Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data.

OBJECTIVE: To identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. METHODS: All consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism. RESULTS: A total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62-0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71-0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. CONCLUSION: A (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.

Trends over time in the incidence and use of hormonal therapy in endometrial cancer: a population-based study in the Netherlands.

INTRODUCTION: According to current guidelines, hormonal therapy may be applied in endometrioid type endometrial cancer as an alternative to surgery for fertility preservation and in medically unfit patients. Since it is unknown how often hormonal therapy is applied, the objective of this study was to investigate trends over time in hormonal therapy use in the background of the overall incidence of endometrial cancer. METHODS: All patients with endometrial cancer (n=48 222) registered in the Netherlands Cancer Registry in the period 1989-2018 were included. European age-standardized incidence rates with corresponding estimated annual percentage change were calculated to describe trends in the incidence of endometrial cancer. The use of hormonal therapy was analyzed in the three periods 1989-1998, 1999-2008, and 2009-2018 for the following sub-groups: primary and adjuvant therapy, International Federation of Gynecology and Oncology (FIGO) stage I-II and III-IV, and by age group. RESULTS: The European age-standardized incidence rate of endometrioid endometrial cancer peaked in 2004 with a significant increase from 1989 to 2004 (annual percentage change 0.55; 95% CI 0.10 to 0.99, p=0.020) and a subsequent decrease from 2005 to 2018 (annual percentage change -1.79; 95% CI -2.28 to -1.31, p<0.001). The incidence rate of non-endometrioid type endometrial cancer increased significantly in the study period. Hormonal therapy was used in 1482 (3.5%) patients with endometrioid endometrial cancer. Among patients with FIGO stage I aged ≤40 years, hormonal therapy increased from 0% in 1989-1998 to 27% in 2009-2018. Primary hormonal treatment increased from 175 patients (5.5%) to 329 patients (7.8%) in those aged ≥75 years. Adjuvant hormonal treatment was mostly used in advanced stage endometrial cancer. CONCLUSIONS: The use of primary hormonal therapy in endometrioid type endometrial cancer increased over time in patients aged ≤40 years and among elderly patients. The observed trends in the current use of hormonal therapy support the need to study the effect of hormonal treatment in elderly patients and as adjuvant treatment in advanced stage endometrial cancer.

The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.

BACKGROUND: The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort. METHODS: All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes. RESULTS: Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days. CONCLUSIONS: Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned.

[Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients]. / De invloed nu van tumorstadium op overleving na borstkanker.

OBJECTIVE: To assess influence of stage at breast cancer diagnosis, tumour biology, and therapy on survival in contemporary times of better (neo-)adjuvant systemic therapy. DESIGN: Prospective nationwide population based study. METHOD: Female primary breast cancer patients diagnosed between 1999 and 2012 (173,797). Participants were subdivided into two time cohorts on the basis of breast cancer diagnosis; 1999 through 2005 (n = 80,228) and 2006 through 2012 (n = 93,569). Main outcome measures were relative survival, compared between both cohorts, and the influence of traditional prognostic factors on overall mortality, analyzed with Cox regression for both cohorts separately. RESULTS: Compared to 1999-2005 patients from 2006-2012 had smaller ( ≤ T1 65 vs. 60%; p < 0.001), more often lymph node negative (N0 68 vs. 65%; p < 0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60 vs. 53%; p < 0.001). Median follow-up was 9.8 years for 1999-2005 and 3.9 years for 2006-2012. Relative 5-years survival rate was 96% in 2006-2012, improved in all tumour and nodal stages compared to 1999-2005, and 100% in tumours ≤ 1 cm. With multivariable analyses, adjusted for age and tumour type, overall mortality decreased by surgery (especially breast conserving), radiotherapy and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006-2012 T1c vs. T1a HR 1.54, 95% CI 1.33 to 1.78), but without significant difference in invasive breast cancers until 1 cm (2006-2012 T1b vs. T1a HR 1.04, 95% CI 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006-2012 N1 vs. N0 HR 1.25, 95% CI 1.17 to 1.32). CONCLUSION: Tumour stage at breast cancer diagnosis influences overall survival significantly also in the current era of effective systemic therapy. Early tumour stage at breast cancer diagnosis remains vital.

Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients.

