H. J. H. van der Pal

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children

. The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline‐induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children.

The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors

BACKGROUND The Late Effects of Childhood Cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) developed a guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors (CCS). In this paper, we present the methods, available evidence and final recommendations of our guideline. MATERIALS AND METHODS A multidisciplinary working group specified clinical questions that should be answered to get to recommendations for the guideline. We carried out short or extensive evidence summaries and determined methodological quality of studies and levels of evidence in order to answer all clinical questions. When evidence was lacking for CCS, we carefully extrapolated evidence from other populations. Final recommendations were based on evidence and consensus. RESULTS There was high-level evidence for the increased risk of cardiac dysfunction in CCS and its main risk factors. Evidence was lacking regarding the prognosis, diagnosis and treatment of cardiac dysfunction in CCS. We recommended echocardiographic screening for asymptomatic cardiac dysfunction in CCS treated with cardiotoxic treatments and counseling about potential advantages and disadvantages of our screening recommendations. CONCLUSION The DCOG LATER guideline recommends risk-based screening for asymptomatic cardiac dysfunction in CCS, but it should be noted that recommendations are not completely supported by evidence in CCS.

Reproductive status in adult male long-term survivors of childhood cancer

BACKGROUND This study assessed the long-term effects of cancer therapies on reproductive status in adult male childhood cancer survivors, evaluated the treatment-related risk factors for hypergonadotropic hypogonadism and assessed the association between the FSH levels and the later need for assisted reproductive techniques (ART). METHODS The study cohort included adult male 5-year survivors of childhood cancer who were treated in our institution between 1966 and 2003. Data concerning patient and treatment characteristics, FSH, LH and testosterone levels and pregnancy outcome were collected. Multivariate regression analyses were performed to evaluate the treatment-related risk factors for disturbances in reproductive endocrine status. The diagnostic and predictive values of FSH and later need for ART were evaluated. RESULTS Data on reproductive endocrine status were available for 488 survivors (86.4%) of the 565 male survivors who visited the outpatient clinic in adulthood. The median follow-up time from initiation of treatment to first visit to the outpatient clinic in adulthood was 15 years. The prevalence rates of elevated FSH levels and decreased testosterone levels were 33 and 12%, respectively. The use of procarbazine, cyclophosphamide, vinca-alkaloids, other alkylating agents, pelvic/abdominal irradiation, total body irradiation and testicular surgery were identified as treatment-related risk factors for elevated FSH levels. During the follow-up period, 73 men reported 120 conceptions, which resulted in 103 live births. Of these men, 56 (77%) were able to achieve conception naturally. All men whose partners conceived by assisted reproductive techniques (n = 13) had elevated FSH levels at their first visit after their 18th birthday (sensitivity: 100%; 95% CI: 71-100%) and all male survivors with a normal FSH level did not need assisted reproductive techniques (negative predictive value: 100%; 95% CI: 89-100%). CONCLUSIONS One-third of young adult male survivors of childhood cancer has elevated FSH levels. FSH appears to be a very sensitive marker for the need of assisted reproductive techniques in male childhood cancer survivors.

Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma - A systematic review

BACKGROUND Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients. METHODS Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE. RESULTS In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity. CONCLUSION Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC.

Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy

Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.

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.

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.

Cardiotoxiciteit van antracyclines

SamenvattingMinstens de helft van de kinderen met kanker wordt met antracyclines behandeld. Dat gaat gepaard met een ernstige bijwerking: cardiotoxiciteit, die zich uit als klinisch hartfalen of als asymptomatische hartschade. Op langere termijn kan de hartschade leiden tot ernstige morbiditeit, verminderde kwaliteit van leven en verhoogde mortaliteit.Het effect van antracyclines op de hartfunctie van individuele patiënten is moeilijk te voorspellen. Om hartschade vroegtijdig op te sporen maakt men bij kinderen periodiek een hartecho. Bij volwassenen wordt de hartfunctie gevolgd met nucleaire angiografie.De behandeling van klinisch hartfalen bestaat uit een symptomatische behandeling metace-remmers (angiotensineconverterendenzymremmers), bètablokkers, digoxine en diuretica. In het eindstadium van klinisch hartfalen is harttransplantatie de enige optie om hartdood te vermijden.Om risico’s op hart- en vaatziekten te beperken is een gezonde levensstijl van belang voor alle overlevenden van jeugdkanker, maar met name voor hen die door de behandeling al een verminderde hartfunctie hebben. Patiënten die behandeld zijn met antracyclines zullen levenslang het gevaar lopen dat hun hartfunctie verslechtert.antracyclinescardiotoxiciteitlangetermijneffectenkinderkanker, overlevenden vanfollow-up, langdurige