All questionnaires will be completed electronically using tablet computers. Different questionnaires are available for survivors of childhood cancer aged 9 to 12 years and their parents (proxy reports) and survivors of childhood cancer aged 13 to 16 years and their parents. The questionnaires comprise mainly validated and standardized questions (Table 1). Questionnaires will be translated into local language if validated translations do not exist, following recommended forward–backward translation procedures. Questionnaire data will be directly uploaded and stored on the secured server for sensitive data at the University of Oslo’s Center for Information Technology.

Items pertaining to exercise in leisure time will be measured by questions extracted from studies of age- and sex-stratified reference material (the Health in Adolescents study, Physical Activity among Norwegian Children study wave 2 [35], and the Relevance of Physical Activity Contexts in the Everyday Life of Adolescents [REPAC]; the REPAC study described below [34-36]) to enable comparisons. The questions target PA and include frequency, duration, and type of PA or exercise and active transportation (questionnaires are available upon request).

Questions regarding attitudes and participation toward physical education before and after the cancer experience are based on the questionnaire of an ongoing study of approximately 3000 Norwegian adolescents (REPAC study) [36].

Perceived barriers to being physically active will be assessed using a self-constructed questionnaire. Survivors of childhood cancer will rate degree of agreement with 15 statements in response to the question “I am less physically active than I want to because;....” The 15 statements reflect potential physical, psychosocial, and mental barriers to PA and were designed based on clinical experience, input from user representatives, and pilot testing. Examples of statements are “I don’t have time for it; I don’t know how active I can or should be; My body feels too heavy; I am too fatigued; I have pain; My parents tell me to be careful.” Each statement is scored on a 5-point Likert-type scale ranging from totally disagree to totally agree.

Screen time (time spent in front of a computer, watching television, playing computer games, surfing on the internet, and chatting) will be assessed by 2 questions from a questionnaire used in a large international study on children and adolescents (the Health Behavior in School-aged Children study) [37].

A total of 3 questions regarding diet were extracted from a nationally representative study on children and adolescents’ dietary habits, called the Norwegian Ungkost study [38].

Participants will report when they usually get out of bed and when they go to bed on school days [43].

QoL will be measured using the Pediatric QoL Inventory (PedsQL) core module [39]. The PedsQL includes four subscales—physical, emotional, social, and school functioning—and has 2 different modules validated for children aged 8 to 12 years and adolescents aged 13 to 18 years. The PedsQL has been used in children with cancer [40]. In addition, parents will be asked to complete the parent module (proxy report) of the PedsQL.

Fatigue will be measured using the PedsQL Multidimensional Fatigue Scale, which measures general fatigue, sleep/rest fatigue, and cognitive fatigue [40]. Parents will complete the respective parent modules.

The Strength and Difficulties Questionnaire (SDQ) will be used to measure psychological adjustment and emotional problems. The SDQ is widely used in children aged 8 to 17 years [41].

Parents will provide sociodemographic variables in their questionnaire (child’s age, child’s sex, parents’ education, and parents’ income).

Outcomes of WP 2 include measurements of cardiorespiratory fitness, muscle strength, power, and muscular endurance. Norway (Oslo and Bergen) and Switzerland (Basel) will participate in WP 2 (Table 1 provides an overview of tests and self-reported measures performed at each site specific to WP 2). In Norway, age- and sex-matched controls will be the same-age friend or sibling of the survivor of childhood cancer, chosen and invited by the survivors of childhood cancer themselves. In Switzerland, age- and sex-matched controls will be recruited from siblings or friends of survivors or within the network of the Swiss PACCS study team.

Before testing, survivors of childhood cancer will undergo a cardiological screening. Peak oxygen uptake (VO₂peak) will be assessed using a cardiopulmonary exercise test (CPET). In Norway, the CPET will be performed by walking and running on a treadmill using a child-friendly continuous graded treadmill protocol until exhaustion [48], whereas in Switzerland, the CPET will be performed on a cycle ergometer using an incremental bike protocol from Godfrey [49]. The starting workload after habituation to the treadmill will be 3.0 km/hour at 0% inclination. The workload will then be increased every minute by alternately increasing the speed by 1 km/hour and the inclination by 2% every other minute. For the bike protocol, the initial workload will be set to 10, 15, or 20 W depending on the child’s height and increased by 10, 15, or 20 W every minute, respectively. The participants will be encouraged to keep a pedaling frequency of 60 to 90 revolutions per minute. Gas exchange and ventilatory variables will be measured continuously, breath by breath, using a Hans Rudolph 2-way breathing mask (Hans Rudolph). Peak heart rate will be measured through a 12-lead electrocardiogram, and blood pressure and transcutaneous oxygen saturation will be measured after 5 minutes of rest in the sitting position, during the test, and shortly after termination. The Borg rating [50] of perceived exertion will be assessed at the end of the test. The VO₂peak is defined as the highest oxygen consumption value sampled over a 30-second interval. The ventilatory threshold will be calculated using the ventilatory equivalent method, expressed as oxygen uptake (VO₂). The minute ventilation (VE) and carbon dioxide responses during exercise will be used to calculate the VE/carbon dioxide uptake slope. The breathing reserve will be calculated using measured maximal voluntary ventilation (MVV) and the maximal VE using the following equation:

The oxygen pulse will be calculated by dividing VO₂peak (in mL) by the peak heart rate [51].

