The effects of gonadotoxic therapy on parenthood and offspring health

Einleitung Überlebende einer Krebserkrankung im Kindes- und Jugendalter können auch Jahre nach Therapieabschluss Langzeitfolgen erleiden. Dazu zählt die Beeinträchtigung der Fruchtbarkeit, die bei Kinderwunsch die Anwendung assistierter Reproduktionstechniken (ART) notwendig machen kann. Trotz einer wachsenden Anzahl Krebsüberlebender, die ART in Anspruch nehmen, ist bisher wenig zur Gesundheit der Nachkommen bekannt. Unsere Arbeitsgruppe untersuchte erstmals das Auftreten perinataler Komplikationen (Frühgeburtlichkeit, niedriges Geburtsgewicht und small for gestational age), maligner Erkrankungen und angeborener Fehlbildungen bei Nachkommen ehemaliger kinderonkologischer Patient:innen nach spontaner und assistierter Konzeption. Methodik Unserer Multizentrischen Nachkommenstudie liegt ein exploratives, retrospektives Kohortenstudiendesign zugrunde. Mithilfe eines 10-seitigen Fragebogens befragten wir ehemalige Patient:innen in fünf europäischen Ländern (n=1 126; davon 852 aus Deutschland) zur Gesundheit ihrer Nachkommen (n=1 780; davon 1 340 aus Deutschland). Als Vergleichs-kohorte dienten die Nachkommen von Geschwistern ehemaliger Patient:innen (n=441) sowie Kinder aus der deutschen Allgemeinbevölkerung, die im Rahmen der KiGGS Studie des Robert Koch-Instituts erfasst wurden (n=17 640). Zur Beantwortung unserer Studienfragen im deutschen Studienkollektiv führten wir eine Matched-Pair Analyse (Nachkommen ehemaliger Patient:innen vs. Kinder der KiGGS Studie) und eine Subgruppen-Analyse (spontan vs. nach ART geborene Nachkommen ehemaliger Patient:innen) durch. Interaktionseffekte wurden mittels binärer logistischer Regression berechnet. Ergebnisse Sorgen hinsichtlich der Gesundheit eigener Nachkommen, insbesondere eine Krebsdiagnose betreffend, waren bei ehemaligen Patient:innen stärker ausgeprägt als bei ihren Geschwistern. Die Nachkommen ehemaliger Patient:innen wurden im Vergleich zu Kindern aus der Allgemeinbevölkerung etwas häufiger vor der 38. Schwangerschaftswoche geboren. Dennoch kam die Mehrheit der Nachkommen ehemaliger Patient:innen, unabhängig vom Konzeptionsmodus, zum Termin und eutroph zur Welt. Maligne Erkrankungen und angeborene Herzfehler traten bei den Nachkommen ehemaliger Patient:innen nicht häufiger als in der Allgemeinbevölkerung auf; Fehlbildungen wurden seltener berichtet. Eine Inanspruchnahme von ART durch Krebspatient:innen hatte keinen negativen Einfluss auf die Nachkommengesundheit. Schlussfolgerung In unserer Studie wurde erstmalig der Einfluss von ART auf die Gesundheit der Nachkommen ehemaliger kinderonkologischer Patient:innen untersucht. Für die untersuchten Parameter ergab sich kein Anhalt für eine gesundheitliche Beeinträchtigung nach Inanspruchnahme von ART durch Überlebende einer Krebserkrankung. Unter Berücksichtigung der Studienlimitationen können unsere Ergebnisse die Aufklärung vor und nach gonadotoxischer Therapie ergänzen und einen Beitrag dazu leisten, Ängste Betroffener zu reduzieren.Introduction Survivors of childhood cancer may suffer long-term treatment-related effects years after the end of therapy. Assisted reproductive techniques (ART) are required for fertility-impaired survivors to have biological children. Despite the increased usage of ART, little is yet known about the health of survivor offspring. Our working group investigated the occurrence of perinatal complications (prematurity, low birth weight, small for gestational age), malignancies and congenital malformations—including heart defects—in offspring born to childhood cancer survivors conceived either spontaneously or with reproductive assistance. Methods The Multicenter Offspring Study is based on an explorative, retrospective cohort study design. Using a 10-page questionnaire, survivors from five European countries (n=1 126; 852 from Germany) were surveyed on the health of their offspring (n=1 780; 1 340 from Germany). Offspring born to survivor siblings (n=441) as well as children from the German general population, who were enrolled in the KiGGS study conducted by the Robert Koch Institute, (n=17.640) served as comparison cohorts. Our study questions were examined in a matched-pair analysis (former patient’s offspring vs. children from KiGGS) and a subgroup analysis (former patient’s offspring conceived spontaneously vs. ART). Interaction effects were calculated using binary logistic regression. Results Concerns regarding offspring health, especially possible cancer occurrence, were more often reported by survivors than their siblings. Compared to the general population, survivor offspring had a slightly higher chance of being born prior to the completion of gestation week 37. Nevertheless, the majority of survivor offspring were born full term and eutrophic regardless of conception mode. Malignancies and congenital heart defects did not occur more frequently in survivor offspring than in children from the German general population; malformations were reported less frequently. Conception facilitated by ART had no effect on the outcomes studied. Conclusion Our study is the first to examine the impact of ART on the health of children born to childhood cancer survivors. The health-related parameters we studied showed no evidence of health impairment for survivors who implemented ART. Considering the study limitations, our results may complement patient education before and after gonadotoxic therapy and help to alleviate fears of those affected

