Quality of therapy in early ovarian cancer: results of the quality assurance program of the AGO Study Group.

OBJECTIVE: The quality assurance program for ovarian cancer (QS-OVAR) evaluates the implementation of treatment standards and impact on survival for International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian cancer. METHODS: Patients with a first diagnosis of ovarian cancer, diagnosed in the third quarter of 2004, 2008, 2012, and 2016, were documented. Surgical quality was categorized as optimal (maximum one surgical item missing) versus suboptimal (≥2 surgical items missing). Chemotherapy was defined as optimal according to national guidelines. Treatment quality was classified into four categories: surgery and chemotherapy were optimal, optimal surgery and suboptimal chemotherapy, suboptimal surgery and optimal chemotherapy, and surgery and chemotherapy were suboptimal. RESULTS: In total, 19.9% (n=700) of ovarian cancer patients were diagnosed with FIGO stage I. Median age was 60 years (range 18-96), 47.1% had FIGO stage IA and 47.9% had stage IC, with 37.1% high grade serous histology. Optimal surgical quality increased over time from 19.9% to 54.1%. The optimal surgery population increased from 42.2% to 70.9%. Disease free survival improved significantly in the optimal surgery population (84% after 48 months vs 71% in the suboptimal surgery population). Overall survival increased with 91% after 48 months in the optimal surgery population versus 76% in the suboptimal surgery population. In total, 20.7% of patients were undertreated concerning systemic treatment and 1% overtreated. Optimal chemotherapy standard was administered increasingly over time (71.4-80.8%). Disease free survival and overall survival were prolonged with adjuvant chemotherapy. The optimal surgery/chemotherapy subgroup increased from 37.9% to 54.1% with significantly longer disease free survival and overall survival (overall survival at 48 months: optimal surgery and chemotherapy 93%; suboptimal surgery and chemotherapy 68%). CONCLUSION: Although QS-OVAR data showed that the quality of therapy has improved over the years, not all surgical standards were met in nearly 50% of patients. The steady increase in the optimal surgery and chemotherapy collective is an important tool for improvement of prognosis of ovarian cancer patients.

AGO-OVAR 28/ENGOT-ov57. Niraparib alone versus niraparib in combination with bevacizumab in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer: a multicenter randomized phase III trial.

BACKGROUND: Phase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian cancers; and, a significant benefit of the combination of olaparib and bevacizumab compared with bevacizumab monotherapy in HRD positive patients. However, it is unclear whether a PARP inhibitor monotherapy is sufficient, or if the addition of bevacizumab is needed. PRIMARY OBJECTIVES: This trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population. STUDY HYPOTHESIS: Adding bevacizumab to chemotherapy followed by niraparib maintenance improves progression-free survival in patients with newly diagnosed advanced ovarian cancer. TRIAL DESIGN: AGO-OVAR 28/ENGOT-ov57 is an international, multicenter, randomized, prospective phase III trial within the the European Network for Gynecological Oncological Trial (ENGOT), led by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group. All patients should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of the Study Run-In-Period. Prior to day 1 of cycle 2, patients with a valid central tumor BRCA (tBRCA) test result were randomized in a 1:1 ratio into either: Arm 1, to receive five additional cycles of carboplatin and paclitaxel q21d, followed by niraparib for up to 3 years; or Arm 2, to receive five additional cycles of carboplatin and paclitaxel plus bevacizumab q21d, followed by bevacizumab q21d (for up to 1 year), and niraparib for up to 3 years. MAJOR INCLUSION/EXCLUSION CRITERIA: The trial population is composed of adult patients with newly diagnosed, advanced high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also eligible for the trial. PRIMARY ENDPOINT: The primary endpoint is progression-free survival. SAMPLE SIZE: The study plans to recruit 970 patients (485 patients in each arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The Last-Patient-In is expected to be enrolled in September 2024, with presentation of the primary endpoint in 2028. TRIAL REGISTRATION: NCT05009082; EudraCT Number: 2021-001271-16.

Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883).

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883.

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).

Adjuvant radiotherapy and local recurrence in vulvar cancer - a subset analysis of the AGO-CaRE-1 study.

BACKGROUND: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. PATIENTS AND METHODS: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. RESULTS: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). CONCLUSION: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors.