Isometric bench press and isometric leg extension will be performed using a custom-built strength ergometer (Gym 2000) with a strain gauge (US2A100 kg, Holtinger) and a custom-made amplifier. The ergometer is specially designed for testing children. In the bench press test, participants will be instructed to push an (upward) static bar with maximal effort for 5 seconds. The participants will lie on the ergometer with the bar height adjusted so that the elbow angle is 90° to get the upper arm in a horizontal position and the lower arm in a vertical position. The participants will be required to maintain the elbow angle throughout the duration of the trial. Each participant will perform at least three trials with 2 minutes of rest between each trial but will be allowed to continue with further trials as long as improvements are observed. The highest value of the trials will be used for later analysis. In the knee extension test, the participant will be seated at the short end of the ergometer bench with his or her back straight, arms down, and hands lightly gripping the seat. During contraction, both hip and knee joint angles will be flexed at 90° (180° will be fully extended), respectively. For the knee extension isometric test, the participants will also perform at least three trials with 2-minute rest between trials but will be allowed to continue with further trials as long as improvement is observed. The best result in each test will be used for later analysis. Hand-grip strength will be measured in the left and right hands (Baseline Life Hand Dynamometer) while the participant will be standing and with the arm extended and pointing down. Each hand will be measured 3 times, with alternating sides, starting with the right hand and approximately 30-second breaks between measurements. The best result for each hand will be used for later analysis.

Muscular endurance will be tested using the 1-minute sit-to-stand (STS) test [52]. The participants will perform 1 test trial at least 20 minutes before the final test. The number of repetitions of standing up and sitting down from a chair within 1 minute in the final test will be recorded. In addition, the Borg rating [50] of perceived exertion will be assessed at the end of the test. The test will be performed on a height-adjustable chair to ensure a 90° knee angle. The 1-minute STS test showed high reliability and good criterion-related validity with other exercise capacity tests such as the 6-minute walk test or stair climbing [53-56].

All jumps will be performed on a portable force plate (FP4; HUR-Laboratories Oy). Hands will be placed on the hips throughout the test, and the angular displacement of the knees will be standardized so that the participants are instructed to squat down until the knees are bent at approximately 90° and then immediately jump vertically as high as possible, landing back on the force plate on both feet at the same time. The jump height and power will be measured [57]. The best result of at least three attempts will be recorded; however, the participants will be allowed to continue to jump as long as improvements are made. There will be 1 minute of rest between the trials.

A known carbon monoxide (CO) dose of approximately 1.2 mL/kg body mass will be administered and rebreathed for 2 minutes. Capillary fingertip blood samples will be collected before the start of the test and 7 minutes after the administration of the CO dose. Both blood samples will be measured a minimum of 5 times to determine the percentage of carboxyhemoglobin using an OSM3 Hemoximeter (Radiometer). Hemoglobin mass will be calculated from the mean change in percentage of carboxyhemoglobin before and after rebreathing CO [58]. Blood volume, plasma volume, and red cell volume will be calculated from hemoglobin mass using venous hemoglobin and venous hematocrit according to Burge and Skinner [59] and Heinicke et al [60].

Lung function will be measured using the maximal expiratory flow volume loops. Forced expiratory volume in 1 second, forced vital capacity (FVC), maximal expiratory flow at 50% of FVC (MEF₅₀), peak expiratory flow, and the ratio of forced expiratory volume in 1 second to FVC will be recorded. Lung volumes (total lung capacity and residual volume) and airway resistance will be measured using standardized whole-body plethysmography. Diffusion capacity will be measured using the single-breath method, and the result will be adjusted for serum hemoglobin levels. All measurements are according to the American Thoracic Society/European Respiratory Societies guidelines. The Global Lung Function Initiative reference equations will be used, and the outcomes will be expressed as absolute values, percent predicted, and z scores and the lower limit of normal.

A full functional echocardiography protocol, including 2D, color, pulsed, continuous, and tissue Doppler registrations, will be performed using a GE Vivid E95 ultrasound machine (GE Healthcare) with 4- and 5 MHz 2D probes (4Vc-D or M5Sc). 3D volumes will be acquired as multi-beat fusions with breath hold. The frame rate for 2D images will be kept between 50 and 90 frames per second for 2D strain measurements. Automatic image optimization will be used as the default setting, supplied by manual optimization, as required. Parasternal, apical, selective right ventricular apical, and subcostal views will be applied. For clinical use, left ventricular ejection fraction, as calculated by the Simpson biplane method, fractional shortening by m-mode (MediMatic Compacs software), and peak systolic left ventricular global longitudinal strain (GE EchoPac software), will be reported in addition to any other positive findings of clinical significance. Additional research-based measurements will be performed as the mean value of 3 consecutive cardiac cycles. Left ventricular 4D volumes will be measured using a semiautomatic method (EchoPac Auto-LVQ).

