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Abstract Background An effective cross-cultural doctor-patient communication is vital for health literacy and patient compliance. Building a good relationship with medical staff is also relevant for the treatment decision-making process for cancer patients. Studies about the role of a specific migrant background regarding patient preferences and expectations are lacking. We therefore conducted a multicentre prospective survey to explore the needs and preferences of patients with a migrant background (PMB) suffering from gynecological malignancies and breast cancer to evaluate the quality of doctor-patient communication and cancer management compared to non-migrants (NM). Methods This multicentre survey recruited patients with primary or recurrence of breast, ovarian, peritoneal, or fallopian tube cancer. The patients either filled out a paper form, participated via an online survey, or were interviewed by trained staff. A 58-item questionnaire was primarily developed in German and then translated into three different languages to reach non-German-speaking patients. Results A total of 606 patients were included in the study: 54.1% (328) were interviewed directly, 9.1% (55) participated via an online survey, and 36.8% (223) used the paper print version. More than one quarter, 27.4% (166) of the participants, had a migrant background. The majority of migrants and NM were highly satisfied with the communication with their doctors. First-generation migrants (FGM) and patients with breast cancer were less often informed about participation in clinical trials (p

Purpose: With growing knowledge about ovarian cancer over the last decades, diagnosis, evaluation and treatment of ovarian cancer patients have become highly specialized, and an individually adapted approach should be made in each woman by interdisciplinary cooperation. The present study aims to show the variety and extent of medical specialties involved at our institution according to the European Society of Gynecologic Oncology (ESGO) Quality indicators (QI)., Methods: A woman, diagnosed with high-grade ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) class IVb was selected for a single case observational study. The observation period (total = 22d) comprised preoperative diagnostic procedures, including imaging, the in-patient stay for cytoreductive surgery, and the postoperative course and case discussion at our interdisciplinary tumor board. Data were obtained by self-reporting and by patient file review., Results: Patient tracking demonstrated an interdisciplinary cooperation of 12 medical specialties [62 physicians (63% male, 37% female)], 8 different types of nursing staff [n = 59 (22% male, 78% female)], and 9 different types of perioperative/administrative staff (n = 23; male 17,4%, female n = 19, 82,6%). Contact with the patient was direct (n = 199; 76%) or without face-to-face interaction (n = 63; 24%)., Conclusion: The present study demonstrates the high diversity of physicians and the affiliated medical staff, as well as interdisciplinary intersections within teams of a specialized hospital. Matching the ESGO QIs, this report underlines the requirement of an adequate infrastructure for the complex management of advanced ovarian cancer patients. Future prospective studies are warranted to evaluate the specific procedures and actions to optimize the interprofessional and interdisciplinary workflows., (© 2024. The Author(s).)

Background: Malnutrition was associated with worse survival outcomes, impaired quality of life, and deteriorated performance status across various cancer types. We aimed to identify risk factors for malnutrition in patients with epithelial ovarian cancer (EOC) and impact on survival., Methods: In our prospective observational monocentric study, we included the patients with primary and recurrent EOC, tubal or peritoneal cancer conducted. We assessed serum laboratory parameters, body mass index, nutritional risk index, nutritional risk screening score (NRS-2002), and bio-electrical impedance analysis., Results: We recruited a total of 152 patients. Patients > 65 years-old, with ascites of >500 mL, or with platinum-resistant EOC showed statistically significant increased risk of malnutrition when evaluated using NRS-2002 ( p -values= 0.014, 0.001, and 0.007, respectively). NRS-2002 < 3 was an independent predictive factor for complete tumor resectability ( p = 0.009). The patients with NRS-2002 ≥ 3 had a median overall survival (OS) of seven months (95% CI = 0-24 months), as compared to the patients with NRS-2002 < 3, where median OS was forty-six months ( p = 0.001). A phase angle (PhAα) ≤ 4.5 was the strongest predictor of OS., Conclusions: In our study, we found malnutrition to be an independent predictor of incomplete cytoreduction and independent prognostic factor for poor OS. Preoperative nutritional assessment is an effective tool in the identification of high-risk EOC groups characterized by poor clinical outcome.

Background: Advanced ovarian cancer is managed by extensive surgery, which could be associated with high morbidity. A personalized pre-habilitation strategy combined with an 'enhanced recovery after surgery' (ERAS) pathway may decrease post-operative morbidity., Primary Objective: To analyze the effects of a combined multi-modal pre-habilitation and ERAS strategy on severe post-operative morbidity for patients with ovarian cancer (primary diagnosis or first recurrence) undergoing cytoreductive surgery., Study Hypothesis: A personalized multi-modal pre-habilitation algorithm entailing a physical fitness intervention, nutritional and psycho-oncological support, completed by an ERAS pathway, reduces post-operative morbidity., Trial Design: This is a prospective, controlled, non-randomized, open, interventional two-center clinical study. Endpoints will be compared with a three-fold control: (a) historic control group (data from institutional ovarian cancer databases); (b) prospective control group (assessed before implementing the intervention); and (c) matched health insurance controls., Inclusion Criteria: Patients with ovarian, fallopian, or primary peritoneal cancer undergoing primary surgical treatment (primary ovarian cancer or first recurrence) can be included. The intervention group receives an additional multi-level study treatment: (1) standardized frailty assessment followed by (2) a personalized tri-modal pre-habilitation program and (3) peri-operative care according to an ERAS pathway., Exclusion Criteria: Inoperable disease or neoadjuvant chemotherapy, simultaneous diagnosis of simultaneous primary tumors, in case of interference with the overall prognosis (except for breast cancer); dementia or other conditions that impair compliance or prognosis., Primary Endpoint: Reduction of severe post-operative complications (according to Clavien- Dindo Classification (CDC) III-V) within 30 days after surgery., Sample Size: Intervention group (n=414, of which approximately 20% insure with the participating health insurance); historic control group (n=198); prospective control group (n=50), health insurance controls (for those intervention patients who are members of the participating health insurance)., Estimated Dates for Completing Accrual and Presenting Results: The intervention phase started in December 2021 and will continue until June 2023. As of March 2023, 280 patients have been enrolled in the intervention group. The expected completion of the entire study is September 2024., Trial Registration: NCT05256576., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC)., Methods: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m 2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573., Results: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment., Conclusion: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit., (© 2023. The Author(s).)

