Longitudinal changes of psychological distress among childhood cancer survivors: The Swiss Childhood Cancer Survivor Study.

BACKGROUND: Childhood cancer survivors may experience psychological distress due to the disease, cancer treatments, and potential late effects. Limited knowledge exists regarding longitudinal changes in psychological distress after childhood cancer. We aimed to determine changes in psychological distress over time and explore determinants of changes. METHODS: The Swiss Childhood Cancer Survivor Study collected data at baseline (2007-2009) and follow-up (2010-2012). Psychological distress was measured using the Brief Symptom Inventory 18 (BSI-18), including three symptom scales (somatization, depression, anxiety) and an overall distress index (Global Severity Index, GSI). Sum-scores were T-standardized (mean = 50; standard deviation [SD] = 10). Survivors with a score ≥57 on the GSI or two symptom scales were classified as cases with distress. We used linear mixed effects regression to identify potential sociodemographic and clinical determinants of change in psychological distress. RESULTS: We analyzed 696 survivors at baseline (mean age = 24 years [SD = 4], 49% females, mean time since diagnosis = 16 years [SD = 4]). On follow-up (2.4 years, SD = 1), 317 survivors were analyzed, including 302 participants with repeated measures. We found that 13% (39/302) were cases at baseline, and 25% (76/302) were cases on follow-up. Those older at study and longer since diagnosis, females, diagnosed with central nervous system (CNS) tumors, and those reporting late effects were more likely to experience higher levels of distress. Females and unemployed are at higher risk for developing or persisting psychological distress than males and those who are employed or in training. CONCLUSION: We observed an increase in psychological distress score over time, with higher proportion of psychological distress on follow-up. Anticipatory guidance and screening should be implemented in regular follow-up care.

Validation of self-reported cardiovascular problems in childhood cancer survivors by contacting general practitioners: feasibility and results.

BACKGROUND: Epidemiological studies often rely on self-reported health problems and validation greatly improves study quality. In a study of late effects after childhood cancer, we validated self-reported cardiovascular problems by contacting general practitioners (GPs). This paper describes: (a) the feasibility of this approach; and (b) the agreement between survivor-reports and reports from their GP. METHODS: The Swiss Childhood Cancer Survivor Study (SCCSS) contacts all childhood cancer survivors registered in the Swiss Childhood Cancer Registry since 1976 who survived at least 5 years from cancer diagnosis. We validated answers of all survivors who reported a cardiovascular problem in the questionnaire. Reported cardiovascular problems were hypertension, arrhythmia, congestive heart failure, myocardial infarction, angina pectoris, stroke, thrombosis, and valvular problems. In the questionnaire, we further asked survivors to provide a valid address of their GP and a consent for contact. We sent case-report forms to survivors' GPs and requested information on cardiovascular diagnoses of their patients. To determine agreement between information reported by survivors and GPs, we calculated Cohen's kappa (κ) coefficients for each category of cardiovascular problems. RESULTS: We used questionnaires from 2172 respondents of the SCCSS. Of 290 survivors (13% of 2172) who reported cardiovascular problems, 166 gave consent to contact their GP and provided a valid address. Of those, 135 GPs (81%) replied, and 128 returned the completed case-report form. Survivor-reports were confirmed by 54/128 GPs (42%). Of the 54 GPs, 36 (28% of 128) confirmed the problems as reported by the survivors; 11 (9% of 128) confirmed the reported problem(s) and gave additional information on more cardiovascular outcomes; and seven GPs (5% of 128) confirmed some, but not all cardiovascular problems. Agreement between GPs and survivors was good for stroke (κ = 0.79), moderate for hypertension (κ = 0.51), arrhythmias (κ = 0.41), valvular problems (κ = 0.41) and thrombosis (κ = 0.56), and poor for coronary heart disease (κ = 0.15) and heart failure (κ = 0.32). CONCLUSIONS: Despite excellent GP compliance, it was found unfeasible to validate self-reported cardiovascular problems via GPs because they do not serve as gatekeepers in the Swiss health care system. It is thus necessary to develop other validation methods to improve the quality of patient-reported outcomes.

Effect of a 1-year physical activity intervention on quality of life, fatigue, and distress in adult childhood cancer survivors-A randomized controlled trial (SURfit).