Novel and flexible ultrasound simulation with smartphones and tablets in fetal echocardiography.

PURPOSE: Evaluation of a novel ultrasound-simulation-app for training fetal echocardiography as a possible useful addition for students, residents and specialist doctors. Furthermore, comparison to a conventional learning-method with special attention on orientation and recognition of physiological structures. METHODS: Prospective two-arm study with the participation of 226 clinical students. 108 students were given an extract from a textbook on fetal echocardiography (PDF-group, n = 108) for 30 min to study. 118 students were able to use the new ultrasound-simulator-app (Simulator-group, n = 118) to learn for 30 min. The knowledge of the students was examined both before and after the learning-period by having them identify sonographic structures in videos using single-choice selection. RESULTS: There were no significant differences between the two groups regarding age (p = 0.87), gender (p = 0.28), and the number of previously performed ultrasound-examinations (p = 0.45). In the Simulator-group, there was a significantly higher learning effect regarding the proportion of students with an increase of correct answers in the video test examination (p = 0.005). At the end of learning, the students in the Simulator-group needed significantly less time to display the structures in the app's simulation (median initially 10.9 s vs. 6.8 s at the end; p < 0.001). CONCLUSIONS: The novel ultrasound-simulation-app seems to be a useful addition and improvement to ultrasound training. Previous difficulties such as simultaneously having patients, ultrasound-machines, and professors at disposal can thus be avoided. This means that another important step towards remote learning can be taken, which has been proven increasingly essential lately, due to the COVID-19 pandemic.

Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer: A Subset Analysis of the AGO-CaRE-1 Study.

BACKGROUND: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades. METHODS: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement. RESULTS: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2-240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1-12]). In these 14 patients, the median number of affected groin nodes was 7 (1-30), with a groin metastases median maximum diameter of 42.5 mm (12-50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months. CONCLUSION: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease.

Ki67 as Proliferative Marker in Patients with Early Breast Cancer and Its Association with Clinicopathological Factors.

INTRODUCTION: Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. MATERIAL AND METHODS: Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (n = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. RESULTS: 595 (64.9%) patients had a Ki67 <20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1-90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2-) disease (n = 717), 20% for HR+/HER2+ (n = 76), 30% for HR-/HER2+ (n = 45), and 60% for HR-/HER2- (n = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (<20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). CONCLUSION: This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.

Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study.

BACKGROUND: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse. METHODS: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months. RESULTS: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001). CONCLUSIONS: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.

p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group.

BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

Endometrial Cancer Lymphadenectomy Trial (ECLAT) (pelvic and para-aortic lymphadenectomy in patients with stage I or II endometrial cancer with high risk of recurrence; AGO-OP.6).

BACKGROUND: The impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident. PRIMARY OBJECTIVE: Evaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence. STUDY HYPOTHESIS: Comprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65. TRIAL DESIGN: Open label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended. MAJOR INCLUSION CRITERIA: Patients with histologically confirmed endometrial cancer stages pT1b-pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible. EXCLUSION CRITERIA: Patients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease. PRIMARY ENDPOINT: Overall survival calculated from the date of randomization until death. SAMPLE SIZE: 640 patients will be enrolled in the study. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: At present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031. TRIAL REGISTRATION: NCT03438474.

[Reconciliation of Family and Work Life in the Department of Gynecology and Obstetrics - Systematic Assessment in Different Occupational Groups of a German University Hospital]. / "Zur Vereinbarkeit von Beruf und Familie bei Beschäftigten einer Universitätsfrauenklinik" ­ Auswertung einer systematischen Berufsgruppen-übergreifenden Befragung.

