Publications by authors named "Petronella B Ottevanger"

66 Publications

Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol.

BMJ Open 2021 11 30;11(11):e050725. Epub 2021 Nov 30.

Department of Tumor Immunology, Radboudumc, Nijmegen, The Netherlands

Introduction: The undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers.

Methods And Analysis: This open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1.

Ethics And Dissemination: The Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal.

Trial Registration Number: NCT04751786.
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http://dx.doi.org/10.1136/bmjopen-2021-050725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634237PMC
November 2021

CD34 progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rg mice.

Oncoimmunology 2021 1;10(1):1981049. Epub 2021 Oct 1.

Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center/Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Combining natural killer (NK) cell adoptive transfer with tumor-sensitizing chemotherapy is an attractive approach against recurrent ovarian cancer (OC), as OC is sensitive to NK cell-mediated immunity. Previously, we showed that CD34 hematopoietic progenitor cell (HPC)-derived NK cells can kill OC cells and inhibit OC tumor growth in mice. Here, we investigated the potential of HPC-NK cell therapy combined with chemotherapeutic gemcitabine (used in recurrent OC patients) against OC. We examined the phenotypical, functional, and cytotoxic effects of gemcitabine on HPC-NK cells and/or OC cells and in OC-bearing mice. To this end, we treated OC cells and/or HPC-NK cells with or without gemcitabine and analyzed the phenotype, cytokine production, and anti-tumor reactivity. We found that gemcitabine did not affect the phenotype and functionality of HPC-NK cells, while on OC cells expression of NK cell activating ligands and death receptors was upregulated. Although gemcitabine pre-treatment of OC cells did not improve the functionality of HPC-NK cells, importantly, HPC-NK cells and gemcitabine additively killed OC cells . Similarly, combined HPC-NK cell and gemcitabine treatment additively decreased tumor growth in OC-bearing mice. Collectively, our results indicate that combination therapy of HPC-NK cells and gemcitabine results in augmented OC killing and . This provides a rationale for exploring this therapeutic strategy in patients with recurrent OC.
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http://dx.doi.org/10.1080/2162402X.2021.1981049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489932PMC
October 2021

Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

Gynecol Oncol 2021 12 30;163(3):531-537. Epub 2021 Sep 30.

Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Background: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement.

Methods: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment.

Results: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity.

Conclusion: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.
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http://dx.doi.org/10.1016/j.ygyno.2021.09.016DOI Listing
December 2021

Evaluation of two strategies to implement physical cancer rehabilitation guidelines for survivors of abdominopelvic cavity tumors: a controlled before-and-after study.

J Cancer Surviv 2021 Sep 14. Epub 2021 Sep 14.

Scientific Institute for Quality of Healthcare (IQ healthcare), Radboud Institute for Health Science (RIHS), Radboud University Medical Center Nijmegen, PO Box 9101, 6500, HB, Nijmegen, the Netherlands.

Purpose: This study evaluates the effectiveness and feasibility of two strategies to implement physical cancer rehabilitation (PCR) guidelines for patients who have survived abdominopelvic cavity malignancies.

Methods: We tested and compared two tailored strategies to implement PCR guidelines for survivors of gastrointestinal, female organ and urogenital organ malignancies, in a clustered controlled before-and-after study. A patient-directed (PD) strategy was tested in five cancer centers, aiming to empower survivors. A multifaceted (MF) strategy was tested in four cancer centers, aiming additionally to influence healthcare professionals and the healthcare organization. Data were collected from existing registration systems, patient questionnaires and professional questionnaires. We measured both implementation- and client outcomes. For insight into the effectiveness we measured indicators related to PCR guidelines: (1) screening with the Distress Thermometer (DT) (=primary outcome measure), (2) information provision concerning physical activity (PA) and physical cancer rehabilitation programs (PCRPs), (3) advice to take part in PA and PCRPs, (4) referral to PCRPs, (5) participation in PCRPs, (6) PA uptake (PAU); and patient reported outcomes (PROs) such as (7) quality of life, (8) fatigue, and (9) empowerment. Furthermore, survivor and center determinants were assessed as possible confounders. Multilevel analyses were performed to compare the scores of the indicators of the PD and MF strategies, as well as the differences between the characteristics of these groups. The use of and experiences with both strategies were measured using questionnaires and Google Analytics to assess feasibility.

Results: In total, 1326 survivors participated in the study, 673 in the before- and 653 in the after-measurement. Regarding our primary outcome measure, we found a significant improvement of screening with the DT between the before- and after-measurement for both strategies, respectively from 34.2 to 43.1% (delta=8.9%; odds ratio (OR)=1.6706; p=0.0072) for the PD strategy and from 41.5 to 56.1% (delta=14.6%; OR=1.7098; p=0.0028) for the MF strategy. For both the primary and secondary outcomes, no statistically significant effect of the MF strategy compared to the PD strategy was observed. We found good use of and positive experiences with both strategies.

Conclusion: Implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT for survivors of abdominopelvic cavity malignancies. Further research is needed to assess the additional effectiveness of strategies that stimulate compliance among healthcare professionals and healthcare organizations.