INTRODUCTION: Childhood cancer survivors (CCS) are at risk of experiencing lower quality-of-life, fatigue, and depression. Few randomized controlled trials have studied the effect of physical activity (PA) on these in adult long-term CCS. This study investigated the effect of a 1-year individualized PA intervention on health-related quality-of-life (HRQOL), fatigue, and distress symptoms in adult CCS. METHODS: The SURfit trial randomized 151 CCS ≥16 years old, <16 at diagnosis and ≥5 years since diagnosis, identified through the Swiss Childhood Cancer Registry. Intervention participants received personalized PA counselling to increase intense PA by ≥2.5 h/week for 1 year. Controls maintained usual PA levels. The authors assessed physical- and mental-HRQOL, fatigue, and distress symptoms at baseline, 3, 6, and 12 months. T-scores were calculated using representative normative populations (mean = 50, standard deviation = 10). Generalized linear mixed-effects models with intention-to-treat (ITT, primary), and three per-protocol allocations were used. RESULTS: At 12 months, ITT (-3.56 larger decrease, 95% confidence interval -5.69 to -1.43, p = .001) and two per-protocol analyses found significantly lower fatigue. Physical-HRQOL improved significantly in two per-protocol analyses at 12 months. No other effects were found. CONCLUSION: SURfit showed that increased intense PA over 1 year improved fatigue in adult CCS. Survivors should be recommended PA to reduce the burden of late-effects.

Chronic health conditions after childhood Langerhans cell histiocytosis: Results from the Swiss Childhood Cancer Survivor Study.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare disease characterized by dysregulated proliferation of myeloid marrow progenitors and subsequent organ infiltration. While LCH is associated with a favorable prognosis, some survivors may develop chronic health conditions (CHC) because of the disease. In this study, we aimed to assess the spectrum and prevalence of CHC among LCH survivors compared with siblings and identify factors associated with the development of CHC. METHODS: The Swiss Childhood Cancer Survivor Study sent questionnaires to all ≥ 5-year LCH survivors registered in the Swiss Childhood Cancer Registry and diagnosed between 1976 and 2015. Siblings also received similar questionnaires. We compared CHC prevalence between LCH survivors and siblings and used logistic regression to identify determinants of CHC. RESULTS: A total of 123 LCH survivors participated in the study, with a response rate of 69%. Median time since diagnosis was 13 years (interquartile range 9-20). Among LCH survivors, 59% had at least one CHC. Cardiovascular (13% vs. 6%), endocrine (15% vs. 2%), musculoskeletal (22% vs. 13%), and digestive (15% vs. 8%) CHC were more common among LCH survivors compared to siblings (all p < 0.05). Factors most strongly associated with the occurrence of CHC were multisystem LCH, multifocal bone involvement, and involvement of the pituitary gland. CONCLUSIONS: More than half of long-term LCH survivors suffered from one or more CHC and were affected considerably more than siblings. IMPLICATIONS FOR CANCER SURVIVORS: LCH survivors in follow-up care should be screened especially for cardiovascular, endocrine, musculoskeletal, and digestive conditions.

Prevalence and factors associated with cancer-related fatigue in Swiss adult survivors of childhood cancer.

PURPOSE: Reported prevalence of cancer-related fatigue (CRF) among childhood cancer survivors (CCS) varies widely, and evidence on factors associated with CRF among CCS is limited. We aimed to investigate the prevalence of CRF and its associated factors among adult CCS in Switzerland. METHODS: In a prospective cohort study, we invited adult CCS who survived at least 5 years since last cancer diagnosis, and were diagnosed when age 0-20 years and treated at Inselspital Bern between 1976 and 2015 to complete two fatigue-measuring instruments: the Checklist Individual Strength subjective fatigue subscale (CIS8R; increased fatigue 27-34, severe fatigue ≥ 35) and the numerical rating scale (NRS; moderate fatigue 4-6, severe fatigue 7-10). We collected information about previous cancer treatment and medical history, and calculated ß coefficients for the association between CIS8R/NRS fatigue scores and potential determinants using multivariable linear regression. RESULTS: We included 158 CCS (participation rate: 30%) with a median age at study of 33 years (interquartile range 26-38). Based on CIS8R, 19% (N = 30) of CCS reported increased fatigue, yet none reported severe fatigue. CRF was associated with female sex, central nervous system (CNS) tumors, sleep disturbance, and endocrine disorders. Lower CRF levels were observed among CCS age 30-39 years compared to those younger. CONCLUSIONS: A considerable proportion of adult CCS reported increased levels of CRF. IMPLICATIONS FOR CANCER SURVIVORS: CCS who are female and < 30 years old, have a history of CNS tumor, report sleep disturbance, or have an endocrine disorder should be screened for CRF.

