, and the rate of T cell recovery only increased by 13%. The latter data are promising as they suggest positive effects of exercise on the innate and adaptive immune defense, which can play an important role in tumor growth suppression [35].

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of survivors had a chronic health condition. Thus, efforts are now being directed toward improving the quality of this survival [6]. With this goal in mind, interest in PA has primarily focused on trying to diminish the side effects of treatments [7] since, PA has beneficial effects on a broad range of physiological systems and functions. Thus, regular exercise increases a patient's capacity to more easily and effectively deal with the physical demands of daily life. Traditionally physicians would recommend avoiding too much activity in pediatric cancer patients during and after treatment. This may be especially problematic in children since PA is essential for health and growth and also has considerable physical, psychological and social benefits. Further, inactive children are likely to become inactive adults. The current recommendations for healthy school-age children are 60 min or more of MVPA every day [34]. Indeed, PA is important for the multiple demands of physical, biological and psychological growth [34] contributing enormously to well-balanced development. Recently, exercise intervention programs have emerged as safe in pediatric cancer patients during and after cancer treatment, and there is strong evidence for improved cardiorespiratory fitness and muscle strength [37]. However, these exercise programs have mainly been conducted in children with hematological malignancies and similar evidence is lacking in children with solid tumors undergoing more aggressive treatments. Based on our hospital records, we predict the following tumor type distribution in our patients: lymphoma and neuroblastoma (~20% each), bone tumors and soft tissue sarcomas (~15% each), Wilm's tumor (~10%), germ cell tumors (~8%), and others (~12%). There is also a clear need for exercise RCTs in pediatric cancer patients [37], since only 4 of this type of studies have been published [8–11]. Additionally, there is a need to deeply explore the beneficial effects of PA as, for example, in the immune system since no previous RCT in pediatric cancer has done it, to the best of our knowledge. Understanding the molecular mechanisms whereby regular exercise exerts beneficial effects on the general health and physical condition of childhood cancer survivors is a new and much needed field of research. Studies have shown that moderate regular exercise can improve immune function [38,39], and that it may even have an impact on cancer control [38]. Several observed mechanisms could be responsible for these beneficial effects of regular exercise in cancer patients, such as: increases in the number and function of NK cells [40], increases in the number of anti-tumor dendritic cells [41], or anti-inflammatory effects of regular exercise [42]. This field of research seems especially important in pediatric cancer since, some suggested that pediatric tumors differ from adult tumors in terms of leukocyte infiltration. Thus, the pediatric tumor infiltrate is composed mainly of macrophages affecting necrotic areas of tumor islands while adult tumors are infiltrated by T cells and natural killer (NK) cells besides macrophages [43]. This relative nonexistence of critical elements of the immune system in pediatric tumors may suggest failure of the antitumor immune response along with a capacity of pediatric tumors to avoid immune elimination [4]. On the other hand, we believe a major strength of our design is that it meets quality criteria for RCTs using exercise as intervention. Indeed, for reaching the methodological fulfillments to support strong medical evidence, an exercise training intervention should meet 4 or more of the following criteria: randomization,

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This study was funded by Fondo de Investigaciones Sanitarias (FIS, ref. # PS09/00194). Luisa Soares-Miranda is supported by the Portuguese Foundation for Science and Technology SFRH/ BPD/76947/2011 and PEst-OE/SAU/UI0617/2011.

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Randomized controlled trial in pediatric cancer patients is scarce, and the PAPEC trial will critically address important research issues in a carefully designed randomized trial. The PAPEC trial will provide insight into biological mechanisms and indicate the potential benefits of exercise during pediatric cancer treatment as a simple way to prevent future long-term treatment effects and improve the general health state of these children. The authors declare they have no financial competing interests.

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intent-to-treat analysis, concurrent comparison group, adherence reported and equaling to at least 70% of the intervention prescription, less than 20% of participants lost to follow-up, documented reliability/validity of the exposure assessment and of the outcome, and blinded measurement [44]. All of these criteria will be likely met. Previous exercise interventions on pediatric patients from our group using the same in-hospital training schema have shown high adherence to the program, e.g. >70% in outpatients [18,20] and >90% in inpatients with cancer respectively [45], and even higher (>95%) in outpatient children with cystic fibrosis [46].

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