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Simple Summary: Cancer antigen 125 (CA-125) is a protein found at a high concentration in the blood of patients with specific types of cancer, mainly ovarian cancer. In 2004, the Gynecologic Cancer Intergroup (GCIG) proposed criteria defining response to treatment, as well as disease progression, based on the CA-125 concentration. Ever since, for the follow-up of ovarian cancer patients, the CA-125 concentration and/or CT-scans are used. This paper aims to compare different summaries of CA-125 evolution in the 3 to 6 months following treatment initiation in newly diagnosed advanced ovarian cancer and explore their prognostic capacity to predict overall survival. Based on individual patient data from the GCIG meta-analysis, we propose the most appropriate timeframe between follow-up and the prediction horizon in order to obtain robust, dynamic, individual predictions. (1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Gynecological cancer patients are routinely followed up for five years after primary treatment. However, the value of such follow up has been debated, as retrospective studies indicate that first recurrence is often symptomatic and occurs within two to three years of primary treatment. We prospectively investigated time to first recurrence, symptoms at recurrence, diagnostic procedures, and recurrence treatment in gynecological cancer patients after primary curative treatment.Material and Methods: Clinicians from 21 hospitals in Norway interviewed 680 patients with first recurrence of gynecological cancer (409 ovarian, 213 uterine, and 58 cervical cancer patients) between 2012 and 2016. A standardized questionnaire was used to collect information on self-reported and clinical variables.Results: Within two years of primary treatment, 72% of ovarian, 64% of uterine, and 66% of cervical cancer patients were diagnosed with first recurrence, and 54, 67, and 72%, respectively, had symptomatic recurrence. Of symptomatic patients, 25-50% failed to make an appointment before their next scheduled follow-up visit. Computer tomography was the most common diagnostic procedure (89% of ovarian, 76% of uterine, and 62% of cervical cancer patients), and recurrence treatment in terms of chemotherapy was most frequently planned (86% of ovarian, 46% of uterine, and 62% of cervical cancer patients).Conclusions: A majority of patients experienced symptomatic recurrence, but many patients failed to make an appointment earlier than scheduled. Most first recurrences occurred within two years of primary treatment; the mean annual incidence rate for years 3-5 after primary treatment was <7%. New models for follow up of gynecological cancer patients could be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The EORTC 55971 trial compared primary debulking surgery (PDS) versus neo-adjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The impact of both treatment arms on quality of life (QOL) is reported. Methods: Patients with stages IIIc or IV ovarian cancer completed the EORTC QLQ-C30 before treatment, at the third and sixth cycle of chemotherapy, and at 6- and 12-month follow-up. Results: Data of 404 patients (N =201 PDS arm; N =203 IDS arm) were included in the QOL analysis. Between treatment arms no statistically significant differences were found in any of the QOL functioning scales. Patients showed a clinically relevant improvement (>10 points) on the global health/QOL, role functioning, emotional functioning and social functioning scales during and after treatment independent of the type of treatment. Clinically relevant differences from baseline to the follow-up assessments were noted for fatigue, pain, insomnia, appetite loss, constipation, diarrhea indicating symptom control in both treatment arms. Institutions with good QOL compliance were associated with better outcomes. There was a statistical significant difference in the overall debulking status with 39.9% optimal debulking surgery in institutions with good QOL compliance compared to 19.9% in institutions with poor QOL compliance (p =0.0011). Overall survival (median 32.30 versus 23.29months; p =0.0006) and progression free survival (median 12.35 versus 9.92months; p =0.0002) were also significantly better. Conclusions: Survival and QOL after NACT followed by surgery was similar to survival and QOL after PDS followed by chemotherapy. However, institutions with good QOL compliance had better survival outcomes. [Copyright &y& Elsevier]

Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Nuclear texture analysis gives information about the spatial arrangement of the pixel gray levels in a digitized microscopic nuclear image, providing texture features that may be used as quantitative tools for prognosis of human cancer. The aim of the study was to evaluate the prognostic value of adaptive nuclear texture features in early stage ovarian cancer. Methods: 246 cases of early stage ovarian cancer were included in the analysis. Isolated nuclei (monolayers) were prepared from 50 μm tissue sections and stained with Feulgen-Schiff. Local gray level entropy was measured within small windows of each nuclear image and stored in gray level entropy matrices. A compact set of adaptive features was computed from these matrices. Results: Univariate Kaplan-Meier analysis showed significantly better relapse-free survival (p < 0.001) for patients with low adaptive feature values compared to patients with high adaptive feature values. The 10-year relapse-free survival was about 78% for patients with low feature values and about 52% for patients with high feature values. Adaptive features were found to be of independent prognostic significance for relapse-free survival in a multivariate analysis. Conclusion: Adaptive nuclear texture features from entropy matrices contain prognostic information and are of independent prognostic significance for relapse-free survival in early stage ovarian cancer. [ABSTRACT FROM AUTHOR]

Reports that ovarian cancer is the second most common gynecological cancer. Discussion of epithelial ovarian carcinoma; Aetiology; Pathogenesis; Pathology; Diagnosis; Treatment; Surgery; Chemotherapy; Conclusions.

Simple Summary: Chromatin organisation affects gene expression and contributes to carcinogenesis. Automatic quantification of chromatin heterogeneity can be applied to identify patients with increased risk of cancer recurrence and death in several cancer types. We aimed to investigate the prognostic role of diversity of chromatin compartments in relation to chromatin heterogeneity and as a potential supplement to pathological risk classifications in gynaecological carcinomas. To this end, we computed the entropy of both chromatin compartment sizes and optical densities within compartments. In analysis of two cohorts consisting of 1037 patients with gynaecological carcinoma, we observed a moderately strong correlation between the prognostic value of the entropies and chromatin heterogeneity. The entropies provided an objective marker, which, integrated with pathological risk classifications, might possibly contribute to the selection of high-risk stage I ovarian carcinoma patients for adjuvant chemotherapy and to preoperative identification of low-risk endometrial carcinoma patients who are candidates for less extensive surgery. Statistical texture analysis of cancer cell nuclei stained for DNA has recently been used to develop a pan-cancer prognostic marker of chromatin heterogeneity. In this study, we instead analysed chromatin organisation by automatically quantifying the diversity of chromatin compartments in cancer cell nuclei. The aim was to investigate the prognostic value of such an assessment in relation to chromatin heterogeneity and as a potential supplement to pathological risk classifications in gynaecological carcinomas. The diversity was quantified by calculating the entropy of both chromatin compartment sizes and optical densities within compartments. We analysed a median of 281 nuclei (interquartile range (IQR), 273 to 289) from 246 ovarian carcinoma patients and a median of 997 nuclei (IQR, 502 to 1452) from 791 endometrial carcinoma patients. The prognostic value of the entropies and chromatin heterogeneity was moderately strongly correlated (r ranged from 0.68 to 0.73), but the novel marker was observed to provide additional prognostic information. In multivariable analysis with clinical and pathological markers, the hazard ratio associated with the novel marker was 2.1 (95% CI, 1.3 to 3.5) in ovarian carcinoma and 2.4 (95% CI, 1.5 to 3.9) in endometrial carcinoma. Integration with pathological risk classifications gave three risk groups with distinctly different prognoses. This suggests that the novel marker of diversity of chromatin compartments might possibly contribute to the selection of high-risk stage I ovarian carcinoma patients for adjuvant chemotherapy and low-risk endometrial carcinoma patients for less extensive surgery. [ABSTRACT FROM AUTHOR]

Objective: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Methods: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. Results: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. Conclusion: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy. [Copyright &y& Elsevier]

Background: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations.Methods: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic.Findings: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049).Interpretation: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.Funding: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer). [ABSTRACT FROM AUTHOR]

Background: Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. Methods: We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). Results: Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. Conclusions: Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.) N Engl J Med 2010;363:943-53. [ABSTRACT FROM AUTHOR]