Article

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

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Abstract

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.

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... 14 The EU-funded project, PanCareLIFE, recognised the need for global consensus on fertility preservation and established an international effort to develop transparent CPGs for fertility preservation in patients with CAYA cancer in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). 15, 16 We provide a systematic review and recommendations for ongoing communication about treatment-related infertility risk and fertility preservation in patients with CAYA cancer, including guidance on the ethical implications that are associated with these procedures. ...
... Existing studies describe some of the facilitators for and barriers to providing information or communicating about treatment-related infertility risk and fertility preser vation in patients with CAYA cancer. Our recommen dations are based on existing knowledge about potential facilitators and barriers and the consensus of the guideline panel (appendix pp [15][16][17]. The panel formulated recommendations regarding provision of information and communication about treatment-related infertility risk and options for fertility preservation (panel 2; recommendations about patient risk groups that should receive information and counselling were formulated by the male and female fertility preservation guideline panels). ...
... This CPG harmonises efforts across Europe, Canada, Australia, New Zealand, and the USA as part of the PanCareLIFE Consortium and in collaboration with the IGHG. 15,16 The global dissemination of this guideline aims to assist health-care providers to effectively communicate with patients with CAYA cancer and their families about potential infertility risk and procedures for fertility preservation while considering ethical issues. This CPG is one of the three CPGs that we have developed in this Series, with the other two Series papers focusing on fertility preservation options for male 119 and female 120 patients with CAYA cancer. ...
Article
on behalf of the PanCareLIFE Consortium ‡ Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.
... 14 The EU-funded project, PanCareLIFE, recognised the need for global consensus on fertility preservation and established an international effort to develop transparent CPGs for fertility preservation in patients with CAYA cancer in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). 15, 16 We provide a systematic review and recommendations for ongoing communication about treatment-related infertility risk and fertility preservation in patients with CAYA cancer, including guidance on the ethical implications that are associated with these procedures. ...
... Existing studies describe some of the facilitators for and barriers to providing information or communicating about treatment-related infertility risk and fertility preser vation in patients with CAYA cancer. Our recommen dations are based on existing knowledge about potential facilitators and barriers and the consensus of the guideline panel (appendix pp [15][16][17]. The panel formulated recommendations regarding provision of information and communication about treatment-related infertility risk and options for fertility preservation (panel 2; recommendations about patient risk groups that should receive information and counselling were formulated by the male and female fertility preservation guideline panels). ...
... This CPG harmonises efforts across Europe, Canada, Australia, New Zealand, and the USA as part of the PanCareLIFE Consortium and in collaboration with the IGHG. 15,16 The global dissemination of this guideline aims to assist health-care providers to effectively communicate with patients with CAYA cancer and their families about potential infertility risk and procedures for fertility preservation while considering ethical issues. This CPG is one of the three CPGs that we have developed in this Series, with the other two Series papers focusing on fertility preservation options for male 119 and female 120 patients with CAYA cancer. ...
Article
Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.
... PanCareLIFE is the second, independent, EU-funded consortium arising from the PanCare network (www.pancare.eu). PanCareLIFE it focusses on fertility, ototoxicity and quality of life and incorporates genetic and clinical studies [8]. ...
... PCSF data came from 13 hospital-and populationbased registries of childhood and adolescent cancer survivors in 12 countriesdDenmark, Finland, Iceland, Norway, Sweden, Slovenia, Switzerland, Great Britain, Hungary, Italy, France and the Netherlands [8]. All data providers had high ascertainment rates. ...
... Large, multinational studies have been set up aiming to fully explore the LEs of CYP cancer and to research how best to improve the lives of survivors. 21,22 Many contemporary trials are investigating the safety of reduced treatment intensities, which should help to reduce the incidence of LEs. 23,24 This review aims to provide a brief overview of the vast array of LEs experienced by survivors of CYP cancer in order to contextualize the issues they might experience while providing a more in-depth review of the reproductive health sequelae. ...
... 28,29 This increased risk is particularly notable among survivors of certain tumour types (eg lymphoma) and those receiving particular treatments (eg high-dose anthracyclines or mediastinal/chest radiation). 21,22 Stroke risk is additionally increased in CYP cancer survivors, with 12% reporting at least 1 stroke by 30 years post diagnosis, 30 and a fifth of these experiencing recurrent strokes. 31 ...
Article
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This paper provides a summary of the areas of survival from childhood, teenage and young adult cancer and the significant late‐effects that can arise from treatment with particular focus on the area of reproductive health and the impact on both fertility and pregnancy. To complete this review, Web of Science and MEDLINE were used. Search terms included: “survival AND childhood OR teenage OR young adult cancer”, “late effects”, “childhood cancer”, “teenage and/or young adult cancer”, “and fertility after cancer”, “pregnancy after cancer” and “fertility preservation”. Additionally, clinical expertise from the authors was drawn upon. Childhood cancer is thankfully a rare occurrence; however, the incidence is increasing. Survival rates remain high and this means that a growing population of childhood and young adult cancer survivors is reaching adulthood. For some of these adults, whilst cured of their cancer they are now facing a future with lasting effects on their health from their treatments. These effects, commonly referred to as Late Effects are defined as health problems related either directly to the underlying cancer or to its treatment and which occur months or years after treatment has finished. Reproductive health is an important consideration for these patients, and whilst many will be able to conceive naturally, some will exhibit impaired fertility after their treatments. This can include difficulties at all points along the path from conception to delivery of a live, healthy offspring. High quality, large population evidence is sparse in many areas relating to fertility risk from treatment and into the maternal and fetal health of childhood cancer survivors. Yet given the potential for complications the authors advocate consideration of fertility at the time of diagnosis and prior to potentially gonadotoxic treatment. This article is protected by copyright. All rights reserved.
... Mortality in survivors is more than 10-times higher than in the general population [4]. While many demographic, clinical, and treatment-related risk factors are known, the contribution of genetic variation in the development of health complications is still poorly understood [5][6][7]. ...
... Of those we contacted, 463 (50%) returned a germline DNA sample. Median age at diagnosis was 8.7 years (interquartile range [IQR] [3][4][5][6][7][8][9][10][11][12][13] and at invitation 26.5 years (IQR 19-37; Table 1). The most common diagnoses were central nervous system tumours (28%) and lymphomas (20%) which reflected our selection process of inviting former childhood cancer patients with pulmotoxic and ototoxic treatments. ...
Article
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Background Research on germline genetic variants relies on enough eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits, participants can contribute genetic samples conveniently from their home. Demographic and clinical factors were identified previously that influenced participation in mailed self-collection. People with pre-existing heritable diagnoses might participate differently in germline DNA collection which might render sampling biased in this group. In this nationwide cross-sectional study, we analysed predictive factors of participation in DNA self-collection including heritable diagnoses. Methods We identified childhood cancer survivors from the Swiss Childhood Cancer Registry for invitation to germline DNA self-sampling in September 2019. Participants received saliva sampling kits by postal mail at their home, were asked to fill them, sign an informed consent, and send them back by mail. Two reminders were sent to non-participants by mail. We compared demographic, clinical, and treatment information of participants with non-participants using univariable and multivariable logistic regression models. Results We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 19-37), of which 463 (50%) participated. After the initial send out of the sampling kit, 291 (63%) had participated, while reminder letters led to 172 additional participants (37%). Foreign nationality (odds ratio [OR] 0.5; 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5; CI 0.4-0.8), and survivors with a known cancer predisposition syndrome (OR 0.5; CI 0.3-1.0) were less likely to participate in germline DNA collection. Survivors with a second primary neoplasm (OR 1.9; CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3; CI 1.0-1.8) tended to participate more. Conclusions We showed that half of childhood cancer survivors participated in germline DNA self-sampling relying completely on mailing of sample kits. Written reminders increased the response by about one third. More targeted recruitment strategies may be advocated for people of foreign nationality, aged 30-39 years, and those with cancer predisposition syndromes. Perceptions of genetic research and potential barriers to participation of survivors need to be better understood. Trial registration Biobank: https://directory.bbmri-eric.eu/#/collection/bbmri-eric:ID:CH_HopitauxUniversitairesGeneve:collection:CH_BaHOP Research project : Clinicaltrials.gov: NCT04702321 .
... This international retrospective study is part of PanCareLIFE, a pan-European research project including 28 institutions from 13 countries addressing ototoxicity, fertility, and quality of life [8,28,29]. Demographic, disease, and treatment data were abstracted from medical records. ...
... So far, large-scale GWAS have identified several SNPs, such as rs11668344 (BRSK1), rs365132 (UIMC1) and rs16991615 (MCM8), relevant for age at natural menopause or premature ovarian insufficiency (POI) in the general population [12,[60][61][62][63][64][65]. Results of a European GWAS study in CCSs exploring genetic susceptibility of cancer treatment-related gonadal damage in girls are currently pending [26,28]. ...
Article
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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.
... PanCareLIFE was conceived to give more insights into genetic susceptibility and to prevent or reduce the impact of these late effects on cancer survivors. A companion paper describes the scientific basis for the PanCareLIFE consortium [20]. This paper focuses on assessing the organizational structure from a retrospective view point and provides an outlook on possibilities for ensuring the sustainability of such collaborative projects in the future. ...
... PanCareLIFE consists of eight work packages (WPs). The five scientific work packages were previously described in detail [20]: There are two accompanying WPs: WP7 Dissemination and Exploitation (K. O´Brien) and WP8 Project Management (P. ...
Article
Full-text available
PanCareLIFE brought together European partners and is the largest study to have evaluated the issues of fertility impairment, hearing loss, and health-related quality of life in survivors of childhood and adolescent cancer. Successful delivery of the project aims did not evolve solely from scientific qualities. Organizational structure and careful information management were key components for its successful completion and are retrospectively assessed in this paper. PanCareLIFE used cohort studies, case-control studies, clinical evaluation of hearing, and genetic testing to study 32,000 survivors from 25 data providers. A management team implemented the organizational structures, was the decision making body, developed and maintained a communication plan, and supervised deadlines, and made timely decisions. A biostatistics support group and an ethical advisory board were established. A publication committee ensured quality and accuracy of publications and is jointly responsible for the sustainability of the project. The chosen management structure of PanCareLIFE can serve as a blueprint for the management of complex international projects. Apart from the survivors themselves, various target audiences like oncology researchers, health care providers, and policy makers can derive benefits from the project. The results can also be used in oncological frontline therapy to reduce toxicity.
