Background and Aims

Childhood cancer survivors experience reduced physiologic reserve, known as frailty, earlier and at higher rates than their peers. Survivors also are at-risk for pain that may impact daily activities and precipitate or exacerbate frail states. Associations between pain and the development or acceleration of frailty in survivors has not been investigated.

Methods

1,299 survivors (mean[SD] age 30.7[7.0] years; time since diagnosis 22.7[7.4] years) recruited from the St. Jude Lifetime Cohort completed clinical assessments at baseline and a median follow-up of 5.3 years. Frailty states were defined as having 2 (pre-frail) or ≥3 (frail) of the following: sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion. Survivors completed self-report measures of pain and pain interference. Multinomial logistic regression, using odds ratios (OR) and 95% confidence intervals (95% CI), examined associations between pain and frailty with adjustment for age, sex, race/ethnicity, and chronic health conditions.

Results

5.5% of survivors were frail at baseline and 5.9% progressed from not frail/pre-frail to frail at follow-up; 15.5% reported pain with interference at baseline and 16.9% reported increased pain at follow-up. Compared to survivors without pain, survivors with pain and daily interference were more likely to be pre-frail (OR: 2.55; 95% CI, 1.72-3.78) or frail (OR: 4.58; 95% CI, 2.45-8.55) at baseline. Pain at baseline was not significantly associated with frailty progression; however, survivors who had persistent (OR: 2.23; 95% CI, 1.20-4.13) or increased pain (OR: 3.59; 95% CI, 1.94-6.63) from baseline to follow-up were more likely to progress from not frail/pre-frail to frail at follow-up.

Conclusions

Pain that interferes with daily functioning is associated with pre-frail and frail states in survivors. These results may inform interventions that target pain and functional daily activities to mitigate the risk of frailty and improve health outcomes in survivors.

Background and Aims

Acute peripheral neuropathy affects 20-60% of children during treatment for acute lymphoblastic leukemia (ALL) with symptoms persisting in up to 40% of survivors, impacting mobility and quality of life. CEP72 genotype (rs924607) is associated with acute vincristine-induced neuropathy. We aimed to evaluate the association between CEP72 genotype and peripheral neuropathy in childhood ALL survivors.

Methods

Participants included 990 (5+ years) childhood ALL survivors (mean age 27.0±8.6 years) treated at St. Jude Children’s Research Hospital (mean time from diagnosis 21.1±8.4 years). Peripheral neuropathy was assessed using the modified Total Neuropathy Score (mTNS) and functional tasks. Sensory or motor neuropathy was classified present if signs and symptoms from the mTNS and functional tasks met National Cancer Institute Common Terminology for Adverse Events (v5) criteria (Grade≥2). CEP72 genotype was determined from DNA in peripheral blood by whole genome sequencing or imputation from the Affymetrix SNP array 6.0.

Results

Neuropathy was present in 16.0% (motor or sensory), 12.5% (sensory) and 7.2% (motor) of survivors. The prevalence of motor neuropathy was higher in individuals with rs924607-T allele (TT genotype, 10.9%, p=0.01; CT genotype, 8.46%, p=0.02) than in those without (CC genotype, 4.5%). In models adjusted for clinical predictors including cumulative vincristine dose (median 54.2 mg/m², IQR 11.7-61.6), survivors with TT (OR 2.47; 95% CI 1.15–5.31) and CT (OR 1.93; 95% CI 1.06–3.51) genotypes had significantly increased motor neuropathy risk compared to those with CC genotype. The CT genotype was associated with higher total (β=0.48; 95% CI 0.15–-0.82) and motor (β=0.33; 95% CI 0.10-0.57) scores on the mTNS than the CC genotype.

Conclusions

Screening for rs924607-T allele may identify children treated for ALL at greatest risk for experiencing motor neuropathy decades after treatment.

Work supported by the National Institutes of Health (R01CA036401 (W.E.E.), U01CA195547 (M.M.H, L.L.R.)), Cancer Center Support Grant (CA 21765 (C.W.M.R.), and the American Lebanese-Syrian Associated Charities.

Background and Aims

Childhood, adolescent and young adult (CAYA) cancer survivors are at increased risk of (very) low bone mineral density (BMD). Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve BMD parameters and prevent fragility fractures. Discordances across current late-effects guidelines necessitated international harmonization of BMD surveillance recommendations.

Methods

The IGHG established a panel of 36 experts from 10 countries, representing a range of relevant medical specialties. The evidence of risk factors for low (Z-score ≤-1) and very low (Z-score ≤-2) BMD and fractures, surveillance modality, timing of BMD surveillance, and treatment of (very) low BMD were evaluated and critically appraised, and harmonized recommendations for CAYA cancer survivors were formulated. We graded the recommendations based on the quality of underlying evidence and the balance between potential benefits and harms.