Background: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC)., Methods: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75)., Results: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP)., Conclusions: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities., Clinical Trial Registration: ClinicalTrials.gov, number NCT01379989., (© 2023. The Author(s).)

Objective: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease., Methods: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021., Results: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy., Conclusion: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Peritoneal carcinomatosis in ovarian cancer is frequent and generally associated with higher stage and poorer outcome. The clinical features of peritoneal carcinomatosis are diverse and their relevance for surgical and long-term outcome remains unclear. We conducted this prospective study to describe intraoperatively the different features of peritoneal carcinomatosis(PC) and correlate them with clinicopathological features, progression-free(PFS) and overall survival (OS),., Methods: We performed a systematic analysis of all patients with documented intraoperative PC and a primary diagnosis of epithelial ovarian, tubal, or peritoneal cancer from January 2001 to September 2018. All data were evaluated by using the systematic tumor bank tool. Specific PC features included texture(soft-hard), consistency(coarse-fine or both), wet vs dry(PC with ascites vs. PC without ascites), and localization(diffuse-local). PC characteristics were then evaluated for correlation with age, FIGO-stage, histology, lymph-node involvement, grade, and presence of residual tumor at primary surgery. Moreover, the influence of PC characteristics on OS and PFS was analyzed., Results: A total of 1686 patients with PC and primary epithelial ovarian cancer were included. Majority of the patients were characterized by diffuse PC(73.9%). The majority of peritoneal nodules were fine in texture (55.3%) and hard in consistency (87.4%). Moreover, 27.6% of patients had dry PC. Diffuse PC localization was significantly associated with higher FIGO-stage (p<0.001), high-grade (p=0.003) and serous tumors (p=0.006) as well as residual tumor as compared to local PC (p<0.001). Wet PC also significantly correlated with diffuse localization (p <0.001) and residual tumor as compared to dry PC (p<0.001). Coarse PC was significantly associated with residual tumor as compared to fine PC (p=0.044). All other PC features didn´t correlate with clinicopathological features. As for survival outcomes, diffuse peritoneal localization (p<0.001), wet PC (p<0.001), and additional lymph node involvement (p<0.001) were associated with lower OS and PFS rates. Other PC features did not significantly impact survival., Conclusion: Diffuse localization of peritoneal carcinomatosis was significant predictor of recurrence. Lower OS and PFS were associated with diffuse peritoneal localization, wet PC, and additional lymph node involvement. Further prospective trials are warranted with the inclusion of translational research aspects to better understand the different peritoneal carcinomatosis patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nasser, Babayeva, Braicu, Richter, Bilir, Chekerov, Muallem, Pietzner, Inci and Sehouli.)

Background: High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach., Objective: Our study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery., Study Design: Firstly, "In silico" analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing. Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns., Results: The Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC Ø0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of Ø0.797., Conclusion: The tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass., Methods: This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC)., Results: Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity., Conclusions: ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients., (© 2022. The Author(s).)