... 9,10 Guidelines for fertility counselling and preservation are available; nevertheless, an overall standard has yet to be established. 11,12 Patient education requires improvement in order to enable self-determined decisions regarding family planning. Increased knowledge directly correlates with higher empowerment, which leads to confidence in decision-making. ...
Article
Introduction/objectives: Fertility preservation is a major concern for adolescent cancer patients; yet, educational gaps remain. Our intervention study examined whether specially designed educational materials regarding fertility preservation increase knowledge and empowerment of patients and parents. Methods: Eleven paediatric-oncological centres in four European countries agreed to enrol all eligible patients and parents in a questionnaire survey at three and six months after diagnosis. Treating physicians were surveyed on their medical consultation regarding fertility. Results: Educational intervention increased knowledge in both patients (n=113 and n=101 in the control and intervention groups respectively) and parents (n=111 and n=99 in the control and intervention groups respectively), but the difference did not achieve statistical significance (knowledge difference patients: 5.6% (t0)/13.1% (t1); parents: 6.4% (t0)/3.8% (t1)). Parents of older patients (OR=1.3, 95%CI=1.1-1.7) and higher educational groups (OR=6.2, 95%CI=2.1-18.3) in the intervention group (OR=1.9, 95%CI=1.03-3.7) achieved higher knowledge levels. Empowerment was significantly improved in both patients (p=0.046, d=0.27) and parents (p=0.046, d=0.48) in the intervention group. Discussion/conclusions: In our study, the use of specifically prepared flyers and brochures successfully raised the level of fertility preservation knowledge in parents of older patients as well as parents with higher educational levels. Overall, the intervention improved patient and parent empowerment. Subsequent projects will include simpler information and digital material to particularly reach out to younger and less educated individuals.
... Within the framework of PanCareLIFE, a project funded by the European Union's Seventh Framework Programme for research, technological development and demonstration (grant agreement no. 602030), we conducted the multicentre intervention study Patient education [4,20]. ...
Article
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Infertility is a relevant late-effect following cancer treatment; yet, a large proportion of survivors cannot recall having been informed of this risk. In an intervention study, we examined if and how supportive patient information material on fertility/fertility-preserving measures influences utilization of cryopreservation in adolescent cancer patients. The control group, recruited 03/2014–01/2016, received the usual patient education at initial diagnosis. The intervention group, recruited 04/2016–10/2017, received patient education supported by a fertility flyer and brochure. Patients and parents were each asked questions on utilization of cryopreservation in a questionnaire 3 and 6 months after initial diagnosis. Patient core and therapy data were obtained from medical records. Overall, cryopreservation rates showed no significant difference between the control (32.7%, n = 37/113) and intervention group (36.6%, n = 37/101). In the control group, cryopreservation was associated with gender (OR 0.100, CI 0.023–0.427), age (OR 1.559, CI 1.077–2.258) and recalling information on fertility protection (OR 33.663, CI 2.100–539.574); in the intervention group, cryopreservation was related to gender (OR 0.093, CI 0.026–0.330) and the estimated infertility risk (OR 43.665, CI 2.157–883.974). Conclusion: Cryopreservation rates did not overall increase following the intervention; however, the individual risk seemed to be brought into attention more: Those at risk, including younger patients, cryopreserved at higher rates.What is Known: •Infertility is a relevant late-effect following adolescent cancer. •Guidelines recommend to offer fertility protection before cancer treatment. •A relevant proportion of adolescents with cancer are not aware of this risk. •Fertility protection seems under-used in cancer patients at risk for infertility. What is New: •Information material on fertility and protection in adolescents did not increase overall rates of cryopreservation. •Cryopreservation rates were improved according to individual risk for infertility. •Our flyers and brochures on fertility in cancer patients are available in various languages.
... We explored fertility-related expectations and concerns of adolescent cancer patients and their parents within a multicenter European study. 13 The following aspects were examined: the desire for biological parenthood; concern of offspring being at higher risk for cancer; anxiety about cancer recurrence; concerns about infertility; and side effects of fertility preservation; as well as the patient's intention/parent's recommendation to use fertility preservation. ...
Article
Purpose: Within a multicenter European study, we explored fertility-related wishes, concerns, and decision-making of adolescent cancer patients and their parents. Patients and Methods: Patients and parents were each asked to complete a fertility-related questionnaire 3 months after initial diagnosis. In total, 113 of 142 (79.6%) eligible patients participated; 53.1% were male and the median age was 16 years (range 13-20 years). The questionnaire was completed by 111 parents. Univariate analyses were conducted using nonparametric methods with alpha = 5%. For multivariate analyses, binary logistic regression was conducted. Results: Both patients (86.1%) and parents (96.3%) indicated a strong desire for biological parenthood for themselves/their children. Female patients (odds ratio [OR] = 3.70; confidence interval [CI]: 1.43-9.50) and parents (OR = 2.70; CI: 1.21-6.00) were more likely to report a high fear of cancer recurrence. Patients who estimated their risk for fertility impairment being high were more likely to be concerned about their fertility (OR = 5.69; CI: 1.41-22.98). Parents who received fertility preservation information were more likely to recommend its use to their children (OR = 5.50; CI: 1.07-28.40), whereas parents of female patients were less likely to do so (OR = 0.13; CI: 0.03-0.61). Conclusions: The prospect of fertility following cancer treatment is important for adolescent cancer patients and their parents, yet it is associated with many concerns. Counseling regarding fertility preservation can be more effective when the individual needs of patients and their parents are taken into consideration.
... To explore the current practice of fertility education for adolescent cancer patients in four European countries, we examined: (I) availability of counselling on the risk for infertility prior to cancer treatment, (II) availability of counselling on fertility preservation options, (III) patients' overall knowledge on fertility, (IV) patients' perception of feeling sufficiently informed to take informed decisions and (V) uptake of cryopreservation. This survey was the first part of a broader intervention study on fertility education in these countries, which received funding within the European project PanCareLIFE (Byrne et al., 2018). to recall counselling on fertility preservation (OR = 0.03, CI: 0.00-0.47) and female gender (OR = 0.11, CI: 0.03-0.48) ...
Article
Full-text available
Objective As adolescent cancer patients may suffer from infertility following treatment, fertility counselling is essential. Our aim was to explore the current situation in four European countries in terms of (I) education about the risk for infertility, (II) counselling on fertility preservation, (III) patients' knowledge on fertility, (IV) sufficiency of information and (V) uptake of cryopreservation. Methods In total, 113 patients (13–20 years) at 11 study centres completed a self‐report questionnaire three and six months after cancer diagnosis. Multivariate logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI). Results As many as 80.2% of participants reported having received education about the risk for infertility prior to treatment, 73.2% recalled counselling on fertility preservation. Only 52.3% stated they felt sufficiently informed to make a decision. Inability to recall counselling on fertility preservation (OR = 0.03, CI: 0.00–0.47) and female gender (OR = 0.11, CI: 0.03–0.48) was associated with lower use of cryopreservation, whereas older age was associated with higher use. Conclusion Fertility counselling was available to a relatively high proportion of patients, and it did influence the utilisation of cryopreservation. However, many patients did not feel sufficiently informed. Further improvement is needed to enable adolescent cancer patients to make an informed decision on fertility preservation.
... Background and methods of the European multicenter PanCareLIFE study have been described previously [1][2][3]. Patients were enrolled after approval was obtained from local review boards and written informed consent was obtained from patients, parents or legal guardians. Participants were enrolled both retrospectively and prospectively (i.e., chemotherapy was started and finished during the 5-year term of PanCareLIFE). ...
Article
Full-text available
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.
... 17,21 It is crucial that illness experiences are socially constructed, value loaded, and culturally shaped. 21,25,26 For instance, it is suggested that Brazilians' identity is derived mainly from the immediate and extended family, where individuals have strong social ties with their social groups, religion, 27 and family and prefer to make group decisions in general. 28 In the Brazilian society, infertility is an increasingly common problem that affects the individual's psychological and emotional wellbeing. ...
Article
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Purpose: This study aimed to uncover the fertility-related concerns and uncertainties in adolescent and young adult (AYA) childhood cancer survivors. Methods: In this qualitative study, participants were recruited from an oncohematology outpatient clinic at a university hospital in Brazil. Twenty-four AYA cancer survivors, aged 18– 24 years (13 men and 11 women), participated in individual semistructured interviews focusing on two parts—sociodemographic and clinical variables and guiding questions that enabled understanding of the concerns and uncertainties regarding the risks of infertility and their impact on relationships and the need for guidance. Data were analyzed using inductive thematic analysis. Results: Four themes were identified from the data—(1) knowledge about fertility, (2) emotional impact and fertility-related uncertainty, (3) sharing the possible risk of infertility with partners, and (4) need for information on possible loss of fertility. Conclusion: The meanings attributed to the loss of fertility after cancer treatment uncovered the need for health professionals to organize survivor services in line with the survivors' needs, and include reproductive concerns and uncertainties in this planning. The study results provide insights for the development of health care services that meet the real needs of this particular population that has long-term follow-up demands. Jardim FA, Lopes-Júnior LC, Nascimento LC, Neves ET, Lima RAG. Fertility-Related Concerns and Uncertainties in Adolescent and Young Adult Childhood Cancer Survivors [published online ahead of print, 2020 Sep 18]. J Adolesc Young Adult Oncol. 2020;10.1089/jayao.2020.0058. doi:10.1089/jayao.2020.0058 https://pubmed.ncbi.nlm.nih.gov/32945713/
... 14 To facilitate global consensus on this topic, we present a systematic review and recommen dations for fertility preservation in male patients who are diagnosed with CAYA cancer. These recommendations have been proposed by the EU-funded research project PanCareLIFE 15 in collab oration with the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). 16 e58 www.thelancet.com/oncology ...
