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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.This multicenter cohort study reports on the long-term effects of prenatal exposure to maternal cancer and its treatment on cognitive and behavioral outcomes in 9-year-old children. In total, 151 children (mean age, 9.3 years; range, 7.8-10.6 years) were assessed using a neurocognitive test battery and parent-report behavioral questionnaires. During pregnancy, 109 children (72.2%) were exposed to chemotherapy (only or in combination with other treatment modalities), 18 (11.9%) to surgery only, 16 (10.6%) to radiotherapy, one to trastuzumab, and 16 (10.6%) were not exposed to oncologic treatment. Mean cognitive and behavioral outcomes were within normal ranges. Gestational age at birth showed a positive association with Full Scale Intelligence Quotient (FSIQ), with the average FSIQ score increasing by 1.6 points for each week increase in gestational age (95% CI, 0.7 to 2.5; P <.001). No difference in FSIQ was found between treatment types (F[4,140] = 0.45, P =.776). In children prenatally exposed to chemotherapy, no associations were found between FSIQ and chemotherapeutic agent, exposure level, or timing during pregnancy. These results indicate a reassuring follow-up during the critical maturational period of late childhood, when complex functions develop and rely on the integrity of early brain development. However, associations were observed with preterm birth, maternal death, and maternal education.

Background: Chemotherapy crosses the placenta, however, it remains unclear to what extent it affects fetal growth. The current literature suggests up to 21% of the offspring of women receiving chemotherapy are small for gestational age (SGA, birth weight <10th percentile). Limiting research to birth weights only might misjudge fetal growth restriction (FGR) in this high-risk population with multiple risk factors for impaired fetal growth. Moreover, the role of the duration of chemotherapy and gestational age at initiation of chemotherapy in fetal growth is yet poorly understood. Objective: This retrospective cohort study evaluates fetal growth and neonatal birthweights in pregnant women receiving chemotherapy. Study design: All pregnant patients, registered by the International Network of Cancer, Infertility and Pregnancy (INCIP), treated with chemotherapy with at least two ultrasounds reporting on fetal growth, were eligible for this study. Duration and gestational age at initiation of chemotherapy were our major determinants, followed by cancer type and stage, maternal characteristics (parity, BMI, ethnicity hypertension, and diabetes) and individual cytotoxic agents (anthracycline, taxanes, and platinum). Fetal growth outcomes were described using the following mutually exclusive groups (1) FGR, based on a Delphi consensus (2016); (2) “low risk SGA” (birth weight below the 10th percentile), but an estimated growth above the 10th percentile; (3) “fetal growth disturbance”, which did not meet all FGR criteria; (4) “non-FGR”. Obstetric and oncological characteristics were compared between the growth impaired groups and non-FGR group. We calculated estimated fetal weight (EFW) according to Hadlock’s formula (1991) and birth weight percentile according to Nicolaides (2018). We used univariable and multivariable regression, and linear mixed effect models to investigate the effect of duration and gestational age at initiation of chemotherapy on birth weight, and feta

Chemotherapy puts a developing fetus at risk of teratogenic effects. The standard recommendation is that chemotherapy be administered after organogenesis is complete, however, the exact gestational age that chemotherapy can be administered safely and avoid causing congenital malformations remains unknown. The goal of this study was to assess the teratogenic role of prenatal chemotherapy by gestational age, to evaluate for the presence of major and minor congenital malformations during pregnancy or at birth.This was a multicenter study that evaluated all pregnant women who received chemotherapy in the International Network on Cancer, Infertility and Pregnancy (INCIP) database between 1977 and 2019.A total of 755 pregnant women treated with chemotherapy between 1977 and 2019 were included in analysis. The median age at cancer diagnosis was 33 (14-48) years. The major congenital malformation rate was 3.6% (95% confidence interval [CI], 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%) among offspring. Chemotherapy exposure before 12 weeks' gestational age was associated with a high rate of major congenital malformations, at 21.7%(95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after 12 weeks' gestation, the frequency of major congenital malformations decreased to 3.0% (95% CI, 1.9%-4.6%), which was comparable to the anticipated rates in the general population. Minor malformations were similar when exposure occurred before or after 12 weeks' gestation (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy before 12 weeks' gestation, 17 (58.6%) were not aware of their pregnancy, and 6 (20.7%) had a miscarriage (3 women [10.3%]) or elected to terminate their pregnancy (3 women [10.3%]).Overall, this study found that chemotherapy was associated with an increased risk of major congenital malformations only when it adminis