Background: Since the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, BRCA testing has evolved as a standard management in epithelial ovarian cancer., Objective: To analyze the implementation of molecular testing and PARP inhibitor therapy in Germany., Methods: The questionnaire contained 40 questions covering real-life data on genetic testing and the use of PARP inhibitors. It was divided into three main parts: basic demographics of respondents, genetic counseling and testing, and treatment with PARP inhibitors. The questionnaire was distributed via mail between August 2020 and May 2021., Results: A total of 315 physicians participated in the survey, of whom 54.9% were specialized in the field of gynecologic oncology. Two-thirds of respondents (67.4%) stated that they tested more than 80% of patients with primary epithelial ovarian cancer for BRCA mutation; however, only 42.5% of gynecologists who performed genetic counseling had an additional qualification in subject-specific genetic counseling, which is mandatory for predictive genetic testing in Germany. The main reasons for failure of BRCA testing were patient refusal (54.6%) and organizational or logistical issues (31.7%). Only 13.7% of respondents felt sufficiently equipped with supportive information material on patient counseling, whereas a high need for information material was indicated by 86.3% of the respondents. Molecular tumor profiling to infer homologous recombination (HR) deficiency status was provided by only 53.3% of institutions. PARP inhibitors were applied on a regular basis by 62.1% of respondents. The most important criteria for selection of appropriate PARP inhibitor therapy were the side effect profile (78.2%) and efficacy (71.2%). The majority of respondents (66.5%) preferred a combination of olaparib and bevacizumab over PARP inhibitors alone in the frontline setting., Conclusion: Adequate structure for BRCA/HR deficiency testing, and systematic education programs are needed to prevent delay in counseling and undertreatment of women with epithelial ovarian cancer. In Germany, a combination of olaparib and bevacizumab seems to be the preferred treatment in the first-line setting., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Women living with HIV have an increased risk of human papillomavirus (HPV) infection and cervical cancer. Little is known about genotype-specific HPV prevalence, the impact of antiretroviral therapy, immunological status, and additional risk factors in women living with HIV in Germany. The goal of this study was to characterize the risk profile for cervical dysplasia in these women., Methods: Patients with HIV infection presenting at Charité-Universitätsmedizin Berlin from October 2017 to September 2020 were included and underwent gynecological examination, colposcopy, cervical cytology and HPV genotype testing. HPV genotypes were stratified by carcinogenicity. Atypical squamous cells of undetermined significance or higher were considered abnormal cytology. Data were analyzed by SPSS software (version 26, 2019). A two-tailed p-value ≤0.05 was considered statistically significant., Results: A total of 84 women were evaluated. The majority (95.2%) received antiretroviral therapy. Median CD4 cell count was 564 cells/µl (range 20-1969). 95.2% were previously screened for cervical cancer. High-risk HPV prevalence was 44%. High-high-risk HPV subtypes (16, 18, 31, 33, 45, 52, 58) were significantly associated with abnormal cytology (p<0.001). HPV16 was the most common genotype (23%), was significantly associated with abnormal cytology (p=0.002) and was the main risk factor for abnormal cytology (OR 8.55, 95% CI 2.15 to 34.13, p=0.002), followed by age <35 years (OR 4.96, 95% CI 1.23 to 19.61, p=0.033) and cigarette smoking (OR 3.944, 95% CI 0.98 to 15.88, p=0.053)., Conclusions: Antiretroviral therapy and adherence to cervical cancer screening was high. High-high-risk HPV, especially HPV16, coincided with high incidence of cytological abnormalities. Women living with HIV in Germany have adequate immune status and are often pre-screened for cervical cancer, and therefore have a different risk profile for cervical dysplasia than in low-income or medium-income countries. Adapted screening programs should be defined., Competing Interests: Competing interests: JS: President Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie (NOGGO e.V.), Member Prevention Committee European Society of Gynaecological Oncology., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The international Charité-MAYO Conference aims to promote international dialog on diagnostics, management, scientific breakthroughs, and state-of-the-art surgical procedures in gynecology and gynecologic oncology and senology. Live surgeries are a fundamental tool of interdisciplinary and international exchange of experts in their respective fields. Currently, there is a controversial and emotional debate about the true value, risks, and safety of live surgical broadcasts. The aim of the current study is to analyze peri-operative risks in patients who were operated live during the Charité-MAYO Conferences., Methods: Live surgeries were performed by the core Charité team consisting of gynecologic oncologic surgeons, breast and plastic surgeons, partly in collaboration with visiting gynecologic oncologic surgeons. We performed a retrospective analysis of live surgeries performed during seven Charité-MAYO Conferences from 2010 to 2019 held in Berlin, Germany. Patients' files and tumor databases were analyzed as required and patients were contacted to update their long-term follow-up., Results: Sixty-nine patients who were operated live were included. The types of surgery were as follows: urogynecologic procedures (n=13), breast surgery (n=21), and gynecologic oncology surgery for ovarian, uterine, vulvar or cervical cancer (n=35). Peri-operative complications were assessed according to the Clavien-Dindo classification. Despite a high rate of complete resection and the high frequency of multivisceral procedures, the rate of peri-operative complications was within the range published in the literature. Time of surgery and length of intensive unit care and hospital stay did not differ from data acquired at the home institution., Conclusions: Based on our analysis, live surgeries appear to be safe when performed within a multidisciplinary setting without an increase in surgical morbidity and mortality compared with historical controls and without compromise of patients' outcome. This is the first analysis of its kind to set the basis for patient information and consent for this type of surgeries., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Mechanical bowel obstruction is a frequent acute and life-threatening event in relapsed ovarian cancer. Salvage surgery after failure of all conservative approaches, resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate patients' surgical and clinical outcome in these highly palliative situations. Previous, limited, data reported a high morbidity and mortality. However, recent surgical and therapeutical improvements in relapsed ovarian cancer (ROC) offer better identification of patients who might benefit from surgery in an effort to extend the window of opportunity to subsequently offer these patients novel systemic therapeutic approaches., Material and Methods: All subsequent ROC patients between 2012 and 2017 with acute mechanical bowel obstruction who underwent salvage extraperitoneal en bloc intestinal resection were retrospectively identified. Data were collected from two ESGO certified Ovarian Cancer Centers of Excellence (Charité Berlin and Imperial College London) and systematically evaluated regarding surgical and clinical outcomes., Results: Overall, 87 ROC patients were included in the analysis (median age 56 years, range 24-88), 47% were platinum resistant. High grade serous was the most common histology (76%) while most of the patients (67%) had at least two previous lines of treatment. Mean observed OS was 7.8 months. After salvage surgery, 46% of the patients had a residual small bowel length < 180 cm and 18% > 180 cm resulting in 41% in need of total parental nutrition. In 80% of the patients a permanent stoma was necessary. 30d morbidity and mortality was 74% and 10%, respectively. More than half of the patients were able to receive further courses of chemotherapy after surgery., Discussion: Salvage surgery for bowel obstruction in ROC patients needs careful consideration and identification of optimal surgical candidates to have the maximal therapeutic benefit. Despite the challenging morbidity profile, most patients managed to proceed to subsequent novel and conventional systemic treatment and so have their window of therapeutic opportunity extended., (© 2021. The Author(s).)

Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment., Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set., Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively., Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

Background: An effective cross-cultural doctor-patient communication is vital for health literacy and patient compliance. Building a good relationship with medical staff is also relevant for the treatment decision-making process for cancer patients. Studies about the role of a specific migrant background regarding patient preferences and expectations are lacking. We therefore conducted a multicentre prospective survey to explore the needs and preferences of patients with a migrant background (PMB) suffering from gynecological malignancies and breast cancer to evaluate the quality of doctor-patient communication and cancer management compared to non-migrants (NM)., Methods: This multicentre survey recruited patients with primary or recurrence of breast, ovarian, peritoneal, or fallopian tube cancer. The patients either filled out a paper form, participated via an online survey, or were interviewed by trained staff. A 58-item questionnaire was primarily developed in German and then translated into three different languages to reach non-German-speaking patients., Results: A total of 606 patients were included in the study: 54.1% (328) were interviewed directly, 9.1% (55) participated via an online survey, and 36.8% (223) used the paper print version. More than one quarter, 27.4% (166) of the participants, had a migrant background. The majority of migrants and NM were highly satisfied with the communication with their doctors. First-generation migrants (FGM) and patients with breast cancer were less often informed about participation in clinical trials (p < 0.05) and 24.5% of them suggested the help of an interpreter to improve the medical consultation. Second and third-generation migrants (SGM and TGM) experienced more fatigue and nausea than expected., Conclusions: Our results allow the hypothesis that training medical staff in intercultural competence and using disease-related patient information in different languages can improve best supportive care management and quality of life in cancer patients with migrant status., (© 2021. The Author(s).)

