The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? SUMMARY ANSWER: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. WHAT IS KNOWN ALREADY: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. STUDY DESIGN, SIZE, DURATION: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. LIMITATIONS, REASONS FOR CAUTION: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. STUDY FUNDING/COMPETING INTEREST(S): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Clinical and self-reported markers of reproductive function in female survivors of childhood Hodgkin lymphoma.

PURPOSE: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes. METHODS: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls. RESULTS: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (< p10) 10.1 [95% CI 4.9; 20.6]; low AFC (< p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (> 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (< 20 ng/l) 3.6 [ 95% CI 1.7; 7.7], p < 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy > 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score. CONCLUSION: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic.

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

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 €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.

Application of the steep ramp test for aerobic fitness testing in children with cancer.

BACKGROUND: Children with and after cancer are found to have a decreased physical fitness, frequently resulting in decreased physical functioning. The gold standard test for assessing aerobic fitness, a component of physical fitness, is the respiratory gas analyses-based cardiopulmonary exercise test (CPET). However, equipment for gas analysis is often unavailable in local physical therapy centres and non-university hospitals. The steep ramp test (SRT), is a cycle ergometer test with a fast increase in workload, a short duration, and does not require respiratory gas analysis equipment. AIM: The aim of this study was to compare the results of the CPET and the SRT, in children with cancer, and to assess whether the SRT can be used for aerobic fitness assessment in clinical practice in this population. DESIGN: This study is a cross-sectional assessment using baseline data of a randomized controlled trial. SETTING: The study was performed in a hospital setting. POPULATION: Sixty-one children (mean age 12.9 years; 33 boys) with cancer were included in the analysis; 16 children were on non-intensive chemotherapy treatment, 45 were in the first year thereafter. METHODS: Participants performed both the SRT and the CPET on a cycle ergometer with respiratory gas analysis. Data of the two tests were compared and regression analyses were performed. RESULTS: CPET test results revealed a higher impact on the cardiovascular system, as shown by higher peak ventilation (47.8 versus 52.0 Litres per min) and peak heart rates (173 versus 191 beats per min), compared to the SRT. In addition, the test time was significantly longer (90 s versus 390 s). Yet, the primary outcome of the SRT (peak work rate) was able to reliably estimate the peak oxygen uptake of the CPET. CONCLUSION: The peak oxygen uptake was comparable between the SRT and the CPET, although the peak work rate was significantly higher during the SRT. This study showed that the SRT is a valid instrument to assess aerobic fitness in children with cancer. CLINICAL REHABILITATION IMPACT: The SRT is less time consuming and can be performed without gas analysis in a non-clinical setting, making it less demanding for children.

Fetal nutrition and timing of puberty.

Over the last decade growing evidence has been documented on the relationship between intrauterine growth retardation (IUGR) and pubertal development indicating changes in timing and progression of puberty. These changes in pubertal development are part of a growing list of IUGR-related diseases, which includes type 2 diabetes mellitus, cardiovascular disease, short stature and polycystic ovary syndrome. The influence of IUGR on the mechanisms behind the onset of puberty is still elusive. In the absence of prospective studies on gonadotropin-releasing hormone pulse patterns in IUGR children, other markers of pubertal development such as age at menarche in girls and progression of puberty have been employed. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) after third trimester growth retardation and children born appropriate for gestational age (AGA). A faster progression of puberty was found in girls but not in boys. DHEAS levels tended to be higher in SGA children than in AGA children. In animal studies using two rat models, growth and onset of puberty based on perinatal undernutrition were also investigated. In one model intrauterine growth retardation was induced by ligation of the uterine arteries (IUGR) at day 17 of gestation and in the other model postnatal food restriction (FR) was induced by increasing litter size after birth until weaning. In both models, the rats showed a persistent growth failure. Onset of puberty was defined by vaginal opening (VO) in female rats and by balanopreputial separation (BPS) in male rats. At onset of puberty IUGR and FR rats had a lower body weight compared to controls, indicating that no threshold for body weight is needed for the onset of puberty. In the IUGR female rats, the onset of puberty was delayed and in the FR female rats the onset of puberty was in time. In both IUGR and FR female rats VO and first cycle were uncoupled. In IUGR female rats, at VO, at first cycle and at the age of 6 months the ovaries showed a decline in number of follicles indicating that intrauterine malnutrition in the female rat has a permanent influence on the growth and development of follicles. In the FR female rats, at VO, the ovaries showed a normal number of follicles but an abnormal maturation pattern. At the time of first cycle and at the age of 6 months normalization in follicle growth pattern was observed. These findings suggest that postnatal undernutrition has a transient influence on follicle growth and development. In male rats, both models showed delayed onset of puberty and impaired testicular function, as shown by decreased testosterone levels. These data indicate that early malnutrition during different critical developmental time windows may result in different long-lasting effects on pubertal development in both humans and rats.