Results

BMD surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy, and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against BMD surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and healthcare provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to perform BMD surveillance using dual-energy X-ray absorptiometry at entry into long-term follow-up (between 2-5 years following treatment cessation), and if normal (Z-score >-1), repeat at 25 years of age when peak bone mass should be achieved. Between these two measurements and thereafter, BMD surveillance should be performed as clinically indicated based on BMD and ongoing risk assessment.

Conclusions

This guideline provides BMD surveillance recommendations that may improve health outcomes by facilitating more consistent care for CAYA cancer survivors internationally. In addition, it promotes strategically planned ongoing research that will inform future guideline updates.

Background and Aims

Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs.

Methods

Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCS, from the pan-European PanCareLIFE cohort (N=743) (age (years): median 25.8, IQR 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (N=391) (age (years): median 31.3, IQR 26.6 – 37.4).

Results

CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta(95% CI): -0.706 (-1.11- -0.298) p-value = 7*10^-4) of CYP3A4*3 (rs4986910) on AMH levels and the estimated relative AMH level is five-fold lower with CYP3A4*3 compared to someone with similar CED and no alternative alleles. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta(95% CI): 0.527 (0.126 – 0.928) p-value = 0.01) on AMH levels in CCSs receiving more than 8000mg/m² CED.

Conclusions

Female CCSs CYP3A4*3 carriers had five-fold lower AMH levels, and CYP2B6*2 has a protective effect on AMH levels. Identification of risk-contributing variants may improve individualised counselling regarding treatment-related risk of infertility and fertility preservation options.

Background and Aims

Survivors of pediatric CNS tumors exhibit considerable variability in cognitive performance following CSI, which may be partly explained by inherited genetic susceptibility. Goals of this study were to: 1) replicate candidate genetic variants previously associated with cognitive performance in both a) pediatric CNS tumor survivors and b) the general population, and 2) identify novel variants associated with cognitive decline using a genome-wide approach.

Methods

Intelligence (IQ), working memory (WMI), and processing speed (PSI) were longitudinally collected from patients treated with CSI (n=249) enrolled on St. Jude medulloblastoma clinical trials or an observational cohort at Texas Children’s Hospital. Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common (>1%) variants associated with cognitive performance change. Novel variants associated with cognitive decline (p<5.0E-5) in individuals of European ancestry (n=167) were considered replicated if they demonstrated consistent genotype-by-time interactions (p<0.05) in individuals of other ancestries (n=82) and achieved genome-wide statistical significance (p<5.0E-8) in a meta-analysis across ancestry groups.

Results

Participants were primarily males (65%) diagnosed with medulloblastoma (98%) at a mean age of 8.9 years. Overall, 1,080 neurocognitive evaluations were collected (median = 4, range: 2-11 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines in our population (PPARA rs6008197, p=0.02). Two of 371 general population loci were associated with declines in IQ after Bonferroni correction (rs9348721 near BTN1A1, p=1.1E-5; rs31771 near RPL7P20, p=3.8E-5). In genome-wide analyses, we identified and replicated novel loci associated with accelerated declines in IQ (rs116595313 near FHDC1, meta-analysis p=3.8E-8) and WMI (rs17774009 near BVES, meta-analysis p=6.3E-11).

Conclusions

We present evidence that inherited genetic variants involved in baseline intellectual functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumors. Genetic variants may inform risk stratification and efforts to preserve cognitive function.

Background and Aims

Attaining upper secondary education is important for future career opportunities, and some survivors of childhood cancer may have difficulties achieving this. Survivors of CNS tumours seem to be at particular risk, but for survivors of other cancer types the evidence is less consistent. In a population- and register-based study including Denmark, Finland, and Sweden, we investigated educational achievements among survivors of childhood cancer and identified particular risk groups.

Methods

Within the SALiCCS (Socioeconomic Consequences in Adult Life after Childhood Cancer in Scandinavia) research program, we included all children, diagnosed with cancer at ages 0-14 during 1971-2005, alive by age 25 (n=7,629), their age-, sex- and country-matched population comparisons (n=35,411) and siblings (n=6,114). Annual individual information on education was retrieved from national registers. We assessed the relative risk (RR) of educational delay, and of failing to achieve upper secondary education by age 25, using log-binomial regression.

Results

Overall, 80% of survivors and 84% of population comparisons and siblings, had achieved upper secondary education by age 25. The RR of failing to achieve upper secondary education was 1.24 (95% CI 1.18-1.31) and differed by cancer type (e.g., survivors of lymphoid leukaemia 1.11 (95% CI 1.00-1.25); survivors of CNS tumours 1.73 (95% CI 1.60-1.87)). Children of parents with high educational level were more likely to achieve a higher education themselves, however, in this group the risk difference of failing (comparing survivors and comparisons) was somewhat larger. A lower proportion of survivors than comparisons achieved upper secondary education without delay.

Conclusions

In this study we demonstrate that some survivors of childhood cancer experience difficulties in educational achievements. This differed by cancer type; while only small differences in achievement of upper secondary education by age 25 were observed for survivors of some cancer types, differences were pronounced among survivors of CNS tumours.