E. van Dulmen-den Broeder

Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases

OBJECTIVE The aim of this study was to evaluate whether values of FSH, LH, estradiol, anti-Müllerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume (OV) determined on day 7 of the hormone-free interval are similar to values measured on days 2-5 of two subsequent natural menstrual cycles. In addition, values measured on day 7 of the hormone-free interval were examined for the purpose of predicting values measured on days 2-5 during the second natural cycle. METHODS In this study, 25 women using hormonal contraception provided a blood sample and underwent transvaginal ultrasound measurements on day 7 of the hormone-free interval and on cycle days 2-5 of two subsequent natural cycles. Changes were compared by repeated measures ANOVA and multivariate linear regression was used for prediction purposes. RESULTS Mean (SD) age of the participants was 26.3 (6.2) years. Overall significant decreases in FSH and inhibin B and significant increases in AMH, AFC and ovarian volume values were measured after discontinuation of hormonal contraception (P < 0.001, P = 0.04, P = 0.01, P < 0.001 and P = 0.004, respectively). Significant changes occurred both from day 7 of the hormone-free interval to natural cycle 1 as well as from natural cycle 1 to natural cycle 2. FSH, AMH and AFC values measured during days 2-5 of natural cycle 2 could be predicted by the corresponding values measured on day 7 of the hormone-free interval. CONCLUSION Hormonal and ultrasound markers of ovarian function in hormonal contraception users measured at the end of the hormone-free interval do not seem to represent subsequent natural early follicular phase values. However, these values can, in some cases (FSH, AMH and AFC), be used to predict early follicular phase values using calculated prediction equations, which need to be validated in future research.

Landelijke richtlijnen voor follow-up van overlevenden van kinderkanker

SamenvattingMembers of the Late Effects Taskforce of the Dutch Childhood Oncology Group (dcog) and of the Haematology-Oncology Section of the Dutch Paediatric Association are involved in the development of guidelines for the follow-up of childhood cancer survivors. The recommendations of these guidelines are based on the best available clinical evidence, current guidelines and clinical experience of late effects specialists. The guidelines will lead to a uniform and standardised post-treatment care and long-term follow-up of childhood cancer survivors in the Netherlands. The information in the guidelines will be of importance for care providers in paediatrics, general medicine, internal medicine, gynaecology/obstetrics as well as for other specialists and particularly for childhood cancer survivors themselves. The information will lead to an increased awareness for all Dutch care providers who are responsible for the health problems of childhood cancer survivors. The development of guidelines for childhood cancer survivors is an important part of a new Dutch project: Late Effects Registry (later). Within this new national project patient and treatment data as well as follow-up data on childhood cancer survivors in the Netherlands will be registered. The project later aims at: to coordinate and to evaluate care of the survivors, and to stimulate new research in the field of late effects of childhood cancer.SamenvattingVanuit de skion (Stichting Kinderoncologie Nederland) en de sectie Kinderoncologie-Hematologie van de Nederlandse Vereniging voor Kindergeneeskunde worden in Nederland richtlijnen opgesteld voor de follow-up van overlevenden van kinderkanker meer dan vijf jaar na diagnose. De aanbevelingen in deze richtlijnen voor follow-up zijn gebaseerd op het beschikbare bewijs, bestaande richtlijnen en het klinische inzicht van experts op het gebied van de late effecten. Deze richtlijnen zullen leiden tot een uniforme en gestandaardiseerde langetermijnzorg voor overlevenden na kinderkanker in Nederland. De informatie van de richtlijnen is belangrijk voor zorgverleners in het veld van kindergeneeskunde, huisartsgeneeskunde, interne geneeskunde, gynaecologie/obstetrie en andere specialisten en ook voor de overlevenden van kinderkanker. De informatie zal bijdragen aan een algemene bewustwording van de Nederlandse zorgverleners voor de gezondheidsproblemen van kinderen en jongvolwassenen die genezen zijn van kinderkanker. De richtlijnontwikkeling voor de follow-up van overlevenden van kinderkanker vormt een belangrijk onderdeel van het nieuwe landelijke project Lange Termijn Effecten Registratie: later. Binnen dit landelijke project zullen patiëntengegevens, gegevens over de oorspronkelijke behandeling en follow-upgegevens van alle overlevenden van kinderkanker in Nederland geregistreerd worden. Het doel van deze registratie is om de patiëntenzorg in Nederland te coördineren, te evalueren en nieuw wetenschappelijk onderzoek te stimuleren.