Optimal metabolic conditions during fluorine-18 fluorodeoxyglucose imaging; a comparative study using different protocols.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) can identify viable myocardium in patients with coronary artery disease. Recently, FDG imaging with single-photon emission tomography (SPET) and 511-keV collimators has been described. To obtain optimal image quality in all patients, cardiac FDG studies should be performed during hyperinsulinaemic glucose clamping. It has been suggested that FDG imaging after the administration of a nicotinic acid derivative may yield comparable image quality to clamping. We studied eight patients and compared the image quality of cardiac FDG SPET studies after oral glucose loading, after administration of a nicotinic acid derivative (acipimox, 250 mg orally) and during hyperinsulinaemic glucose clamping. The image quality was expressed as the myocardial to blood pool (M/B) activity ratio, which is used as a measure of the target-to-background ratio The M/B ratios were comparable after clamping and acipimox (2.8+/-0.8 vs 2.9+/-0.7), whereas the M/B ratio was lower after oral glucose loading (2.2+/-0.3, P<0.05 vs clamp and acipimox). To determine the clearance of FDG from the plasma, blood samples were drawn at fixed time intervals and the FDG activity was measured in a gamma well counter. The FDG clearance was significantly lower after oral glucose loading (T(1/2) oral load=16. 2+/-5.7 min) as compared with clamping (T(1/2) clamp=8.1+/-3.1 min) and acipimox (T(1/2) acipimox=10.7+/-4.0 min, NS vs clamp, P<0.05 vs oral load). It may be concluded that FDG SPET imaging after acipimox administration yields image quality and clearance rates comparable to those obtained during clamping. FDG SPET in combination with acipimox may useful in clinical routine for the assessment of myocardial viability.

Comparison of myocardial uptake of fluorine-18-fluorodeoxyglucose imaged with PET and SPECT in dyssynergic myocardium.

UNLABELLED: PET with 18F-fluorodeoxyglucose (FDG) can detect viable myocardium and predict functional recovery after revascularization. The use of PET for clinical routine, however, is limited. Recently, imaging FDG with SPECT was proposed. The aim of this study was to compare the diagnostic value of FDG-PET and FDG-SPECT in the detection of viable myocardium in segments with abnormal wall motion. METHODS: Twenty patients with previous myocardial infarction were studied. All underwent FDG-PET and FDG-SPECT during hyperinsulinemic glucose clamping. Regional perfusion was assessed with 13N-ammonia PET and early resting 201TI- SPECT. Regional wall motion was assessed with two-dimensional echocardiography. The agreement between FDG/13N-ammonia PET and FDG/201TISPECT to detect viability in dyssynergic myocardium was 76%. On a patient basis, PET and SPECT yielded comparable results in 17 of 20 patients. In a subgroup of patients with LVEF < or = 35% (n = 12), all PET and SPECT viability data were identical. CONCLUSION: This study shows a good correlation between the detection of viability in dyssynergic myocardium with FDG/13N-ammonia PET and FDG/201TI SPECT, both on a segmental and patient basis.