Longitudinal assessment of lung function in Swiss childhood cancer survivors-A multicenter cohort study.

OBJECTIVE: Childhood cancer survivors are at risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapeutics, radiotherapy, and surgery. Longitudinal data on lung function and its change over time are scarce. We investigated lung function trajectories in survivors over time and the association with lung-toxic treatments. METHODS: This retrospective, multicenter cohort study included Swiss survivors diagnosed between 1990 and 2013 and exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs), including forced expiration volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity,  and diffusion capacity of the lung for carbon monoxide, were obtained from hospital charts. We calculated z-scores and percentage predicted, described lung function over time, and determined risk factors for change in FEV1 and FVC using multivariable linear regression. RESULTS: We included 790 PFTs from 183 survivors, with a median age of 12 years at diagnosis and 5.5 years of follow-up. Most common diagnosis was lymphoma (55%). Half (49%) of survivors had at least one abnormal pulmonary function parameter, mainly restrictive (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. Survivors treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (-2.02 to -0.15) and an FVC of -1.42 z-scores (-2.27 to -0.57) compared to those without surgery. CONCLUSION: Reduced pulmonary function was frequent but mainly of mild to moderate severity. Nevertheless, more research and long-term surveillance of this vulnerable population is needed.

Risk factors for overweight and obesity after childhood acute lymphoblastic leukemia in North America and Switzerland: A comparison of two cohort studies.

BACKGROUND: After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5-year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. METHODS: We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self-reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25-29.9 kg/m2 ) and obesity (≥30 kg/m2 ) using multinomial regression. RESULTS: We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27-32 vs. 24%, 21-29; obesity: 29%, 27-32 vs. 7%, 5-10] and siblings (overweight: 30%, 27-32 vs. 25%, 22-29; obesity: 24%, 22-26 vs. 6%, 4-8). Survivors in North America [odds ratio (OR) = 1.24, 1.01-1.53] and Switzerland (1.27, 0.74-2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7-9.0); male (1.7, 1.3-2.3); attained age (≥45 years: 5.1, 2.4-10.8); Non-Hispanic Black (3.4, 1.6-7.0); low household income (2.3, 1.4-3.5); young age at diagnosis (1.6, 1.1-2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0-1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. CONCLUSIONS: Although treatment-related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.

Effect of a 1-year physical activity intervention on cardiovascular health in long-term childhood cancer survivors-a randomised controlled trial (SURfit).

BACKGROUND: This randomised controlled trial (RCT) assessed the effect of a 1-year, partially supervised, physical activity (PA) intervention on a cardiovascular disease (CVD) risk score in adult survivors of childhood cancer. METHODS: We included childhood cancer survivors ≥16 y at enrolment, <16 y at diagnosis and ≥5 y in remission. The intervention group was asked to perform an additional ≥2.5 h of intense physical activity/week, controls continued exercise as usual; assessments were performed at baseline, 6 months (T6) and 12 months (T12). The primary endpoint was change in a CVD risk score (average z-score of waist circumference, blood pressure, fasting glucose, inverted high-density lipoprotein cholesterol, triglycerides, and inverted cardiorespiratory fitness) from baseline to T12. We performed intention-to-treat (ITT, primary) and 3 per protocol analyses. RESULTS: We randomised 151 survivors (44% females, 30.4 ± 8.6 years). We found a significant and robust reduction of the CVD risk score in the intervention compared to the control group at T6 and T12 across all analyses; with a difference in the reduction of the CVD risk z-score of -0.18 (95% confidence interval -0.29 to -0.06, P = 0.003) at T12 in favour of the intervention group (ITT analysis). CONCLUSIONS: This RCT showed that a long-term PA intervention can reduce CVD risk in long-term survivors of childhood cancer. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02730767.

