Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

The impact of cancer and chemotherapy during pregnancy on child neurodevelopment: A multimodal neuroimaging analysis.

BACKGROUND: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. METHODS: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state blood-oxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-by-GA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. FINDINGS: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR ≤ 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. INTERPRETATION: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. FUNDING: This project has received funding from the European Union's Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014-152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N).

Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

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.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.

Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel.

BACKGROUND: Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. PATIENTS AND METHODS: A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients. RESULTS: The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%). CONCLUSION: Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.

Estradiol and weight are covariates of paracetamol clearance in young women.

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Polypoid endometriosis of the bladder during pregnancy mimicking urachal carcinoma.

We report a case of polypoid bladder endometriosis in pregnancy. Diagnostic workup showed a vesicouterine well-vascularized polypoid mass, suspicious for malignancy. During pregnancy, the mass was surgically resected with safe oncological margins. Pathological examination of the resected specimen revealed pseudotumoral polypoid endometriosis of the bladder. We illustrate diagnostic pitfalls in the differentiation between bladder endometriosis during pregnancy and malignancy. As a result of pregnancy-related decidualization of vesical endometriosis, differentiation between this rare occurrence and malignant transformation is challenging.

Postpartum breast cancer behaves differently.

BACKGROUND AND AIM: Previous studies suggest a worse prognosis for postpartum breast cancer (PPBC) diagnosed within the first 12 months following delivery. We investigated this hypothesis in our setting through a retrospective pilot study. METHODS: A retrospective multicentre paired case-control study of breast cancer patients diagnosed under age 45 from the UZ Leuven database or affiliated centres. We compared disease outcome of women with a PPBC and those without a pregnancy associated breast cancer (PABC). They were matched for the following prognostic markers: age at diagnosis, tumour type, characteristics and stage. Kaplan-Meier statistics were applied for overall and disease free survival. RESULTS: 53 PPBC cases were matched with 103 controls. All PPBC patients were diagnosed with an invasive ductal carcinoma. Axillary lymph nodes were involved in 56.6% of cases and 13% were primary metastasized at diagnosis. A third was triple-negative and another third was HER-2-positive.The 5-year overall survival was 60% and 84% respec-tively for PPBC cases and control group. 5-year disease free survival was respectively 53% and 68%. CONCLUSIONS: We confirm that postpartum breast cancer behaves more aggressively than the matched non-PABC group. Longer follow-up and extension of the study group are necessary to confirm these findings.

Chemotherapy during pregnancy: pharmacokinetics and impact on foetal neurological development.

Based on an estimated incidence of cancer during pregnancy of 1 per 1000-1500 pregnancies, annualy 3000-5000 new patients can be expected in Europe. The treatment of cancer in pregnant women is a challenge since both the maternal and the foetal well-being need to be considered. This study was initiated to gain better insights into the problems associated with cancer and chemotherapy during pregnancy. A multicentric registration study was set up to evaluate the currently applied treatment modalities for cancer during pregnancy, and the consequences of their use for the pregnancy. Secondly, a preclinical and clinical pharmacological study addressing pharmacokinetics of chemotherapy in pregnant women and transplacental passage of chemotherapy was performed. Thirdly, we investigated the effects of prenatal exposure to chemotherapy on foetal neurological development. We observed an equal distribution of tumour types between pregnant and age matched nonpregnant women. Data on neonatal outcome suggest that exposure to chemotherapy in the 2nd or 3rd trimester of pregnancy does not worsen the outcome. This finding is explained by the fact that chemotherapy is not administered during the period of organogenesis and by the foetal protection by the placental barrier-function. Physiological changes of pregnancy resulted in a decreased plasma drug exposure of chemotherapeutic agents. Before major conclusions can be drawn with regard to the long term foetal outcome and the efficacy of chemotherapy during pregnancy, more patients and a longer follow up period is required. Therefore, this research project is continued and expanded nationally and internationally.

Breast cancer during pregnancy: a literature review.