Objective: To provide contemporary gestational age-specific recommendations for management, a retrospective series of patients with renal or bladder cancer during pregnancy is reported. Methods: Obstetric and oncological data of pregnant patients with a diagnosis of renal or bladder cancer were selected from the worldwide registry of the International Network of Cancer, Infertility and Pregnancy. In addition, the literature was reviewed for recent case reports since last reviews in 2014 for renal cancer and 2004 for bladder cancer. Results: International Network of Cancer, Infertility and Pregnancy registered 22 cases (14 renal cancer and 8 bladder cancer), diagnosed between 1999 and 2017, and the literature reported 15 cases with renal cancer and 10 cases with bladder cancer between 2004 and 2019. Most common symptoms for renal and bladder cancer were pain (28%) and hematuria (66%), respectively. In more than half of the patients, surgical treatment was performed during pregnancy. Preterm deliveries were mostly medically induced (12 of 17, 71%) and all patients with a planned delivery before 34 weeks had advanced cancer. For renal and bladder cancer respectively, 79% and 87% of patients obtained complete remission. Advanced cancer stages had worse prognosis; 3 of 7 patients with known follow-up deceased within 15 months after diagnosis. Conclusion: Gestational age at diagnosis determines further management of renal and bladder cancers during pregnancy. Advanced stages challenge decision-making. The maternal needs for immediate treatment, and the neonatal risks including the impact of a preterm delivery should be discussed in a multidisciplinary setting while respecting the patient's autonomy.

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

Background: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. Methods: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. Results: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5–101.8, versus 104.4, 95% CI: 100.4–108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6–4.3, versus 4.5, 95% CI: 4.1–4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). Conclusions: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. Clinical trial registration: The study is registered at ClinicalTrials.gov, NCT00330447.

This manuscript is an accompanying resource of the original research article entitled “Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy” and present data that compare the outcome of 6-year-old-children born to women diagnosed with cancer during pregnancy (with or without treatment during pregnancy) (study group) with children born after an uncomplicated pregnancy (control group). Oncological, obstetrical and neonatal data were collected. Neurodevelopment was examined by clinical evaluation and neuropsychological testing (including intelligence, attention and memory tests) and by general health and behavior questionnaires. Cardiac evaluation included electro- and echocardiography. Univariate analyses of covariance were used to investigate between-group differences. A subgroup analysis was performed in chemotherapy-exposed children versus controls and anthracycline-exposed versus controls. Additionally, the incidence of behaviour problems was compared to matched controls for children whose mothers died and for those with surviving mothers.

Data on the long-term neurodevelopmental outcomes of children exposed to hematological maternal cancer with or without treatment during pregnancy are lacking. A total of 57 children, of whom 33 males and 24 females, prenatally exposed to hematological malignancies and its treatment, were invited for neuropsychological and physical examinations at 18months, 36months, 6, 9, 12, 15 and 18years of age. Oncological, obstetrical, neonatal and follow-up data of these children were collected. Parents were asked to complete questionnaires on their child's general health, school performances, social situation, behavioral development, executive functioning, and if their child receives supportive care. Non-Hodgkin lymphoma was diagnosed in 35.1%, Hodgkin lymphoma in 28.1%, acute myeloid leukemia in 15.8%, chronic myeloid leukemia in 12.3%, and acute lymphoblastic leukemia in 8.8%. Cognitive development at a median age of 10.7years was within the normal range. In subgroup analyses of children in early childhood, the gestational age at birth was correlated with the cognitive outcome at a median age of 1.7years. Scores for language development, intelligence, attention, memory and behavior, as well as clinical neurological and general pediatric examinations were within normal ranges. In subgroup analyses, the need for supportive care in the child was associated with the loss of the mother. Prenatal exposure to hematological maternal malignancies with or without treatment did not affect the neurodevelopment of the child in the long term. Yet, caution is indicated and surveillance of the emotional development of the child is needed, especially when the mother is deceased to cancer.

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extr

Introduction: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. Material and methods: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. Results: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, eight out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of six women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and one of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. Conclusions: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.c

Treatment of cervical cancer during pregnancy is often complex and challenging. This study aimed to analyze current patterns of practice in the management of pregnant patients diagnosed with cervical cancer.

Background: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. Methods: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. Findings: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05–1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20–1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01–1·06) and fewer

Objectives/Hypothesis: Thyroid cancer, with 6% to 10% of cancer diagnoses, is one of the most common malignancies during pregnancy. Its treatment poses a risk for the pregnancy, as the thyroid gland plays a crucial role in the evolution of pregnancy. The aim of this study is to evaluate treatment of primary well-differentiated thyroid carcinoma during pregnancy and fetal and maternal outcomes. Study Design: This is an international cohort study. Methods: Primary thyroid cancer patients were identified from the database of the International Network on Cancer, Infertility, and Pregnancy registration study. Data on histopathological characteristics, diagnostic and therapeutic interventions, outcome (obstetrical, neonatal, and maternal) and maternal follow-up were analyzed. Results: Thirty-five patients with well-differentiated thyroid carcinoma were eligible. All 35 patients underwent surgery, 29 (83%) of which during pregnancy. Procedures during pregnancy were mainly total thyroidectomies (n = 24). The median number of days between diagnosis and surgical treatment was different between the groups with surgery during and after pregnancy (27 vs. 139 days, P < .001). Both maternal and neonatal outcomes were uncomplicated, regardless of gestational age during surgery. Conclusions: Well-differentiated thyroid carcinoma diagnosed during pregnancy has a favorable outcome for both mother and child. Surgical management during pregnancy has no negative impact on the pregnancy regardless of the trimester at the time of surgery. However, the potential negative effects of thyroid surgery early in pregnancy demand management of these patients in an experienced multidisciplinary team to provide the best possible care for these patients and their unborn babies

The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.

Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor.