Subspecialty training in Europe: a report by the European Network of Young Gynaecological Oncologists.

BACKGROUND: ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees. METHODOLOGY: National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used. RESULTS: National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system. CONCLUSION: Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training.

Confounders other than comorbidity explain survival differences in Danish and Swedish ovarian cancer patients - a comparative cohort study.

OBJECTIVE: Danish ovarian cancer (OC) patients have previously been found to have worse prognosis than Swedish patients, and comorbidity has been suggested as a possible explanation for this survival difference. We aimed to investigate the prognostic impact of comorbidity in surgically treated OC patients in Denmark and Sweden. METHODS: This comparative cohort study was based on data from 3118 surgically treated OC patients diagnosed in 2012-2015. The Swedish subcohort (n = 1472) was identified through the Swedish National Quality Register of Gynecological Surgery, whereas the Danish subcohort (n = 1646) originated from the Danish Gynecological Cancer Database. The clinical databases have high coverage and similar variables included. Comorbidity was classified according to the Ovarian Cancer Comorbidity Index and overall survival was the primary outcome. Data were analyzed using Kaplan Meier and Cox regression analyses. Multiple imputation was used to handle missing data. RESULTS: We found comparable frequencies of the following comorbidities: Hypertension, diabetes and 'Any comorbidity'. Arteriosclerotic cardiac disease and chronic pulmonary disease were more common among Swedish patients. Univariable survival analysis revealed a significant better prognosis for Swedish than for Danish patients (HR 0.84 [95% CI 0.74-0.95], p < .01). In adjusted multivariable analysis, Swedish patients had nonsignificant better prognosis compared to Danish patients (HR 0.91 [95% CI 0.80-1.04], p = .16). Comorbidity was associated with survival (p = .02) but comorbidity did not explain the survival difference between the two countries. CONCLUSIONS: Danish OC patients have a poorer prognosis than patients in Sweden but the difference in survival seems to be explained by other factors than comorbidity.

Type I Versus Type II Endometrial Cancer: Differential Impact of Comorbidity.

OBJECTIVE: Two distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer comorbidity index (OCCI) is useful for prediction of survival in EC. MATERIALS AND METHODS: This nationwide register-based cohort study was based on data from 6487 EC patients diagnosed in Denmark between 2005 and 2015. Patients were assigned a comorbidity index score according to the Charlson comorbidity index (CCI) and the OCCI. Kaplan-Meier survival statistics and adjusted multivariate Cox regression analyses were used to investigate the differential association between comorbidity and overall survival in types I and II EC. RESULTS: The distribution of comorbidities varied between the 2 EC types. A consistent association between increasing levels of comorbidity and poorer survival was observed for both types. Cox regression analyses revealed a significant interaction between cancer stage and comorbidity indicating that the impact of comorbidity varied with stage. In contrast, the interaction between comorbidity and EC type was not significant. Both the CCI and the OCCI were useful measurements of comorbidity, but the CCI was the strongest predictor in this patient population. CONCLUSIONS: Comorbidity is an important prognostic factor in type I as well as in type II EC although the overall prognosis differs significantly between the 2 types of EC. The prognostic impact of comorbidity varies with stage but not with type of EC.

Ovarian Cancer and Comorbidity: Is Poor Survival Explained by Choice of Primary Treatment or System Delay?