Adherence and contamination in a 1-year physical activity program in childhood cancer survivors: A report from the SURfit study.

PURPOSE: Meeting intervention requirements is crucial in behavioral trials. We examined patterns and predictors of physical activity (PA) adherence and contamination in a 1-year individualized randomized controlled PA behavioral intervention in childhood cancer survivors (CCS). METHODS: CCS aged ≥16 at enrolment, <16 at diagnosis, and ≥5 years in remission were identified from the Swiss Childhood Cancer Registry. We asked participants randomized to the intervention group to perform an additional ≥2.5 h of intense PA/week and controls to continue as usual. Adherence to the intervention was assessed by online diary (adherent if ≥2/3 of individual PA goal reached) and contamination for the control group by pre- and post-questionnaire including PA levels (contaminated if >60 min increase/week in PA). Predictors of adherence/contamination including quality of life (36-Item Short Form Survey) were assessed by questionnaire. We used logistic (control group) and mixed logistic regression models (exercise group) to estimate predictors of study adherence and contamination. RESULTS: One hundred and forty-four survivors (30.4 ± 8.7 years old, 43% females) were included. Adherence was 48% (35/73) in the intervention group, while 17% (12/71) of controls contaminated group allocation. Predictors for PA adherence were female sex (OR 2.35, p = 0.03), higher physical (OR 1.34, p = 0.01) and mental quality of life (OR 1.37, p = 0.001), and week into the intervention (OR 0.98, p < 0.001). Clear differences in PA behavior of adherent and non-adherent participants were seen from week four. No significant predictors for contamination were found for controls. CONCLUSION: Adherence to PA behavior interventions remain challenging in both groups. Further long-term trials should consider intense motivational support within the first month, more detailed data collection for the control group, adjustments to power calculations and other study designs to minimize non-adherence and contamination.

Effect of a physical activity intervention on lower body bone health in childhood cancer survivors: A randomized controlled trial (SURfit).

It remains controversial whether physical activity promotes bone health in childhood cancer survivors (CCS). We aimed to assess the effect of a one-year general exercise intervention on lower body bone parameters of CCS. CCS ≥16 years at enrollment, <16 years at diagnosis and ≥5 years in remission were identified from the national Childhood Cancer Registry. Participants randomized to the intervention group were asked to perform an additional ≥2.5 hours of intense physical activity/week, controls continued exercise as usual. Bone health was assessed as a secondary trial endpoint at baseline and after 12-months. We measured tibia bone mineral density (BMD) and morphology by peripheral quantitative computed tomography and lumbar spine, hip and femoral neck BMD by dual-energy x-ray absorptiometry. We performed intention-to-treat, per protocol, and an explorative subgroup analyses looking at low BMD using multiple linear regressions. One hundred fifty-one survivors (44% females, 7.5 ± 4.9 years at diagnosis, 30.4 ± 8.6 years at baseline) were included. Intention-to-treat analysis revealed no differences in changes between the intervention and control group. Per protocol analyses showed evidence for an improvement in femoral neck and trabecular BMD between 1.5% and 1.8% more in participants being compliant with the exercise program. Trabecular BMD increased 2.8% more in survivors of the intervention group with BMD z-score ≤-1 compared to those starting at z-score >-1. A nonstandardized personalized exercise programs might not be specific enough to promote bone health in CCS, although those compliant and those most in need may benefit. Future trials should include bone stimulating exercise programs targeting risk groups with reduced bone health and motivational features to maximize compliance.

Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted.

Severity of hearing loss after platinum chemotherapy in childhood cancer survivors.

BACKGROUND: Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. PROCEDURE: We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. RESULTS: We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for <5 years); (b) treatment in earlier years (OR 4.8, 95% CI: 2.1-11.0 for 1990-1995); (c) higher cumulative cisplatin doses (OR 13.5, 95% CI: 4.7-38.8 for >450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). CONCLUSION: Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care.

Social, emotional, and behavioral functioning in young childhood cancer survivors with chronic health conditions.

