Fédération Internationale De Gynécologie Et d'Obstétrique Research Articles

Efficacy and Safety of AEZS-108 (LHRH Agonist Linked to Doxorubicin) in Women With Advanced or Recurrent Endometrial Cancer Expressing LHRH Receptors: A Multicenter Phase 2 Trial (AGO-GYN5)

ObjectiveAdvanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone–releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients.MethodsPatients had FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) III or IV or recurrent EC, LHRH receptor–positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors.ResultsFrom April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).ConclusionsAEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor–positive EC, supporting the principle of receptor-mediated targeted chemotherapy.

L1CAM in Early-Stage Type I Endometrial Cancer: Results of a Large Multicenter Evaluation

Despite the excellent prognosis of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.

Prognostic Factors for Carcinoma of the Uterine Cervix Treated with Concurrent-Chemoradiotherapy

Carcinoma of the uterine cervix is most commonly staged with the FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) system, which is essentially based upon benevolent intentions of simplicity and accessibility. Locally advanced carcinoma of the cervix (LACC) is defined as disease belonging to stages which are not amenable to routine upfront surgery. Staging for any cancer can be expected to provide valuable information with regards to prognosis and in choosing the appropriate and optimal pathway of clinical management. Hence, it could be said that improper staging or inadequate staging can lead to improper management. Carcinoma of the cervix (CC) continues to be staged by the FIGO system, which continues to ignore proven prognostic factors such as lymph nodal involvement, volume of disease and various other factors. This review intends to acquaint the reader about the exhaustive list of prognostic variables which are of potential significance in predicting prognosis, in determining optimal treatment, in predicting outcomes of treatment and possibly suggesting a subset of patients who may benefit with modified or intensified treatment strategies.

Fetal state assessment using fuzzy analysis of fetal heart rate signals—Agreement with the neonatal outcome

Fetal monitoring is based on analysis of fetal heart rate signal. Visual interpretation is difficult so computer-aided systems for quantitative analysis are commonly used. The clinical interpretation guidelines provided by FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) were used to develop the weighted fuzzy scoring system for qualitative assessment of the fetal state. In this work, agreement of the fuzzy classification system with the neonatal outcome assessment was analyzed. Various datasets were evaluated, depending on interpretation method of the signals which were recorded from patients. The obtained results confirmed possibility of the efficient fetal state assessment using the fuzzy inference method proposed.

Uterine Endometrial Carcinoma: 10 Years’ Experience with Long-Term Follow-Up at a Single Korean Institution

Aim: To evaluate prognostic factors in Korean patients with endometrial cancer. Methods: A retrospective analysis was conducted on 248 patients who were staged surgically at the Samsung Medical Center between 1995 and 2004. Survival data were analyzed using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression method. Results: The median age was 51 years (range 21–75), which was younger than in previous studies in Western patients, and the age of 50 years was the cutoff to predict survival. More than half (55.6%) were normal weight or underweight (BMI <25). Multivariate analysis revealed that age, Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage, and histopathology were independent predictors of disease-free survival, and FIGO stage and p53 mutation were independent prognostic factors for disease-specific survival (DSS). The 5-year DSS for patients with stage I, II, III and IV disease was 95.6, 93.8, 69.8 and 50%, respectively. The 5-year DSS rate for patients with a p53 mutation was 84.4%, compared with 97.1% for patients without. Conclusions: Korean patients with endometrial cancer were younger and had a lower BMI than previously reported. Furthermore, age greater than 50 years was predictive of a poor outcome. Age, FIGO stage, histopathology and a p53 mutation were independent prognostic factors for survival.

Clinical significance of peritumoral lymphatic vessel density and lymphatic vessel invasion detected by D2-40 immunostaining in FIGO Ib1-IIa squamous cell cervical cancer

