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Fertility among female survivors of childhood, adolescent and young adult cancer: design, methods and cohort characteristics of two pan-European studies (PanCareLIFE) (Preprint)

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Background: Despite a significant number of studies on female fertility following childhood, adolescent, and young adult (CAYA) cancer, studies establishing precise (dose-related) estimates of treatment-related risks are still scarce. Previous studies have been underpowered, did not include detailed treatment information, or were based on self-report only without any hormonal assessments. More precise assessments of who is at risk for sub- or infertility are needed. Objective: The objective of our study is to describe the design and methods of 2 studies on female fertility (a cohort study and a nested case-control study) among female survivors of CAYA cancer performed within the European PanCareLIFE project. Methods: For the cohort study, which aims to evaluate the overall risk of fertility impairment, as well as the risk for specific subgroups of female CAYA cancer survivors, 13 institutions from 9 countries provide data on fertility impairment. Survivors are defined as being fertility impaired if they meet at least one of 8 different criteria based on self-reported and hormonal data. For the nested case-control study, which aims to identify specific treatment-related risk factors associated with fertility impairment in addition to possible dose-response relationships, cases (fertility impaired survivors) are selected from the cohort study and matched to controls (survivors without fertility impairment) on a 1:2 basis. Results: Of the 10,964 survivors invited for the cohort study, data are available from 6619 survivors, either questionnaire-based only (n=4979), hormonal-based only (n=72), or both (n=1568). For the nested case-control study, a total of 450 cases and 882 controls are identified. Conclusions: Results of both PanCareLIFE fertility studies will provide detailed insight into the risk of fertility impairment following CAYA cancer and diagnostic- or treatment-related factors associated with an increased risk. This will help clinicians to adequately counsel both girls and young women, who are about to start anticancer treatment, as well as adult female CAYA cancer survivors, concerning future parenthood and to timely refer them for fertility preservation. Ultimately, we aim to empower patients and survivors and improve their quality of life. Registered report identifier: RR1-10.2196/10824.
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... The increasing population of childhood cancer survivors (CCSs) has a life-long risk of treatment-related adverse health effects, one of which is gonadal function impairment [3][4][5][6][7]. The use of alkylating agents and radiotherapy exposing the ovaries are well-described risk factors for treatment-related gonadal damage [8][9][10][11]. However, inter-individual variability in gonadal injury among survivors exposed to similar gonadotoxic cancer therapy suggests a role for genetic susceptibility [9,12,13]. ...
... Additionally, functional SNPs in drug-metabolizing enzymes (DME) have been shown to be associated with cancer-related outcomes [21][22][23][24]. Therefore, we hypothesized that genetic variation in DMEs that involves the metabolism of alkylating agents may be associated with the risk of long-term gonadal damage in CCSs [8][9][10][11]25]. ...
... 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. ...
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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.
... However, further confirmation of the present data in large cohorts is mandatory [59,60]. A limitation to the field could be the lack of a registry for oocyte cryopreservation. ...
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The preservation of fertility in cancer patients is a crucial aspect of modern reproductive medicine. Amenorrhea and infertility often occur after cancer therapy, worsening the quality of life. Cryopreservation of oocytes in young cancer patients is a therapeutic option for preserving fertility. A prospective study was conducted on 508 cancer patients who underwent oocyte cryopreservation to preserve fertility between 1996 and 2021 including the COVID-19 pandemic period. Patients underwent ovarian stimulation, followed by egg retrieval, and oocytes were cryopreserved by slow freezing or vitrification. Sixty-four thawing/warming cycles were performed. Survival, fertilization, pregnancy, and birth rate over the thawing/warming cycles were obtained. The data were compared with those from a group of 1042 nononcological patients who cryopreserved supernumerary oocytes. An average of 8.8 ± 6.9 oocytes were retrieved per cycle, and 6.1 ± 4.2 oocytes were cryopreserved. With their own stored oocytes, 44 patients returned to attempt pregnancy. From a total of 194 thawed/warmed oocytes, 157 survived (80%). In total, 100 embryos were transferred in 57 transfer/cycles, and 18 pregnancies were achieved. The pregnancy rate per transfer and pregnancy rate per patient were 31% and 41%, respectively. No statistically significant differences were observed between oncological patients and nononcological patients. A total of 15 babies were born from oncological patients. Children born showed normal growth and development. One minor malformation was detected.