OBJECTIVES: To assess the influence of stage at breast cancer diagnosis, tumour biology, and treatment on survival in contemporary times of better (neo-)adjuvant systemic therapy. DESIGN: Prospective nationwide population based study. SETTING: Nationwide Netherlands Cancer Registry. PARTICIPANTS: Female patients with primary breast cancer diagnosed between 1999 and 2012 (n=173,797), subdivided into two time cohorts on the basis of breast cancer diagnosis: 1999-2005 (n=80,228) and 2006-12 (n=93,569). MAIN OUTCOME MEASURES: Relative survival was compared between the two cohorts. Influence of traditional prognostic factors on overall mortality was analysed with Cox regression for each cohort separately. RESULTS: Compared with 1999-2005, patients from 2006-12 had smaller (≤ T1 65% (n=60,570) v 60% (n=48,031); P<0.001), more often lymph node negative (N0 68% (n=63,544) v 65% (n=52,238); P<0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60% (n=56,402) v 53% (n=42,185); P<0.001). Median follow-up was 9.8 years for 1999-2005 and 3.9 years for 2006-12. The relative five year survival rate in 2006-12 was 96%, improved in all tumour and nodal stages compared with 1999-2005, and 100% in tumours ≤ 1 cm. In multivariable analyses adjusted for age and tumour type, overall mortality was decreased by surgery (especially breast conserving), radiotherapy, and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006-12 T1c v T1a: hazard ratio 1.54, 95% confidence interval 1.33 to 1.78), but without a significant difference in invasive breast cancers until 1 cm (2006-12 T1b v T1a: hazard ratio 1.04, 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006-12 N1 v N0: 1.25, 1.17 to 1.32). CONCLUSIONS: Tumour stage at diagnosis of breast cancer still influences overall survival significantly in the current era of effective systemic therapy. Diagnosis of breast cancer at an early tumour stage remains vital.

Rationale and design of the PRegnancy and Infant DEvelopment (PRIDE) Study.

BACKGROUND: To optimise the health of pregnant women and their children by evidence-based primary and secondary prevention, more scientific knowledge is needed. To overcome the methodological limitations of many studies on pregnancy and child health, which often use a retrospective design, we established the PRIDE (PRegnancy and Infant DEvelopment) Study. METHODS AND RESULTS: The PRIDE Study is a large prospective cohort study that aims at including 150 000-200 000 women in early pregnancy to study a broad range of research questions pertaining to pregnancy complications, maternal and child health, and adverse developmental effects in offspring. Women are invited to participate by their prenatal care provider before or at their first prenatal care visit and are asked to fill out web-based questionnaires in gestational weeks 8-10, 17, and 34, as well as biannually throughout childhood. In addition, a food frequency questionnaire and a paternal questionnaire are administered and medical records are consulted. Multiple validation studies will be conducted and paper-and-pencil questionnaires are available for women who cannot or do not want to participate through the Internet. For subgroups of participants, blood and saliva samples for genetic and biochemical analyses are being collected. The pilot phase, which started in July 2011, showed a response rate of 47%. Recruitment will eventually cover all of the Netherlands. CONCLUSIONS: We expect that this study, which will be the largest birth cohort in the world so far, will provide new insights in the aetiology of disorders and diseases that originate in pregnancy. The PRIDE Study is open for collaboration.

Estrogenic and androgenic activities in total plasma measured with reporter-gene bioassays: relevant exposure measures for endocrine disruptors in epidemiologic studies?

Measurements of estrogenic and androgenic activities in total plasma with Chemically Activated LUciferase gene eXpression (CALUX®) bioassays could provide biologically relevant measures for exposure to endocrine disruptors in epidemiologic studies. The objective of this study was to explore the effects of a variety of sources of potential endocrine disruptors on estrogenic and androgenic activities in total plasma measured by CALUX®. Plasma samples and interview data on sources of potential endocrine disruptors were collected from 108 men with different exposures profiles. CALUX® measurements (BioDetection Services) involved human U2-OS cell lines controlled by the estrogen receptor alpha and the androgen receptor. Mean differences (beta) in 17ß-estradiol equivalents (EEQs) and dihydrotestosterone equivalents (AEQs) between exposure groups were estimated using general linear models. Mean plasma AEQs and EEQs were 9.1×10(-1)ng/ml and 12.0pg/ml, respectively. Elevated AEQs were found in smokers (beta 1.9 (95%CI 0.1-3.6)×10(-1)ng/ml) and heavy drinkers (1.4 (0.2-3.1)×10(-1)ng/ml), and in men occupationally exposed to disinfectants (1.6 (0.3-3.5)×10(-1)ng/ml) or welding/soldering fumes (1.4 (-0.2-2.9)×10(-1)ng/ml). Occupational exposure to pesticides, disinfectants, and exhaust fumes seemed to be associated with increased plasma EEQs: 1.5 (-0.2-3.2)pg/ml, 2.1 (0.2-3.9)pg/ml, and 2.9 (0.6-5.2)pg/ml, respectively. Moderate to high plasma dioxin levels, measured in a subgroup by the dioxin-responsive CALUX®, were accompanied by a 20% increase in AEQs. This is the first study in which CALUX® was used to assess hormone activities in total plasma. Although the results are not yet readily interpretable, they indicate that these measurements can be valuable for epidemiologic studies on endocrine disruptors and give direction for further research.