Article
Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life.
... Firstly, the effect of the therapy on gametogenesis (Zapata-Restrepo et al. 2019), secondly the quantity and the quality of the sperm pre-and post-treatment, thirdly the medications administered during the prognosis, and fourthly susceptibility of the patient post-treatment and the type of cancer with its correlation with male fertility play an essential role in determining the fate of the reproductive life of a patient after recovery. The overall regime opted by the medical practitioner also influences the sperm count and quality (Byrne et al. 2018). Prediction of the same is also a challenging aspect of the cancer treatment process. ...
Article
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Diagnosis of any ailment especially cancer is found to be pivotal to evaluating the type of treatment that needs to be administered to man. It aids in subsequent prognosis and timely recovery in patients. When concerned with male cancer survivors, the emphasis on their fertility health is always an issue. As the numbers of survivors are increasing day by day due to the advanced medical and technological approaches, man could look with confidence to a life of ease from cancer. To review and compile all the feasible as well as relevant information about the preservation of male fertility from published resources. Reputed databases were searched for content based on specific keywords like “fertility preservation after cancer treatment", "methods of male gamete preservation", "methods of semen collection for preservation", "fertility preservation", "erectile dysfunction" and "testicular cancer and fertility". The year of publication for articles under study was restricted from 2016-2021 in most of the databases. It was found that oncologists generally recommended preservation of the male fertility before the commencement of the cancer treatment procedures. Preservation of fertility among young men should be considered in all patients before initiating any kind of prognosis related to the disease.
... 10 To facilitate global consensus regarding this topic, the EU-funded project, PanCareLIFE, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG), organised a multidisciplinary group of international experts to develop a transparent evidence-based CPG for fertility preservation in female patients with CAYA cancer. 11,12 We provide a systematic review and recommendations for fertility preservation in female patients who are diagnosed with CAYA cancer. ...
Article
Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.
... unites professionals, childhood cancer survivors and their families with the aim of reducing the frequency, severity and impact of late adverse effects by establishing high-quality and sustainable survivorship care for all survivors in Europe [21]. PanCare has initiated and/or contributed to multiple European-funded projects to improve survivors' health and QoL, such as PanCareSurFup [22], PanCareLIFE [23], the European Network for Cancer Research in Children and Adolescents (ENCCA), the Joint Action on Rare Cancers and the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment. The PanCareFollowUp Consortium was established in 2018, consisting of 14 project partners from ten European countries. ...
Article
Background The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care. Methods The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline–based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors. Results Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years. Conclusions The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions.
... Therapies for cancer experienced during infancy or adolescence are known to harm fertility due to direct and indirect damage to the ovaries, with a significant loss of the ovarian reserves [1]. Evidence has proven that alkylating agents and body irradiation should be considered the most dangerous treatments for their toxic potential on the ovaries [2][3][4]. Nonetheless, it is still unknown which exact toxic doses, chemotherapeutic schemes, or radiotherapy protocols should be considered the most harmful [5,6]. A critical long-term side effect in women who survived cancer during youth or adolescence is the boost in follicle loss with impaired ovarian function, leading to absent puberty or premature menopause [7]. ...
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Background: Female childhood cancer survivors (CCS) might have impaired ovarian reserves, especially after alkylating agents or radiotherapy. The purpose of this systematic review and network meta-analysis is to evaluate the role of serum anti-Müllerian hormone (AMH) for ovarian reserve screening and the risk of premature ovarian insufficiency (POI) according to the subtype of childhood cancer. (2) Methods: PRISMA-NMA guidelines were followed. We carried out a network meta-analysis based on a random effects model for mixed multiple treatment comparisons to rank childhood cancers effects on fertility by surface under the cumulative ranking curve (SUCRA). Studies were selected only if they had an age-matched control group. Quality assessment was performed using Newcastle-Ottawa Scale. The co-primary outcomes were mean AMH levels and the incidence of POI. (3) Results: A total of 8 studies (1303 participants) were included. Women treated for a neuroblastoma during infancy were more likely to be ranked first for impaired AMH levels (SUCRA = 65.4%), followed by mixed CCS (SUCRA = 29.6%). The greatest rates of POI were found in neuroblastoma survivors (SUCRA = 42.5%), followed by acute lymphoid leukemia (SUCRA = 26.3%) or any other neoplasia (SUCR A = 20.5%). (4) Conclusions: AMH represents a trustworthy approach for ovarian reserve screening. Direct and indirect comparisons found no differences in mean AMH levels and POI risk between subtypes of CCS and healthy controls. SUCRA analysis showed that female neuroblastoma survivors were more at risk for reduced serum AMH levels and increased risk of POI.
... For a practical example on array choice in a new study, we would like to focus on the PanCareLife study [42,43]. In the PanCareLife study, we were interested in both pharmacogenetics as well as GWAS, in order to study the late-life effects of treatment in childhood cancer survivors. ...
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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.
... In Europe, efforts to improve knowledge of oncofertility preservation options have included the establishment of a pan-European Consortium (PanCareLIFE) that aims to develop FP guidelines for children and adolescents diagnosed with cancer. 51 Funding of FP represents an Box 1. The Edinburgh selection criteria 41 Age younger than 35 years No previous chemotherapy or radiotherapy if aged 15 years or older at diagnosis, but mild, nongonadotoxic chemotherapy acceptable if younger than 15 years A realistic chance of surviving for 5 years A high risk of premature ovarian insufficiency (>50%) Informed consent (from parents and, where possible, the patient) Negative serology results for HIV, syphilis and hepatitis B Not pregnant and no existing children ª 2021 Royal College of Obstetricians and Gynaecologists additional barrier in many healthcare systems. ...
Article
Continued advances in oncology treatments have led to better survival rates for children and young adults with cancer. An important ‘late effect’ of cancer treatment is the loss of fertility. Although many survivors of childhood cancers go on to conceive without difficulty, the potential loss of fertility is a concern for children and young adults with cancer, their parents and caregivers. We review current options for fertility preservation (FP) for prepubertal and postpubertal girls and boys, including oocyte cryopreservation, ovarian tissue cryopreservation, sperm cryopreservation and testicular tissue cryopreservation. To understand the different fertility preservation methods available for children and adolescents, the barriers to fertility preservation and ethical and psychological considerations To raise awareness of the importance of early discussions about fertility preservation with patients who are at risk of infertility from their cancer treatment. Autotransplantation of ovarian tissue in survivors of haematological malignancies, particularly leukaemia, carries a strong risk of re‐introducing the malignancy and should be avoided. Clinicians must consider suitability of the patient for FP, taking into account emotional maturity, patient and parent desire for FP and the physical fitness of the patient, including their immunosuppressive state.
Article
Background Survival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors’ health-related quality of life (HRQoL). Objective The project PanCareLIFE aims to establish a large database with comprehensive data on childhood cancer survivors from different European countries, including data on HRQoL. Within PanCareLIFE, this study aims to describe HRQoL in survivors, investigate predictors of HRQoL, and describe the association of HRQoL with hearing and female fertility impairment. This paper describes the design of the HRQoL study, the origin of data, strategies for data collection, and sampling characteristics of survivors from each contributing country. Methods A total of 6 institutions from 5 European countries (the Czech Republic, France, Germany, the Netherlands, and Switzerland) provided data on HRQoL assessed with the Short Form 36 and on relevant predictors. The central PanCareLIFE data center aggregated the data and harmonized the variables between the institutions. Survivors were eligible if they received a diagnosis of cancer according to the 12 main groups of the International Classification of Childhood Cancer, 3rd edition, or Langerhans cell histiocytosis; were aged ≤18 years at the time of diagnosis; were residents of the respective country at the time of diagnosis; had survived ≥5 years after cancer diagnosis; were aged ≥18 years at the time of the questionnaire survey; and did not refuse to registration in the national or local childhood cancer cohort. Results We identified 24,993 eligible survivors. Of those, 19,268 survivors received a questionnaire and 9871 survivors participated, resulting in response rates of 9871/24,993 (39.50%) of eligible survivors and of 9871/19,268 (51.23%) invited survivors. Most participants were diagnosed with cancer between the ages of 10 and 14 years (3448/9871, 34.93%) or <5 years (3201/9871, 32.43%). The median age was 8 years. Of the 9871 participants, 3157 (31.97%) were survivors of leukemia, 2075 (21.02%) lymphoma, and 1356 (13.7%) central nervous system (CNS) tumors. Most participants (9225/9871, 93.46%) had no history of a subsequent tumor; 77.45% (7645/9871) received chemotherapy with or without other treatments. More than half (5460/9871, 55.31%) were aged 25 to 34 years at the time of the HRQoL study. Participating survivors differed from nonparticipants; participants were more often women, survivors of leukemia or lymphoma, and less frequently, survivors of CNS tumors than nonparticipants. Conclusions PanCareLIFE successfully assessed HRQoL and its predictors in 9871 European survivors of childhood cancer. This large population will permit detailed investigations of HRQoL after childhood cancer, particularly the impact of hearing and female fertility impairment on HRQoL. International Registered Report Identifier (IRRID) RR1-10.2196/21851
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Multimodal osteosarcoma therapy according to past and current European and American protocols is described. This includes both local treatment (usually surgery) and systemic antineoplastic therapy, which is often based on high-dose methotrexate, doxorubicin (Adriamycin), cisplatin, and sometimes ifosfamide. As all must be employed at relatively high doses, early and late adverse effects have long been a major research focus. Their long-term late effects on organ function are described, and recommendations for lifelong follow-up are given. These are meant to comply with the evidence-based recommendations of the International Guideline Harmonization Group. Follow-up after surgery of the primary tumor and (endoprosthetic) reconstruction require the expertise of specialized centers.