Implications For Cancer Survivors: Using implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT and might improve the quality of care of patients who have survived abdominopelvic cavity malignancies.
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http://dx.doi.org/10.1007/s11764-021-01045-3DOI Listing
September 2021

Association of Chemotherapy Timing in Pregnancy With Congenital Malformation.

JAMA Netw Open 2021 06 1;4(6):e2113180. Epub 2021 Jun 1.

Center for Gynecological Oncology Amsterdam, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Amsterdam, the Netherlands.

Importance: Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear.

Objective: To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer.

Design, Setting, And Participants: This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020.

Exposures: Cancer treatment with chemotherapy during pregnancy.

Main Outcomes And Measures: Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth.

Results: A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 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 gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (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 prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%]).

Conclusions And Relevance: This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.13180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190627PMC
June 2021

Immune cell composition in the endometrium of patients with a complete molar pregnancy: Effects on outcome.

Gynecol Oncol 2021 02 17;160(2):450-456. Epub 2020 Nov 17.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Objective: In 15% of patients with complete hydatidiform mole (CHM), disease progresses to post-molar gestational trophoblastic neoplasia (GTN) after curettage. Tumor infiltrating lymphocytes (TILs) are essential in overcoming disease in many tumors. Infiltrating lymphocyte composition and density may influence trophoblast regression and development of post-molar GTN. We analyzed immune cell composition and density in curettaged endometrium of patients with CHM which spontaneously regressed, and of patients with CHM which progressed to post-molar GTN.

Methods: Sixteen patients with CHM and spontaneous regression, and 16 patients with CHM which progressed to post-molar GTN were selected. Immune cell composition and density of natural killer (NK) cells, natural killer T (NKT)-like cells, Cytotoxic T cells, T-Regulatory and T-Helper cells, were determined by multiplex immunohistochemistry (mIHC).

Results: Curettaged endometrium of patients with CHM and spontaneous regression contained a slightly higher number of immune cells compared to patients with CHM which progressed to post-molar GTN. NKT-like cell density was significantly higher in patients with spontaneous regression compared to patients with CHM which progressed to post-molar GTN (483 ± 296 vs.295 ± 143 (mean ± SD), p = 0.03) respectively. NKT-like cell density in the spontaneous regression group was split in 'high' and 'low' (i.e. above and below the median number of NKT-like cells). In patients with high NKT-like cell density, hCG normalized earlier than in patients with low NKT-like cell density (9.5 weeks, (range 3.7-14) vs. 12.9 weeks, (range 8.6-17.9), p = 0.05).

Conclusion: A high number of NKT-like cells in the endometrium of CHMs may contribute to spontaneous regression of molar trophoblast cells.
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http://dx.doi.org/10.1016/j.ygyno.2020.11.005DOI Listing
February 2021

High Health-Related Quality of Life During Dendritic Cell Vaccination Therapy in Patients With Castration-Resistant Prostate Cancer.

Front Oncol 2020 26;10:536700. Epub 2020 Oct 26.

Department of Medical Oncology, Radboudumc, Nijmegen, Netherlands.

Background: Maintaining health-related quality of life (HRQoL) is highly desirable during systemic therapies for patients with castration-resistant prostate cancer (CRPC). Patient-reported outcome measures (PROs) were studied in our phase IIa trial on cellular-based immunotherapy with dendritic cells (DC).

Methods: We treated 21 chemo-naive asymptomatic or minimally symptomatic patients with CRPC with maximally three cycles of DC vaccinations (ClinicalTrials.gov, NCT02692976). Here, we report the impact of DC vaccination on HRQoL. PROs were assessed using the EORTC-QLQ-C30, the EORTC-QLQ-PR25, Checklist Individual Strength (CIS20-R), and Beck Depression Inventory Primary Care questionnaires. Short-term and long-term vaccine-related effects on HRQoL were studied.

Results: Questionnaires were collected at baseline (n=20), week 6 (n=19), week 12 (n=18), week 24 (n=13), week 50 (n=8) and week 100 (n=2). No clinically relevant differences in symptom-related outcome, functioning-related outcome, and Global Health Status were observed directly after the first cycle of DC vaccinations (week 6) and at follow-up (week 12) compared to baseline. HRQoL remained high throughout the vaccination cycle and six weeks afterward. In radiographic non-progressive patients, who continued DC vaccination, high HRQoL scores were observed up to one and two years after study enrolment.

Conclusions: Patients with asymptomatic or minimally symptomatic CRPC show high HRQoL throughout DC-based immunotherapy. This is a clinically relevant finding in this older-aged patient population with advanced prostate cancer.
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http://dx.doi.org/10.3389/fonc.2020.536700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649342PMC
October 2020

Determinants of adherence to physical cancer rehabilitation guidelines among cancer patients and cancer centers: a cross-sectional observational study.

J Cancer Surviv 2021 02 28;15(1):163-177. Epub 2020 Sep 28.

Scientific Institute for Quality of Healthcare (IQ Healthcare), Radboud Institute for Health Science (RIHS), Radboud University Medical Center Nijmegen, PO Box 9101, Nijmegen, 6500, HB, The Netherlands.

