Quality of life in children and adolescents after treatment for acute lymphoblastic leukemia according to the NOPHO ALL2008 protocol.

BACKGROUND: The improved outcome of childhood acute lymphoblastic leukemia (ALL) over the last decades has increased the importance of assessing late effects and health-related quality of life (HRQoL), particularly when evaluating and comparing outcomes in clinical trials. This study aimed to assess HRQoL in children treated for ALL according to the NOPHO ALL2008 protocol. PROCEDURE: Children, aged 1 to less than 18 years at diagnosis, alive in first remission, and their parents, were asked to complete PedsQL 4.0 Generic Core Scales (self- and proxy-report) at ≥6 months after end of therapy. Data on socioeconomic factors and parent-reported toxicity were collected through a study-specific questionnaire, and the NOPHO ALL2008 database was used to identify eligible families and add additional disease- and treatment-related data. HRQoL data were collected during 2013-2019 in Sweden, Finland, and Denmark. RESULTS: A total of 299 children were included. The older children (8 years and older) reported similar HRQoL scores compared to Finnish reference data, except lower scores for School Functioning in high-risk patients. Scores from the parent-proxy and self-reports from 5-7-year olds were notably lower than reference. Parent-reported toxicity was associated with lower total and physical HRQoL scores in adjusted models for younger as well as older children in the self-report and parent-proxy versions, and also with lower psychosocial score in the parent-proxy. CONCLUSIONS: Self-reported HRQoL was similar to reference population. The most important determinant for HRQoL after end of ALL treatment was parent-reported toxicity during treatment. Thus, minimizing complications is an obvious focus for future treatment protocols.

Reproductive late effects and testosterone replacement therapy in male childhood cancer survivors: A population-based study (the Fex-Can study).

Childhood cancer survivors are at risk of various endocrine late effects affecting their quality of life. The aim of this study was to assess the prevalence and predictors of endocrine and reproductive outcomes in young adult survivors. A secondary aim was to assess possible associations between testosterone replacement therapy (TRT) and other endocrine, cardiovascular and psychosocial late effects. This nationwide study comprised 1212 male childhood cancer survivors aged 19-40 years, identified through the National Quality Registry for Childhood Cancer in Sweden. Median age at diagnosis during 1981-2017 was 7 (range 0-17) and at study 29 (19-40) years. The study combined self-report survey data with cancer treatment data from the national registry. Hormone-induced puberty was self-reported by 3.8% of the survivors and ongoing TRT by 6.0%. In separate logistic regression analyses, these treatments were associated with hematopoietic stem cell transplantation and cranial radiotherapy. Hormone-induced puberty was additionally associated with younger age at diagnosis. Men with TRT had a higher prevalence of other endocrine deficiencies, cholesterol medication, depressive symptoms and fatigue as well as a lower probability of living with a partner, having a biological child or current occupation. In the total male cohort, 28.2% reported having a biological child. Reassuring reproductive outcomes after less intensive therapies and low frequency of TRT were observed in young adult male childhood cancer survivors treated in the most recent treatment era. However, men with TRT suffered from several other endocrine, cardiovascular and psychosocial late effects, indicating a need for long-term monitoring of this high-risk group.

Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

Physical Activity Among Adolescent Cancer Survivors: The PACCS Study.

OBJECTIVES: Physical activity (PA) may modify risks of late effects after cancer. We aimed to examine levels of PA and sedentary time (ST) in a large, international sample of adolescent childhood cancer survivors in relation to sociodemographic and cancer-related factors and compare levels of PA and ST to reference cohorts. METHODS: Survivors from any cancer diagnosis who had completed cancer treatment ≥1 year ago, aged 9 to 16 years, were eligible for the multicenter Physical Activity in Childhood Cancer Survivors study. PA and ST were measured by ActiGraph GT3X+ accelerometers. We performed linear regression analyses to assess factors associated with moderate-to-vigorous PA (MVPA) and ST, and compared marginal means of total PA, MVPA, and ST in 432 survivors to sex- and age-stratified references (2-year intervals) using immediate t-tests for aggregated data. RESULTS: Among survivors, 34% fulfilled the World Health Organization's PA recommendation of ≥60 min of daily MVPA on average and their ST was 8.7 hours per day. Being female, older, overweight, a survivor of central nervous system tumor, or having experienced relapse were associated with lower MVPA and/or higher ST. Generally, male survivors spent less time in MVPA compared with references, whereas female survivors had similar levels. Both male and female survivors had higher ST than references in nearly all age groups. CONCLUSIONS: The low PA and high ST in this large sample of adolescent childhood cancer survivors is worrisome. Combined, our results call for targeted interventions addressing both PA and ST in follow-up care after childhood cancer.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Early disc degeneration in radiotherapy-treated childhood brain tumor survivors.