Research Question: What is the potential role of immune cells and their inflammatory cytokines in the pathogenesis, development and establishment of endometriosis?, Design: Peritoneal fluid from 59 women (43 with endometriosis and 16 controls) who had undergone laparoscopic surgery was analysed. Changes in the population of innate and adaptive immune cells, cytokines, chemokines and growth factor expression were measured by flow cytometry, Luminex Technology and enzyme-linked immunosorbent assay., Results: No differences were found in the frequencies of the innate and adaptive immune cells between women with and without endometriosis. In the peritoneal fluid of women with endometriosis, IL-1β, IL-1RN, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-17α, FGF2, G-CSF, MCP-1, MIP-1α and TNF-α were significantly increased compared with controls. A correlation between IL-2, MCP-1, MIP-1α, TNF-α and the severity of endometriosis was observed. The concentration of neopterin, a possible biomarker for this disease, was increased in women with endometriosis compared with controls., Conclusions: The functional activity of immune cells seemed to be reduced despite their numbers remaining unchanged. The data indicate that a shift of T H cytokine profile occurs, which increases the T H 1-T H 2 ratio. This is driven by the increased levels of the cytokines (TNF-α and IL-2) in women with severe endometriosis., (Copyright © 2021. Published by Elsevier Ltd.)

Background/aim: Postoperative pancreatic fistula after distal pancreatectomy represents the most frequent procedure-related complication; however, a standard treatment is currently not available., Case Report: We herein report a case of postoperative pancreatic fistula after distal pancreatectomy and splenectomy in a patient affected by a platinum-sensitive ovarian cancer recurrence. The 59-year-old patient developed a pancreatic fistula on postoperative day 4. An endoscopic transgastric double-pigtail drainage was placed on postoperative day 13. The patient was discharged after 5 days and referred to adjuvant medical treatment. A month later, computed tomography revealed complete resolution of the fistula, the drainage was removed, and the patient continued chemotherapy. She recovered uneventfully at a 3-month follow-up., Conclusion: EUS-guided drainage is a viable option in the management of postoperative pancreatic fistula, which can lead to a rapid resolution of peripancreatic fluid collections and to initiation of adjuvant chemotherapy with the slightest delay in ovarian cancer patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Patients with platinum-resistant ovarian cancer (PROC) have a high need for reliable prognostic markers. Since significance of primary platinum resistance (PPR) versus secondary platinum resistance (SPR) was identified for patients receiving anti-angiogenic therapy, it has not been confirmed for chemotherapy only., Methods: PROC patients from 3 prospective trials of the NOGGO study group (TOWER, NOGGO-Treosulfan, and TRIAS) were included in this meta-analysis. Exploratory Cox and logistic regression analyses were performed to correlate progression-free survival (PFS) and overall survival (OS) with the timing when platinum resistance developed., Results: Of 477 patients, 264 (55.3%) were classified as PPR, compared to 213 (44.7%) with SPR. For patients receiving chemotherapy only, SPR was associated with a significantly longer median PFS of 3.9 compared to 3.1 months for PPR (hazard ratio [HR]=0.78; p=0.015). SPR versus PPR was confirmed to be an independent prognostic factor for better PFS in multivariate analysis (HR=0.74; p=0.029). Benefit from adding sorafenib to chemotherapy was mainly seen in PPR (HR=0.40; p<0.001) compared to SPR patients (HR=0.83; p=0.465)., Conclusions: Prognostic significance of SPR versus PPR could be elucidated for patients receiving chemotherapy only. In contrast to bevacizumab, the multi-kinase inhibitor sorafenib exhibits profound therapeutic efficacy in PPR patients indicating potential to overcome this negative prognostic impact., Competing Interests: Fabian Trillsch: grants and personal fees from AstraZeneca, Clovis, Medac, MSD, PharmaMar, Roche, and Tesaro/GSK. Sven Mahner: grants and personal fees from AstraZeneca, Clovis, Medac, Novartis, Olympus Europe, PharmaMar, Pfizer, Roche, Sensor Kinesis, Tesaro/GSK, and TEVA. Pauline Wimberger: grants and personal fees from AstraZeneca, Amgen, Clovis, Medac, MSD, Pfizer, PharmaMar, Roche, Tesaro/GSK, Novartis, Eisai, Celgene and TEVA. Jalid Sehouli: grants and personal fees from Astra Zeneca, Bayer, Eisai, Clovis, Olympus, Johnsons and Johnson, PharmaMar, Pfizer, TEVA, Tesaro/GSK, MSD, Lilly, Roche and Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background/aim: Angiosarcoma of primary gynecologic origin is an extremely rare and highly malignant tumor of endothelial origin with a 5-year survival rate of less than 35%. To date, only 61 cases have been described in the literature. The aim of this study was to present more cases and discuss potential therapy options., Case Report: The following case series presents three cases of gynecologic angiosarcomas that were under therapy at the Charité - University medicine of Berlin from June 2014 to February 2018., Results: Two of the cases deal with primary angiosarcomas of the uterus whereas the third case was diagnosed after the suspicion of a recurrence of a poorly differentiated squamous cell carcinoma of the cervix uteri. In case one a 75-year old patient with initial postmenopausal bleeding and a tumor mass of the uterus is described. After surgery a hemangiosarcoma of the uterus was confirmed. After two months the patient presented with a presacral peritoneal sarcomatosis. Chemotherapy of weekly paclitaxel was administered. Case two deals with a patient presenting with abdominal pain. A uterine sarcoma with infiltration of the parametry and angiosarcomatosis peritonei was diagnosed during an emergency laparotomy because of spontaneous peritoneal bleeding. Moreover, osseous metastasis was found. The patient underwent weekly paclitaxel. Due to tumor progression, chemotherapy was changed to doxorubicin and olaratumab and radiotherapy was induced. The patient died 33 months after initial diagnosis. Case three describes a 34-year old patient with suspected local recurrence of cervical cancer with infiltration of the bladder. During TURB an angiosarcoma was found. Following laparoscopy revealed peritoneal metastasis. The patient underwent weekly paclitaxel followed by a paclitaxel and pazopanib maintainance therapy which showed a regression. Due to progression afterwards, chemotherapy was changed to gemcitabine and docetaxel and gemcitabine monotherapy. The patient died 33 months after initial diagnosis., Conclusion: Even though there is no evidence on standard treatment of this extremely rare and aggressive tumor entity of the female genital tract the patients showed the longest stability of disease during chemotherapy with weekly paclitaxel., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Aim of this study was to analyze the impact of pain on quality of life and survival in recurrent OC patients., Methods: Raw data including the QLQ-C30 questionnaire from three phase II/III trials ("Topotecan phase III," "Hector," and "TRIAS") conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) were synthesized and analyzed using logistic and Cox regression analyses., Results: Data on pain was available for 952 patients out of 1226. Moderate to severe pain, which was defined as pain ≥ 50 in the QLQ-C30 symptom scale, was experienced by more than one-third of patients (36.6%). A total of 31% were taking non-opioid pain medication and 16% opioids. Median age at randomization was 61 years (range 25-84). Most patients (84.7%) were diagnosed in FIGO III/IV. Pain was independent from age, FIGO stage, grading, amount of recurrences, and chemotherapy-free interval. ECOG was significantly worse in patients with pain (p < 0.001). Fatigue, nausea/vomiting, sleeping disorders, and abdominal symptoms such as loss of appetite, diarrhea, and constipation were more frequently found in patients with pain (all p < 0.001). Quality of life was significantly diminished (p < 0.001). Pain was also an independent marker for overall survival (OS). Median OS was 18.2 months in patients with pain compared with 22.0 months in patients without pain (p = 0.013, HR 1.25, 95% confidence interval 1.05-1.48). OS was shorter in patients with pain and without pain medication compared with those on sufficient pain medication, whereas OS was mostly decreased in patients having pain despite pain medication (18.5, 19.6, and 15.0 months respectively; p = 0.026). Progression-free survival and prior treatment discontinuation were not associated with pain., Conclusion: Best supportive care including sufficient pain medication should be delivered as early as possible because effective pain management is crucial for both quality of life and overall survival in patients with recurrent ovarian cancer.