Purpose: To tailor implementation strategies that maximize adherence to physical cancer rehabilitation (PCR) guidelines, greater knowledge concerning determinants of adherence to those guidelines is needed. To this end, we assessed the determinants of adherence to PCR guidelines in the patient and cancer center.

Methods: We investigated adherence variation of PCR guideline-based indicators regarding [1] screening with the Distress Thermometer (DT), [2] information provision concerning physical activity (PA) and physical cancer rehabilitation programs (PCRPs), [3] advice to take part in PA and PCRPs, [4] referral to PCRPs, [5] participation in PCRPs, and [6] PA uptake (PAU) in nine cancer centers. Furthermore, we assessed patient and cancer center characteristics as possible determinants of adherence. Regression analyses were used to determine associations between guideline adherence and patient and cancer center characteristics. In these analyses, we assumed the patient (level 1) nested within the cancer center (level 2).

Results: Nine hundred and ninety-nine patients diagnosed with cancer between January 2014 and June 2015 were included. Of the 999 patients included in the study, 468 (47%) received screening with the DT and 427 (44%) received information provision concerning PA and PCRPs. Subsequently, 550 (56%) patients were advised to take part in PA and PCRPs, which resulted in 174 (18%) official referrals. Ultimately, 280 (29%) patients participated in PCRPs, and 446 (45%) started PAU. Screening with the DT was significantly associated with information provision concerning PA and PCRPs (OR 1.99, 95% CI 1.47-2.71), advice to take part in PA and PCRPs (OR 1.79, 95% CI 1.31-2.45), referral to PCRPs (OR 1.81, 95% CI 1.18-2.78), participation in PCRPs (OR 2.04, 95% CI 1.43-2.91), and PAU (OR 1.69, 95% CI 1.25-2.29). Younger age, male gender, breast cancer as the tumor type, ≥2 cancer treatments, post-cancer treatment weight gain/loss, employment, and fatigue were determinants of guideline adherence. Less variation in scores of the indicators between the different cancer centers was found. This variation between centers was too low to detect any association between center characteristics with the indicators.

Conclusions: The implementation of PCR guidelines is in need of improvement. We found determinants at the patient level associated with guideline-based PCR care.

Implications For Cancer Survivors: Implementation strategies that deal with the determinants of adherence to PCR guidelines might improve the implementation of PCR guidelines and the quality of life of cancer survivors.
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http://dx.doi.org/10.1007/s11764-020-00921-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822788PMC
February 2021

Maternal and neonatal outcomes in 80 patients diagnosed with non-Hodgkin lymphoma during pregnancy: results from the International Network of Cancer, Infertility and Pregnancy.

Br J Haematol 2021 04 18;193(1):52-62. Epub 2020 Sep 18.

Department of Oncology, KU Leuven, Leuven, Belgium.

This cohort study of the International Network on Cancer, Infertility and Pregnancy (INCIP) reports the maternal and neonatal outcomes of 80 pregnant patients diagnosed with non-Hodgkin lymphoma (NHL) between 1986 and 2019, focussing on 57 (71%) patients with diffuse large B-cell lymphoma (DLBCL). Of all 80 patients, 54 (68%) pregnant patients received chemotherapy; mostly (89%) CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens. Four early pregnancies were terminated. Among 76 ongoing pregnancies, there was one stillbirth (1·3%). Overall, there was a high incidence of small for gestational age neonates (39%), preterm delivery (52%), obstetric (41%) and neonatal complications (12·5%), and this could not exclusively be explained by the receipt of antenatal chemotherapy. Half of preterm deliveries (46%) were planned in order to tailor oncological treatment. The 3-year progression-free and overall survival for patients with DLBCL treated with rituximab-CHOP was 83·4% and 95·7% for limited stage (n = 29) and 60·6% and 73·3% for advanced stage (n = 15). Of 36 pregnant patients who received rituximab, five (13%) cases with neonatal complications and three (8%) with maternal infections were reported. In conclusion, standard treatment for DLBCL can be offered to pregnant patients in obstetric centres that cater for high-risk patients.
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http://dx.doi.org/10.1111/bjh.17103DOI Listing
April 2021

Data describing child development at 6 years after maternal cancer diagnosis and treatment during pregnancy.

Data Brief 2020 Oct 21;32:106209. Epub 2020 Aug 21.

Center for Gynecologic Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.dib.2020.106209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479323PMC
October 2020

Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy.

Eur J Cancer 2020 10 25;138:57-67. Epub 2020 Aug 25.

Department of Oncology, KU Leuven, Leuven, Belgium; Center for Gynecologic Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Department of Obstetrics and Gynecology, Amsterdam UMC, Location Amsterdam Medical Center and University of Amsterdam, the Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejca.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532701PMC
October 2020

Impact of different adjuvant treatment approaches on survival in stage III endometrial cancer: A population-based study.

Eur J Cancer 2020 07 23;133:104-111. Epub 2020 May 23.

Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Background: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage III endometrial cancer (EC) have a substantial risk of adverse outcomes. After surgery, adjuvant therapy is recommended with external beam radiotherapy (EBRT), chemotherapy (CT) or both EBRT and CT. Recent trials suggest that EBRT + CT is superior to EBRT or CT alone but also results in more toxicity. We have compared the outcome of different adjuvant treatments in a population-based cohort to identify subgroups that benefit most from EBRT + CT.