BACKGROUND: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. METHODS: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5-33.1), 67 survivors (mean age 28.4, range 16.2-43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. RESULTS: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). CONCLUSIONS: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Premature ovarian insufficiency and chance of pregnancy after childhood cancer: A population-based study (the Fex-Can study).

Endocrine complications are a common late effect after childhood cancer. Our study assessed the prevalence and predictors of premature ovarian insufficiency (POI) and prospects of pregnancy in young female survivors. This nationwide study combined registry and survey data for female childhood cancer survivors aged 19 to 40 years, identified through the National Quality Registry for Childhood Cancer in Sweden. Of 1989 approached young women, 1333 (67%) participated by completing a survey. Median age at diagnosis 1981 to 2017 was 6 (range 0-17) and at study 28 (19-40) years. There were two indicators of POI, induced puberty reported in 5.3% and estrogen replacement therapy (ERT) in 9.3% at assessment. In separate logistic regression analyses (P < .001), induced puberty and ERT were significantly predicted by hematopoietic stem cell transplantation (HSCT), abdominal irradiation, central nervous system irradiation and chemotherapy. ERT was also associated with older age at diagnosis. Of the 626 women (48% of responders) who had tried to become pregnant, 25% had undergone fertility investigations and 72% reported having a biological child. Treatment with HSCT was associated with 5.4 times the odds of needing fertility investigations (P < .001). Having a biological child was associated with non-HSCT treatment, but also with ever having had a partner and older age at the time of study (all P < .001). In conclusion, the majority of those female childhood cancer survivors who had tried to conceive were able to successfully give birth. However, a small identifiable group of female survivors are at risk of subfertility and early menopause.

Cardiovascular morbidity following conventional therapy versus allogeneic hematopoietic stem cell transplantation after childhood, adolescent, and young adult leukemia in Finland.

Allogeneic hematopoietic stem cell transplantation (aHSCT) represents a therapeutic choice for high-risk and relapsed leukemia at a young age. In this retrospective population-based study, we evaluated cardiovascular complications after aHSCT (N = 272) vs conventional therapy (N = 1098) among patients diagnosed with acute lymphoblastic or acute myeloid leukemia below 35 years between 1985 and 2004. Additionally, siblings from a prior comparison group served as population controls (N = 39 217). Childhood leukemia and aHSCT was associated with a 16-fold HR for developing arterial hypertension (HR 16.8, 95%CI 1.5-185.5) compared with conventional therapy. A 2-fold HR for any cardiovascular complication was observed after AYA leukemia and aHSCT vs conventional treatment (HR 2.7, 95% CI 1.4-5.1). After AYA leukemia and aHSCT, the HR of cardiac arrhythmia was significantly elevated vs conventional therapy (HR 14.4, 95% CI 1.5-125.2). Moreover, after aHSCT in childhood, elevated hazard ratios (HRs) were found for cardiomyopathy/ cardiac insufficiency (HR 105.0, 95% CI 10.0-1100.0), cardiac arrhythmia, and arterial hypertension (HR 20.1, 95%CI 2.5-159.7 and HR 20.0, 95%CI 4.1-97.4) compared with healthy controls. After adolescent and young adult (AYA) leukemia and aHSCT, markedly increased HRs were observed for cardiac arrhythmia (HR 29.2, 95%CI 6.6-129.2), brain vascular thrombosis/ atherosclerosis and cardiomyopathy/cardiac insufficiency (HR 23.4, 95%CI 7.1-77.4 and HR 19.2, 95%CI 1.5-245.2) compared with healthy controls. As the cumulative incidence for cardiovascular complications rose during the follow-up of childhood and AYA leukemia patients, long-term cardiovascular surveillance is warranted to optimize the quality of life after childhood and AYA leukemia following both conventional treatment and aHSCT.

Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks. METHODS: The PanCareSurFup cohort includes 69,460 5-year survivors of childhood cancer across Europe. Risks of oral SPNs were defined by standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: One hundred and forty-five oral SPNs (64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) were ascertained among 143 survivors. Survivors were at 5-fold risk of an oral SPN (95% CI: 4.4-5.6). Survivors of leukaemia were at greatest risk (SIR = 19.2; 95% CI: 14.6-25.2) followed by bone sarcoma (SIR = 6.4, 95% CI: 3.7-11.0), Hodgkin lymphoma (SIR = 6.2, 95% CI: 3.9-9.9) and soft-tissue sarcoma (SIR = 5.0, 95% CI: 3.0-8.5). Survivors treated with radiotherapy were at 33-fold risk of salivary gland SPNs (95% CI: 25.3-44.5), particularly Hodgkin lymphoma (SIR = 66.2, 95% CI: 43.6-100.5) and leukaemia (SIR = 50.5, 95% CI: 36.1-70.7) survivors. Survivors treated with chemotherapy had a substantially increased risk of a tongue SPN (SIR = 15.9, 95% CI: 10.6-23.7). CONCLUSIONS: Previous radiotherapy increases the risk of salivary gland SPNs considerably, while chemotherapy increases the risk of tongue SPNs substantially. Awareness of these risks among both health-care professionals and survivors could play a crucial role in detecting oral SPNs early.

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. METHODS: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. RESULTS: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). CONCLUSIONS: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Mortality Among Pediatric Patients With Acute Lymphoblastic Leukemia in Sweden From 1988 to 2017.

Importance: Acute lymphoblastic leukemia (ALL) constitutes 20% to 30% of all pediatric cancers. The 5-year overall survival among pediatric patients with ALL in high-income countries such as Sweden is currently more than 90%, but long-term unselected nationwide mortality data and mortality data in relation to the general population are lacking. Objective: To compare mortality between pediatric patients with ALL and the general population during a 30-year period in Sweden and to assess the incidence of ALL in Sweden. Design, Setting, and Participants: This cohort study included pediatric patients (aged <18 years) with a morphologically verified ALL diagnosis in the Swedish Cancer Register and/or at least 2 ALL diagnoses in the Swedish National Patient Register between January 1, 1988, and December 31, 2017. Data were cross-linked to the Swedish Cause of Death Register. Data were analyzed from May 2019 to January 2022. Main Outcomes and Measures: The main outcomes were mortality among patients with ALL compared with that in the general population and mortality in different subgroups within the cohort. Standardized mortality ratios (SMRs) were calculated using the general Swedish population as a reference. Within-cohort survival analyses were performed. Results: A total of 2397 patients (1354 [56%] male; mean [SD] age at diagnosis, 6.1 [4.7] years) were included in the study. The mean (SD) incidence of pediatric ALL during the study period was 4.11 (0.60) cases per 100 000 persons per year (females, 3.68 [0.65] cases per 100 000 persons per year; males, 4.52 [0.81] cases per 100 000 persons per year; P < .001). The observed number of deaths among pediatric patients with ALL was 409 vs the 9.5 deaths expected in the general population, resulting in an overall SMR of 43.1 (95% CI, 39.0-47.5); females had a higher SMR than males (57.8 [95% CI, 49.5-67.2] vs 34.5 [95% CI, 32.0-41.4]; P < .001). Analysis within the cohort showed a continued decrease in survival throughout the 30-year follow-up. The association between calendar year of ALL diagnosis, corresponding with different ALL treatment protocols, and mortality showed the lowest survival for the 1988-1991 group and the highest for the 2008-2017 group (χ2 = 20.3; P < .001). Conclusions and Relevance: In this cohort study, a consistently high SMR was seen among pediatric patients with ALL. Within the ALL cohort, survival evolved to a similar extent as in the young general population of Sweden. Furthermore, survival among patients with ALL decreased throughout the whole follow-up period without any trend difference after the 5-year follow-up time point. The changes in ALL treatment protocols were associated with overall improved absolute survival over time.

Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study.