Background: Maintenance therapy induces remission and prolongs disease free interval in primary and recurrent ovarian disease. For the treatment decision making process, aspects of quality of life and patients' preferences are crucial, despite the fact that scientific data are lacking. Therefore, we conducted this European-wide study in patients with ovarian cancer., Methods: A 25 item questionnaire was provided to ovarian cancer patients via the internet or as a paper version in 10 European countries (Austria, Belgium, France, Germany, Italy, Romania, Slovenia, Finland, Turkey, and Spain). Data recorded were demographics, tumor stage, therapy after firstline and recurrent disease, preferences for administration, and expectations concerning maintenance therapy., Results: Overall, 1954 patients participated from September 2013 to March 2016; 42% had recurrent disease. Most patients (98%) with primary epithelial ovarian cancer underwent surgery followed by chemotherapy (91%). Almost one-third of participants (29%) were receiving maintenance therapy whereas 45% had only heard of it. For 70% of patients with primary epithelial ovarian cancer, they heard about maintenance therapy from their doctor, 10% heard about maintenance therapy from other patients, and 8% from the internet. The main source of information about maintenance therapy in patients with epithelial ovarian cancer relapse was from the treating physician (72%), from other patients (8%), and from the internet (7%). For patients undergoing maintenance therapy, the four most disturbing adverse effects were polyneuropathy (37%), nausea (36%), hair loss (34%), and vomiting (34%). The main objective of maintenance treatment, as perceived by patients, was to increase the chances of cure (73%), improvement in quality of life (47%), and delay in tumor growth (37%). Many patients were willing to undergo maintenance therapy until tumor progression (38%) and 39% would prefer oral administration. No significant differences were detected in the cross country subanalysis regarding expectations of maintenance therapy and patients with primary or relapsed ovarian cancer., Conclusion: Patients with ovarian cancer were willing to accept maintenance therapy of prolonged duration and preferred oral administration. There is still a gap between the efficacy of maintenance therapy and patient expectations. Patients need more information on the adverse effects and treatment goals of maintenance therapy to avoid misunderstandings., Competing Interests: Competing interests: FJ is on the advisory board and symposium of Astra Zeneca, Roche, Tesaro, Ipsen Pharma GmbH, Janssen, Pfizer, Bristol-Myers Squibb and MSD, outside the submitted work. RB reports personal fees from Roche and from AstraZeneca, outside the submitted work. AdB reports personal fees from Astra Zeneca, Roche, BioCard, Tesaro, Pfizer, Clovis, Genmab, and MSD, outside the submitted work. IV reports consulting or advisory role (institution) for Advaxis Inc, Eisai Inc, MSD Belgium, Roche NV, Genmab A/S, Genmab US, F Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc, AstraZeneca NV, Tesaro Bio GmbH, Tesaro Inc, Oncoinvent AS, Immunen Inc; research funding (via KU Leuven) from Oncoinvent AS, Genmab A/S-Genmab BV; corporate sponsored research grants from Amgen, Roche, and Stichting teen Kanker; travel, accommodation, and expenses from Takeda Oncology, Pharmamar, Genmab, Roche, AstraZeneca, and Tesaro, outside the submitted work. DL reports grants and personal fees from Tesaro, personal fees from Astra Zeneca, grants and personal fees from Merck, grants and personal fees from Clovis, and personal fees from Merrimack, outside the submitted work. JM reports personal fees and non-financial support from Roche, and personal fees from Tesaro, AstraZeneca, and Clovis, outside the submitted work. JS reports honoraria from Astra Zeneca, Eisai, Clovis, Olympus, Johnson&Johnson, PharmaMar, Pfizer, TEVA, TESARO, and MSD; consulting or advisory role for Astra Zeneca, Clovis, Lilly, PharmaMar, Pfizer, Roche, TESARO, and MSD; research funding from Astra Zeneca, Clovis, Merck, Bayer, PharmaMar, Pfizer, TESARO, and MSD; travel, accommodation, and expenses from Astra Zeneca, Clovis, PharmaMar, Roche, Pfizer, TESARO, and MSD, outside the submitted work., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation., (© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: The aim of this study was to analyze the potential impact of chemotherapy-induced nausea and vomiting (CINV) on dose reductions, discontinuation of chemotherapy, and survival., Patients and Methods: This study was designed as individual participant data meta-analysis with the original study data of three phase II/III trials that were conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients with recurrent ovarian cancer. Logistic and Cox regression analyses were used to estimate odds and hazard ratios after adjusting for age, ECOG, amount of delivered cycles, amount of recurrences, and amount of comedications and study., Results: The majority of patients developed nausea (58.1%) and almost one third experienced vomiting (31.0%). CINV was not associated with FIGO stage, grading, histology, and number of recurrences. The necessity of dose reduction and discontinuation of chemotherapy did not correlate to nausea and vomiting (p = 0.88, p = 0.39 and p = 0.25, p = 0.54 respectively). Progression-free survival was shorter in patients with grade III/IV nausea and vomiting (p = 0.02; hazard ratio (HR) for grade III/IV nausea 1.58, 95% CI 1.14-2.20, and p = 0.02; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CINV grade III/IV was also associated with poorer overall survival (p < 0.001; HR for grade III/IV nausea 2.35, 95% CI 1.64-3.37, and p < 0.001; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively)., Conclusion: CINV is significantly associated with poorer prognosis in recurrent ovarian cancer patients while there was no correlation found with the necessity of dose reduction and prior discontinuation of treatment. This study underlines the importance of prevention and treatment of CINV as part of early best supportive care.