BACKGROUND: The cancer diagnosis and its intensive treatment may affect the long-term psycho-social adjustment of childhood cancer survivors. We aimed to describe social, emotional, and behavioral functioning and their determinants in young childhood cancer survivors. PROCEDURE: The nationwide Swiss Childhood Cancer Survivor Study sends questionnaires to parents of survivors aged 5-15 years, who have survived at least 5 years after diagnosis. We assessed social, emotional, and behavioral functioning using the Strengths and Difficulties Questionnaire (SDQ). The SDQ includes four difficulties scales (emotional, conduct, hyperactivity, peer problems), a total difficulties indicator, and one strength scale (prosocial). We compared the proportion of survivors with borderline and abnormal scores to reference values and used multivariable logistic regression to identify determinants. RESULTS: Our study included 756 families (response rate of 72%). Thirteen percent of survivors had abnormal scores for the total difficulties indicator compared to 10% in the general population. The proportion of survivors with abnormal scores was highest for the emotional scale (15% vs. 8% in the general population), followed by the peer problems scale (14% vs. 7%), hyperactivity (8% vs. 10%), and conduct scale (6% vs. 7%). Few survivors (4% vs. 7%) had abnormal scores on the prosocial scale. Children with chronic health conditions had a higher risk of borderline and abnormal scores on all difficulties scales (all p < 0.05). CONCLUSION: Most childhood cancer survivors do well in social, emotional, and behavioral life domains, but children with chronic health conditions experience difficulties. Therefore, healthcare professionals should offer specific psycho-social support to these survivors.

39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial.

BACKGROUND: Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety. METHODS: This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231. FINDINGS: 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98). INTERPRETATION: In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation. FUNDING: Swiss Cancer League (KLS-3645-02-2015).

High impact physical activity and bone health of lower extremities in childhood cancer survivors: A cross-sectional study of SURfit.

Childhood cancer survivors (CCS) are at risk of reduced bone health and premature osteoporosis. As physical activity with high impact loading (IL-PA) is known to promote bone health, we compared bone densitometry and microstructure between groups of CCS who performed different amounts of physical activities in their daily life. We used baseline data of a single-center PA trial including 161 CCS from the Swiss Childhood Cancer Registry, aged <16 at diagnosis, ≥16 at study and ≥5 years since diagnosis. Lower body bone health was assessed with peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA). Daily IL-PA (duration in activities >2 g acceleration and numbers of vertical impacts/hr >2 g) was captured using hip-worn accelerometers (1-3 weeks). For both IL-PA approaches, we formed low, middle and high activity groups based on tertiles. Bone health of the high and middle active groups was compared to the low active group. 63% of CCS had indication of at least one bone mineral density z-score ≤ -1 measured by pQCT or DXA. The high IL-PA group performing 2.8 min/day or 19.1 impact peaks/hr > 2 g (median) showed about 3-13% better microstructural and densitometric bone health as compared to the low IL-PA group with 0.38 min/day or 0.85 peaks/hr > 2 g. Just a few minutes and repetitions of high IL-PA as easily modifiable lifestyle factor may be sufficient to improve bone health in adult CCS. Future longitudinal research is needed to better understand pattern and dosage of minimal impact loading needed to strengthen bone in growing and adult CCS.

Cardiovascular disease after childhood acute lymphoblastic leukaemia: a cohort study.