Reconciliation of family and work life is an important topic for employees. Due to common work in shifts within the health care sector, this is even more essential for health care workers and has great implications in work satisfaction and individuals ́ health. Within all employees of the department of OB/GYN of the German university hospital Ulm, an anonymous and voluntary survey on compatibility of work and family was performed in the summer of 2017. The questionnaires consisted of established and newly designed tools to assess reconciliation of family/work life as well as work-family (WFC) and family-work conflict (FWC). Return rate of questionnaires was 63% (n=136). Physicians (n=33), nurses (n=53), and midwives (n=31) were grouped together as "medical staff" (n=115). There was no significant difference between employees with (n=73) or without children (n=59) regarding WFC and FWC. The group of nurses/midwives and the group of physicians had a significantly higher inter-role conflict (p<0.001) than the group of administrative staff. A negative correlation with "work satisfaction" was found for WFC and FWC. The group of nurses/midwives has significantly higher inter-role conflicts than the administrative staff. Especially the negative correlation of work satisfaction and inter-role conflicts shows the enormous need for improvement in sufficient compatibility of work and family life of employees in the health care sector. This needs to be addressed quickly and effectively as there is an alarming deficit of nurses and midwives in the German health care system.

Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.

BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Influence of the New FIGO Classification for Cervical Cancer on Patient Survival: A Retrospective Analysis of 265 Histologically Confirmed Cases with FIGO Stages IA to IIB.

OBJECTIVE: At the end of the year 2018, a new FIGO classification for cervical cancer was published, mainly revising stage IB and introducing a new stage IIIC, which includes irrespectively of tumor size and local spread all patients with lymph node metastasis. METHODS: We retrospectively analyzed all cases of cervical cancer stage I to IIB who underwent surgery as primary treatment at our institution from 2000 until 2016 and therefore had a histological confirmation of tumor stage. We reclassified all histologies according to the new FIGO classification and calculated outcome according to the new stages. RESULTS: Out of 265 patients, 146 (55%) patients were reclassified into a higher FIGO stage. Most changes appeared within stage IB and from any stage to stage IIIC1. Kaplan-Meier curves for new stages showed a significant difference in disease-free survival (DFS) and overall survival (OS) between stages I versus II versus III (log-rank test, both p < 0.001). Overall, patients that were upstaged had a significant worse DFS (p = 0.012) and OS (p = 0.008) than patients whose stage did not change. Similar observations were made within sub-stages, when node-positive IB or IIB tumors were upstaged to IIIC tumors. CONCLUSION: The new FIGO classification for cervical cancer reflects the strong impact of lymph node metastases on survival and is a clear improvement compared to the old FIGO classification with regard to risk stratification.

Association between obesity and vulvar cancer recurrence: an analysis of the AGO-CaRE-1 study.

OBJECTIVE: Obesity is associated with worse survival and an increased risk of relapse in several malignancies. The influence of obesity on vulvar cancer recurrence has not been previously described. The primary objective of this study was to evaluate the association between obesity and tumor recurrence in patients with vulvar cancer. METHODS: This is an analysis of the AGO-CaRE-1 study. Patients diagnosed with squamous cell vulvar cancer (stage IB and higher), treated in 29 cancer centers between January 1998 and December 2008, were registered in a centralized database. The cohort was divided into two gropus depending on the body mass index (BMI) (<30 vs ≥30 kg/m²). Descriptive statistics, survival analyses, and multivariate Cox regression analyses were performed in order to evaluate the association between obesity and progression-free and overall survival. RESULTS: In 849 (52.4%) of 1618 patients in the database, the BMI was documented. Patients were grouped according to their BMI (<30 vs ≥30 kg/m²). There were 621 patients with a BMI <30 kg/m² and 228 patients with a BMI ≥30 kg/m². Besides age, there was no difference in baseline variables (tumor diameter, depth of infiltration, tumor stage, nodal metastasis, tumor grade). Treatment variables (R0 resection, chemotherapy, radiotherapy, continuation of adjuvant therapy) did not differ between groups. However, patients with BMI ≥30 kg/m² underwent radical vulvectomy more often (61.1% vs 51.8%, p=0.04). During follow-up there was a higher recurrence rate in the group with BMI ≥30 kg/m² (43.4% vs 28.3%, p<0.01) due to an increased rate of local recurrences (33.3% vs 18.5%, p<0.01). There was a significantly shorter time to recurrence in obese patients on univariate analysis (BMI ≥30 kg/m² vs <30 kg/m²: 43.8 months (95% CI 23.3 to 64.3) vs 102.3 months (95% CI 72.6 to 131.9), p=0.001) and on multivariate Cox regression analysis (HR 1.94 (95% CI 1.4 to 2.8), p<0.001). CONCLUSIONS: In this study a BMI ≥30 kg/m² was associated with a shorter time to recurrence in patients with vulvar cancer and this was mainly attributed to a higher risk of local recurrence.