Objective: Low-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival with high-grade disease, as well as in regard to "platinum-sensitive" and "-resistant" recurrences according to platinum-free interval., Methods: This is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models., Results: Out of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) (8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS (p = 0.91) and OS (p = 0.25) differences between platinum-sensitive and -resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology (p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC., Conclusion: Our study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression., (Copyright © 2019. Published by Elsevier Inc.)

Detection of epithelial ovarian cancer (EOC) poses a critical medical challenge. However, novel biomarkers for diagnosis remain to be discovered. Therefore, innovative approaches are of the utmost importance for patient outcome. Here, we present a concept for blood-based biomarker discovery, investigating both epithelial and specifically stromal compartments, which have been neglected in search for novel candidates. We queried gene expression profiles of EOC including microdissected epithelium and adjacent stroma from benign and malignant tumours. Genes significantly differentially expressed within either the epithelial or the stromal compartments were retrieved. The expression of genes whose products are secreted yet absent in the blood of healthy donors were validated in tissue and blood from patients with pelvic mass by NanoString analysis. Results were confirmed by the comprehensive gene expression database, CSIOVDB (Ovarian cancer database of Cancer Science Institute Singapore). The top 25% of candidate genes were explored for their biomarker potential, and twelve were able to discriminate between benign and malignant tumours on transcript levels ( p < 0.05). Among them T-cell differentiation protein myelin and lymphocyte (MAL), aurora kinase A (AURKA), stroma-derived candidates versican (VCAN), and syndecan-3 (SDC), which performed significantly better than the recently reported biomarker fibroblast growth factor 18 (FGF18) to discern malignant from benign conditions. Furthermore, elevated MAL and AURKA expression levels correlated significantly with a poor prognosis. We identified promising novel candidates and found the stroma of EOC to be a suitable compartment for biomarker discovery.

Background: Elderly patients are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate the disposition and apprehension of elderly patients toward study participation., Methods: 112 elderly gynecological cancer patients (median age 70) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for refusal and anticipated advantages/disadvantages that might evolve from participation were inquired., Results: Willingness to participate in a clinical study was generally high (72%, 74/102). Reasons for potential study participation were: 'better monitoring of the disease' (67.1%), 'better medical care' (46.1%), 'to help medical research' (44.7%), 'better medication' (35.5%) and 'because of my doctor's recommendation' (22.4%). Reasons for potential refusal were: 'too time consuming' (24.4%), 'fear of side effects' (21.8%), 'misuse as experimental animal' (18%), 'long distance to clinic' (14.1%) and 'too little or unclear information' (10.3%). 37.2% (29/78) of the patients stated that they had 'no objection' at all against study participation. The question if patients anticipated having a longer life due to study participation was answered with 'yes' or 'rather yes' in 42% (38/90); 28.9% answered 'no' or 'rather no' (29% undecided). No statistical significant relation between willingness to participate in a study and general fitness (p = 0.133), education (p = 0.122), age (p = 0.474) or domestic situation (p = 0.123) could be observed in a multivariate logistic regression model., Conclusions: Elderly patients are generally willing to participate in clinical studies, in our cohort regardless of their fitness. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore, it might be decisive to provide more general information regarding benefits and safety for elderly patients in a clinical trial.