Methods: All patients diagnosed with FIGO stage III EC and treated with surgery in 2005-2016 were identified from the Netherlands Cancer Registry. The primary outcome was overall survival (OS); associations with adjuvant treatment were analysed using Cox regression analysis.

Results: Among 1241 eligible patients, EBRT + CT was associated with a better OS than CT (hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34-2.52) and EBRT alone (HR = 1.37, 95% CI = 1.05-1.79). In stage IIIC, there was a significant benefit of EBRT + CT compared with CT or EBRT alone. In stage IIIA-B, there was no difference between EBRT + CT or EBRT alone. In endometrioid EC (EEC) and carcinosarcomas, EBRT + CT was associated with a better OS than CT or EBRT alone. For uterine serous cancers, there was no survival benefit of EBRT + CT over CT. In all analysis by stage and histology, any adjuvant treatment was superior to no adjuvant therapy.

Conclusions: In this population-based study, adjuvant EBRT + CT was associated with improved OS compared with CT or EBRT alone in FIGO stage IIIC EC, EEC and carcinosarcoma. This suggests that application of EBRT + CT in stage III should be further stratified according to these subgroups.
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http://dx.doi.org/10.1016/j.ejca.2020.04.012DOI Listing
July 2020

Neoadjuvant Chemotherapy Followed by Vaginal Radical Trachelectomy as Fertility-Preserving Treatment for Patients with FIGO 2018 Stage 1B2 Cervical Cancer.

Oncologist 2020 07 11;25(7):e1051-e1059. Epub 2020 May 11.

Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (i.e., tumor size between 2 and 4 cm) is a radical hysterectomy (RH) with pelvic lymph node dissection (PLND). We evaluated the oncological and fertility outcomes treatment in patients receiving a fertility-sparing alternative consisting of neoadjuvant chemotherapy (NACT) followed by vaginal radical trachelectomy (VRT).

Methods: Patients with stage 1B2 cervical cancer who wished to preserve fertility were included from September 2009 to September 2018. NACT consisted of 6-week cycles of cisplatin or carboplatin with paclitaxel. If tumor size decreased to 2 cm or smaller, NACT was followed by a robot-assisted PLND and VRT.

Results: Eighteen patients were included. Median follow-up time was 49.7 months (range 11.4-110.8). Median tumor size was 32 mm (range 22-40 mm). Complete remission after NACT occurred in seven women. Four women had a poor response on NACT. Three underwent RH with PLND; one received chemoradiation after PLND instead of VRT because of positive lymph nodes. The remaining 14 patients received VRT 3-4 weeks after NACT. Four recurrences occurred: three after NACT and VRT and one after NACT and RH. Median time to recurrence was 20.8 months (range 17.0-105.7). Three recurrences occurred in women with adenocarcinoma with lymph vascular space invasion (LVSI). In four women fertility could not be preserved. To date, four women had six pregnancies, including three live births born at term, two first trimester miscarriages, and one currently ongoing pregnancy.

Conclusion: NACT and VRT in women with stage 1B2 cervical cancer showed promising results. In 78% fertility was preserved. However, patients with poor response on NACT and with adenocarcinoma and/or LVSI were possibly at risk for recurrence. Long-term results in relation to fertility and oncological outcome are needed to corroborate these findings.

Implications For Practice: Standard treatment for women with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (tumor size 2-4 cm) is a radical hysterectomy and pelvic lymph node dissection (PLND). However, many of these women are young and wish to preserve fertility. Data on fertility-sparing treatment options are sparse, but neoadjuvant chemotherapy followed by a vaginal radical trachelectomy and PLND could be an alternative. Since 2009 we performed an observational cohort study in which 18 women opted for this treatment in our center. In 14 women fertility could be preserved. In four patients the tumor recurred. In four women six pregnancies occurred. After careful selection this treatment could be a good fertility-sparing treatment option.
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http://dx.doi.org/10.1634/theoncologist.2020-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356752PMC
July 2020

Strong vaccine responses during chemotherapy are associated with prolonged cancer survival.

Sci Transl Med 2020 03;12(535)

Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, Netherlands.

Therapeutic cancer vaccines have effectively induced durable regressions of premalignant oncogenic human papilloma virus type 16 (HPV16)-induced anogenital lesions. However, the treatment of HPV16-induced cancers requires appropriate countermeasures to overcome cancer-induced immune suppression. We previously showed that standard-of-care carboplatin/paclitaxel chemotherapy can reduce abnormally high numbers of immunosuppressive myeloid cells in patients, allowing the development of much stronger therapeutic HPV16 vaccine (ISA101)-induced tumor immunity. We now show the clinical effects of ISA101 vaccination during chemotherapy in 77 patients with advanced, recurrent, or metastatic cervical cancer in a dose assessment study of ISA101. Tumor regressions were observed in 43% of 72 evaluable patients. The depletion of myeloid suppressive cells by carboplatin/paclitaxel was associated with detection of low frequency of spontaneous HPV16-specific immunity in 21 of 62 tested patients. Patients mounted type 1 T cell responses to the vaccine across all doses. The group of patients with higher than median vaccine-induced immune responses lived longer, with a flat tail on the survival curve. This demonstrates that chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.
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http://dx.doi.org/10.1126/scitranslmed.aaz8235DOI Listing
March 2020

Effect of a Skills Training for Oncologists and a Patient Communication Aid on Shared Decision Making About Palliative Systemic Treatment: A Randomized Clinical Trial.