... WT survivors should receive personalized counselling about the type and magnitude of reproductive health risks on the basis of their specific treatment exposure, with older girls with unfavourable histology or high risk WT being at increased risk. Patients at the highest risk should be offered fertility preservation whenever possible, and after accurate counselling 195 . In this view, prior abdom inopelvic surgery (done to perform nephrectomy as part of initial cancer treatment) should not be regarded as a barrier to laparoscopic oophorectomy with tissue cryopreservation for fertility preservation. ...
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Wilms tumour (WT) is a childhood embryonal tumour that is paradigmatic of the intersection between disrupted organogenesis and tumorigenesis. Many WT genes play a critical (non-redundant) role in early nephrogenesis. Improving patient outcomes requires advances in understanding and targeting of the multiple genes and cellular control pathways now identified as active in WT development. Decades of clinical and basic research have helped to gradually optimize clinical care. Curative therapy is achievable in 90% of affected children, even those with disseminated disease, yet survival disparities within and between countries exist and deserve commitment to change. Updated epidemiological studies have also provided novel insights into global incidence variations. Introduction of biology-driven approaches to risk stratification and new drug development has been slower in WT than in other childhood tumours. Current prognostic classification for children with WT is grounded in clinical and pathological findings and in dedicated protocols on molecular alterations. Treatment includes conventional cytotoxic chemotherapy and surgery, and radiation therapy in some cases. Advanced imaging to capture tumour composition, optimizing irradiation techniques to reduce target volumes, and evaluation of newer surgical procedures are key areas for future research. Wilms tumour (WT) is the most common renal tumour in infants and young children. This Primer reviews the epidemiology, mechanisms, diagnosis and management of WT. In addition, the authors outline potential opportunities to translate novel biological targets to improve clinical outcomes.
... Thus, PanCareLIFE will help to quantify the toll of cancer treatment in relation to specific deficits. Some results were published at virtually the same time as the project ended (e.g., [24][25][26]). ...
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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.
Article
Infertility is a serious early, as well as late effect of childhood cancer treatment. If addressed timely at diagnosis, fertility preservation measures can be taken, preferably before start of cancer treatment. However, pediatric oncologists may remain reluctant to offer counseling on fertility preservation methods, while infrastructure to freeze ovarian tissue has become available and is currently considered standard care for pre- and post-pubertal girls at high risk of gonadal damage. More importantly, risk factors have been identified for cancer treatment-related impairment of gonadal function, and the first successful pregnancies have been reported after auto-transplanted ovarian tissue, which has been harvested from children. Additionally, great progress has been made in the field of ex vivo maturation of oocytes in frozen ovarian tissue, which provides opportunities for those at risk of ovarian micrometastasis. Hence, it is time to counsel girls at risk and make every effort to cryopreserve their ovarian tissue, now more than ever before.
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Women's health status may affect their opportunities and preferences for children through various mechanisms. We examine the relationship between health and fertility using Norwegian registry data (2004-18). Measuring verifiable and persistent health problems, we use uptake of doctor-certified sickness absence and long-term health-related benefits as proxies for health. In contrast to the expectation that poor health limits women's opportunities for children, our results show that sickness absence is positively associated with transitions to parenthood. The uptake of long-term benefits is, however, negatively associated with fertility. The selection of healthy women into parenthood weakens the association for higher-order births. The impact of long-term health indicators on fertility is comparable in magnitude to that observed for more conventional predictors, such as education and income. With continued postponement of childbearing and thus higher maternal ages, the influence of health as a fertility determinant is likely to grow and further research appears warranted.Supplementary material for this article is available at: http://doi.org/10.1080/00324728.2022.2041075.
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 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
Chapter
The specific group of long-term survivors of younger ages, like children, adolescents and young adults, are constantly growing due to enhanced diagnostic tools and more effective treatment strategies. Thus their specific survivorship care needs to be addressed in a holistic approach. Whilst a lot of scientific work has focused on somatic late effects of survivors, a growing body of research has recently been directed towards psychosocial outcomes of survivors. A part of them are reaching psychosocial stability after they had overcome the cancer disease and its treatment. In the following chapter, we aim to point out social outcomes of survivors and risk factors for adverse outcomes. The latter thus define subgroups for intensified follow-up and care. An early identification of groups at high risk is crucial, in order to understand, and later prevent the pathways leading to poor socioeconomic outcomes. We also provide information how reintegration into everyday life takes place, i.e., which challenges are faced and how they may be overcome.