PURPOSE AND METHODS: To analyze physical fitness, physical activity and the prevalence of frailty in male long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We performed a Nordic two-center study of 98 male survivors (mean age 28.7 years, range 18.5-47.0) treated with pediatric allogeneic hematopoietic stem cell transplantation (HSCT) 1980-2010 in denmark or finland. physical fitness was evaluated by the dominant hand grip-strength, timed up-and-go, sit-to-stand, gait speed and two-minute walk tests. RESULTS: Survivors presented significantly lower muscle strength and muscle endurance in the dominant hand-grip strength (median Z-score -0.7, range -4.3-3.9) and sit-to-stand tests (median Z-score -1.5, range -3.5-2.5) compared to age and sex matched normative values of the tests. However, mobility and gait speed were not affected on a group level. The prevalence of frailty (pre-frail 20% or frail 10%) was high among the survivors. In multiple regression analysis, chronic graft-versus-host disease, shorter stature, higher body fat mass and hazardous drinking predicted prefrail/frail status. Common cardiovascular risk factors, such as increased levels of serum triglycerides, higher resting heart rate and diastolic blood pressure, were associated with lower physical fitness. CONCLUSION: Low muscle strength and a high incidence of frailty were observed in survivors of pediatric HSCT. There is a predominant risk of cardiovascular and metabolic diseases in the long-term.

Quality of life in mothers and fathers of children treated for acute lymphoblastic leukaemia in Sweden, Finland and Denmark.

Acute lymphoblastic leukaemia (ALL) has a high survival rate, but treatment is lengthy with risk of severe side-effects, which may also impact parents' health-related quality of life (HRQOL). We present data on 526 parents of 310 children treated for ALL according to the NOPHO ALL2008-protocol, in Sweden, Finland and Denmark. Parents were asked to complete the 36-Item Short Form Survey (SF-36) at least 6 months after end of treatment and data were compared with Norwegian reference data. Parental background factors were collected via a study-specific questionnaire. Participating parents scored significantly lower than the reference population on both physical and mental summary indexes, but only surpassed a minimal clinically important difference for the mental summary index (Mental Component Summary [MCS]). Mothers scored lower than fathers in the MCS and stopped working and took care of the affected child more often than the fathers. Higher mental HRQOL was associated with male gender and living in Finland or Denmark (compared to Sweden). Correlations within spouses in physical and mental scores were weak to moderate. In conclusion, ALL negatively affects parental HRQOL, especially the mental domains, even after treatment. Findings suggest that mothers are more affected than fathers and may require extra support.

Temporal changes in incidence of relapse and outcome after relapse of childhood acute lymphoblastic leukemia over three decades; a Nordic population-based cohort study.

Relapse remains the main obstacle to curing childhood acute lymphoblastic leukemia (ALL). The aims of this study were to compare incidence of relapse, prognostic factors, and survival after relapse between three consecutive Nordic Society of Pediatric Hematology and Oncology trials. Relapse occurred as a primary event in 638 of 4 458 children (1.0-14.9 years) diagnosed with Ph-negative ALL between 1992 and 2018. The 5-year cumulative incidence of relapse was 17.3% (95% CI 15.4-19.2%) and 16.5% (95% CI 14.3-18.8%) for patients in the ALL1992 and ALL2000 trials, respectively, but decreased to 8.4% (95% CI 7.0-10.1%) for patients in the ALL2008 trial. No changes in duration of first complete remission and site of relapse were observed over time; however, high hyperdiploidy, and t(12;21) decreased in the ALL2008 trial. The 4-year overall survival after relapse was 56.6% (95% CI 52.5-60.5%) and no statistically significant temporal improvements were observed. Age ≥10 years, T-cell immunophenotype, bone-marrow involvement, early and very early relapse, hypodiploidy, and Down syndrome all independently predicted worse outcome after relapse. Improvements in the primary treatment of childhood ALL has resulted in fewer relapses. However, failure to improve outcome of remaining relapses suggests a selection of harder-to-cure relapses and calls for new therapeutic strategies.

Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.

Male breast cancer after childhood cancer: Systematic review and analyses in the PanCareSurFup cohort.