OBJECTIVES: Comorbidity influences survival in ovarian cancer, but the causal relations between prognosis and comorbidity are not well characterized. The aim of this study was to investigate the associations between comorbidity, system delay, the choice of primary treatment, and survival in Danish ovarian cancer patients. METHODS: This population-based study was conducted on data from 5317 ovarian cancer patients registered in the Danish Gynecological Cancer Database. Comorbidity was classified according to the Charlson Comorbidity Index and the Ovarian Cancer Comorbidity Index. Pearson χ test and multivariate logistic regression analyses were used to investigate the association between comorbidity and primary outcome measures: primary treatment ("primary debulking surgery" vs "no primary surgery") and system delay (more vs less than required by the National Cancer Patient Pathways [NCPPs]). Cox regression analyses, including hypothesized mediators stepwise, were used to investigate if the impact of comorbidity on overall survival is mediated by the choice of treatment or system delay. RESULTS: A total of 3945 patients (74.2%) underwent primary debulking surgery, whereas 1160 (21.8%) received neoadjuvant chemotherapy. When adjusting for confounders, comorbidity was not significantly associated to the choice of treatment. Surgically treated patients with moderate/severe comorbidity were more often experiencing system delay longer than required by the NCPP. No association between comorbidity and system delay was observed for patients treated with neoadjuvant chemotherapy. Survival analyses demonstrated that system delay longer than NCPP requirement positively impacts survival (hazard ratio, 0.90 [95% confidence interval, 0.82-0.98]), whereas primary treatment modality has no significant impact on survival. CONCLUSIONS: Patients with moderate/severe comorbidity experience often a longer system delay than patients with no or mild comorbidity. Age, stage, and comorbidity are factors influencing the choice of treatment, with stage being the most important factor and comorbidity of lesser importance. The impact of comorbidity on survival does not seem to be mediated by the choice of treatment or system delay.

A new clinically applicable age-specific comorbidity index for preoperative risk assessment of ovarian cancer patients.

OBJECTIVE: To develop and validate a new feasible comorbidity index based on self-reported information suited for preoperative risk assessment of ovarian cancer patients. METHODS: The study was based on patient self-reported data from ovarian cancer patients registered in the Danish Gynecological Cancer Database between January 1, 2005 and December 31, 2012. The study population was divided into a development cohort (n=2020) and a validation cohort (n=1975). Age-stratified multivariate Cox regression analyses were conducted to identify comorbidities significantly impacting five-year overall survival in the development cohort, and regression coefficients were used to construct a new weighted comorbidity index. The index was applied to the validation cohort, and its predictive ability in regard to overall and cancer-specific five-year-survival was investigated. Finally, the performance of the new index was compared to that of the Charlson Comorbidity Index. RESULTS: Regression coefficients of age and five comorbidities (atherosclerotic cardiac disease, chronic obstructive pulmonary disease, diabetes, dementia and hypertension) were included in the new comorbidity index. The validation study found the new index to be significantly associated to both overall survival (HR 1.44, p=0.013) and cancer-specific survival (HR 1.51, p=0.017) in multivariate analyses adjusted for other prognostic factors. The index was a significantly better predictor than the Charlson Comorbidity Index. CONCLUSION: This new age-specific comorbidity index based on self-reported information is a significant predictor of overall and cancer-specific survival in ovarian cancer. It can be used to quickly identify those ovarian cancer patients requiring special attention in terms of preoperative optimization and postoperative care.

Differences in regional diagnostic strategies and in intended versus actual first-line treatment of patients with advanced ovarian cancer in Denmark.

BACKGROUND: Triage of patients with ovarian cancer to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) is challenging. In Denmark, the use of NACT has increased, but substantial differences in the use of NACT or PDS exist among centers. We aimed to characterize the differences between intended and actual first-line treatments in addition to the differences in the triage process among the centers and to evaluate the different diagnostic modalities and the clinical aspects' influence in the triage process. MATERIALS AND METHODS: From 4 centers, forms containing data about the diagnostic process and intended treatment were prospectively collected and merged with data from the Danish Gynecological Cancer Database and medical records. RESULTS: Of the 671 completed forms, 540 patients had stage IIIC or IV epithelial ovarian cancer. Of the 238 (44%) referred to PDS, 91% received PDS and 4% never had debulking surgery. Of the 288 patients (53%) referred to NACT, 44% were never debulked. Fourteen patients (3%) were referred to palliative treatment. The use of different imaging modalities, diagnostic laparoscopy, and laparotomy varied significantly among the centers. Diagnostic surgical procedures were considered to be most influential in the triage process. Regardless of the intended first-line treatment or center, the tumor size and dissemination was the most influential clinical aspect. CONCLUSIONS: In Denmark, substantial differences exist between intended and actual first-line treatments as well as in the diagnostic process and use of NACT, calling for further discussion on diagnostic strategy and therapeutically approach for patients with advanced ovarian cancer.