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).

BACKGROUND: For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? METHODS: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. RESULTS: The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. CONCLUSION: Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors. TRIAL REGISTRATION NUMBER: NCT02222883.

Prognostic role of thrombocytosis in recurrent ovarian cancer: a pooled analysis of the AGO Study Group.

PURPOSE: Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer. METHODS: In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅109/L. RESULTS: Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84-1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00-2.14, P = 0.047). CONCLUSIONS: The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.

Feasibility of a large multi-center translational research project for newly diagnosed breast and ovarian cancer patients with affiliated biobank: the BRandO biology and outcome (BiO)-project.

INTRODUCTION: Large translational research projects may contribute to further progress in cancer treatment by exploring molecular biology, immunologic approaches and identification of new prognostic and predictive factors. Therefore, the BRandOBio-project combines a clinical registry for collection of patient and tumor characteristics with a biobank comprising tumor and liquid biopsies. In addition, sociodemographic, environmental and lifestyle factors of included patients with primary newly diagnosed breast or ovarian cancer, other rare malignant ovarian tumors or gestational trophoblastic disease are prospectively collected. METHODS: The target population includes the German "Alb-Allgäu-Bodensee Region" which constitutes the outreach area of the University Hospital Ulm with affiliated academic centers and private practices. Clinical data combined with primary tumor tissue samples and longitudinal repeatedly collected blood samples [before, 6 (in high-risk situations), 12, 36 and 60 months after treatment and at relapse] will be acquired from more than 4000 patients within the next years. Standardized questionnaires are given to patients of the University Hospital Ulm and eight selected external sites for assessing life style and cancer risk factors. Concomitantly, storage of paraffin-embedded tumor samples as well as liquid biopsy samples will allow translational research projects, for example in terms of investigating circulating DNA and germ line DNA from cell pellets. RESULTS: Starting in January 2016 at the University Hospital Ulm, 19 additional external sites started recruiting patients in March 2017. As of September 15th 2019, 2151 patients with newly diagnosed cancers could be recruited (2044 breast cancer; 107 ovarian cancer). Nearly all patients provided biological samples (tumor and liquid biopsy) and about 80% returned the standardized questionnaire. After 1 year follow-up, blood samples were available from more than 80% of the participating patients. CONCLUSIONS: The BRandO BIO study is a large prospective cohort study with integrated comprehensive biobank and evaluation of sociodemographic and life style factors of gynecological cancer patients in a well-defined geographical area in the South West of Germany. Continuous high patient recruitment and stable rates over 80% for returned questionnaires as well as for repeated blood sampling show high acceptance of the BRandO study program and confirms feasibility of the project.

Predicting the course of disease in recurrent vulvar cancer - A subset analysis of the AGO-CaRE-1 study.

OBJECTIVE: In vulvar cancer (VSCC), the course of disease with regard to localization of recurrence and relation of different recurrence sites is poorly described. METHODS: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Patients (pts) with primary VSCC, FIGO stage ≥1B treated in Germany from 1998 to 2008 were included in a centralized database (n = 1618). In the current subgroup analysis, different sites of primary recurrence and their impact on disease course and survival were analyzed using multistate and competing risks methods. RESULTS: 1249 pts with surgical groin staging and known lymph-node status (35.8% N+) were included in the analysis. 360 pts (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only, with a cumulative incidence of 12.6% after 2 years. Generally, prognosis after disease depended on recurrence site: Hazard ratios (HRs) (95% confidence interval) to die for pts with compared to without recurrence at the same time: vulvar only: 5.9 (4.3-8.2); groins only: 6.0 (3.0-10.2); vulvar and groins: 14.1 (7.6-26.4); pelvic/distant: 21.2 (15.3-29.4). Fifty-eight (30.1%) pts with local recurrence developed second recurrence. 2-year mortality after any recurrence was 56.3%. After vulvar recurrence pts had a 2-year and 5-year overall survival rate of 82.2% and 66.9%. CONCLUSIONS: Prognosis after recurrence is highly depending on recurrence site. Pts with isolated vulvar recurrence have an impaired prognosis as many affected pts develop second recurrences.