Validity of self-reported data on pregnancies for childhood cancer survivors: a comparison with data from a nationwide population-based registry

STUDY QUESTION To what degree do records registered in the Netherlands Perinatal Registry (PRN) agree with self-report in a study questionnaire on pregnancy outcomes in childhood cancer survivors (CCSs)? SUMMARY ANSWER This study suggests that self-reported pregnancy outcomes of CCSs agree well with registry data and that outcomes reported by CCSs agree better with registry data than do those of controls. WHAT IS KNOWN ALREADY Many studies have shown that childhood cancer treatment may affect fertility outcomes in female CCSs; however, these conclusions were often based on questionnaire data, and it remains unclear whether self-report agrees well with more objective sources of information. STUDY DESIGN, SIZE, DURATION In an nationwide cohort study on fertility (inclusion period January 2008 and April 2011, trial number: NTR2922), 1420 CCSs and 354 sibling controls were invited to complete a questionnaire regarding socio-demographic characteristics and reproductive history. In total, 879 CCSs (62%) and 287 controls (81%) returned the questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS The current validation study compared the agreement between pregnancy outcomes as registered in the PRN and self-reported outcomes in the study questionnaire. A total of 589 pregnancies were reported in CCSs, and 300 pregnancies in sibling controls, of which 524 could be linked to the PRN. MAIN RESULTS AND THE ROLE OF CHANCE A high intra-class correlation coefficient (ICC) was found for birthweight (BW) (0.94 and 0.87 for CCSs and controls, respectively). The self-reported BWs tended to be higher than reported in the PRN. For gestational age (GA), the ICC was high for CCSs (0.88), but moderate for controls (0.49). CCSs overestimated GA more often than controls. The Kappa values for method of conception and for method of delivery were moderate to good. Multilevel analyses on the mean difference with regard to BW and GA showed no differences associated with time since pregnancy or educational level. LIMITATIONS, REASONS FOR CAUTION Not all pregnancies reported could be linked to the registry data. In addition, the completeness of the PRN could not be assessed precisely, because there is no information on the number of missing records. Finally, for some outcomes there were high proportions of missing values in the PRN registry. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that questionnaires are a reliable method of data collection, and that for most variables, self-report agrees well with registry data. STUDY FUNDING/COMPETING INTEREST This work was supported by the Dutch Cancer Society (grant no. VU 2006-3622) and by Foundation Children Cancer Free. None of the authors report a conflict of interest. TRIAL REGISTRATION NUMBER NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922.

Fertility studies in female childhood cancer survivors: selecting appropriate comparison groups

Little information is available on the use of appropriate comparison groups for studies investigating late effects of childhood cancer. Two comparison groups in a nationwide study on reproductive function and ovarian reserve in female childhood cancer survivors were recruited (The Dutch Childhood Oncology Group Long-Term Effects After Childhood Cancer Cohort Study). Experiences of this process are reported. Two types of comparison groups were used: sisters of participating survivors and controls from the general population. A total of 352 out of 580 (61%) of the participating survivors who had a sister gave permission to invite them for the study. The participation rate of sisters was much higher than control participants from the general population (74% versus 21%, respectively), whereas considerably more effort was involved in recruiting controls from the general population. Participants in this group were significantly older and more highly educated than sister controls (P < 0.001 for both groups). No significant differences were observed between both types of comparison groups in several fertility-related characteristics, suggesting minimal bias owing to selective participation. Researchers setting up a study to investigate late effects among survivors of childhood cancer should carefully consider the advantages and disadvantages of using various types of comparison groups.

Reproductive intentions and use of reproductive health care among female survivors of childhood cancer

STUDY QUESTION Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer? SUMMARY ANSWER Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving. WHAT IS KNOWN ALREADY Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment. STUDY DESIGN, SIZE, DURATION This study is part of the DCOG LATER-VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2). LIMITATIONS, REASONS FOR CAUTION Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment-related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS Decisions about parenthood affect all CCSs. Its important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20). TRIAL REGISTRATION NUMBER NTR2922.

Cost-effectiveness of a combined physical exercise and psychosocial training intervention for children with cancer: Results from the quality of life in motion study.