Web-based questionnaires: the future in epidemiology?

The traditional epidemiologic modes of data collection, including paper-and-pencil questionnaires and interviews, have several limitations, such as decreasing response rates over the last decades and high costs in large study populations. The use of Web-based questionnaires may be an attractive alternative but is still scarce in epidemiologic research because of major concerns about selective nonresponse and reliability of the data obtained. The authors discuss advantages and disadvantages of Web-based questionnaires and current developments in this area. In addition, they focus on some practical issues and safety concerns involved in the application of Web-based questionnaires in epidemiologic research. They conclude that many problems related to the use of Web-based questionnaires have been solved or will most likely be solved in the near future and that this mode of data collection offers serious benefits. However, questionnaire design issues may have a major impact on response and completion rates and on reliability of the data. Theoretically, Web-based questionnaires could be considered an alternative or complementary mode in the range of epidemiologic methods of data collection. Practice and comparisons with the traditional survey techniques should reveal whether they can fulfill their expectations.

The impact of pesticides on male fertility.

PURPOSE OF REVIEW: Observations in several Western countries point toward a decline in semen quality which may be associated with exposure to environmental endocrine disruptors such as several frequently used pesticides. The scarce literature on the effects of pesticides on male fertility will be reviewed with a focus on semen quality and time-to-pregnancy. RECENT FINDINGS: The majority of studies published since 2000 reported some effects of pesticide exposure on semen quality or time-to-pregnancy. The results are not consistent, however, with some studies showing reduced sperm concentrations and others showing low percentages of morphologically normal and/or motile sperm. In time-to-pregnancy studies, reduced male fertility measured as prolonged time-to-pregnancy related to pesticide exposure was observed for first pregnancies only. Some of the inconsistencies may be explained by heterogeneity in populations, pesticide exposure, and study design. SUMMARY: Despite this heterogeneity, the conclusion can be drawn that pesticide exposure may affect spermatogenesis leading to poor semen quality and reduced male fertility. More research is needed to unravel the pathophysiological mechanisms and the role of endocrine disruption.

Reproductive disorders among male and female greenhouse workers.

The aim of this study was to evaluate reproductive disorders in male and female greenhouse workers. In 2002, data were collected from 4872 Dutch greenhouse workers and 8133 referents through postal questionnaires with detailed questions on reproductive disorders of the most recent pregnancy, lifestyle habits, and occupational exposures (e.g. pesticides) prior to conception. Different reproductive outcome measures were compared between 957 male and 101 female greenhouse workers and 1408 referents by means of logistic regression analyses. The analyses of primigravidous couples showed a slightly elevated risk of prolonged TTP (OR(women)=1.9; 95% CI: 0.8-4.4) and an increased risk of spontaneous abortion among female greenhouse workers (OR(women)=4.0; 95% CI: 1.1-14.0). A decreased risk of preterm birth was found among male greenhouse workers (OR(men)=0.1; 95% CI: 0.03-0.5). This study may offer some evidence for the hypothesis that pesticide exposure affects human reproduction leading to spontaneous abortion and possibly to prolonged time-to-pregnancy.

Influence of pesticides on male fertility.

Several studies have shown a decline in human semen quality and increased risks of male subfertility. This paper provides an overview of the mechanisms of pesticide-induced reproductive toxicity and the effects on male fertility since exposure to pesticides may be one of the causes of these disorders. Pesticides may directly damage spermatozoa, alter Sertoli cell or Leydig cell function, or disrupt the endocrine function in any stage of hormonal regulation (hormone synthesis, release, storage, transport, and clearance; receptor recognition and binding; thyroid function; and the central nervous system). These mechanisms are described with respect to the effects of pesticide exposure in vitro and in vivo. In epidemiologic studies, effects on sperm quality and time to pregnancy are reviewed. Clear effects on male fertility have been demonstrated for some pesticides [eg, dibromochloropropane, ethylene dibromide]. But results from more recent studies are inconsistent, and no uniform conclusion can be drawn about the effects of pesticides on male reproduction.

Exposure profiles of pesticides among greenhouse workers: implications for epidemiological studies.