Oncologist 2020 03 26;25(3):e578-e588. Epub 2019 Nov 26.

Department of Medical Psychology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM.

Methods: In this multicenter randomized controlled trial with four parallel arms (2016-2018), oncologists (n = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients (n = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio-recorded consultations. Secondary outcomes included patient-reported SDM, patient and oncologist satisfaction, patients' decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made.

Results: The oncologist training had a large positive effect on observed SDM (Cohen's d = 1.12) and on patient-reported SDM (d = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients' decisional conflict, quality of life, consultation duration, or the decision made.

Conclusion: Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient-reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice.

Trial Registration: Netherlands Trial Registry NTR 5489.

Implications For Practice: Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient-reported SDM in clinical encounters (n = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists' practice and should be implemented in (continuing) educational programs.
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http://dx.doi.org/10.1634/theoncologist.2019-0453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066716PMC
March 2020

Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 01 3;3(1):e1918939. Epub 2020 Jan 3.

SGCTG, Beatson West of Scotland Cancer Centre, NHS (National Health Service) Greater Glasgow and Clyde, Glasgow, United Kingdom.

Importance: The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types.

Objective: To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer.

Data Sources: In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials.

Study Selection: Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm.

Data Extraction And Synthesis: Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019.

Main Outcomes And Measures: Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria.

Results: In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS.

Conclusions And Relevance: This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.18939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991254PMC
January 2020

Does a regular nurse-led distress screening and discussion improve quality of life of breast cancer patients treated with curative intent? A randomized controlled trial.

Psychooncology 2020 04 11;29(4):719-728. Epub 2020 Feb 11.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Objective: We performed a randomized controlled trial (RCT) to investigate whether regular screening with the distress thermometer (DT) by a nurse improved global quality of life (QOL) of patients with breast cancer (BC) treated with curative intent.

Methods: BC patients were randomized between regular screening for distress with a nurse-led DT intervention (NDTI) and usual care (UC). Both groups filled out questionnaires at baseline, after each received treatment modality and at follow-up visits up to 2 years. At these points, the intervention group received also the NDTI. The primary outcome was the global QOL of the EORTC QLQ C30 at 2 years after the end of treatment. Analyses were done on an intention-to-treat basis, using analysis of covariance (ANCOVA), generalized least squares, and interaction analyses.

Results: Of 194 randomized patients, 153 filled out the questionnaires up to 2 years after treatment. There was no significant difference between NDTI and UC in global QOL 2 years after the end of treatment (mean diff. = -1∙273, P = .610; 95% CI [-6.195; 3.649]). Subgroup analysis of patients who received multimodality treatment (surgery, radiotherapy, and chemotherapy, n = 66) showed a significant between-group difference in global QOL over time (mean diff. = -10, P < .001; 95% CI [-14.835; -5.167]) together with other secondary outcome measures in favor of the NDTI.

Conclusion: NDTI did not lead to a significant improvement in global QOL 2 years after the end of treatment for patients with BC. However, the findings indicate that BC patients who received multimodality treatment may benefit from NDTI.
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http://dx.doi.org/10.1002/pon.5324DOI Listing
April 2020

Healthcare professionals' perspectives of barriers and facilitators in implementing physical activity programmes delivered to cancer survivors in a shared-care model: a qualitative study.

Support Care Cancer 2020 Jul 2;28(7):3429-3440. Epub 2019 Dec 2.

Radboud Institute for Health Science (RIHS), Department of Medical Oncology, Radboud University Medical Center Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: The positive impact of physical activity programmes has been recognised, but the current uptake is low. Authorities believe delivering these programmes in a shared-care model is a future perspective. The present study aimed to identify the barriers and facilitators affecting physical activity programme implementation in a shared-care model delivered with the cooperation of all the types of healthcare professionals involved.

Methods: Thirty-one individual interviews with primary healthcare professionals (PHPs) and four focus group interviews with 39 secondary healthcare professionals (SHPs) were undertaken. We used Grol and Flottorp's theoretical models to identify barriers and facilitators in six domains: (1) physical activity programmes, (2) patients, (3) healthcare professionals, (4) social setting, (5) organisation and (6) law and governance.

Results: In the domain of physical activity programmes, those physical activity programmes that were non-tailored to the patients' needs impeded successful implementation. In the domain of healthcare professionals, the knowledge and skills pertaining to physical activity programmes and non-commitment of healthcare professionals impeded implementation. HCPs expressed their concerns about the negative influence of the patient's social network. Most barriers occurred in the domain of organisation. The PHPs and SHPs raised concerns about ineffective collaboration and networks between hospitals. Only the PHPs raised concerns about poor communication, indeterminate roles, and lack of collaboration with SHPs. Insufficient and unclear insurance coverage of physical activity programmes was a barrier in the domain of law and governance.