&NA; This study was performed to estimate the cost‐effectiveness of a combined physical exercise and psychosocial intervention for children with cancer compared with usual care. Sixty‐eight children, aged 8‐18 years old, during or within the first year post‐cancer treatment were randomised to the intervention (n = 30) and control group (n = 38). Health outcomes included fitness, muscle strength and quality adjusted life years; all administered at baseline, 4‐ and 12‐month follow‐up. Costs were gathered by 1 monthly cost questionnaires over 12 months, supplemented by medication data obtained from pharmacies. Results showed no significant differences in costs and effects between the intervention and control group at 12‐month follow‐up. On average, societal costs were &U20AC;299 higher in the intervention group than in the control group, but this difference was not significant. Cost‐effectiveness acceptability curves indicated that the intervention needs large societal investments to reach reasonable probabilities of cost‐effectiveness for quality of life and lower body muscle strength. Based on the results of this study, the intervention is not cost‐effective in comparison with usual care.

Longitudinal follow-up in female Childhood Cancer Survivors: no signs of accelerated ovarian function loss

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 INTEREST(S) 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.

Gezondheidsproblemen na de behandeling van kinderkanker

SamenvattingChildhood cancer survivors are at increased risk for adverse late effects due to the tumour itself or secondary to treatment with chemotherapy and/or radiotherapy. In the Netherlands paediatric oncology centres have established dedicated late effects clinics. Here specialised care is offered to the survivors, who are also screened for unknown late effects. If necessary, survivors are referred for further diagnostic work-up and treatment. Furthermore the paediatric oncology centres are exploring ways to provide adequate care for adult survivors. Finally, the centres are initiating research in the field of late treatment effects. Two representative case histories are presented.SamenvattingBehandeling van kanker op de kinderleeftijd kan op de (zeer) lange termijn leiden tot late schadelijke effecten met een grote diversiteit, en in ernst variërend van mild tot ernstig of zelfs levensbedreigend. In de kinderoncologische centra zijn speciale poliklinieken voor follow-up op lange termijn in het leven geroepen waar gespecialiseerde zorg geboden wordt aan overlevenden met late effecten en waar nog niet bekende late effecten worden opgespoord. Zo nodig worden patiënten voor aanvullend onderzoek en behandeling doorverwezen. In de verschillende klinieken wordt naar oplossingen gezocht om de overlevenden ook op de volwassen leeftijd de benodigde zorg te kunnen bieden. Naast deze patiëntenzorg wordt er vanuit de kinderoncologische centra wetenschappelijk onderzoek naar de problematiek van late effecten geïnitieerd. De problematiek wordt geschetst aan de hand van twee ziektegeschiedenissen.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review

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.

Fertiliteitsproblemen na behandeling wegens kanker op de kinderleeftijd: signalering, diagnostiek en therapie

SamenvattingIn de afgelopen decennia is de overlevingskans voor kinderen die wegens kanker werden behandeld sterk gestegen, van een gemiddeld overlevingspercentage van 10% in de jaren zestig tot ruim 70% thans. Dat betekent onder andere dat in de nabije toekomst één op de zeshonderd jonge volwassenen in de kinderjaren behandeld is geweest voor een maligne aandoening. Die jonge volwassenen zullen hun hele verdere leven geconfronteerd kunnen worden met bijwerkingen van de behandeling (chemotherapie, al dan niet in combinatie met chirurgie en/of radiotherapie). Enkele jaren is in alle Nederlandse kinderoncologische en beenmergtransplantatiecentra een programma van start gegaan waarin gelijkgerichte protocollaire aandacht wordt gegeven aan de late effecten van behandeling van maligne aandoeningen op de kinderleeftijd: de landelijke langetermijneffectenregistratie (later). De poliklinieken voor late effecten van kindertumoren (plek- oflater-poliklinieken) richten zich op de langetermijneffecten van de therapie van destijds. Die neveneffecten kunnen zich manifesteren op allerlei gebied, in dit hoofdstuk richten we ons op het effect op de gonaden en de kans op voortplanting.jeugdkankerkinderkankerlangetermijneffectengonadenvruchtbaarheidonvruchtbaarheidfollow-up, langdurigefertiliteitsproblemen na behandelingkinderkanker, overlevenden van