The aim of this study was to assess exposure to pesticides for a longitudinal epidemiological study on adverse reproduction effects among greenhouse workers. Detailed information on pesticide use among greenhouse workers was obtained on a monthly basis through self-administered questionnaires and subsequent workplace surveys. Questionnaires were filled in for a whole year. Dermal exposure rankings were developed for each task using the observational method Dermal Exposure Assessment Method (DREAM). Exposure scores were calculated for each worker for each month during the year, taking into account frequency, duration and exposure intensity for each task. A total number of 116 different active ingredients were used in the population, whereas a mean number of 15 active ingredients were applied per greenhouse. DREAM observations provided insight into the exposure intensity of 12 application techniques and three mixing and loading activities. Relatively high DREAM scores were obtained for scattering, fogging, dusting, and mixing and loading of powders. Observations with DREAM indicated that application with a horizontal ground-boom, motor driven boom, and bulb shower resulted in low dermal exposure. Exposure scores showed substantial variation between workers and over the year. It can be concluded that exposure variation between- and within greenhouses is very large, both in terms of chemical composition and exposure intensity. This may be a significant contributor to the inconsistent results of studies evaluating health effects of pesticide exposure.

Time to pregnancy among female greenhouse workers.

OBJECTIVES: Female greenhouse workers, who constitute a major occupational group exposed to pesticides at childbearing age, were studied to measure the effects of pesticide exposure on time to pregnancy. METHODS: Data were collected through postal questionnaires with detailed questions on time to pregnancy, lifestyle factors (eg, smoking habits, coffee and alcohol consumption), and worktasks (eg, application of pesticides, re-entry activities, and workhours) of the respondents and their partners in a 6-month period prior to conception of the most recent pregnancy. The relation between time to pregnancy and exposure to pesticides among 398 female greenhouse workers and 524 referents was studied in a Cox's proportional hazards model. RESULTS: The crude fecundability ratio for female greenhouse workers versus the reference group was 1.18 [95% confidence interval (95% CI) 1.03-1.35], but correction for confounding changed the fecundability ratio to 1.11 (95% CI 0.96-1.29). An evaluation of specific biases for time-to-pregnancy studies showed that these results were biased by the reproductively unhealthy worker effect. Restricting the analyses to full-time workers or first pregnancies only resulted in an adjusted fecundability ratio of 0.89 (95% CI 0.67-1.19) and 0.90 (95% CI 0.62-1.32), respectively. Among the primigravidous greenhouse workers, an association was observed between prolonged time to pregnancy and gathering flowers (fecundability ratio 0.46, 95% CI 0.18-1.19). CONCLUSIONS: This study may offer some evidence for the hypothesis of adverse effects of pesticide exposure on time to pregnancy, but more research is needed to elucidate these effects.

Pesticide exposure: the hormonal function of the female reproductive system disrupted?

Some pesticides may interfere with the female hormonal function, which may lead to negative effects on the reproductive system through disruption of the hormonal balance necessary for proper functioning. Previous studies primarily focused on interference with the estrogen and/or androgen receptor, but the hormonal function may be disrupted in many more ways through pesticide exposure. The aim of this review is to give an overview of the various ways in which pesticides may disrupt the hormonal function of the female reproductive system and in particular the ovarian cycle. Disruption can occur in all stages of hormonal regulation: 1. hormone synthesis; 2. hormone release and storage; 3. hormone transport and clearance; 4. hormone receptor recognition and binding; 5. hormone postreceptor activation; 6. the thyroid function; and 7. the central nervous system. These mechanisms are described for effects of pesticide exposure in vitro and on experimental animals in vivo. For the latter, potential effects of endocrine disrupting pesticides on the female reproductive system, i.e. modulation of hormone concentrations, ovarian cycle irregularities, and impaired fertility, are also reviewed. In epidemiological studies, exposure to pesticides has been associated with menstrual cycle disturbances, reduced fertility, prolonged time-to-pregnancy, spontaneous abortion, stillbirths, and developmental defects, which may or may not be due to disruption of the female hormonal function. Because pesticides comprise a large number of distinct substances with dissimilar structures and diverse toxicity, it is most likely that several of the above-mentioned mechanisms are involved in the pathophysiological pathways explaining the role of pesticide exposure in ovarian cycle disturbances, ultimately leading to fertility problems and other reproductive effects. In future research, information on the ways in which pesticides may disrupt the hormonal function as described in this review, can be used to generate specific hypotheses for studies on the effects of pesticides on the ovarian cycle, both in toxicological and epidemiological settings.