Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments.

BACKGROUND: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. METHODS: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. RESULTS: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time. CONCLUSIONS: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.

Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study.

BACKGROUND: 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 CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1-30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed 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 log-transformed 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 log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126-0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. CONCLUSIONS: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

A comparison of genotyping arrays.

Array technology to genotype single-nucleotide variants (SNVs) is widely used in genome-wide association studies (GWAS), clinical diagnostics, and linkage studies. Arrays have undergone a tremendous growth in both number and content over recent years making a comprehensive comparison all the more important. We have compared 28 genotyping arrays on their overall content, genome-wide coverage, imputation quality, presence of known GWAS loci, mtDNA variants and clinically relevant genes (i.e., American College of Medical Genetics (ACMG) actionable genes, pharmacogenetic genes, human leukocyte antigen (HLA) genes and SNV density). Our comparison shows that genome-wide coverage is highly correlated with the number of SNVs on the array but does not correlate with imputation quality, which is the main determinant of GWAS usability. Average imputation quality for all tested arrays was similar for European and African populations, indicating that this is not a good criterion for choosing a genotyping array. Rather, the additional content on the array, such as pharmacogenetics or HLA variants, should be the deciding factor. As the research question of a study will in large part determine which class of genes are of interest, there is not just one perfect array for all different research questions. This study can thus help as a guideline to determine which array best suits a study's requirements.

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Risk factors associated with tinnitus in 2948 Dutch survivors of childhood cancer: a Dutch LATER questionnaire study.

BACKGROUND: Tinnitus is a serious late effect of childhood cancer treatment. The aim of this study was to determine the occurrence and risk factors for tinnitus in a national cohort of childhood cancer survivors (CCS). METHODS: Data were collected within the national Dutch Childhood Oncology Group - Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort by a self-reported health questionnaire among 5327 Dutch CCS treated between 1963 and 2002. Siblings (N = 1663) were invited to complete the same questionnaire. Relevant patient characteristics and treatment factors were obtained from the Dutch LATER database. The occurrence of tinnitus in survivors was compared to siblings. To study the effect of risk factors, multivariate logistic regression models were estimated. RESULTS: In total, 2948 CCS and 1055 siblings completed the tinnitus item. Tinnitus was reported in 9.5% of survivors and in 3.7% of siblings (odds ratio [OR] 3.0, 95% confidence interval [CI] 2.9-3.1). Risk factors associated with tinnitus in CCS were total cumulative dose cisplatin ≥400 mg/m2 (OR 2.4, 95% CI 1.4-4.0), age at diagnosis (≥10 years: OR 2.1, 95% CI 1.6-2.8), cranial irradiation/total body irradiation (TBI; OR 1.9, 95% CI 1.5-2.5), and neuro/ear, nose, throat (ENT) surgery (OR 1.8, 95% CI 1.1-2.9). Fifty-one percent of CCS with tinnitus had received treatment with either cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery. CONCLUSIONS: Tinnitus in CCS was present nearly 3 times more often than in siblings. Awareness in CCS previously treated with cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery is warranted. As only half of affected CCS had a history of these treatments, it seems that other factors might be associated with tinnitus occurrence in this population.

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study.

BACKGROUND: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. OBJECTIVE: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity. METHODS: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. RESULTS: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. CONCLUSIONS: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11868.

Tinnitus during and after childhood cancer: A systematic review.

BACKGROUND: Tinnitus can occur during and after treatment for childhood cancer. Studies on the occurrence of, and risk factors for tinnitus during and after childhood cancer treatment are scarce. The aim of this study is to get insight into the frequency and risk factors of tinnitus during and after childhood cancer therapy, based on a review of all previously reported literature. MATERIALS AND METHODS: Systematic electronic literature searches that combined childhood cancer with different treatments and tinnitus terms were performed in the databases EMBASE, Medline, Cochrane, Web of Science, and Google Scholar. Studies were included based on reporting the frequency of tinnitus during and/or after childhood cancer, with 75% of participants being under the age of 25 at time of diagnosis, diagnosed with any type of childhood malignancy and treated with any type of chemotherapy and/or radiotherapy. A risk of bias assessment per research question was performed. RESULTS: Tinnitus incidence rates were reported up to 15.9 (95% CI 11.8-21.4) during therapy and up to 5.4 (95% CI 4.3-6.9) more than 5 years after diagnosis. The relative risk of developing tinnitus as compared to siblings during and after childhood cancer therapy were reported up to 17.2 (95% CI 11.8-25.0) during therapy and up to 3.7 (95% CI 2.7-5.1) more than 5 years after diagnosis. Independent risk factors for tinnitus development included high dose cranial radiation and platinum based chemotherapy. CONCLUSION: The frequency of and risk to develop tinnitus seems to be higher in childhood cancer patients and survivors as compared to the normal population. Regular tinnitus screening before, during and after therapy with standardized questionnaires for early detection seems therefore reasonable in order to identify high-risk patients and eventually develop successful clinical preventive, supportive and management strategies.

Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents.

AIMS: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. METHODS: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. RESULTS: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. CONCLUSIONS: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol.

BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS. METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. DISCUSSION: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.

Health-related fitness in very long-term survivors of childhood cancer: A cross-sectional study.

BACKGROUND: Impairment of health-related physical fitness (HRPF) in survivors of acute lymphoblastic leukemia has been shown. However, evidence of impairment in survivors of other pediatric malignancies and possible risk factors is limited. PARTICIPANTS AND METHODS: HRPF of 17 survivors of pediatric acute myeloid leukemia (AML), 26 survivors of neuroblastoma (NBL), 28 survivors of Wilms tumor (WT) (median age 28.8 [18.8-62.6] years) after a median follow-up time of 24.5 (6.5-43.6) years, and 74 healthy controls (median age 26.9 [17.9-61.7] years). Risk factors were investigated. Testing included submaximal cardiovascular endurance (6-Minute Walk Test (6 MWT), flexibility, and muscle strength. RESULTS: Results are expressed as mean (standard error). Survivors scored significantly lower than controls on the 6 MWT (588 ± 6.1 m vs. controls 611 ± 6.0 m; P = 0.008), on side flexion of the trunk (20.1 ± 0.4 cm vs. controls 22.4 ±0.4 cm; P < 0.001), and on vertical jump (39.7 ± 0.8 cm vs. controls 43.8 ± 0.8 cm; P < 0.001). Survivors of AML had lower scores on the 6 MWT (563 ± 12.4 m) than survivors of NBL (585 ± 9.9 m) and survivors of WT (606 ± 9.6 m), P = 0.046. Being a survivor, higher body mass index (BMI) and no participation in sports were independently associated with lower scores on the 6 MWT. CONCLUSION: Survivors of NBL, WT, and especially AML have impaired HRPF. Higher BMI and physical inactivity at adult age appeared prominent risk factors for impaired HRPF in these survivors.

Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors.

Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Münster criteria (>20 dB at ≥4-8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m2 and median total cumulative dose carboplatin: 2520 mg/m2). Median follow-up time was 5.5 years (range: 1.0-28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Münster degrees was observed in five of 61 survivors after 1.6-19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale.

Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study.

Platinum-containing chemotherapeutics are efficacious for a variety of pediatric malignancies, nevertheless these drugs can induce ototoxicity. However, ototoxicity data on large cohorts of childhood cancer survivors (CCSs) who received platinum agents, but not cranial irradiation are scarce. Therefore, we have studied the frequency and determinants of ototoxicity in a cross-sectional multicenter CCS cohort, including the role of co-medication since it has been suggested that these play a role in ototoxicity. We have collected treatment data and audiograms from the medical records of CCS treated in the seven pediatric oncology centres in The Netherlands. Ototoxicity was defined as Münster grade ≥2b (>20 dB at ≥4-8 kHz). Four-hundred-fifty-one CCS who received platinum agents, but not cranial irradiation (median age at diagnosis: 4.9 years, range: 0.01-19 years) were included. The overall frequency of ototoxicity was 42%. Ototoxicity was observed in 45% of the cisplatin-treated CCS, in 17% of the carboplatin-treated CCS and in 75% of the CCS that had received both agents. Multivariate analysis showed that younger age at diagnosis (odds ratio [OR]: 0.6, 95% confidence interval [CI]: 0.5-0.6 per 5 years increase); higher total cumulative dose cisplatin (OR: 1.2, 95% CI: 1.2-1.5 per 100 mg/m2 increase); and co-treatment with furosemide (OR: 2.3, 95% CI: 1.4-3.9) were associated with ototoxicity. We conclude that treatment with (higher total cumulative dose of) cisplatin, young age and furosemide co-medication independently are associated with an increased risk of ototoxicity in CCS. Future prospective studies are necessary to confirm the additive risk of co-medication on the development of ototoxicity.