Conclusions: Improving the domain of organisation seems the most challenging because the collaboration, communication, networks, and interactive roles between the PHPs and SHPs are all inadequate. Survivor care plans, more use of health information technology, improved rehabilitation guidelines, and better networks might benefit implementing physical activity programmes.
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http://dx.doi.org/10.1007/s00520-019-05108-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256088PMC
July 2020

Effect of a Skills Training for Oncologists and a Patient Communication Aid on Shared Decision Making About Palliative Systemic Treatment: A Randomized Clinical Trial.

Oncologist 2019 Nov 26. Epub 2019 Nov 26.

Department of Medical Psychology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM.

Methods: In this multicenter randomized controlled trial with four parallel arms (2016-2018), oncologists ( = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients ( = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio-recorded consultations. Secondary outcomes included patient-reported SDM, patient and oncologist satisfaction, patients' decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made.

Results: The oncologist training had a large positive effect on observed SDM (Cohen's = 1.12) and on patient-reported SDM ( = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients' decisional conflict, quality of life, consultation duration, or the decision made.

Conclusion: Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient-reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice. . Netherlands Trial Registry NTR 5489.

Implications For Practice: Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient-reported SDM in clinical encounters ( = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists' practice and should be implemented in (continuing) educational programs.
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November 2019

Obstetric and maternal outcomes in patients diagnosed with Hodgkin lymphoma during pregnancy: a multicentre, retrospective, cohort study.

Lancet Haematol 2019 11 26;6(11):e551-e561. Epub 2019 Sep 26.

Department of Obstetrics and Gynaecology, University Hospitals Leuven and Department of Oncology, KU Leuven, Leuven, Belgium; Centre for Gynaecologic Oncology Amsterdam, Amsterdam University Medical Centres, Amsterdam, Netherlands; Centre for Gynaecological Oncology Amsterdam, Antoni van Leeuwenhoek, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address:

Background: Outcomes for mother and child following a diagnosis of Hodgkin lymphoma during pregnancy are underinvestigated, and antenatal management of the disease has not been reported on widely. The aim of this study was to assess obstetric outcomes, antenatal management, and maternal survival in patients with Hodgkin lymphoma diagnosed during pregnancy who were registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database.

Methods: We did a multicentre, retrospective cohort study including oncological and obstetric data from 134 pregnant patients diagnosed with Hodgkin lymphoma between Jan 1, 1969, and Aug 1, 2018. Data collected from the INCIP database were obtained from 17 academic centres in Belgium, Czech Republic, Denmark, Greece, Israel, Italy, Mexico, the Netherlands, Russia, the UK, and the USA. We analysed patients' management over three epochs (before 1995, 1995-2004, and 2005-18). Obstetric outcomes (birthweight, obstetric or neonatal complications, and admission to a neonatal intensive care unit [NICU]) of patients who received antenatal chemotherapy were compared to those of patients who did not receive antenatal treatment. Maternal progression-free and overall survival was assessed by disease stage at diagnosis in pregnant patients and compared with outcomes of non-pregnant patients with Hodgkin lymphoma selected from databases of three tertiary centres, matched for stage and prognostic score. All patients included in survival analyses received standard doxorubicin, bleomycin, vinblastine and dacarbazone (ABVD) therapy since Jan 1, 1997.

Findings: Of the 134 pregnant patients diagnosed with Hodgkin lymphoma during pregnancy. 72 (54%) patients initiated antenatal chemotherapy, 56 (42%) did not receive treatment during pregnancy, and 6 (4%) received only radiotherapy. Over the years, chemotherapy was increasingly commenced during pregnancy. The incidence of neonates who were small for gestational age did not differ between chemotherapy-exposed neonates (15 [22%] of 69) and non-exposed neonates (six [16%] of 42; p=0·455). Admission to NICU also did not differ between groups (19 [29%] exposed to antenatal chemotherapy vs 12 [35%] unexposed to antenatal chemotherapy). Birthweight percentiles were lower in neonates prenatally exposed to chemotherapy compared with non-exposed neonates (p=0·035). Patients receiving antenatal therapy had more obstetric complications than those without antenatal therapy (p=0·005), the most common complications being preterm contractions (nine [12%] vs three [7%]) and preterm rupture of membranes (four [5%] vs 0). For the maternal survival analyses, we compared 77 pregnant patients and 211 non-pregnant, matched controls. 5-year progression-free survival for patients with early-stage Hodgkin lymphoma was 82·6% (95% CI 67·4-91·1) for 62 pregnant patients and 88·3% (81·6-92·7) for 142 controls (hazard ratio [HR] 1·80, 95% CI 0·84-3·87; p=0·130; 5-year overall survival was 97·3% (82·3-99·6) and 98·4% (93·6-99·6; HR 1·63, 0·35-7·65; p=0·534). In patients with advanced-stage disease (15 pregnant patients and 69 non-pregnant controls), 5-year progression-free survival was 90·9% (95% CI 50·8-98·7) versus 74·0% (60·9-83·3); HR 0·36, 95% CI 0·04-2·90; p=0·334. 5-year overall survival was 100% (no events occurred) and 96·2% (95% CI 85·5-99·1; HR cannot be estimated; p=0·146).