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The treatment of children and adolescents with soft tissue sarcoma (STS) consists of a multimodality approach involving surgery, chemotherapy and radiotherapy. The optimal timing and intensity of these three treatment modalities must be planned with regard to the prognostic factors and considering possible late effects of treatment. The multimodality approach according to different strategies and different chemotherapy regimens has been tested in several clinical trials by the Cooperative Weichteilsarkomstudiengruppe (CWS). Improved survival was seen over the last decades. Histology, staging (IRS grouping), nodal involvement, tumor site, tumor size and patients’ age have been identified as major prognostic factors. A group of patients with localized rhabdomyosarcoma (RMS), who can be treated with less intensive treatment (VA alone + radiotherapy), has been selected. The acute and late sequelae of alkylating agents and anthracyclines can be avoided in this group without compromising survival. Local treatment is a fundamental part of RMS, but late effects for young children and adolescents should be taken into account. Regular examinations are recommended for patients to evaluate late effects. Pain in the primary site 5–10 years after therapy warrants investigation for the development of secondary bone tumors. The risk of a second malignant neoplasm should be considered. The main aims are the analyses of incidence, risk factors and prognosis of late effects. Patients registered in CWS guidance SoTiSaR will be included in these projects.
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Forty-two chapters have been structured according to the toxicities in cancer entities, and the late effects and follow-up proposals have been discussed by European and American authors. Cancer diseases in children, adolescents and young adults are treated within specific treatment protocols and can produce different late effects that will have to be cared for by specific follow-up recommendations. Over the last decades, the therapy which was considered the best was used to save patients’ lives. The pattern of toxicities and late effects have changed over time, depending on the treatment protocols used. Rather than delivering standard and conclusive recommendations for survivorship care in all healthcare systems, this book gives an instantaneous picture of the current and fast developing practices, as well as the work in progress. Its common, yet important aim will be to point out the development of harmonized guidelines for cancer survivors that could be implemented in different health-care systems.
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Ototoxicity (i.e., toxic damage to the ear) is a side effect of many drugs that are used in cancer treatment, including anticancer drugs and co-medication such as aminoglycoside antibiotics, glycopeptide antibiotics, macrolides, nonsteroidal anti-inflammatory drugs, loop diuretics, ototopical medication, and cranial irradiation, among others. Aminoglycosides and platinum-based chemotherapy agents are of greatest concern as they often lead to permanent ototoxicity. Ototoxic drugs can have severe short- and long-term effects on patients’ hearing and balance systems, such as impaired speech perception, which impedes language development, psychosocial development, educational attainment, employment prospects, and quality of life. Oncology professionals must balance the benefits of any planned drug treatment against these potential effects. Susceptibility to ototoxic effects is defined by genetic and non-genetic risk factors, such as age or other concomitant ototoxic treatment. Various subjective and objective audiological tests can be used to identify ototoxicity in individual patients, such as pure-tone or play audiometry alongside otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing. The pros and cons of diagnostic audiological practice, treatment options, and current research into otoprotective medication are discussed in this chapter.
Article
STUDY QUESTION Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION The current case–control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE A positive dose–effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9–3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S) This study has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER n/a
Article
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.
Article
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Importance Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. Objective To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. Methods An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. Findings The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. Conclusions and Relevance This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.
Article
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.
Article
Objective: The present systematic review and meta-analysis aimed to analyse the effects of administered interventions on the quality of life of children with cancer in Turkey. Methods: The quantitative studies conducted with paediatric oncology patients, analysing the quality of life of Turkish children, and published papers from 2009 to 2019 were searched. Joanna Briggs Institution MAStARI Experimental and Quasi-Experimental Research Control List and Quality Index were used for methodological assessment. Five studies comprising a total of 264 samples were included. Four studies were nonrandomised controlled trials, and one was a quasi-experimental study. Results: Tests for heterogeneity showed that the studies, which included interventions increasing the quality of life of children with cancer, were heterogeneous. The common effect size of all studies on quality of life was determined as having a strong positive effect. Conclusions: This meta-analysis and systematic review contribute to the knowledge of Turkish health care professionals regarding these interventions by producing results with high levels of evidence on the improvement of the quality of life among children with cancer. The present study also significantly raises awareness and encourages health care professionals to implement interventions for the improvement of quality of life among children with cancer.
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Zusammenfassung Hintergrund und Ziel Ein Drittel der Langzeitüberlebenden nach Krebs im Kindes- und Jugendalter leidet unter schweren Spätfolgen (z. B. Zweittumoren, kardiale Probleme). Am Deutschen Kinderkrebsregister (DKKR) sind ca. 70.000 inzidente Erkrankungsfälle dokumentiert, von denen sich über 41.000 in Langzeitbeobachtung befinden und für Spätfolgenstudien kontaktiert werden können. Diese Kohorte wird beschrieben, die bisher mit dem DKKR durchgeführten Spätfolgenstudien werden charakterisiert, die Teilnahmebereitschaft wird analysiert. Methoden Für die von 1980 bis 2019 mit Krebs diagnostizierten und am DKKR in der Langzeitbeobachtung befindlichen Patienten wurde die Verteilung nach Diagnose, aktuellem Alter, Beobachtungsdauer, Zahl an Zweittumoren zum Stichtag 16.07.2021 ermittelt. Berechnet wurden die Raten derer, die jeweils auf Verlaufsabfragen reagiert haben. Der Einfluss von Determinanten auf die Teilnahmebereitschaft wurde mithilfe von generalisierten Schätzgleichungen geschätzt. Ergebnisse In der Kohorte von 41.466 kontaktierbaren Langzeitüberlebenden sind über 10 % der Betroffenen über 40 Jahre alt, bei über 40 % liegt die Erkrankung über 20 Jahre zurück. Die Teilnahmebereitschaft bei den Befragungen liegt zwischen 30 % und 60 %. Sie ist abhängig vom Alter bei Diagnose, dem Befragungsumfang, der Zahl der zuvor schon durchgeführten Befragungen. Optimal erscheint ein Abstand zwischen Kontaktierungen von mindestens 4 Jahren. Diskussion Mit dieser einzigartigen Kohorte ist eine für Deutschland repräsentative Spätfolgenforschung möglich. Ein geeignetes Maß zu finden, wie häufig Überlebende kontaktiert werden dürfen, ist essenziell. Um nicht zu oft zu kontaktieren, sollte die Zahl der in eine Studie einzubeziehenden Betroffenen jeweils möglichst niedrig gehalten werden.
Article
Dank verbesserter Therapiemöglichkeiten haben sich die Langzeitüberlebensraten der Patienten mit einer Krebserkrankung im Kindes- und Jugendalter in den letzten Jahrzehnten deutlich verbessert. Durch die zur Heilung der Krebserkrankung eingesetzten Therapien können jedoch Folgeerkrankungen bestehen bleiben oder auch viele Jahre nach Therapieende noch Spätfolgen auftreten, die zu einer hohen Morbidität und verminderten gesundheitsbezogenen Lebensqualität der Langzeitüberlebenden führen. Das Auftreten vieler Spätfolgen kann mit einem langen Abstand zum Behandlungsende erfolgen und durch die erhaltene Behandlung und individuelle Risikofaktoren bestimmt werden. Dabei können die Spätfolgen unterschiedliche Organe oder auch psychische Bereiche betreffen und von leichten Störungen bis zu lebensbedrohlichen Erkrankungen reichen. Am Beispiel von Zweittumoren sowie endokrinologischen und kardialen Erkrankungen wird auf das Thema Langzeitnachsorge in diesem Beitrag eingegangen. Ferner wird die Thematik Transition und neue Versorgungsstrukturen im In- und Ausland beschrieben, da die meisten Patienten zum Zeitpunkt des Auftretens der Spätfolgen bereits erwachsen sind und sich nicht mehr in regelmäßiger pädiatrisch-onkologischer Betreuung befinden. Mithilfe der neuen Versorgungsstrukturen sollen die Personen, die noch nie über ihr Risiko für Folgeerkrankungen aufgeklärt wurden, adaptierte Nachsorgeinformationen und einen Nachsorgeplan erhalten. Diese neuen Versorgungsstrukturen werden die derzeit bestehende Versorgungslücke schließen.
Article
The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are pre‐pubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for pre‐pubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for pre‐pubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.
Article
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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.
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Introduction The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. Methods A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. Results Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. Conclusion Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.
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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.
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Background Hearing loss is a potential late effect after childhood cancer. Questionnaires are often used to assess hearing in large cohorts of childhood cancer survivors and it is important to know if they can provide valid measures of hearing loss. We therefore assessed agreement and validity of questionnaire-reported hearing in childhood cancer survivors using medical records as reference. Procedure In this validation study, we studied 361 survivors of childhood cancer from the Swiss Childhood Cancer Survivor Study (SCCSS) who had been diagnosed after 1989 and had been exposed to ototoxic cancer treatment. Questionnaire-reported hearing was compared to the information in medical records. Hearing loss was defined as ≥ grade 1 according to the SIOP Boston Ototoxicity Scale. We assessed agreement and validity of questionnaire-reported hearing overall and stratified by questionnaire respondents (survivor or parent), sociodemographic characteristics, time between follow-up and questionnaire and severity of hearing loss. Results Questionnaire reports agreed with medical records in 85% of respondents (kappa 0.62), normal hearing was correctly assessed in 92% of those with normal hearing (n = 249), and hearing loss was correctly assessed in 69% of those with hearing loss (n = 112). Sensitivity of the questionnaires was 92%, 74%, and 39% for assessment of severe, moderate and mild bilateral hearing loss; and 50%, 33% and 10% for severe, moderate and mild unilateral hearing loss, respectively. Results did not differ by sociodemographic characteristics of the respondents, and survivor- and parent-reports were equally valid. Conclusions Questionnaires are a useful tool to assess hearing in large cohorts of childhood cancer survivors, but underestimate mild and unilateral hearing loss. Further research should investigate whether the addition of questions with higher sensitivity for mild degrees of hearing loss could improve the results.
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Background: Fertility preservation care for children, adolescents, and young adults (CAYAs) with cancer is not uniform among practitioners. To ensure high-quality care, evidence-based clinical practice guidelines (CPGs) are essential. The authors identified existing CPGs for fertility preservation in CAYAs with cancer, evaluated their quality, and explored differences in recommendations. Methods: A systematic search in PubMed (January 2000-October 2014); guideline databases; and Web sites of oncology, pediatric, and fertility organizations was performed. Two reviewers evaluated the quality of the identified CPGs using the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II). From high-quality CPGs, the authors evaluated concordant and discordant areas among the recommendations. Results: A total of 25 CPGs regarding fertility preservation were identified. The average AGREE II domain scores (scale of 0%-100%) varied from 15% on applicability to 100% on clarity of presentation. The authors considered 8 CPGs (32%) to be of high quality, which was defined as scores ≥60% in any 4 domains. Large variations in the recommendations of the high-quality CPGs were observed, with 87.2% and 88.6%, respectively, of discordant guideline areas among the fertility preservation recommendations for female and male patients with cancer. Conclusions: Only approximately one-third of the identified CPGs were found to be of sufficient quality. Of these CPGs, the fertility preservation recommendations varied substantially, which can be a reflection of inadequate evidence for specific recommendations, thereby hindering the ability of providers to deliver high-quality care. CPGs including a transparent decision process for fertility preservation can help health care providers to deliver optimal and uniform care, thus improving the quality of life of CAYAs with cancer and cancer survivors. Cancer 2016;122:2216-23. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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Purpose: Many adolescent and young adult (AYA) cancer survivors place great importance on fertility. This study explored AYAs' discussions of fertility in the context of discussing their survivorship experiences. Methods: Secondary analyses of a qualitative study of young adult survivors of adolescent cancers ("AYA survivors") was performed using semistructured individual interviews and focus groups. Analyses were conducted using grounded theory using thematic content analysis with an inductive data-driven approach. Results: Participants (n = 43) were 16-24 years old, diagnosed with cancer between ages 14 and 18 years, and were at least 6 months post-treatment. Before treatment, 5 males banked sperm and no females preserved fertility. More males (50%) than females (39%) reported uncertainty about their fertility. Three major categories emerged from the data: fertility concerns, emotions raised when discussing fertility, and strategies used to manage fertility concerns. Fertility concerns focused on dating/partner reactions, health risks, and what potential infertility would mean for their life narrative. Emotions included distress, feeling overwhelmed and hopeful/wishful thinking. Females were more likely to feel distressed and overwhelmed than males. Strategies to manage concerns included acceptance/"making do," desire to postpone concerns, and reliance on assisted reproductive technology. Conclusions: Most AYAs in our study reported a number of reproductive concerns and fertility-related distress after treatment, which may affect other areas of psychosocial functioning. Females may be more at-risk for distress than males, particularly in situations of uncertainty and limited knowledge. Future work should explore how to best incorporate fertility-related informational and support services more fully into survivorship care. Implications for survivorship care are discussed.
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STUDY QUESTION Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer?
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For many childhood cancer survivors follow-up care is important long after treatment completion. We aimed to describe the availability and characteristics of long-term follow-up programs (LTFU) across Europe, their content and aims, their problems, and to assess opinions on different models of LTFU. We asked 179 pediatric oncology institutions in 20 European countries to complete an online survey on LTFU available at their institution. Of 110 respondents (62% response), 66% reported having LTFU for pediatric survivors, 38% for adult survivors of childhood cancer. Availability varied widely across European regions, from 9% of institutions in Northern Europe reporting LTFU for adult survivors to 83% of institution on the British Isles reporting LTFU for pediatric survivors. Pediatric and adult LTFU were usually located in pediatric hospitals and run by pediatric oncologists. Content of follow-up included screening for adverse outcomes and health education. Important problems included lack of time, personnel and funding. Most institutions without LTFU reported that they would like to offer a program (86%). Despite general agreement on the need of follow-up care, there is still a lack of well-organized LTFU for survivors of childhood cancer across Europe.
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BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin's lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin's lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of >30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin's lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.
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Although physician discussion with patients regarding fertility preservation (FP) options prior to cancer treatment can provide important information for survivors concerning their future fertility, little is known about the extent to which physicians discuss FP with patients. This qualitative study sought to identify current physician FP communication practices and determine factors that may impact communication efforts regarding FP. Qualitative data were collected using semi structured interviews with 16 physicians practicing at a major cancer center in the South. All providers were board certified in medical oncology, radiation oncology or surgical oncology. The main factors that emerged from qualitative analysis included distinct variations in quality of discussion about FP, knowledge of FP resources, attitudes, practice behaviors and perceptions of patient characteristics. While most physicians discussed potential fertility loss as a side effect of cancer treatment, few provided information to patients about preserving fertility. Patient characteristics such as gender and cancer site may impact the discussion, as well as system factors such as costs of procedures and access to FP resources. Education and training for physicians about FP options for cancer patients, particularly females, may promote discussion of FP. In addition, system barriers related to availability and affordability of FP resources must also be addressed. Physicians should consider providing patients with timely, understandable information related to their FP options, prior to the administration of treatment. Such discussions may lead to improved quality of life for individuals as they transition from patients to survivors.
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We used data from the first large-scale overwhelmingly population-based study (a) to quantify the risk of adverse pregnancy outcomes in survivors of childhood cancer in relation to cancer type and treatment and (b) to assess live birth rates relative to the general population. A questionnaire, including questions inquiring about pregnancy outcomes, was completed by 10,483 survivors. A total of 7,300 pregnancies were reported. Odds ratios (OR) for live birth, miscarriage, termination, stillbirth, premature birth, and low birth weight were calculated for different types of childhood cancer and by whether initial treatment involved chemotherapy and abdominal or brain irradiation. For females, the observed number of live births was compared with that expected based on the general population of England and Wales. Female survivors exposed to abdominal irradiation had a significantly increased OR of delivering preterm [OR, 3.2; 95% confidence interval (95% CI), 2.1-4.7] and producing offspring with a low birth weight (OR, 1.9; 95% CI, 1.1-3.2). An increased OR of miscarriage was also associated with abdominal radiotherapy (OR, 1.4; 95% CI, 1.0-1.9). The number of live births observed from all female survivors was two thirds of that expected (O/E, 0.64; 95% CI, 0.62-0.66) and lowest among survivors treated with brain (O/E, 0.52; 95% CI, 0.48-0.56) and abdominal radiotherapy (O/E, 0.55; 95% CI, 0.50-0.61). Female survivors of childhood cancer treated with abdominal radiotherapy are at 3-fold increased risk of delivering preterm, 2-fold increased risk of low birth weight, and a small increased risk of miscarriage. Overall, female survivors produce considerably fewer offspring than expected, particularly those treated with abdominal or brain radiotherapy.
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Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. To assess the total burden of adverse health outcomes (clinical or subclinical disorders ["adverse events"]) following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. Retrospective cohort study of 1362 five-year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and 1996. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease (> or =2 severe or > or =1 life-threatening or disabling adverse events) associated with various treatments. Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2.18 [95% confidence interval, 1.62-2.95] and 0.65 [95% confidence interval, 0.46-0.90], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors.
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In female cancer survivors, the accelerated loss of primordial follicles as a result of gonadal damage may lead to premature ovarian failure (POF). However, the extent of the damage is unpredictable. Anti-Müllerian hormone (AMH) constitutes a sensitive marker of ovarian reserve. Serum AMH levels were measured to assess sub-clinical ovarian damage in patients treated with gonadotoxic therapy. In 25 patients with haematological malignancies, serum AMH concentrations were measured prior to and after cancer therapy and were compared with normo-ovulatory controls. In all patients, AMH concentrations were lower than controls prior to treatment. Thirteen patients were treated with multi-drug chemotherapy. Although in most patients treated with chemotherapy menstrual cyclicity was restored, median serum AMH levels were lower than in controls. Twelve patients had stem cell transplantation (SCT) after total body irradiation. They all developed POF and their serum AMH concentrations were undetectable. Female cancer survivors treated with SCT all developed POF. Hence, in these patients fertility preservation should be considered. In patients treated with chemotherapy, ovarian reserve seems to be compromised as well.
Article
Study question: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? Summary answer: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. What is known already: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. Study design, size, duration: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. Participants/materials, setting, methods: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. Main results and the role of chance: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. Limitations, reasons for caution: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. Wider implications of the findings: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. Study funding/competing interests: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. Trial registration number: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.
Article
Background Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. Methods We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. Results A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin–sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin–sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin–sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. Conclusions The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007-002402-21.)
Article
Purpose: To describe fecundity in female survivors of childhood cancer and consider the correlation with quality of life (QOL). Materials and methods: Of 1744 women treated for childhood cancer before the age of 15 years at one of eight French cancer treatment centers between 1948 and 1992, 1187 who were alive in 2005 were sent a self-administered questionnaire, including questions about health status, QOL (MOS SF-36), and fecundity. A standardized fecundity ratio (SFR) was calculated (SFR: observed/expected number of children) for each individual based on a national reference. Results: Of the 972 individuals (82%) who responded, 53% had at least 1 child. The overall SFR, 0.65, was dependent upon the initial diagnosis, more decreased in Central Nervous System tumors (0.24; p < 10-3) than in Germ cell (0.46; p = 0.03) or Sympathetic Nervous System tumors (0.79; p = 0.02). The average QOL motor score was 72.5 ± 19.5, and the average mental score was 61.4 ± 16.7. After adjusting for age, pathology, and self-reported sequelae in the questionnaires, it was determined that SF-36 mental (p = 0.002) and motor (p < 0.0002) scores correlated positively with fecundity, and SF-36 scores correlated negatively with locomotor late effects (p < 0.0001), growth insufficiency (p = 0.002), and psychological disorders (p < 0.001). Gonadal insufficiency was correlated with neither motor nor mental scores. Conclusion: Women treated for childhood cancer demonstrated impaired fecundity that correlated with poor QOL, as registered by the SF-36. Patients should be warned of the risk of impaired fecundity early during the follow-up. If possible, preservation of fertility should be prioritized at initiation of therapy.