BACKGROUND AND AIMS: Cardiovascular diseases (CVD) increase late morbidity and mortality in survivors of acute lymphoblastic leukaemia (ALL). We compared the risk of CVD in ALL survivors to siblings, examined time trends, quantified treatment-related risks, and investigated whether risk extends beyond patients treated with anthracyclines and chest radiotherapy. METHODS: The Swiss Childhood Cancer Survivor Study assessed CVD by patient questionnaire in 5-year ALL survivors diagnosed between 1976 and 2005 and their siblings. Participants were asked whether a physician had ever told them that they had hypertension, arrhythmia, heart failure, myocardial infarction, angina pectoris, stroke, thrombosis or valvular problems. We investigated treatment-related risk factors for CVD using multivariable logistic regression, adjusting for demographic and socioeconomic factors, BMI, smoking, diabetes mellitus, alcohol consumption and physical activity. RESULTS: We contacted 707 survivors and 1299 siblings, 511 (72%) and 709 (55%) of whom responded, respectively. Survivors had a higher risk of developing CVD than siblings (odds ratio [OR] 1.9, 95% confidence interval 1.3–2.8), in particular heart failure (OR 13.9, 1.8–107.4). Compared to patients treated 1976–85, the risk of CVD was 1.4 (0.7–2.8) for those treated 1985–1994 and 1.5 (0.6–3.7) for those treated 1995–2005. The overall CVD risks after anthracycline treatment (OR 3.1, 2.0–4.7), haematopoietic stem cell transplantation (OR 8.0, 2.4–26.9) or relapse (OR 4.1, 1.9–8.8) were increased compared to those of siblings, while the CVD risks of survivors treated without anthracycline or chest radiotherapy were similar (OR 1.0; 0.5–2.0). CONCLUSIONS: Despite attempts to reduce cardiotoxicity in childhood cancer treatment, CVD risks in ALL survivors treated more recently do not seem to have declined.

No evidence of overweight in long-term survivors of childhood cancer after glucocorticoid treatment.

BACKGROUND: Glucocorticoids can lead to weight gain during cancer treatment, but to the authors' knowledge, little is known regarding their long-term effects in childhood cancer survivors (CCS). METHODS: As part of the Swiss Childhood Cancer Survivor Study, the authors sent a questionnaire to CCS aged <21 years at diagnosis who were residing in Switzerland, had survived ≥5 years, and were aged 15 to 45 years at the time of the survey. Cumulative doses of glucocorticoids were assessed from medical records and study protocols and body mass index was calculated from self-reported height and weight at the time of the survey. The authors compared the prevalence of overweight between CCS, their siblings, and the general population (Swiss Health Survey [SHS]) and investigated the association between overweight and treatment-related risk factors using multivariable logistic regression. RESULTS: The study included 1936 CCS, 546 siblings, and 9591 SHS participants. The median age of the CCS at the time of the survey was 24 years (interquartile range, 20-31 years) and the median time since diagnosis was 17 years (interquartile range, 12-22 years). At the time of the survey, approximately 26% of CCS were overweight, a percentage that was comparable to that among siblings (24%) and the SHS participants (25%). The prevalence of overweight was 24% in CCS treated with glucocorticoids only (686 CCS), 37% in those treated with cranial radiotherapy (CRT) (127 CCS), and 49% in those who received treatment with both glucocorticoids and CRT (101 CCS) (P < .001). The authors found no evidence of a dose-response relationship between cumulative glucocorticoid doses and overweight and no evidence that CRT modified the effect of the cumulative glucocorticoid dose on overweight. CONCLUSIONS: The results of the current study suggest that glucocorticoids used for the treatment of childhood cancer are not associated with long-term risk of overweight.

Monitoring pulmonary health in Swiss childhood cancer survivors.

BACKGROUND: Childhood cancer survivors are at increased risk for pulmonary morbidity and mortality. International guidelines recommend pulmonary function tests (PFT) during follow-up care. This nationwide study assessed how many children received PFT within 5 years after pulmotoxic treatment in Switzerland, types of tests, and predictors for testing. METHODS: We included all children from the Swiss Childhood Cancer Registry who were diagnosed with cancer from 1990 to 2013 at age 0-16 years, survived for ≥2 years from diagnosis, and had pulmotoxic chemotherapy with bleomycin, busulfan, nitrosoureas, and/or chest radiotherapy. We searched medical records in all Swiss pediatric oncology clinics for PFT (spirometry, plethysmography, diffusion capacity of carbon monoxide [DLCO]) and treatment details. RESULTS: We found medical records for 372 children, of whom 147 had pulmotoxic chemotherapy and 323 chest radiotherapy. Only 185 had plethysmography and/or spirometry (50%), 122 had DLCO (33%). Testing varied by cancer center from 3% to 79% (P = 0.001). Central nervous system tumor survivors and those not treated according to study protocols had less plethysmography and/or spirometry (odds ratio (OR) 0.3 and 0.3), lymphoma survivors and those who were symptomatic had more PFT (plethysmography and/or spirometry: OR 5.9 and 8.7; DLCO: OR 3.4 and 2.3). Cumulative incidence (CuI) of PFT was 52% in the first 5 years after pulmotoxic treatment; most of the tests were done in the first 2 years after treatment (CuI 44%). CONCLUSION: Only half of the survivors exposed to pulmotoxic treatment have been followed up with PFT in Switzerland. We need to optimize, update, and implement monitoring guidelines.