SUVmax of 18FDG PET/CT as a predictor of high-risk endometrial cancer patients.

OBJECTIVE: To evaluate SUVmax in the assessment of endometrial cancer preoperatively with particular focus on myometrial invasion (MI), cervical invasion (CI), FIGO stage, risk-stratification and lymph node metastases (LNM). METHODS: A total of 268 women with endometrial cancer or atypical endometrial hyperplasia underwent FDG PET/CT imaging before surgical treatment. SUVmax of the primary tumour was compared with histological prognostic factors. RESULTS: SUVmax was significantly higher in patients with high FIGO stages (p<0.0001), deep MI (p=0.002), CI (p=0.04), LNM (p=0.04) and high risk tumours (p=0.003). Linear regression found that SUVmax was dependent of MI (p=0.001, 95% CI 2.863-11.098), CI (p=0.001, 95% CI 2.896-11.499), risk (p=0.004, 95% CI 0.077-0.397), LNM (p=0.04, 95% CI 0.011-0.482) and FIGO stage (p<0.0001, 95% CI 0.158-0.473). CONCLUSIONS: Preoperative PET/CT scanning and SUVmax measurements of the primary tumour may provide additional clinical and prognostic information about MI, CI, LNM and high risk disease in patients with endometrial cancer and allow for individualization of patient care. However, the sensitivity and specificity of the SUVmax in staging endometrial cancer is not high enough to reliably replace surgical staging.

MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study.

OBJECTIVES: The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS: 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS: For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS: None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

Patients with atypical hyperplasia of the endometrium should be treated in oncological centers.

OBJECTIVES: To examine the prevalence of undiagnosed endometrial carcinoma (EC) among women with a preoperative diagnosis of atypical endometrial hyperplasia (AEH) in correlation to age, BMI and menopause. METHODS: Data extracted from the Danish Gynecological Cancer Database (DGCD) covering women diagnosed with AEH between January 1, 2005 and November 1, 2010 undergoing surgery. DGCD is a multidisciplinary, nationwide, clinical database of all cases of gynecological cancer and AEH in Denmark diagnosed after January 1, 2005. Registration is mandatory. Primary outcome was preoperative- and postoperative diagnoses. Secondary outcomes were relationship to BMI, age and menopause. RESULTS: The preoperative diagnosis of AEH was retained in 41% of 773 cases and 59% had endometrial cancer. Of the cancer cases, 18% had more than Stage I disease and 3% were non-endometrioid. Cancer risk was significantly related to age (p<0.0001) and menopause (p<0.0001). The 80% who were postmenopausal had a significantly higher risk of a postoperative cancer diagnosis compared with the premenopausal group (OR 2.8). There was no significant difference regarding BMI (p=0.25). CONCLUSION: More than half of the 773 Danish women primarily diagnosed with AEH had undiagnosed cancer. Failure to diagnose endometrial carcinoma preoperatively can lead to inadequate staging and potentially suboptimal treatment. We recommend that atypical endometrial hyperplasia should be treated as carcinoma in specialized gynecological-oncology centers.

Adjustment of serum HE4 to reduced glomerular filtration and its use in biomarker-based prediction of deep myometrial invasion in endometrial cancer.