Background/aim: Chemotherapy-associated toxicity is one of the limiting factors regarding treatment efficacy, patient outcome and quality of life in this collective. Underweight or obese patients represent a major group in which the therapy seems to be more challenging. The aim of this analysis was to evaluate the impact of BMI on the toxicity in patients undergoing chemotherapy., Patients and Methods: The data of three prospective phase II/III studies ('Tower', 'Topotecan phase III' and 'Hector') of the North-Eastern German Society of Gynecological Oncology including 1,213 patients with recurrent ovarian cancer were retrospectively analyzed. The study was performed using logistic regression and Cox regression analysis., Results: The median age at diagnosis was 59 years. Sixty-seven (5.5%) patients had BMI <20 and 272 (22.4%) patients had BMI >30. Preterm termination of the chemotherapy was associated with lower BMI (p=0.017). Moreover, non-hematological toxicity grade III/IV was mainly observed in underweighted women as well (p<0.001). Patients with higher BMI more often presented with grade III/IV anemia (p=0.019) and as a consequence required blood transfusions more frequently (p=0.005). The overweight group was also associated with a higher number of co-medications. However, no difference in survival regarding BMI was observed in our study., Conclusion: Fewer chemotherapy cycles and preterm discontinuation were more frequent in patients with lower BMI. Hematological toxicity and higher medication intake appeared more often in patients with higher BMI., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer., Methods: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m 2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891., Findings: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%])., Interpretation: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies., Funding: Bayer, Amgen, and GlaxoSmithKline., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment., Patients and Methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version., Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included., Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

Purpose: Palmoplantar erythrodysesthesia (PPE) is one of the most frequent side effects during systemic treatment with pegylated liposomal doxorubicin (PLD, Caelyx®). PPE lesions show a range of symptoms, from numbness to painful erosions, and can have a major impact on the quality of life in affected patients. Previously, a possible pathomechanism of PPE was found in doxorubicin-treated patients based on radical formation in the skin. Here, a preventive strategy using a topically applied ointment with a high radical protection factor was investigated., Methods: In this randomized placebo-controlled double-blind study the antioxidant-containing ointment was compared with a placebo ointment regarding PPE grade III occurrence, overall PPE grade I-III occurrence and PPE severity in PLD patients. The verum or placebo cream was topically applied for a period of 16 weeks, starting 3 days prior to the first cycle of chemotherapy. Clinical evaluations were carried out by a dermatologist prior to the first cycle of chemotherapy and every 4 weeks for the duration of 16 weeks., Results: Thirty-two patients were enrolled in total, of which 17 (66%) completed the study. No PPE grade III was found in the verum group, while five out of seven patients (71%) had to be unblinded in the placebo arm due to PPE grade III (p = 0.003). General PPE occurrence of all grades was 60% under verum and 86% under placebo treatment., Conclusions: The preventive application of an antioxidant-containing ointment was shown to be significantly more effective in the prevention of PPE grade III compared to placebo treatment.

Objectives: The aim of the present study was to assess in a large cohort of primary epithelial ovarian cancer patients the incidence and the clinical effect of BRCA1 genetic and epigenetic silencing mechanisms., Methods: A total of 188 primary epithelial ovarian cancer patients, treated between 2000 and 2011 at the Charité University Hospital of Berlin, were included. The patients' tumor and blood samples were obtained from the Tumor Bank Ovarian Cancer Network (www.toc-network.de). Direct sequencing of BRCA1 exon 11 was performed to detect germline mutations, whereas tumor samples were assessed for BRCA1 promoter hypermethylation by bisulphite-converted methylation-specific polymerase chain reaction. Basing on their BRCA1 status, patients were compared regarding clinicopathological variables and survival., Results: Twenty-one patients (11.2%) showed hypermethylation in BRCA1 promoter (HMB), and 18 patients (9.6%) presented germline mutations in BRCA1 exon 11 (GMB). Patients with HMB showed a significantly younger age at diagnosis compared with BRCA1 wild type (BWT) patients (54 vs 61 years, P = 0.045), and both GMB and HMB patients were more likely to have high-grade serous ovarian cancer (76.2% and 77.8% vs 52.7%, P = 0.043 and P = 0.043). Positive family history of breast or ovarian cancer (OC) was more frequently reported among GMB patients with respect to BWT patients (44.4% vs 13.5%, P = 0.003); GMB, HMB, and BWT patients did not show significant differences in terms of tumor dissemination pattern, surgical outcomes, platinum response or survival; neither mutational nor hypermethylation BRCA1 status was found to be an independent prognostic factor for OC patients., Conclusions: Hypermethylation in BRCA1 is associated with earlier occurrence of OC. In addition, the coexistence of both GBM and HMB is an infrequent event, occurring in 0.5% of OC cases. Silencing of BRCA1 through mutation and hypermethylation confers to distinct clinical characteristics of OC patients but similar clinical outcome with respect to BWT patients.

Background: Palliative systemic treatment in elderly gynaecological cancer patients remains a major challenge. In recurrent ovarian cancer (ROC), treosulfan an active alkylating drug showed similar cytotoxicity whether as oral (p.o.) or intravenous (i.v.) application. The aim of this innovative trial was to evaluate the preference of elderly patients (≥65 years) for p.o. or i.v. chemotherapy focusing compliance, outcome, toxicities, and geriatric aspects as secondary endpoints., Methods: Patients with ROC had the free choice between treosulfan i.v. (7000 mg/m 2 d1, q29d) or p.o. (600 mg/m 2 daily d1-28, q57d). Only indecisive participants were randomized., Results: Overall 123 patients with 2 nd to 5 th recurrence were registered and 119 received at least one cycle of chemotherapy. 85.7% preferred treosulfan i.v. and 14.3% oral, where only three patients were randomized. Main reasons for i.v. preference associated with individual expectations of lower rate of gastrointestinal disorders, higher activity and tolerability of treatment. Median of applied chemotherapies was three (range 1-12 cycles), with most common grade 3/4 toxicities thrombopenia (18.7%), leukopenia (15.7%), ascites (7.6%), bowel obstruction (6.7%), and abdominal pain (4.2%). Median time until progression/overall survival was 5.2/7.8 months (i.v.), and 5.6/10.4 months (p.o.), respectively, without significant differences in efficacy., Conclusions: Elderly patients with recurrent ovarian cancer asked and demonstrated active participation in the decision-making process of their oncological treatment and favoured predominantly the i.v. application. Treosulfan was generally well-tolerated despite comorbidities and heavy pre-treatment. Our study demonstrates that patients' preference did not influence prognosis negatively and remains important in gynaecologic oncology decision practice., Eudract Nr: 2004-000719-25; NCT 00170690.