Article
Objective: Childhood cancer survivors (CCS) treated with platinum-based chemotherapy are at risk of treatment-induced ototoxicity. To date, there is limited knowledge on the effect of ototoxicity on socio-demographic factors, the burden to obtain insurances and psychological distress in CCS. Design: Of the 653 CCS with completed questionnaires, 54 survivors had been treated with platinum. Ototoxicity (Münster score ≥ 2b) data were retrieved from pure-tone audiometry. All survivors completed a questionnaire consisting of the Distress Thermometer (DT), measuring the severity of distress and was recoded to a 0 (no distress)-10 (extreme distress) scale. The Hospital Anxiety and Depression Scale (HADS) was used to study the psychological distress (a score ≥ 15 is indicative for clinically significant distress). Results: Median age at diagnosis was 6.2 years (range: 0.01-17.8) and median follow-up time from end of treatment to questionnaire was 15.6 years (range: 3.2-43.7). There were no differences in attempts to obtain insurances, highest education achievement and (un) employment between platinum-treated survivors and non-platinum treated survivors. Among the 54 platinum-treated CCS, median HADS score of hearing impaired survivors (n=22 (median score: 4.5, range: 0.0-29)) was not significantly different from survivors without ototoxicity (n=32 (median score 5.5, range: 0.0-11, p=0.337)). Similarly, DT scores were not significantly different between survivors with or without ototoxicity (p=0.441). Compared to the 599 non-platinum treated survivors, median HADS and DT scores of platinum-treated survivors were not significantly different. Conclusion: Based on this first, small study, we didn't find differences between CCS who suffer from platinum-related ototoxicity and survivors without hearing impairment, suggesting that CCS with ototoxicity do not necessarily encounter more socio-demographic challenges and psychological distress than CCS without ototoxicity.
Article
Background: Full audiological monitoring is the best strategy to detect hearing loss early and to provide timely intervention in the absence of a clinical method of otoprotection. Full monitoring requires audiological evaluation before, and then during and after ototoxic cancer treatment. In a worldwide context of monitoring protocols that vary substantially, we analyzed the audiological monitoring of childhood cancer patients over the last decade across treatment centers in Switzerland. Procedure: We retrospectively searched for audiological evaluations in all nine Swiss Pediatric Oncology Centers. We analyzed proportions of patients who had audiological monitoring and described type and timing of monitoring. We determined predictors of audiological monitoring using multivariable logistic regression and described time trends. Results: We included 185 patients from the Swiss Childhood Cancer Registry diagnosed 2005-2013 who had platinum chemotherapy and/or cranial radiation ≥30 Gray and who were alive at time of study. Less than half of children, 43%, had full audiological monitoring (before, during, and after treatment), while 72% were tested after cancer treatment. Non-study patients were less likely to have had monitoring in all phases of cancer treatment. Patients who received treatment with cisplatin or both platinum chemotherapy and cranial radiation were more likely to have had monitoring after treatment. Monitoring during and after treatment increased over the study period, but monitoring before treatment was insufficient in all time periods. Conclusions: Our population-based study indicates that audiological monitoring is insufficient in Switzerland, particularly for non-study patients. Clinicians’ must become more aware of the importance of full audiological monitoring.
Article
Purpose: To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (Dmean), and total cisplatin dose. Material and methods: In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. Results: Bilateral high-frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p < 0.05) was found after tomotherapy at the 6 kHz bone-conduction threshold (BCT) and left-sided 8 kHz air-conduction threshold (ACT) than after a combined radiotherapy technique (CT). Fraction dose was not found to have any impact on the incidence, degree, and time-to-onset of SNHL. Patients treated with CT had a greater risk of SNHL at high frequencies than tomotherapy patients even though Dmean was similar. Increase in severity of SNHL was seen when the total cisplatin dose reached above 210 mg/m(2), with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. Conclusion: The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when Dmean exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies.
Article
Study question: Is the long-term decline of ovarian function, as reflected by a decrease in serum anti-Müllerian hormone (AMH) concentration, accelerated over time in female childhood cancer survivors (CCS) as compared to healthy women of the same age? Summary answer: The median decline of AMH levels in long-term female CCS is not accelerated and similar to that observed in healthy controls. What is known already: Gonadal function is compromised in female CCS treated with chemotherapy and/or radiation therapy. Ovarian function is most compromised in survivors treated with total body irradiation, abdominal or pelvic irradiation, stem cell transplantation or high doses of alkylating agents. Study design size, duration: Longitudinal single-centre cohort study in 192 CCS in Rotterdam, The Netherlands, between 2001 and 2014. Participants/materials, setting, methods: Serum AMH levels of 192 adult female CCS were assessed, at least five years after cessation of treatment and at a follow-up visit with a median of 3.2 years (range: 2.1-6.0) later and were compared to the age-based P50 of AMH in healthy controls. Main results and the role of chance: Median AMH levels were below the P50 at both visit 1 (-0.59 µg/L) and at visit 2 (-0.22 µg/L). In women with a sustained ovarian function (AMH > 1.0 µg/L), the decline in AMH is similar to that in the normal population (difference in decline per year: -0.07 µg/L (range: -2.86 to 4.92), P = 0.75). None of the treatment modalities was correlated with a significant acceleration of decline of AMH per year. Limitations reasons for caution: We selected CCS that visited our late effect outpatient clinic and who had two AMH levels available. It is conceivable that women without any apparent late effects of treatment as well as women with extreme late effects, which might be the ones with the largest impact on ovarian function, could be more likely to be lost to follow-up. However, general characteristics did not differ between the included and excluded patients. Wider implications of the findings: While prospective longitudinal research is required to strengthen our findings, they may help physicians to counsel female CCS about their expected reproductive lifespan. Study funding/competing interests: A.L.F.v.d.K., M.M.v.d.H.-E. and S.M.F.P. are supported by FP7-PanCare LIFE. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. The other authors have no conflicts of interest to declare.
Article
Background: Auditory complications are an adverse event of childhood cancer treatment, especially common in children treated with platinum chemotherapy or cranial radiation. Variation between diagnostic childhood cancer groups has rarely been studied, and we do not know if the burden of auditory complications has changed over the last decades. Procedure: Within the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to all survivors who were diagnosed at age 16 years or less between 1976 and 2005. We compared prevalence of self-reported hearing loss and tinnitus between all diagnostic childhood cancer groups and siblings, used multivariable logistic regression to analyze the effect of treatment-related factors on hearing loss, and compared the cumulative incidence of hearing loss between different periods of cancer diagnosis. Results: Prevalence of self-reported hearing loss was higher in survivors (10%) than in siblings (3%, P < 0.001), and highest in survivors of central nervous system tumors (25%). Significant risk factors were treatment with platinum compounds (carboplatin: odds ratio [OR] 2.4; cisplatin: OR 9.4), cranial radiation (>29 Gy: OR >1.7), or brain surgery (OR 2.2). Children diagnosed in 1986-1995, when platinum compounds came into widespread use, had a significantly higher cumulative incidence of hearing loss than those diagnosed in 1976-1985. In the most recent period, 1996-2005, the risk decreased again, both for patients treated with platinum compounds and with cranial radiation. Conclusions: Our data show that the burden of hearing loss has stabilized in recently treated survivors, suggesting that survivors have benefited from new treatment regimens that use less ototoxic radiation and more carefully dosed platinum compounds.
Article
BACKGROUND Young adult female cancer survivors have unmet reproductive concerns and informational needs that are associated with poorer quality of life. The purpose of this study was to examine the association between current reproductive concerns and moderate to severe depression among young survivors.METHODS This cross-sectional study included 200 female cancer survivors between the ages of 18 and 35 years who completed a Web-based survey measuring reproductive history, parenthood desires, reproductive concerns after cancer, and quality-of-life indicators.RESULTSThe mean age of the participants was 28 years (standard deviation, 4.4 years), and almost two-thirds were diagnosed within 5 years of survey completion. A multivariate logistic regression analysis controlling for education, duration of survivorship, and social support revealed an association between experiencing reproductive concerns and moderate to severe depression (odds ratio for each 5-unit increase in the Reproductive Concerns After Cancer [RCAC] score, 1.30; 95% confidence interval, 1.06-1.60). Among those with moderate to severe depression, 23% had high RCAC scores, whereas 6% of those with minimal to mild depression did (P < .001).CONCLUSIONSA higher level of reproductive concerns was associated with greater odds of experiencing moderate to severe depression. Almost a quarter of survivors in this sample reported moderate to severe depression, and addressing reproductive concerns represents one potential area of intervention for improving the psychosocial health of young survivors. Cancer 2014. © 2014 American Cancer Society.
Article
Background Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe.ProceduresOn behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation.ResultsOne hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions.Conclusions There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility. Pediatr Blood Cancer 2014;9999:1–5. © 2014 Wiley Periodicals, Inc.
Article
Introduction The influence of specific health problems on health-related quality of life (HRQoL) in childhood cancer survivors is unknown. We compared HRQoL between survivors of childhood cancer and their siblings, determined factors associated with HRQoL, and investigated the influence of chronic health problems on HRQoL. Methods Within the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to all survivors (≥16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976–2005 aged <16 years. Siblings received similar questionnaires. We assessed HRQoL using Short Form-36 (SF-36). Health problems from a standard questionnaire were classified into overweight, vision impairment, hearing, memory, digestive, musculoskeletal or neurological, and thyroid problems. Results The sample included 1,593 survivors and 695 siblings. Survivors scored significantly lower than siblings in physical function, role limitation, general health, and the Physical Component Summary (PCS). Lower score in PCS was associated with a diagnosis of central nervous system tumor, retinoblastoma or bone tumor, having had surgery, cranio-spinal irradiation, or bone marrow transplantation. Lower score in Mental Component Summary was associated with older age. All health problems decreased HRQoL in all scales. Most affected were survivors reporting memory problems and musculoskeletal or neurological problems. Health problems had the biggest impact on physical functioning, general health, and energy and vitality. Conclusions In this study, we showed the negative impact of specific chronic health problems on survivors’ HRQoL. Implications for Cancer Survivors Therapeutic preventive measures, risk-targeted follow-up, and interventions might help decrease health problems and, consequently, improve survivors’ quality of life.