BACKGROUND: We investigated the efficacy of circulating biomarkers together with histological grade and age to predict deep myometrial invasion (dMI) in endometrial cancer patients. METHODS: HE4ren was developed adjusting HE4 serum levels towards decreased glomerular filtration rate as quantified by the eGFR-EPI formula. Preoperative HE4, HE4ren, CA125, age, and grade were evaluated in the context of perioperative depth of myometrial invasion in endometrial cancer (EC) patients. Continuous and categorized models were developed by binary logistic regression for any-grade and for G1-or-G2 patients based on single-institution data from 120 EC patients and validated against multicentric data from 379 EC patients. RESULTS: In non-cancer individuals, serum HE4 levels increase log-linearly with reduced glomerular filtration of eGFR ≤ 90 ml/min/1.73 m2. HE4ren, adjusting HE4 serum levels to decreased eGFR, was calculated as follows: HE4ren = exp[ln(HE4) + 2.182 × (eGFR-90) × 10-2]. Serum HE4 but not HE4ren is correlated with age. Model with continuous HE4ren, age, and grade predicted dMI in G1-or-G2 EC patients with AUC = 0.833 and AUC = 0.715, respectively, in two validation sets. In a simplified categorical model for G1-or-G2 patients, risk factors were determined as grade 2, HE4ren ≥ 45 pmol/l, CA125 ≥ 35 U/ml, and age ≥ 60. Cumulation of weighted risk factors enabled classification of EC patients to low-risk or high-risk for dMI. CONCLUSIONS: We have introduced the HE4ren formula, adjusting serum HE4 levels to reduced eGFR that enables quantification of time-dependent changes in HE4 production and elimination irrespective of age and renal function in women. Utilizing HE4ren improves performance of biomarker-based models for prediction of dMI in endometrial cancer patients.

Biomarkers for predicting complete debulking in ovarian cancer: lessons to be learned.

AIM: We aimed to construct and validate a model based on biomarkers to predict complete primary debulking surgery for ovarian cancer patients. PATIENTS AND METHODS: The study consisted of three parts: Part I: Biomarker data obtained from mass spectrometry, baseline data and, surgical outcome were used to construct predictive indices for complete tumour resection; Part II: sera from randomly selected patients from part I were analyzed using enzyme-linked immunosorbent assay (ELISA) to investigate the correlation to mass spectrometry; Part III: the indices from part I were validated in a new cohort of patients. RESULTS: Part I: The area under the receiver operating characteristic curve (AUC) was 0.82 for both indices. Part II: Linear regression analysis gave an R(2) value of 0.52 and 0.63 for transferrin and ß2-microglobulin, respectively. Part III: The AUC of the two indices decreased to 0.64. CONCLUSION: Our validated model based on biomarkers was unable to predict surgical outcome for patients with ovarian cancer.

EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women.

INTRODUCTION: Invasive as well as non-invasive methods are available for assessment of the endometrium. AIMS: The purpose of this clinical guide is to provide evidence-based advice on endometrial assessment in peri and postmenopausal women. MATERIAL AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Presuming speculum examination and cervical cytology are assessed, transvaginal ultrasound should be undertaken initially as it is non-invasive and will not only measure endometrial thickness, but will also detect other pelvic pathology such as leiomyomas and ovarian tumours. The main indication for invasive methods is to obtain endometrial tissue to diagnose or exclude the presence of endometrial cancer or pre-malignancies. Biopsy is mainly undertaken as an outpatient procedure, but sampling is 'blind'. Hysteroscopy is used when focal lesions affecting the uterine cavity are suspected such as endometrial polyps or sub-mucous fibroids. None of the available methods are perfect. Ultrasound evaluation is dependent on the experience of the examiner, the equipment and the quality of visualization. Hysteroscopy too is dependent on the examiner and fibroids may obstruct visualization. Blind endometrial biopsy procedures often miss focal lesions. Thus re-examination is necessary when symptoms persist and no explanation for these has been identified. This clinical guide will evaluate the different methods of endometrial assessment, their indications and limitations. Guidance is also given about dealing with inconclusive investigations and persistent symptoms.

[Need of better preoperative staging of endometrial cancer]. / Behov for bedre præoperativ stadieinddeling af endometriecancer.

Endometrial cancer is one of the most frequent gynaecological cancers in Danish women. The staging of the cancer is done surgically in accordance with guidelines from the International Federation of Gynaecology and Obstetrics. The method has proven insufficient and unsuitable because treatment is frequently decided during surgery and the final staging is done by the pathologist when examining the specimen. Too many patients are over- or under-treated and there is a high demand for new diagnostic tools for preoperative staging of endometrial cancer. We have reviewed recent literature on the subject.