The clinical significance of lymphangiogenesis in cervical cancer remains controversial. Our aim was to investigate the correlation between lymphangiogenesis, lymphatic vessel invasion (LVI) and tumor metastasis, invasion and prognosis in squamous cell cervical cancer. Paraffin sections of 90 patients with FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) Ib1-IIa squamous cell cervical cancer were stained for immunohistochemistry with a D2-40 monoclonal antibody against the carcinoembryonic antigen M2A. The lymphatic vessel density (LVD) and LVI were measured, and their relationship with the clinicopathological data was analyzed. D2-40-positive lymphatic vessels were found in 75 of the 90 patients (83.3 %). All D2-40-positive vessels were located in peritumoral areas. The mean±SD of the peritumoral LVD was 10.08±4.16. The positive rate of LVI was 32.0 % (24/75). The recurrence rate of patients with LVD >10 (62.1 %, 18/29) was significantly higher than that of patients with LVD ≤10 (34.8 %, 16/46, P = 0.021). The 5-year recurrence-free survival rate of patients with LVD >10 (41.0 %) was significantly lower than that of patients with LVD ≤10 (67.0 %, P = 0.045). Univariate analysis showed that the peritumoral LVD (≤10 vs >10) was correlated with LVI (absent vs present, P = 0.016). The peritumoral LVD and LVI showed no correlation with age, FIGO stage, tumor size, tumor grade, depth of invasion, or pelvic lymph node metastasis (all: P > 0.05). Peritumoral lymphangiogenesis was correlated with the recurrence and recurrence-free survival in patients with squamous cell cervical cancer. Examination of peritumoral LVD in these patients might therefore help to estimate the risk of recurrence.

The FIGO classification of causes of abnormal uterine bleeding in the reproductive years

At this juncture, clinical management, education for medical providers, and the design and interpretation of clinical trials have been hampered by the absence of a consensus system for nomenclature for the description of symptoms as well as classification of causes or potential causes of abnormal uterine bleeding (AUB). To address this issue, the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) has designed the PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy and Hyperplasia, Coagulopathy, Ovulatory Disorders, Endometrial Disorders, Iatrogenic Causes, and Not Classified) classification system for causes of AUB in the reproductive years.

Which staging system to use for gynaecological cancers: a survey with recommendations for practice in the UK

AimsThere are two commonly used staging systems for gynaecological cancers, namely Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) and TNM. The authors wished to ascertain which staging system is most...

Prognostic Impact of Additional Extended Surgical Procedures in Advanced-Stage Primary Ovarian Cancer

Treatment of advanced-stage ovarian carcinoma includes radical cytoreductive surgery, which aims at removing all visible tumor tissue followed by platinum and paclitaxel chemotherapy. Complete tumor resection may require extended surgical procedures. This paper reports on the prognostic impact of extensive surgery and surgical morbidity in patients with advanced-stage ovarian carcinoma. Patients with ovarian carcinoma [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIB-IV] undergoing primary surgery in our tertiary gynecologic oncology unit between 1997 and 2007 were eligible for this study. The impact of established prognostic factors and the interaction with extent of surgical procedures on survival were assessed. A total of 267 patients aged between 29 and 88 years (median 64 years) were eligible for this study. Overall survival time was improved in patients who underwent complete tumor resection [hazard ratio (HR) 3.61 (1.91-6.61), P < 0.001]. No significant survival difference was observed between completely operated patients in whom extended or standard surgical procedures were applied [HR 1.37 (0.70-2.69), P = 0.358], and severe surgical complications were found to be equally distributed between the two patient groups. Our results may encourage the application of extended surgical procedures in patients who would otherwise be rendered incompletely debulked after primary cytoreduction. We could demonstrate an impact of complete tumor resection on patient prognosis and this was not traded off for extensive additional surgical morbidity.

Utility of p16 Expression for Distinction of Uterine Serous Carcinomas From Endometrial Endometrioid and Endocervical Adenocarcinomas