Article
Although there has been an increase in fertility preservation treatment options in recent years, existing evidence would suggest that many young women who have breast cancer do not feel well supported in making decisions in this area. A breast cancer diagnosis and the possibility of becoming infertile are known to cause psychological issues for young women and many find it difficult to make decisions at this time, causing them a great deal of stress and anxiety. Given the need for patient-centred care, this literature review looked at the decision-making support given to women with a diagnosis of breast cancer as part of fertility preservation treatment. The review found that women lacked support and struggled to make decisions at this critical point in their lives. The findings of the review suggest that women would benefit from a wide range of decision support interventions prior to and following diagnosis.
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Study question: To what extent does oral contraception (OC) impair ovarian reserve parameters in women who seek fertility assessment and counselling to get advice on whether their remaining reproductive lifespan is reduced? Summary answer: Ovarian reserve parameters defined by anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume were found to be significantly decreased by 19% (95% CI 9.1-29.3%), 18% (95% CI 11.2-24.8%) and 50% (95% CI 45.1-53.7%) among OC users compared with non-users. What is known already: AMH and AFC have proved to be reliable predictors of ovarian ageing. In women, AMH declines with age and data suggest a relationship with remaining reproductive lifespan and age at menopause. OC may alter parameters related to ovarian reserve assessment but the extent of the reduction is uncertain. Study design, size, duration: A cross-sectional study of 887 women aged 19-46 attending the Fertility Assessment and Counselling Clinic (FACC) from 2011 to 2014 comparing ovarian reserve parameters in OC users with non-OC users. Participants/materials, setting, methods: The FAC Clinic was initiated to provide individual fertility assessment and counselling. All women were examined on a random cycle day by a fertility specialist. Consultation included; transvaginal ultrasound (AFC, ovarian volume, pathology), a full reproductive history and AMH measurement. Women were grouped into non-users and users of OC (all combinations of estrogen-progestin products and the contraceptive vaginal ring). Non-users included women with an intrauterine device (IUD) or no hormonal contraception. Main results and the role of chance: Of the 887 women, 244 (27.5%) used OC. In a linear regression analyses adjusted for age, ovarian volume was 50% lower (95% CI 45.1-53.7%), AMH was 19% lower (95% CI 9.1-29.3%), and AFC was 18% lower (95% CI 11.2-24.8%) in OC users compared with non-users. Comparison of AMH at values of <10 pmol/l OC was found to have a significant negative influence on AMH (OR 1.6, 95% CI 1.1; 2.4, P = 0.03). Furthermore, we found a significant decrease in antral follicles sized 5-7 mm (P < 0.001) and antral follicles sized 8-10 mm (P < 0.001) but an increase in antral follicles sized 2-4 mm (P = 0.008) among OC users. The two groups (OC users versus non-users) were comparable regarding age, BMI, smoking and maternal age at menopause. Limitations, reason for caution: The study population comprised women attending the FAC Clinic. Recruitment was based on self-referral, which could imply a potential selection bias. Ovarian reserve was examined at a random cycle day. However, both AMH and AFC can be assessed independently of the menstrual cycle. The accuracy in predicting residual reproductive lifespan is still needed in both users and non-users of OC. Wider implications of the findings: OC has a major impact on the ovarian volume, and a moderate impact on AFC and AMH with a shift towards the smaller sized antral follicle subclasses. The most evident reduction occurs in the antral follicles of 5-7 and 8-10 mm with the highest number of AMH secreting granulosa cells. It is essential to be aware of the impact of OC use on ovarian reserve parameters when guiding OC users on their fertility status and reproductive lifespan. Study funding/competing interests: The FAC Clinic was established in 2011 as part of the ReproHigh collaboration. This study received funding through the Capital Region Research Fund and by EU-regional funding. There are no competing interests. Trial registration number: The biobank connected to FAC Clinic is approved by the Scientific Ethical Committee (H-1-2011-081).
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
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. It's 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.
Article
Background Young women treated with chest radiotherapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. Methods We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC cases and 466 controls. Radiation dose to breast tumor location was estimated based on RT charts, simulation films and mammography reports. Results We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gray (95%CI:2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR:0.13, 95%CI:0.03-0.51) than women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<0.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR:0.86, 95%CI:0.32-2.32), while this risk was non-significantly increased among women without early menopause (OR:3.69, 95%CI:0.97-14.0, P for interaction:0.06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. Conclusion BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.
Article
Context: Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. Context: To describe the prevalence of POI, its risk factors and associated long-term adverse health outcomes. Design: Cross-sectional. Setting: The St. Jude Lifetime Cohort Study - established cohort in a tertiary care center. Patients: 921 participants (median age 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. Main outcome measure: POI was defined by persistent amenorrhea combined with a follicle stimulating hormone level >30 IU/L before 40 years of age. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD) and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). Results: The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ?8,000 mg/m2. Patients with a BMI ?30 kg/m2 at the time of the SJLIFE assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. Conclusion: High dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.