Breast cancer during pregnancy is relatively uncommon. However, the incidence is expected to increase as more women delay childbearing. A challenging situation emerges for all persons involved ­ patient, family and medical care workers ­ since two lives are at risk with contradicting priorities. Breast cancer treatment is possible during pregnancy. The treatment plan needs to adhere as closely as possible to standardised protocols for nonpregnant patients, with some considerations to minimize fetal exposure and risks. This concerns mainly limiting radiation exposure and timing of chemotherapy to start in the second trimester. The prognosis of pregnant women does not seem to differ from that of nonpregnant patients when matched for age and stage of the disease. This literature review concentrates on the diagnosis, treatment and outcome of patients diagnosed with breast cancer during pregnancy.

Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model.

OBJECTIVE: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS: Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS: In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.

Chemotherapy during pregnancy: pharmacokinetics and impact on foetal neurological development.

Based on an estimated incidence of of 1 cancer case per 1000-1500 pregnancies, 3000-5000 new patients can be -expected in Europe annually. The treatment of cancer in pregnant women is a challenge since both the maternal and the fetal well-being need to be considered. This study was initiated to gain more insight into the problems associated with cancer and chemotherapy during pregnancy. A multicentric registration study was set up to evaluate the currently applied treatment modalities for cancer during pregnancy, and the consequences of their use for pregnancy. Secondly, a preclinical and clinical pharmacological study addressing pharmacokinetics of chemotherapy in pregnant women and transplacental passage of chemotherapy was performed. Thirdly, we investigated the effects of prenatal exposure to chemotherapy on fetal neurological development. We observed an equal distribution of tumour types between pregnant and age-matched nonpregnant women. Data on neonatal outcome suggest that exposure to chemotherapy in the 2nd or 3rd trimester of pregnancy does not worsen outcome. This finding is explained by the fact that chemotherapy is not administered during the period of organogenesis and by the fetal protection offered by the placental barrier-function. Physiological changes of pregnancy resulted in a decreased plasma drug exposure of chemotherapeutic agents. Before major conclusions can be drawn with regard to the long term fetal outcome and the efficacy of chemotherapy during pregnancy, more patients and a longer follow up period is required. Therefore, this research project is continued and expanded nationally and internationally.

Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: report of a case and review of the literature.

Although cervical carcinoma is among the most frequently encountered malignancies during pregnancy, only four cases of neoadjuvant chemotherapy during pregnancy have been reported. A 28-year-old A0P1G2M0 was diagnosed at 15 weeks with stage Ib1 invasive squamous cervical cancer. Because she strongly desired the continuation of this pregnancy, after extensive counseling she was treated with 75 mg/m(2) cisplatin every 10 days starting at 17 weeks. After six cycles, clinically and radiologically stable disease with normalization of the squamous cell carcinoma tumor marker was obtained. An elective cesarean delivery followed by radical hysterectomy and lymphadenectomy was performed at 32 weeks gestation. The pathology report revealed a moderately differentiated squamous cell carcinoma of 3.5 cm, and all 33 lymph nodes were free of disease. Neonatal examination of the baby could not reveal any abnormalities, and this was confirmed at 6 months. The use of neoadjuvant chemotherapy enabled us to continue this pregnancy until the fetus was viable. Cisplatin did not influence the short-term outcome, but only a long-term follow-up will inform us on its safety during pregnancy.

Cervical neoplasia during pregnancy: diagnosis, management and prognosis.

Pregnancy represents an exceptional opportunity for the early diagnosis of cervical cancer since visual inspection, cytological examination and bimanual palpation are considered to be part of routine antenatal care. An abnormal cervical smear should generally be managed as in the non-pregnant state. However, colposcopy and biopsies are mainly intended to exclude invasive disease because a conservative approach is preferred in cases of pre-invasive disease. The only absolute indication for conization in pregnancy is to rule out (micro-)invasive disease or make the diagnosis of invasive carcinoma when such a diagnosis will alter the timing or mode of delivery. Overall, earlier stages of cervical cancer are encountered during pregnancy compared with the general population. Although stage of disease and gestational age will largely influence the timing of the interventions, treatment of invasive cervical cancer is similar to the non-pregnant state. In strongly desired pregnancies, the use of neo-adjuvant chemotherapy in order to obtain fetal maturity should be considered and discussed with the patient. Although good evidence supports short-term safety, long-term data regarding the in-utero exposure of cytotoxic drugs need to be consolidated. After stratifying for stage, the outcome is similar to the non-pregnant state.