Interpretation: Occurrence of preterm contractions or preterm rupture of membranes was higher in patients with Hodgkin lymphoma receiving antenatal treatment compared with those who did not initiate treatment during pregnancy. Maternal survival did not differ between pregnant and non-pregnant patients with Hodgkin lymphoma, suggesting that antenatal chemotherapy or deferral of treatment until postpartum in selected patients can be considered, with regular obstetric follow-up to safeguard foetal growth.

Funding: European Research Council, Research foundation Flanders, and Charles University Ministry of Health of the Czech Republic.
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http://dx.doi.org/10.1016/S2352-3026(19)30195-4DOI Listing
November 2019

Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy.

Acta Obstet Gynecol Scand 2020 01 16;99(1):79-88. Epub 2019 Oct 16.

Department of Oncology, KU Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1111/aogs.13731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972614PMC
January 2020

Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.

Int J Cancer 2020 01 6;146(2):439-448. Epub 2019 Sep 6.

AGO and Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.
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http://dx.doi.org/10.1002/ijc.32606DOI Listing
January 2020

Implementing physical activity programs for patients with cancer in current practice: patients' experienced barriers and facilitators.

J Cancer Surviv 2019 Oct 25;13(5):703-712. Epub 2019 Jul 25.

Radboud Institute for Health Science (RIHS), Department of Medical Oncology, Radboud University Medical Centre Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Purpose: The present study aimed to identify patients' experienced barriers and facilitators in implementing physical activity programs for patients with cancer.

Methods: We interviewed 34 patients in focus-group-interviews from three different hospital-types. We included patients with cancer who were either receiving curative treatment or had recently completed it. Barriers and facilitators were explored in six domains: (1) physical activity programs, (2) patients, (3) healthcare professionals (HCPs), (4) social setting, (5) organization, and (6) law and governance.

Results: We found 12 barriers and 1 facilitator that affect the implementation of physical activity programs. In the domain of physical activity programs, the barrier was physical activity programs not being tailored to the patient's needs. In the domain of patients, lacking responsibility for one's own health was a barrier. Knowledge and skills for physical activity programs and non-commitment of HCPs impeded implementation in the domain of HCPs. Barriers in the domain of organization included inconvenient place, time of day, and point in the health treatment schedule for offering the physical activity programs, inadequate capacity, inaccessibility of contact persons, lack of information about physical activity programs, non-involvement of the general practitioner in the cancer care process, and poor communication between secondary and primary HCPs. Insufficient insurance-coverage of physical activity programs was a barrier in the domain of law and governance. In the domain of physical activity programs, contact with peers facilitated implementation. We found no barriers or facilitators at the social setting.

Conclusions: Factors affecting the implementation of physical activity programs occurred in various domains. Most of the barriers occurred in the domain of organization.

Implications For Cancer Survivors: An implementation strategy that deals with the barriers might improve the implementation of physical activity programs and quality of life of cancer survivors.
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http://dx.doi.org/10.1007/s11764-019-00789-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828940PMC
October 2019

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

Lancet Oncol 2019 09 22;20(9):1273-1285. Epub 2019 Jul 22.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

Background: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.

Methods: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.

Findings: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.

Interpretation: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.

Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.
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http://dx.doi.org/10.1016/S1470-2045(19)30395-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722042PMC
September 2019

Psychometric properties of the 45-item supportive care needs survey-partners and caregivers - Dutch (SCNS-P&C45-D) in partners of patients with breast cancer.

J Patient Rep Outcomes 2019 Jan 11;3(1). Epub 2019 Jan 11.

Department Of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Objective: To test the psychometric properties of the Dutch 45-item Supportive Care Needs Survey-Partners and Caregivers (SCNS-P&C45-D) among partners of women with breast cancer living in the Netherlands.

Methods: In this cross-sectional validation study, partners of patients with breast cancer were invited to complete a survey on the patient's cancer and the caregiver's level of unmet needs (SCNS-P&C45-D), psychological distress (HADS) and burden (EDIZ).

Results: 43% of the invited informal caregivers responded (n = 302). Flooring effects were identified for three items of the SCNS-P&C45-D,which were then deleted from further analysis. The original factor structure and loading pattern of the SCNS-P&C45-D was not replicated. Internal consistency of the SCNS-P&C45-D and all subscales' (emotional and relational needs, health care and illness related needs, practical needs, work and social needs) Cronbach's alpha coefficients exceeded 0.80, the entire measure's Cronbach's alpha is 0.98. Most SCNS-P&C45-D subscales showed moderate correlations with distress and burden from informal care which was in line with expectations based on validity. The domain 'Work and Social needs' showed a high correlation with burden from informal care. Participants reported significantly more or higher unmet needs if they were younger (25.5% vs. 20.3% in older patients, p = 0.004), if diagnosis was less than 1 year ago in one subscale (Health Care and Illness related needs; 19.5% and 18%, p = 0.029, and the total SCNS-P&C45-D; 23.2% vs. 22.4%, p = 0.018).