Article
Purpose To compare the probability of a first live birth, age at time of birth, and time between diagnosis/referent date and birth between childhood and adolescent cancer survivors and an age-matched comparison group. Materials and Methods A total of 1,206 survivors was included in the study, together with 2,412 age-matched individuals from the general population. A Cox proportional hazards model was used to investigate first live birth after diagnosis/referent date. Data were stratified by sex, age at diagnosis, and diagnostic era (ie, diagnosis before 1988 v in 1988 or later). Results Overall, the probability of having a first live birth (hazard ratio [HR]) was significantly lower; men had lower HRs than women (HR, 0.65 v 0.79). There were no significant differences in the probability of having a first live birth among women diagnosed during adolescence (HR, 0.89), but the HR was lower among women with childhood cancers (HR, 0.47). Among male survivors, the situation was the opposite; men diagnosed during adolescence had lower HRs than survivors of childhood cancer (HR, 0.56 v 0.70). Examination of the data from the two diagnostic eras (before 1988 and 1988 or later) shows that the HR increased among female survivors after 1988 (HR, 0.71 v 0.90) and decreased among male survivors (HR, 0.72 v 0.59). A shorter time had elapsed between diagnosis/referent date and the birth of a first child among both male and female survivors compared with controls. In addition, female survivors were younger at time of birth. Conclusion The study demonstrates reduced probability of having a first live birth among cancer survivors diagnosed during childhood or adolescence; men were particularly vulnerable.
Article
Background: Anti-cancer treatment may reduce the fertile life span and induce premature menopause. This review aims to provide an overview of the available literature on effects of chemotherapy only on the incidence of ovarian dysfunction and to evaluate the relationship between dose of chemotherapy, age at time of treatment, and time since treatment in female survivors of childhood and young adult cancer. Methods: A comprehensive search of electronic databases was performed (search date December 2015). Results: 45 studies were included, describing, in total, 5607 female survivors. Median age at menopause was earlier in cancer survivors than in the general population. The prevalence of amenorrhoea varied from 0% to 83%. Those exposed to MVPP protocols were at highest risk for amenorrhoea (39-79%), as were breast cancer survivors receiving cyclophosphamide-containing regimens, in whom the prevalence of amenorrhoea was 40-80%. The most important risk factors for ovarian dysfunction were: (1) alkylating agents, specifically procarbazine and busulfan, (2) older age at treatment. Conclusion: Breast cancer survivors, those treated with procarbazine or other alkylating agents and those with a higher age at diagnosis are at highest risk of diminished ovarian function. However, all studies included in this review showed methodological limitations. It is imperative that nation-wide registries guarantee long term follow-up during the adult life of cancer survivors.
Article
Purpose: Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. Patients and methods: The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. Results and conclusion: The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer.
Article
Objectives: Anti-Müllenria hormone (AMH) is an established biomarker for assessing ovarian reserve and predicting response to controlled ovarian stimulation. Its routine clinical use is hampered by the variability and low-throughput of available enzyme-linked immunosorbent assays (ELISA). The presented study examined if a fully automated AMH electrochemiluminescence assay (ECLIA; Elecsys® AMH assay, Roche Diagnostics) was suitable for measuring AMH levels in healthy women and in those diagnosed with polycystic ovary syndrome (PCOS). Design and methods: Five European laboratories evaluated the Elecsys® AMH assay independently under routine conditions over eight months. Within-run imprecision, repeatability, intermediate precision, linearity and functional sensitivity were assessed. The Elecsys® AMH assay was compared to a manual ELISA microtiter plate format test (AMH Gen II ELISA, modified version; Beckman Coulter Inc.) using 1729 routine serum samples. AMH reference intervals were determined in 887 healthy women with regular menstrual cycle aged 20–50 years, and 149 women diagnosed with PCOS. Results: The fully automated Elecsys® AMH assay showed excellent precision, linearity, and functional sensitivity. The coefficient of variation was 1.8% for repeatability and 4.4% for intermediate precision. Values measured with the Elecsys® AMH assay were highly correlated with the manual ELISA method (modified version) but 24–28% lower. Reference intervals showed the expected AMH decline with age in healthy women and increased AMH levels in women with PCOS. Conclusions: The Elecsys® AMH assay demonstrated good precision under routine conditions, and is suitable for determining AMH levels in serum and lithium-heparin plasma.