Detailed patient history and clinical neurological examination will be performed. The symptoms and findings relevant for polyneuropathy and neuropathic pain will be scored according to the Toronto Neuropathy Symptom Score, Douleur Neuropathique 4, and Neupsig criteria for neuropathic pain [61-63]. Standard nerve conduction studies on three motor nerves (ulnar, peroneal, and tibial), four sensory nerves (ulnar, radial, superficial peroneal, and sural), and one mixed motor or sensory nerve (tibial plantar nerve) will be performed. Assessment of small fiber function will be conducted by quantitative thermal testing (cold perception threshold and warmth perception threshold) on the hands and feet. All measurements will be performed on the right extremities. The temperature will be maintained at >30 °C in feet and >32 °C in hand. Polyneuropathy will be diagnosed and classified according to the criteria suggested by Tesfaye et al [64] as possible, probable, or confirmed polyneuropathy (clinical grading) and according to the Tesfaye neurophysiological criteria (stadium 0, 1a, 1b, 2a, and 2b), which includes subclinical polyneuropathy.

Body weight will be measured using a digital scale (SECA 876 GmbH and Co), with participants wearing light clothing and no shoes. Height will be measured using a stadiometer (SECA 217 GmbH and Co). Body composition will be assessed by dual-energy x-ray absorptiometry (Lunar iDXA GE Healthcare using the enCORE software Version 14.10.022). Participants will be scanned from head to toe in a supine position, providing values for total lean tissue (kg), fat mass (kg), bone mineral content, and bone mineral density. In WP 2, the puberty stage of survivors of childhood cancer will be assessed clinically by a medical physician at the first visit in Norway. In addition, all participants (survivor of childhood cancer and controls) will self-assess their puberty stage using a modified Tanner method [65].

Muscle thickness and pennation angle of the musculus vastus lateralis and thickness of the musculus biceps brachii will be measured by B-mode ultrasound using a linear-array transducer (50 mm, 5-12 MHz, HD11XE, Philips Ultrasound, revision 2.0.3). The sites for the measurements will be on one-third of the humerus length measured from the lateral epicondyle for the musculus biceps brachii and on 40% of the femur length measured from the lateral epicondyle for the musculus vastus lateralis.

Whenever the time between participation in WP 1 and recruitment in WP 2 exceeds 3 months, PA will be remeasured by accelerometers as described above (WP 1).

The number of contacted and recruited survivors with reasons for nonrecruitment will be recorded by the study nurses at each site.

PA will be measured by an accelerometer as described for WP 1 at baseline and after 6 months. In addition, the PA will be tracked continuously with the Polar watch (Polar Global). At each follow-up discussion with the central coaches, the survivors will be asked about their participation in the agreed PA program and, if applicable, reasons for nonparticipation.

Compliance with the PA intervention will be assessed based on the PA measurements described above. In addition, we will record the number of contacts of each survivor with the central and local coaches and the number of missing information at each study time point. Dropouts and reasons for dropout will be assessed by the study nurses.

Safety and adverse events will be assessed by the central coaches during follow-up calls.

At the end of the intervention, the survivors will give their subjective rating of satisfaction with participation in and intended sustainability of the PA intervention. The questions will be developed specifically for this study.

Attitudes toward PA will be assessed at baseline and at 2 and 6 months. The same questions as in WP 1 will be used to assess barriers to PA. Perceived physical competence (3 items) and perceived enjoyment (5 items) will be measured by items from the Children’s Attraction to PA scale [76-78]. Motivation toward PA will be measured using the Behavioral Regulation in Exercise Questionnaire 2 [79].

At baseline and 6 months, survivors will fill in the same questionnaires as in WP 1 to assess QoL and fatigue (only self-reported version and no parent module).

PF will be assessed during the study visits at baseline and after 6 months. All sites will perform a CPET and 1-minute STS test according to the same protocol as described for WP 2. In addition, Oslo and Bergen will perform the same isometric strength tests (knee extension and chest press) as in WP 2. Turku will perform the same knee extension test as WP2 but on its own device as well as a dynamic upper extremity lifting test (standing with 5 kg dumbbells for women and 10 kg for men; number of repetitions are reported). Essen will perform the same isometric knee extension and chest press as in WP2 but on their own devices.

As this is a feasibility study, we will mainly use descriptive statistics to present the study results. We will use numbers and proportions to describe categorical variables and means, SDs (or median and IQR if the data are skewed), and ranges to describe continuous variables. P values will be calculated based on appropriate univariable and multivariable models depending on the outcome and adjusted for the study site by introducing a random intercept (mixed model). P values are interpreted as flagging trends and not as hypothesis tests.

Qualitative content analyses of interview transcripts will be performed [70].