Article
Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients' quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized.
Article
High frequency hearing loss following cisplatin chemotherapy is frequent in children and often necessitates the fitting of hearing aids. During therapy, hearing is usually monitored. Post-therapeutic follow-up does not routinely include monitoring of hearing, although there are indications that hearing thresholds can decline after therapy. Pure-tone audiograms taken from 27 children (17 males, 10 females) treated with cisplatin at Muenster university hospital (mean age 9.84 years, standard deviation 3.67 years) including an audiological follow-up at least 6 months after therapy, were analyzed retrospectively. In follow-up tests after completion of therapy, 24.1% of all ears showed an increase in mean high frequency hearing thresholds (4-8 kHz). Post-therapeutic hearing deterioration was significant at 4 kHz and significantly more pronounced in children without measurable spontaneous otoacoustic emissions (SOAE) before therapy. Post-therapeutic hearing deterioration did not occur in ears with normal pure tone thresholds (≤ 10dB at all frequencies) after cisplatin therapy. No correlation was found between post-therapeutic hearing deterioration and cranial irradiation. Cisplatin chemotherapy follow-up should include audiological monitoring in all children with elevated pure tone thresholds after therapy. Routine SOAE measurements taken as part of baseline audiometry before the start of chemotherapy can be taken into consideration.
Article
Gonadal function decades after treatment for childhood lymphoma (CL) is not well described. This cross-sectional study had two aims: (1) describe long-term gonadal function and fertility in childhood lymphoma survivors (CLSs), and (2) explore anti-Mullerian hormone (AMH) as a measure of ovarian function in CLSs. Seventy-four male and 62 female CLSs participated in a survey consisting of a questionnaire, clinical examination, and blood/semen analysis. Prior treatment was categorized according to gonadotoxicity. Hypogonadism was determined by levels of gonadal hormones based on luteinizing hormone, follicle-stimulating hormone, testosterone (males), AMH (females <40 years), and menstrual status. Fertility was explored according to pregnancies achieved, semen analysis, and AMH. Hypogonadism was observed in 7 of 66 males (11%). Seven of 64 males (11%) were categorized as infertile. Nine of 45 females <40 years (20%) were at risk to develop premature ovarian failure (POF). Twenty of 45 females (44%) showed low-AMH levels indicating decreased fertility. Four "critically low" females reported pregnancies within the preceding 2 years. Sixty-four percent of the males and 93% of the females attempting parenthood had been successful (P = 0.01). Hypogonadism and low-AMH were related to treatment burden. Twenty years after treatment of CL, female CLSs' attempts of pregnancy initiation are mostly successful, while males seem at higher risk of infertility. Hypogonadism is a problem in 10% of the male CLSs. Based on AMH levels, POF is a risk in 20% of the female CLSs. The clinical significance of AMH reflecting true probability of fertility needs further research in cancer survivors.
Article
Fertility can be impaired by radiation and chemotherapy among childhood cancer survivors. Therefore, timely and adequate patient counselling about the risk of infertility and preservation methods is needed. The primary study objective was to assess remembered counselling among childhood cancer survivors. As a second objective, the impact of lacking patient counselling on offspring-related attitudes and behaviour was examined. Counselling regarding the late effects of gonadotoxicity that could be recalled by patients was assessed using a questionnaire sent by the German Childhood Cancer Registry. The questionnaire was answered by 2754 adult childhood cancer survivors (53.1% female, mean = 25.7 years). The proportion of patients who could not remember patient counselling about the late effects of chemo-/radiotherapy on fertility decreased significantly over time. In 1980 to 1984 67%, in 2000 to 2004 50% of the patients reported no memories of counselling (p < .001). Counselled patients feared significantly less that their children may have an increased cancer risk (4.4% vs. 6.7%, p = .03). They were also more likely to undergo fertility testing than patients who could not recall counselling (odds ratio = 2.91, 95% confidence interval [2.12, 3.99]). Patients reported an increased memory of patient counselling over the past 25 years. Still, a 50% rate of recalled counselling shows an ongoing need for adequate and especially sustainable counselling of paediatric cancer patients about infertility and other long-term adverse treatment effects. Those who reported a lack of counselling had offspring-related fears more frequently, which stopped them from having children.
Article
High survival rates after childhood cancer raise attention to possible psychosocial late effects. We focus on predictors of psychosocial outcomes based on diagnosis, treatment, demography, somatic disease, and methodological problems. Overall, survivors evaluate their health-related quality of life to be normal or even better than controls, although virtually all diagnostic subgroups report psychosocial impairment. Central nervous system tumor survivors have significant psychosocial problems. Negative outcomes were associated with cranial radiation therapy, female gender, and young age at diagnosis. Significant methodological problems hamper current knowledge. Systematic registration of psychosocial and somatic problems at diagnosis and prospectively through protocols is needed.
Article
Low levels of awareness about hereditary breast cancer and ovarian cancer and underutilization of genetic services combined with the high incidence of early onset breast cancer in the black community underscore the urgent need to provide information about hereditary breast and ovarian cancer to black women. The primary goal of the present study was to develop a culturally targeted brochure designed to increase awareness about inherited breast cancer among black women using the principles of Learner Verification. Three focus groups were conducted with black women, including those with or without a history of breast cancer (n = 46), to evaluate the brochure. Data were analyzed through hand coding using a simple classification system placing participants' responses in the predetermined Learner Verification categories. On the basis of the feedback obtained, the brochure has been modified to improve cultural-targeting, relevance, and clarity and has been made available for dissemination. Our study illustrates the importance of obtaining feedback from the target audience when developing a culturally targeted informational brochure for black women. Further, the complexity of our subject matter (i.e., inherited breast and ovarian cancer) underscores the importance of using inviting visuals and personal vignettes, while maintaining a simple and clear message.
Article
To assess the long-term ototoxicity effect of platinum chemotherapy in a series of pediatric patients. A prospective cohort study. Patients who received platinum chemotherapy were identified through review of the pharmacy records from 2000 to 2005. Audiograms pre- and post-treatment with cisplatin were noted. The patients were brought back long after treatment for a repeat audiogram and a questionnaire to assess the impact of ototoxicity on their quality of life. Forty-nine patients received platinum chemotherapy. Patients' exclusion: two had no pre-chemo audiograms, one had retinoblastoma with congenital hearing loss, three were lost to follow up, five deceased, and seven refused participation. The total number of patients included was 31 with long-term follow up total of 21 patients. The follow up period ranged from 1.5 to 6.6 years (median of 3.4 years). Fourty-two percent (13/31) of the patients suffered from otoxicity (3 mild, 3 moderate, 7 severe-profound). Thirty-three (7/21) of audiograms worsened on long-term follow up. Questionnaire revealed 70% subjective hearing loss with 40% requiring hearing aids. Ototoxicity after platinum chemotherapy can present or worsen years after completion of therapy. Therefore, we recommend long-term follow up.
Article
The present contribution reports childhood cancer incidence and survival rates as well as time trends and geographical variation. The report is based on the databases of population-based cancer registries which joined forces in cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE. According to these data, which refer to the International Classification of Childhood Cancer, leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, represent the largest diagnostic groups among the under 15-year-olds. The most frequent single diagnoses are: acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the mid of the last century. In Europe, the yearly increase averages 1.1% for the 1978-1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas. The probability of survival has risen considerably over the past decades, with the EUROCARE data showing an improvement of the relative risk of death by 8% when comparing the 2000-2002 time span to the 1995-1999 period. Regarding the years 1995-2002, the data show an overall 5-year survival probability of 81% for Europe and similar values for the USA. The data presented here describe the cancer situation with a specific, European focus. They are drawn from population-based cancer registries that ensure excellent data quality, and as a consequence represent the most valid European population-based data existing at present. It is also apparent that not all countries have data available from nationwide childhood cancer registries, a situation which warrants further improvement.
Article
The introduction of multi-agent chemotherapy dramatically improved the outcome for patients with osteosarcoma. However, we appear to have reached a plateau in outcome with a long-term event-free survival of 60-70%. Therefore, detection of further improvements will likely require larger numbers of patients. This goal is best achieved via randomized clinical trials (RCTs) requiring large-scale cooperation and collaboration. With this background, four multinational groups agreed on the merits of collaboration: Children’s Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG); they designed a study to determine whether altering postoperative therapy based on histological response improved the outcome. The study design includes a backbone of 10 weeks of preoperative therapy using MAP (methotrexate, Adriamycin and cisplatin). Following surgery, patients are stratified according to histological response. Patients classified as “good responders” (≥90% necrosis) are randomized to continue MAP or to receive MAP followed by maintenance pegylated interferon, while “poor responders” (<90% necrosis) are randomized to either continue MAP or to receive MAPIE (MAP+ifosfamide, etoposide). The design includes the registration of 1,400 patients over 4 years as well as the evaluation of quality of life using two different instruments. The group has established an efficient infrastructure to ensure successful implementation of the trial. This has included the EURAMOS Intergroup Safety Desk, which has established an international system for SAE, SAR and SUSAR reporting to the relevant competent authorities and ethics committees for each participating country. The group has also developed trial site monitoring and data center audits with funding from the European Science Foundation (ESF). The ESF has also funded three training courses to familiarize institutional staff with the requirements of multinational GCP trials. We have established a successful collaboration, and as of February 2008, 901 patients have been enrolled (COG 448; COSS 226; EOI 181; SSG 46) from 249 institutions in 16 different countries. As expected, 80% of the patients are <18 years of age, and accrual into the Quality of Life sub-study is proceeding as planned with 90% of the subjects agreeing to participate. International awareness is increasing and procedures for applicant countries wishing to join the collaboration have been implemented. Details about EURAMOS can be found at www. euramos. org. International trials in rare diseases are practicable with appropriate funding, planning and support. Although the implementation of such trials is difficult and time consuming, it is a worthwhile effort to rapidly complete RCTs and identify interventions that will improve the outcome of all osteosarcoma patients.EURAMOS-1 is the fastest accruing osteosarcoma trial and is already the largest osteosarcoma study conducted.