Health‐related quality of life of children born to childhood cancer survivors in Germany

Objective: Rising childhood cancer survival rates have increased the importance of health-related quality of life (HRQL) assessment. While survivors show comparable HRQL to peers, concerns that cancer treatment could impact the health of prospective children were reported. No previous publications address HRQL of childhood cancer survivor offspring. Methods: We assessed survivor offspring HRQL using the parental KINDL questionnaire. Matched-pair analysis was conducted with data from the general population (KiGGS study) using age, gender and education (1:1, n = 1206 cases). Multivariate analyses were conducted to detect the influence of parental diagnose and treatment on offspring HRQL. Results: Overall, within KINDL dimensions, survivors reported comparable to higher HRQL for their children than the general population. Survivor parents reported significantly (p < 0.001) higher psychological (86.7% vs. 83.0%, Cohen's d = 0.3) and self-esteem (79.1% vs. 73.3%, Cohen's d = 0.5) well-being scores for younger children (3-6-year-olds). As time since diagnosis increased, parents reported higher well-being scores. Accordingly, recently diagnosed survivors reported significantly lower psychological well-being scores (p = 0.28; OR = 0.457; 95% CI = 0.228-0.918) for their children. With increasing age, average HRQL scores decreased in both cohorts; yet, this drop was less pronounced for survivor offspring. The biggest difference between age groups (7-10- vs. 14-17-year-olds) was found for school-specific well-being (6.2-point drop in survivor offspring vs. 18.2-point drop in KiGGS offspring). Conclusion: Comparable to higher parentally assessed HRQL was reported for survivor offspring compared to peers. These findings are reassuring and consistent with self-reported HRQL in childhood cancer survivors. Type of parental cancer diagnosis and treatment showed no negative impact on offspring HRQL

Health‐relatedquality of life of children born to childhood cancer survivors in Germany

Objective: Rising childhood cancer survival rates have increased the importance of health-related quality of life (HRQL) assessment. While survivors show comparable HRQL to peers, concerns that cancer treatment could impact the health of prospective children were reported. No previous publications address HRQL of childhood cancer survivor offspring. Methods: We assessed survivor offspring HRQL using the parental KINDL questionnaire. Matched-pair analysis was conducted with data from the general population (KiGGS study) using age, gender and education (1:1, n = 1206 cases). Multivariate analyses were conducted to detect the influence of parental diagnose and treatment on offspring HRQL. Results: Overall, within KINDL dimensions, survivors reported comparable to higher HRQL for their children than the general population. Survivor parents reported significantly (p < 0.001) higher psychological (86.7% vs. 83.0%, Cohen's d = 0.3) and self-esteem (79.1% vs. 73.3%, Cohen's d = 0.5) well-being scores for younger children (3–6-year-olds). As time since diagnosis increased, parents reported higher well-being scores. Accordingly, recently diagnosed survivors reported significantly lower psychological well-being scores (p = 0.28; OR = 0.457; 95% CI = 0.228–0.918) for their children. With increasing age, average HRQL scores decreased in both cohorts; yet, this drop was less pronounced for survivor offspring. The biggest difference between age groups (7–10- vs. 14–17-year-olds) was found for school-specific well-being (6.2-point drop in survivor offspring vs. 18.2-point drop in KiGGS offspring). Conclusion: Comparable to higher parentally assessed HRQL was reported for survivor offspring compared to peers. These findings are reassuring and consistent with self-reported HRQL in childhood cancer survivors. Type of parental cancer diagnosis and treatment showed no negative impact on offspring HRQL.Peer Reviewe

Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies

Purpose: An increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART. Methods: The FeCt Multicenter Offspring Study surveyed the health of offspring of childhood cancer survivors. Health outcomes in offspring born to survivors following ART (n = 57, 4.6%) or after spontaneous conception (n = 1182) were assessed in the German cohort (n = 1239) using bivariate analysis. Findings were put into the context of the general German population by health outcome assessment in 1:1 matched-pair analysis (n = 2478). Results: Nearly twice the survivors used ART compared with numbers reported for the German general population (4.6% vs. 2.6%). Successful pregnancies were achieved after a median of two cycles, mainly using non-cryopreserved oocytes/sperm. Multiple sibling births (p < 0.001, 28.1% vs. 3.0%) and low birth weight (p = 0.008; OR = 2.659, 95% CI = 1.258-5.621) occurred significantly more often in offspring born to survivors who utilized ART than spontaneously conceived children, whereas similar percentages were born preterm or too small for their gestational age. ART did not increase the prevalence of childhood cancer or congenital malformations in offspring born to survivors. Conclusion: ART use by childhood cancer survivors was successful with both fresh and cryopreserved oocytes/sperm, and did not influence perinatal health or health outcomes when known confounders were taken into account. Implications for cancer survivors: Oncofertility is an important component of patient care. Our study implicates that the utilization of ART by adult survivors of childhood cancer does not put offspring at additional risk for adverse perinatal or health outcomes

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

Background: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. Methods: FIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m(2) body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. Discussion: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy

Desire for biological parenthood and patient counseling on the risk of infertility among adolescents and adults with hemoglobinopathies.

BACKGROUND Both diagnosis and treatment of hemoglobinopathies have been associated with an increased risk of fertility impairment. German guidelines recommend annual monitoring of fertility parameters to enable early detection of fertility impairment and/or to offer fertility preservation (FP) when indicated. We explored the general desire for parenthood, the frequency of recalling fertility counseling and testing, and the utilization of FP in adolescents and adults with hemoglobinopathies. PROCEDURE In a cross-sectional study, patients aged 12-50 years, treated in Germany, Austria, or Switzerland, were surveyed on fertility-related aspects. Medical data, including fertility testing results, were collected from patient records. RESULTS Overall, 116/121 eligible patients, diagnosed with sickle cell disease (70.7%), thalassemia (27.6%), or other hemoglobinopathy (1.7%), participated in our study (57.8% female, median age 17.0 years, range 12-50 years). All participants required treatment of the underlying hemoglobinopathy: 68.1% received hydroxyurea, 25.9% required regular blood transfusions, and 6.0% underwent hematopoietic stem cell transplantation (HSCT). Most patients (82/108, 75.9%) stated a considerable to strong desire for (future) parenthood, independent of sex, education, diagnosis, or subjective health status. Fertility counseling was only recalled by 32/111 patients (28.8%) and least frequently by younger patients (12-16 years) or those treated with regular blood transfusions or hydroxyurea. While fertility testing was documented for 59.5% (69/116) in medical records, only 11.6% (13/112) recalled previous assessments. FP was only used by 5.4% (6/111) of patients. CONCLUSION Most patients with hemoglobinopathies wish to have biological children, yet only few recalled fertility counseling and testing. Adequate patient counseling should be offered to all patients at risk for infertility

Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials

Background: Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. // Methods: We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. // Results: A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. // Conclusions: This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features