Uterine serous carcinomas typically have a characteristic morphology (papillary architecture, high-grade nuclei) and immunoprofile (diffuse/strong p53 expression, loss of hormone receptor expression) that distinguish them from most endometrial endometrioid carcinomas. However, glandular variants of serous carcinoma can simulate Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade 2 endometrioid carcinomas, and some serous carcinomas lack p53 expression and retain hormone receptor expression, making classification difficult. P16 expression patterns distinguish endometrioid carcinomas (patchy) from human papillomavirus (HPV)-related endocervical adenocarcinomas (diffuse/strong) but utility for distinction of serous carcinomas from endometrioid carcinomas and endocervical adenocarcinomas has not been evaluated in a large series. Immunohistochemical analysis of p16 expression was performed on 201 uterine and endocervical adenocarcinomas in hysterectomy specimens, including 49 serous carcinomas, 101 endometrial endometrioid carcinomas (44 FIGO grade 1, 40 FIGO grade 2, and 17 FIGO grade 3), and 51 HPV-related endocervical adenocarcinomas. All serous carcinomas demonstrated diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 95%/100%). In contrast, endometrial endometrioid carcinomas exhibited less diffuse and less intense expression, with percent of positive tumor cells ranging from 10% to 90% (mean/median: 38%/30%; staining intensity: variable). Similar to serous carcinomas, all endocervical adenocarcinomas exhibited diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 94%/90%). P16 can serve as an additional diagnostic marker, used as part of an immunohistochemical panel, including p53 and hormone receptors, for distinction of uterine serous carcinomas from endometrioid carcinomas. Distinction of serous carcinomas from endocervical adenocarcinomas (HPV-related type), both of which share diffuse p16 expression and frequently lack hormone receptor expression, relies on morphology and diffuse/strong p53 expression in the former and detection of HPV in the latter.

Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Incidence of Invasive Cervical Cancer and Direct Costs Associated with its Management in Italy

Cervical cancer is the second most common cancer in European women aged 15-44 years. The aim of this study was to estimate the direct cost of managing invasive cervical cancer in Italy. Data from the Italian Network of Cancer Registries were used to estimate the annual number of new cervical cancer cases. To assess the management costs, a typical management pathway for each FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) cervical cancer stage was derived from published guidelines. Data from the Modena Cancer Registry were used to estimate the proportion of patients by FIGO stage. This algorithm was combined with tariffs for outpatient and inpatient procedures to obtain a mean cost for each FIGO stage. An estimated 2,927 new cases of cervical cancer occurred in Italy in 2005 (crude incidence 9.7/100,000; world age-standardized incidence 6.0/100,000). The estimated numbers of new cases by FIGO stage were: FIGO I, 1,927; FIGO II, 556; FIGO III, 259; and FIGO IV, 185. Costs for the most frequent procedures were estimated as: Euro 6,041 for radical hysterectomy or other surgery; Euro 4,901 for radio-chemotherapy; Euro 1,588 for brachytherapy; and Euro 3,795 for palliative chemotherapy. Mean management costs for incident cases (including 10 years of follow-up) were estimated at: FIGO I, Euro 6,024; FIGO II, Euro 10,572; FIGO III, Euro 11,367; FIGO IV, Euro 8707; and Euro 5,854 for the terminal phase (1 month). The total direct management cost was estimated at Euro 28.3 million per year. This is one of the first studies to estimate the direct cost of treating patients newly diagnosed with invasive cervical cancer in Italy. Although according to current management pathways real treatment costs are likely to be underestimated, this information is necessary to design evidence-based vaccination policies able to harmonize primary and secondary prevention of cervical cancer.

Prognostic significance of TPA versus SCC-Ag, CEA and neopterin in carcinoma of the uterine cervix

Introduction: Prognostic significance of squamous cell carcinoma antigen (SCC-Ag), tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA) and neopterin in cervical cancer patients was compared. Materials and methods: Pretreatment concentrations were determined in 138 women. Results: Median age was 52 years, 85% squamous cell carcinomas, 15% adeno- or adenosquamous carcinomas were seen. In 36% Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage I, 24% stage II, 32% stage III and 8% stage IV was diagnosed. TPA was elevated in 22%, SCC in 68%, CEA in 42% and neopterin in 29%. These patients showed significantly worse overall survival in univariate analysis ( p < 0.001). TPA remained as independent prognostic factor in multivariate analysis. Conclusions: Elevation of TPA was associated with worse overall survival.

Positive peritoneal cytology in early-stage endometrial cancer does not influence prognosis.