BACKGROUND: Breast cancer is a well-recognised late adverse effect in female childhood cancer survivors (CCSs), especially after chest radiotherapy; information on subsequent male breast cancer (SMBC) is limited. We summarised the existing evidence on SMBC after childhood cancer in a systematic review and investigated the risk of SMBC among males in a Pan-European cohort. METHODS: We searched Medline/PubMed for cohort studies and case reports/series that assessed SMBC after childhood cancer (≤21 years). Furthermore, we analysed data on SMBC in the PanCareSurFup cohort, reporting standardised incidence ratios (SIRs), absolute excess risks (AERs), and 5- and 10-year survival rates. RESULTS: The systematic review included 38 of 7080 potentially eligible articles. Cohort-specific SMBC frequencies were 0-0.40% (31 studies). SMBC occurred after a follow-up ranging from 24.0 to 42.0 years. Nine case reports/series described 11 SMBC cases, occurring 11.0-42.5 years after primary childhood cancer. In the PanCareSurFup cohort (16 SMBC/37,738 males; 0.04%), we observed a 22.3-fold increased risk of SMBC relative to the general male population (95% CI 12.7-36.2; absolute excess risk/100,000 person-years: 2.3, 95% CI 1.3-3.7). The five- and ten-year survival rates after SMBC diagnosis were 60.3% (95% CI 35.6%-85.0%) and 43.0% (95% CI 16.1%-69.9%), respectively. Clear evidence of risk factors did not emerge from these comprehensive efforts. CONCLUSIONS: Compared to the general population, male CCSs have an elevated risk of developing subsequent breast cancer, although the absolute risk is low. Health care providers should be aware of this rare yet serious late effect; male CCSs with symptoms potentially related to SMBC warrant careful examination.

Sexual dysfunction in young adult survivors of childhood cancer - A population-based study.

OBJECTIVE: To determine the prevalence of sexual dysfunction and to identify the factors associated with sexual dysfunction in young adult childhood cancer survivors. METHODS: All survivors of childhood cancer (aged 19-40 years) in Sweden were invited to this population-based study, and 2546 men and women (59%) participated. Sexual function was examined with the PROMIS Sexual Function and Satisfaction Measure. Logistic regression was used to assess the differences between survivors and a general population sample (n = 819) and to identify the factors associated with sexual dysfunction in survivors. RESULTS: Sexual dysfunction in at least one domain was reported by 57% of female and 35% of male survivors. Among females, dysfunction was most common for Sexual interest (36%), Orgasm - ability (32%) and Vulvar discomfort - labial (19%). Among males, dysfunction was most common for the domains satisfaction with sex life (20%), Sexual interest (14%) and Erectile function (9%). Compared with the general population, male survivors more frequently reported sexual dysfunction in ≥2 domains (OR = 1.67, 95% CI: 1.03-2.71), with an increased likelihood of dysfunction regarding Orgasm - ability (OR = 1.82; 95% CI: 1.01-3.28) and Erectile function (OR = 2.30; 95% CI: 1.18-4.49). Female survivors reported more dysfunction regarding Orgasm - pleasure (9% versus 5%, OR = 1.86; 95% CI: 1.11-3.13). A more intensive cancer treatment, emotional distress and body image disturbance were associated with sexual dysfunction in survivors. CONCLUSIONS: The findings underscore the need for routine assessment of sexual health in follow-up care of childhood cancer survivors and highlight that those treated with more intensive cancer treatment and who experience concurrent psychological concerns may benefit from targeted screening and interventions.

Neurocognitive impairment, employment, and social status in radiotherapy-treated adult survivors of childhood brain tumors.

BACKGROUND: Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. METHODS: Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. RESULTS: Survivors' (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, -3.5 SD [range: -25.0 to 1.3 SD]), and processing speed and attention (median z score, -2.5 SD [range: -24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. CONCLUSIONS: Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.

Detection mode of childhood acute lymphoblastic leukaemia relapse and its effect on survival: a Nordic population-based cohort study.

Relapse constitutes the greatest threat to event-free survival after completion of treatment for childhood acute lymphoblastic leukaemia (ALL). However, evidence on optimal follow-up schedules is limited. The aims of the present population-based cohort study were to assess the value of current follow-up schedules after completion of Nordic Society of Paediatric Haematology and Oncology ALL protocol treatment and to estimate the impact of relapse detection mode on overall survival (OS). Among 3262 patients diagnosed between 1992 and 2014 and who completed treatment, 338 developed a relapse. Relapse detection was equally distributed between extra visits (50·8%) and scheduled follow-up visits (49·2%). All cases detected at an extra visit and 64·3% of cases detected at a scheduled visit presented with symptoms or objective findings. Neither the mode of detection {adjusted hazard ratio 0·95, [95% confidence interval (CI) 0·61-1·48] for scheduled visits} nor the duration of symptoms was an independent risk factor for OS after relapse. The estimated number of scheduled blood samples needed to diagnose one subclinical relapse during the first 5 years after treatment cessation was 1269 (95% CI 902-1637). In conclusion, based on OS data, scheduled visits after cessation of therapy seem to yield no extra benefit. These results should frame future follow-up strategies.