Long-term pulmonary disease among Swiss childhood cancer survivors.

BACKGROUND: Pulmonary diseases are potentially severe late complications of childhood cancer treatment that increase mortality risk among survivors. This nationwide study assesses the prevalence and incidence of pulmonary diseases in long-term childhood cancer survivors (CCS) and their siblings, and quantifies treatment-related risks. METHODS: As part of the Swiss Childhood Cancer Survivor Study, we studied CCS who were diagnosed between 1976 and 2005 and alive at least 5 years after diagnosis. We compared prevalence of self-reported pulmonary diseases (pneumonia, chest wall abnormalities, lung fibrosis, emphysema) between CCS and their siblings, calculated cumulative incidence of pulmonary diseases using the Kaplan-Meier method, and determined risk factors using multivariable logistic regression. RESULTS: CCS reported more pneumonias (10% vs. 7%, P = 0.020) and chest wall abnormalities (2% vs. 0.4%, P = 0.003) than siblings. Treatment with busulfan was associated with prevalence of pneumonia (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.1-14.9), and thoracic surgery was associated with chest wall abnormalities and lung fibrosis (OR 4.1, 95% CI 1.6-10.7 and OR 6.3, 95% CI 1.7-26.6). Cumulative incidence of any pulmonary disease after 35 years of follow-up was 21%. For pneumonia, the highest cumulative incidence was seen in CCS treated with both pulmotoxic chemotherapy and radiotherapy to the thorax (23%). CONCLUSION: This nationwide study in CCS found an increased risk for pulmonary diseases, especially pneumonia, while still young, which indicates that CCS need long-term pulmonary follow-up.

A partially supervised physical activity program for adult and adolescent survivors of childhood cancer (SURfit): study design of a randomized controlled trial [NCT02730767].

BACKGROUND: Beyond survival of nowadays >80%, modern childhood cancer treatment strives to preserve long-term health and quality of life. However, the majority of today's survivors suffer from short- and long-term adverse effects such as cardiovascular and pulmonary diseases, obesity, osteoporosis, fatigue, depression, and reduced physical fitness and quality of life. Regular exercise can play a major role to mitigate or prevent such late-effects. Despite this, there are no data on the effects of regular exercise in childhood cancer survivors from randomized controlled trials (RCTs). Primary outcome of the current RCT is therefore the effect of a 12-months exercise program on a composite cardiovascular disease risk score in childhood cancer survivors. Secondary outcomes are single cardiovascular disease risk factors, glycaemic control, bone health, body composition, physical fitness, physical activity, quality of life, mental health, fatigue and adverse events (safety). METHODS: A total of 150 childhood cancer survivors aged ≥16 years and diagnosed ≥5 years prior to the study are recruited from Swiss paediatric oncology clinics. Following the baseline assessments patients are randomized 1:1 into an intervention and control group. Thereafter, they are seen at month 3, 6 and 12 for follow-up assessments. The intervention group is asked to add ≥2.5 h of intense physical activity/week, including 30 min of strength building and 2 h of aerobic exercises. In addition, they are told to reduce screen time by 25%. Regular consulting by physiotherapists, individual web-based activity diaries, and pedometer devices are used as motivational tools for the intervention group. The control group is asked to keep their physical activity levels constant. DISCUSSION: The results of this study will show whether a partially supervised exercise intervention can improve cardiovascular disease risk factors, bone health, body composition, physical activity and fitness, fatigue, mental health and quality of life in childhood cancer survivors. If the program will be effective, all relevant information of the SURfit physical activity intervention will be made available to interested clinics that treat and follow-up childhood cancer patients to promote exercise in their patients. TRIAL REGISTRATION: Prospectively registered in clinicaltrials.gov [ NCT02730767 ], registration date: 10.12.2015.