Article
Background: Little is known about the longitudinal course of health-related quality of life (HRQoL) in patients with Hodgkin's lymphoma during their post-treatment follow-up and re-adaptation to normal life. We report on the HRQoL of patients treated in the randomised H8 trial of the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess HRQoL and fatigue following treatment, to analyse relations with treatment, and to identify factors that predict persistent fatigue. Methods: Patients received HRQoL questionnaires at the end of primary therapy and during follow-up. The EORTC QLQ-C30 was used to assess HRQoL, and the Multidimensional Fatigue Inventory (MFI-20) was used to assess fatigue. Changes of mean HRQoL scores over time were analysed with mixed models. Multiple polytomic nominal logistic regression was done to identify independent baseline predictors of fatigue within MFI-20 dimensions. Analyses were done on an intention-to-treat basis. This study is registered with www.ClinicalTrials.gov, number NCT00379041. Findings: 2666 assessments from 935 patients were analysed. Mean follow-up was 90 months (range 52-118). Age affected all functioning and symptom scores except emotional functioning, with younger age associated with higher functioning and lower severity of symptoms; improvement with time showed similar patterns between age groups. Women reported lower HRQoL and higher symptom scores than did men. Overall, 3.2% (14/439 for role functioning) to 9.7% (43/442 for social functioning) and 5.8% (29/498 for reduced motivation) to 9.9% (49/498 for general fatigue) of patients reported impairments of 10 points or more (on a 0-100 scale) in QLQ-C30 and MFI-20 scores, respectively, independent of age and sex. Emotional domains were more affected than physical ones. There was no relation between HRQoL outcome and type of treatment. Fatigue (MFI-20 scores) at the end of treatment was the only predictive variable for persistent fatigue, with odds ratios varying from 2.58 (95% CI 1.00-6.67) to 41.51 (12.02-143.33; p</=0.0001). Sensitivity analyses adjusting for missing data were much the same as the main results. Interpretation: HRQoL data after treatment for early-stage Hodgkin's lymphoma show that patients experience strain and limitations in all subdomains apart from cognitive functioning (QLQ-C30), and also have reduced motivation (MFI-20). Differences in HRQoL improvement with time were linked to age and sex, but not type of treatment. Fatigue status at the end of treatment seems to predict subsequent HRQoL. Funding: French Ministry of Health, Programme Hospitalier de Recherche Clinique 1994, and French National League Against Cancer.
Article
To review and summarize current evidence on the health consequences of premature menopause and early menopause. We reviewed existing literature and combined graphically some results from the Mayo Clinic Cohort Study of Oophorectomy and Aging. Premature menopause or early menopause may be either spontaneous or induced. Women who experience premature menopause (before age 40 years) or early menopause (between ages 40 and 45 years) experience an increased risk of overall mortality, cardiovascular diseases, neurological diseases, psychiatric diseases, osteoporosis, and other sequelae. The risk of adverse outcomes increases with earlier age at the time of menopause. Some of the adverse outcomes may be prevented by estrogen treatment initiated after the onset of menopause. However, estrogen alone does not prevent all long-term consequences, and other hormonal mechanisms are likely involved. Regardless of the cause, women who experience hormonal menopause and estrogen deficiency before reaching the median age of natural menopause are at increased risk for morbidity and mortality. Estrogen treatment should be considered for these women, but may not eliminate all of the adverse outcomes.
Article
We attempted to investigate the risk of early menopause after treatment for cancer during childhood or adolescence. We interviewed 1067 women in whom cancer was diagnosed before age 20, who were at least 5-year survivors, and who were still menstruating at age 21. Self-reported menopause status in survivors was compared with that in 1599 control women. Cancer survivors, with disease diagnosed between ages 13 and 19, had a risk of menopause four times greater than that of controls during the ages 21 to 25; the risk relative to controls declined thereafter. Significantly increased relative risks of menopause during the early 20s occurred after treatment with either radiotherapy alone (relative risk 3.7) or alkylating agents alone (relative risk 9.2). During ages 21 to 25 the risk of menopause increased 27-fold for women treated with both radiation below the diaphragm and alkylating agent chemotherapy. By age 31, 42% of these women had reached menopause compared with 5% for controls. Treatment for cancer during adolescence carries a substantial risk for early menopause among women still menstruating at age 21. Increasing use of radiation and chemotherapy, together with the continued trend toward delayed childbearing, suggests that these women should be made aware of their smaller window of fertility so that they can plan their families accordingly.
Article
In a retrospective cohort study of survivors of cancer and of controls, we estimated the risk of infertility after treatment for cancer during childhood or adolescence. We interviewed 2283 long-term survivors of childhood or adolescent cancer diagnosed in the period from 1945 through 1975, who were identified at five cancer centers in the United States. Requirements for admission to the study were diagnosis before the age of 20, survival for at least five years, and attainment of the age of 21. In addition, 3270 controls selected from among the survivors' siblings were interviewed. Cox regression analysis showed that cancer survivors who married and were presumed to be at risk of pregnancy were less likely than their sibling controls to have ever begun a pregnancy (relative fertility, 0.85; 95 percent confidence interval, 0.78 to 0.92). Radiation therapy directed below the diaphragm depressed fertility in both sexes by about 25 percent. Chemotherapy with alkylating agents, with or without radiation to sites below the diaphragm, was associated with a fertility deficit of about 60 percent in the men. Among the women, there was no apparent effect of alkylating-agent therapy administered alone (relative fertility, 1.02) and only a moderate fertility deficit when alkylating-agent therapy was combined with radiation below the diaphragm (relative fertility, 0.81). Relative fertility in the survivors varied considerably according to sex, site of cancer, and type of treatment; these factors should be taken into consideration in counseling survivors about the long-term consequences of disease.
Article
This study was designed to determine the prevalence of minimal sensorineural hearing loss (MSHL) in school-age children and to assess the relationship of MSHL to educational performance and functional status. To determine prevalence, a single-staged sampling frame of all schools in the district was created for 3rd, 6th, and 9th grades. Schools were selected with probability proportional to size in each grade group. The final study sample was 1218 children. To assess the association of MSHL with educational performance, children identified with MSHL were assigned as cases into a subsequent case-control study. Scores of the Comprehensive Test of Basic Skills (4th Edition) (CTBS/4) then were compared between children with MSHL and children with normal hearing. School teachers completed the Screening Instrument for Targeting Education Risk (SIFTER) and the Revised Behavior Problem Checklist for a subsample of children with MSHL and their normally hearing counterparts. Finally, data on grade retention for a sample of children with MSHL were obtained from school records and compared with school district norm data. To assess the relationship between MSHL and functional status, test scores of all children with MSHL and all children with normal hearing in grades 6 and 9 were compared on the COOP Adolescent Chart Method (COOP), a screening tool for functional status. MSHL was exhibited by 5.4% of the study sample. The prevalence of all types of hearing impairment was 11.3%. Third grade children with MSHL exhibited significantly lower scores than normally hearing controls on a series of subtests of the CTBS/4; however, no differences were noted at the 6th and 9th grade levels. The SIFTER results revealed that children with MSHL scored poorer on the communication subtest than normal-hearing controls. Thirty-seven percent of the children with MSHL failed at least one grade. Finally, children with MSHL exhibited significantly greater dysfunction than children with normal hearing on several subtests of the COOP including behavior, energy, stress, social support, and self-esteem. The prevalence of hearing loss in the schools almost doubles when children with MSHL are included. This large, education-based study shows clinically important associations between MSHL and school behavior and performance. Children with MSHL experienced more difficulty than normally hearing children on a series of educational and functional test measures. Although additional research is necessary, results suggest the need for audiologists, speech-language pathologists, and educators to evaluate carefully our identification and management approaches with this population. Better efforts to manage these children could result in meaningful improvement in their educational progress and psychosocial well-being.
Article
Seventy percent of children with cancer survive. Radiation and chemotherapy may, however, impair ovarian function. The aim of this population-based study was to achieve a comprehensive knowledge of the degree of ovarian damage. Ovarian function was evaluated in 100 childhood cancer survivors and 21 controls of similar age. Menstrual cycle pattern was recorded, and strictly timed ovarian sonography and hormonal assessment were performed. The median age of the survivors was 5.4 yr (range, 0.1–15.3) at the time of diagnosis and 25.7 yr (18.5–44.4) at study entry. Seventeen survivors with premature ovarian failure had follicle-depleted or nondetectable ovaries, elevated FSH and LH, and immeasurable inhibin B. Thirteen survivors used oral contraception. Survivors with spontaneous menstrual cycles (n = 70) had smaller ovarian volume per ovary than controls (median, 4.8 vs. 6.8 cm3; P < 0.001) and a lower number of antral follicles per ovary (median, 7.5 vs. 11; P < 0.001). Further, they had lower inhibin B levels than controls (median, 94 vs. 111 pg/ml; P = 0.03) and higher estradiol levels (median, 0.12 vs. 0.08 pm; P = 0.04). Multiple linear regression analysis was performed to predict the total antral follicle number per ovary, and it showed a reduced number with ovarian irradiation (β = −0.40, P < 0.001), alkylating chemotherapy (β = −0.25, P = 0.01), older age at diagnosis (β = −0.25, P = 0.01), and longer time period off treatment (β = −0.19, P = 0.044). One in every six female survivors may develop premature ovarian failure. In survivors with spontaneous menstrual cycles, the results indicate a diminished ovarian reserve. Consequently, cessation of fertility may occur much earlier than anticipated. Adult survivors with spontaneous cycles should be informed hereof to plan childbearing.
Article
The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.