The aim of this study was to assess the prognostic importance of positive peritoneal cytology in early-stage endometrial cancer. All 278 stage I and 53 stage IIIA (without cervical involvement) endometrial cancer patients operated between 1980 and 1996, recorded at the Geneva Cancer registry, were included. Stage IIIA cancers were recategorised into ‘cytological’ stage IIIA (positive peritoneal cytology alone, n=33) and ‘histological’ stage IIIA (serosal or adnexal infiltration, n=20). Survival rates were analysed by Kaplan–Meier method and compared using log-rank test. The prognostic importance of cytology was analysed using a Cox model, accounting for other prognostic factors. The 5-year disease-specific survival of cytological stage IIIA cancer was similar to stage I (91 vs 92%) and better than histological stage IIIA cancer (50%, P<0.001). After adjustment for age, myometrial invasion, differentiation and radiotherapy, cytological stage IIIA patients were still at similar risk to die from endometrial cancer compared to stage I patients (hazard ratio (HR) 0.7, 95% confidence interval (CI): 0.18–2.3), while histological stage IIIA patients were at a four-fold increased risk to die from their disease (HR 4.2, 95% CI: 1.7–10.3). This population-based study shows that positive peritoneal cytology in itself has no impact on survival of patients with localised endometrial cancer. Based on the present and previous studies, FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) might consider reviewing its classification system.

Correlation Between MIB1-Determined Tumor Growth Fraction and Incidence of Tumor Recurrence in Early Ovarian Carcinomas

Purpose: The decision concerning adjuvant therapy remains difficult in patients with very early stage ovarian carcinomas [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) Ia/b]. Therefore, we compared the MIB1-determined tumor growth fraction in archival tumor tissue with tumor recurrence and outcome of disease, and in relationship to other stages and clinical and morphological findings. Patients and Methods: Ninety-two patients were followed in early stages of ovarian carcinomas (FIGO I and II) with no tumor residuals and were analyzed for tumor recurrences and long-term overall survival (mean 6.0 years, median 5.5). Fifty-eight patients had stage I tumors, among these were 38 in the sub-stages Ia/b. Tumor growth fraction (MIB1) in tissues from primary surgery was compared with the status of patients and disease, histology, and immunohistochemistry for carcinoembryonic antigen (CEA), CA125, CA153, steroid hormone receptors, and angiogenesis (chi-square test, Kaplan–Meier and discriminant analyses). Results: Tumor-associated deaths occurred in 27 cases, tumor recurrences occurred in 35 cases. In contrast to the advanced stages of disease, the MIB1-determined tumor growth fraction outweighed all other parameters in the prediction of the course of disease (p < 0.001), followed by tumor grading (p = 0.001) and FIGO-substages (p = 0.026) in this retrospective study. Particularly in the very early stages, MIB1 predicted tumor recurrences in 84% of the cases (p < 0.001). Recurrences were not observed below a tumor growth fraction of 10% but prevailed in cases of more than 15%. Conclusion: Our data suggest MIB1 as an interesting additional tool for the decision of adjuvant therapy in patients with very early stages of ovarian carcinomas, which should be tested in prospective trials.

Ascitic interleukin-12 is an independent prognostic factor in ovarian cancer.

The clinical impact of endogenous cytokines supplied with deterministic properties in the generation of either T helper (Th)1 -type or Th2-type immune response was investigated in patients with ovarian cancer. Whereas interleukin (IL)- 12 initiates the differentiation of naive Th0 cells toward Th1 phenotype, IL-4 and IL-10 mediate the development of Th2-type immunity. Cytokines were determined before treatment by means of enzyme-linked immunosorbent assay (ELISA) in ascites fluid and serum of 76 patients with ovarian cancer. Cytokine levels were compared with each other and with standard clinicopathologic parameters. A stepwise logistic regression was calculated to rule out interdependence in the associations of the various variables. Survival analyses were performed with the Kaplan-Meier method and differences in survival were examined according to Mantel and Breslow. Cox proportional hazards analysis was used to identify independent prognostic factors. Whereas IL-10 and IL-12 were detectable in all ascites-fluid samples, IL-4 was measurable in only 43% of the specimens. With the exception of neopterin, macrophage colony-stimulating factor (M-CSF), and IL-4, determined cytokine levels were significantly elevated in ascites fluid compared with serum (P < .01). In univariate analyses, high ascitic-fluid concentrations of either neopterin, tumor necrosis factor-alpha (TNF-alpha), or IL-12 were associated with poor disease-free (P < .005) and overall (P < .01) survival. Multivariate Cox regression analysis showed ascitic-fluid IL-12 levels to be the only immunologic variable that retained independent prognostic significance (P < .03 for disease-free and P < .01 for overall survival), together with residual disease, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO)-stage, and patient age. In ovarian cancer, high ascitic-fluid IL-12 levels, which may indicate a local Th1-generated immune response, are associated with disease progression.