Conclusions: The SCNS-P&C45-D is able to identify those partners of patients with breast cancer in need and those who are not.
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http://dx.doi.org/10.1186/s41687-019-0092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329686PMC
January 2019

Adjuvant Gemcitabine Plus Docetaxel Followed by Doxorubicin Versus Observation for High-Grade Uterine Leiomyosarcoma: A Phase III NRG Oncology/Gynecologic Oncology Group Study.

J Clin Oncol 2018 Oct 5:JCO1800454. Epub 2018 Oct 5.

Martee L. Hensley, Memorial Sloan Kettering Cancer Center; Martee L. Hensley and Oliver Zivanovic, Weill Cornell Medical College, New York City; Danielle Enserro and Shashikant B. Lele, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Helen Hatcher, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge; Cyril Fisher, University of Birmingham, Birmingham, United Kingdom; Petronella B. Ottevanger, Radboud University Medical Center, Nijmegen, the Netherlands; Anders Krarup-Hansen, University Hospital Copenhagen, Copenhagen, Denmark; Jean-Yves Blay, Centre Leon Berard, Lyon, France; Katherine M. Moxley, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Jayanthi S. Lea, and David S. Miller, The University of Texas Southwestern Medical Center, Dallas, TX; Krishnansu S. Tewari, University of California at Irvine, Orange, CA; Premal H. Thaker, Washington University School of Medicine, and Siteman Cancer Center, St Louis, MO; David M. O'Malley, The Ohio State University College of Medicine, Columbus, OH; Katina Robison, Women and Infants Hospital in Rhode Island, Providence, RI.

Purpose: We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma.

Methods: Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS).

Results: With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy, n = 5; observation, n = 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size.

Conclusion: Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy.
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http://dx.doi.org/10.1200/JCO.18.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241678PMC
October 2018

Training for Medical Oncologists on Shared Decision-Making About Palliative Chemotherapy: A Randomized Controlled Trial.

Oncologist 2019 02 29;24(2):259-265. Epub 2018 Jun 29.

Department of Medical Psychology, Academic Medical Center, University of Amsterdam, The Netherlands.

Background: Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. This study examines the effect of shared decision-making (SDM) training for medical oncologists on observed SDM in standardized patient assessments.

Materials And Methods: A randomized controlled trial comparing training with standard practice was conducted. Medical oncologists and oncologists-in-training ( = 31) participated in a video-recorded, standardized patient assessment at baseline (T0) and after 4 months (T1, after training). The training was based on a four-stage SDM model and consisted of a reader, two group sessions (3.5 hours each), a booster session (1.5 hours), and a consultation card. The primary outcome was observed SDM as assessed with the Observing Patient Involvement scale (OPTION12) coded by observers blinded for arm. Secondary outcomes were observed SDM per stage, communication skills, and oncologists' satisfaction with communication.

Results: The training had a significant and large effect on observed SDM in the simulated consultations (Cohen's f = 0.62) and improved observed SDM behavior in all four SDM stages (f = 0.39-0.72). The training improved oncologists' information provision skills (f = 0.77), skills related to anticipating/responding to emotions (f = 0.42), and their satisfaction with the consultation (f = 0.53).

Conclusion: Training medical oncologists in SDM about palliative systemic treatment improves their performance in simulated consultations. The next step is to examine the effect of such training on SDM in clinical practice and on patient outcomes.

Implications For Practice: Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. Hence, applying the premises of shared decision-making (SDM) is recommended. SDM is increasingly advocated based on the ethical imperative to provide patient-centered care and the increasing evidence for beneficial patient outcomes. Few studies examined the effectiveness of SDM training in robust designs. This randomized controlled trial demonstrated that SDM training (10 hours) improves oncologists' performance in consultations with standardized patients. The next step is to examine the effect of training on oncologists' performance and patient outcomes in clinical practice.
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http://dx.doi.org/10.1634/theoncologist.2018-0090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369949PMC
February 2019

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2018 03 12;19(3):295-309. Epub 2018 Feb 12.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

Background: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer.

Methods: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.

Results: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity.

Interpretation: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival.

Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.
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http://dx.doi.org/10.1016/S1470-2045(18)30079-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840256PMC
March 2018

Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.

Lancet Oncol 2018 03 26;19(3):337-346. Epub 2018 Jan 26.

Department of Oncology, KU Leuven, Leuven, Belgium; Division of Gynaecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Center for Gynaecologic Oncology Amsterdam, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Amsterdam, Netherlands; Centre for Gynaecologic Oncology Amsterdam, Academical Medical Center, Amsterdam, Netherlands. Electronic address:

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 iatrogenic preterm deliveries (0·91, 0·84-0·98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3·12, 95% CI 1·45-6·70), and between taxane chemotherapy and NICU admission (OR 2·37, 95% CI 1·31-4·28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7·13, 95% CI 2·86-17·7) and thyroid cancers having lowest risk (0·14, 0·02-0·90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0·30, 95% CI 0·17-0·55). Other associations between treatment or cancer type and outcomes were less clear.

Interpretation: Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients.

Funding: Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic.
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http://dx.doi.org/10.1016/S1470-2045(18)30059-7DOI Listing
March 2018
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