Objective: In recurrent ovarian cancer (ROC), there is a high demand on effective therapies with a mild toxicity profile. Treosulfan is an alkylating agent approved as oral (p.o.) and intravenous (i.v.) formulation for the treatment of recurrent ovarian cancer. Data on safety and efficacy for either formulation are rare. For the first time we conducted a randomized phase III study comparing both formulations in women with ROC., Methods: Patients having received at least two previous lines of chemotherapy were randomly assigned to one of two treatment arms: treosulfan i.v. 7000 mg/m 2 d1 q4w or treosulfan p.o. 600 mg/m 2 d1-28 q8w. Primary endpoint was safety regarding hematological and gastrointestinal toxicity grade III/IV, secondary endpoints were other toxicities, clinical benefit rate (CBR), time to progression (TTP), overall survival (OS) and quality of life., Results: 250 patients were treated with treosulfan i.v. (128) or treosulfan p.o. (122). In general treosulfan therapy was well tolerated in both treatment arms. Leukopenia grade III/IV occurred significantly more frequently in the p.o. arm (3.9% i.v. arm, 14.8% p.o. arm, p = 0.002). Other toxicities were similar in both arms. CBR was comparable between arms (41.4% i.v. arm, 36.9% p.o. arm). No difference in TTP (3.7 months i.v. arm, 3.5 months p.o. arm) or OS (13.6 months i.v. arm, 10.4 months p.o. arm, p = 0.087) occurred., Conclusions: Given the safety and efficacy results treosulfan is an acceptable option for heavily pretreated OC patients. Regarding the toxicity profile the i.v. application was better tolerated with less grade III and IV toxicities., Competing Interests: Compliance with ethical standardsConflict of interestJalid Sehouli declares that he received an educational grant from medac. Michael Patrick Lux declares that he received honoraria for lectures, honoraria for editorial board membership of a journal as well as non-financial support for congress visit from medac. Tanja Trarbach declares that iOMEDICO received financial support from medac. Oliver Tomè, Oumar Camara, Ingo Bernhard Runnebaum, Hans Werner Tessen, Beate Rautenberg, Radoslav Chekerov and Gerald Gitsch declare that there are no conflicts of interest.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Informed consentInformed consent was obtained from all individual participants included in the study.

Background: Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC)., Patients and Methods: Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m 2 / days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points., Results: A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia., Conclusion: The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The cold shock Y-box binding protein-1 (YB-1) fulfills important roles in regulating cell proliferation and differentiation. Overexpression occurs in various tumor cells. Given the existence of extracellular YB-1 we set out to determine the diagnostic, predictive and prognostic role of serum YB-1/p18 for patients with primary epithelial ovarian cancer (EOC)., Methods: The protein fragment YB-1/p18 was quantified by sandwich ELISA in serum samples from 132 healthy female volunteers and 206 patients with histological diagnosis of primary EOC. The ELISA sensitivity and specificity to detect EOC were calculated using receiver operating curves. Survival data were calculated using Kaplan Maier curves., Results: Median age at the time of diagnosis was 60years and follow-up ended with a mean of 44.8month. 188 (91%) patients were diagnosed at advanced stages (FIGO III/IV) and 188 patients (91%) suffered from high-grade serous ovarian carcinoma. YB-1/p18 levels were significantly decreased in older patients (p=0.021). Significantly lower serum levels of YB-1/p18 were detected in the EOC cohort when compared to the control group (p<0.0001, AUC=0.827; 95% CI, 0.787-0.867). Using the expression of serum YB-1/p18 in early stages I and II cases these could be differentiated from control cases (p<0.0001, AUC=0.816; 95% CI 0.704-0.929). No other significant associations between clinical prognostic factors and YB-1/p18 serum levels were detected. Immunoblotting results with serum samples suggest that masking of epitopes by the YB-1/p18 fragment in multiprotein-complexes under non reducing conditions leads to the observed reduced ELISA readings in the EOC cohort., Conclusions: The quantification of fragment YB-1/p18 derived from cold shock protein YB-1 in serum samples could be useful for the early diagnosis of EOC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Palmoplantar erythrodysesthesia is a frequent dermal side-effect during chemotherapy. Previous investigations showed radical formation subsequent to doxorubicin infusion and preventative and therapeutic effects of an antioxidant-containing ointment., Patients and Methods: Using a non-invasive vivomeasuring system (Biozoom®; Biozoom Services GmbH, Kassel, Germany) changes in the antioxidant status (as measured by relative carotenoid concentration) of the skin prior to and after intravenous administration of paclitaxel, docetaxel and 5-fluorouracil were investigated in 42 patients with cancer., Results: A significant decrease of antioxidant concentration subsequent to intravenous administration was found for all investigated chemotherapeutic agents. The mean concentration of carotenoids decreased from 3.59±1.26 arbitrary units (a.u.) to 3.41±1.28 a.u. (p<0.001) after paclitaxel administration, from 6.33±2.43 to 5.63±2.29 a.u. after docetaxel (p=0.027) and from 4.26±1.81 to 3.98±1.53 a.u. (p=0.042) after 5-fluorouracil infusion., Conclusion: Oxidative stress might play a significant role in the pathomechanism of palmoplantar erythrodysesthesia associated with paclitaxel, docetaxel and 5-fluorouracil. Therefore, an antioxidant-containing ointment might serve as preventative and therapeutic option., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Barriers for optimal treatment and enrolment in clinical trials are the physicians' perceptions towards age, comorbidities and fear of toxicity as well as the eligibility criteria of clinical trials. There is a high need to gain more knowledge about this patient group in order to optimize treatment. We aimed to evaluate the influence of age above 65 years on comorbidities, comedication, grade III/IV toxicity, prior discontinuation of chemotherapy and survival., Patients and Methods: An individual participant data meta-analysis of three phase II/III studies ('Tower', 'Topotecan phase III' and 'Hector') of the North-Eastern German Society of Gynecological Oncology including 1213 patients with recurrent ovarian cancer was conducted using logistic regression and Cox regression analysis., Results: Median age at diagnosis was 59 years. The patient group ≥65 years included 349 versus 864 patients younger than 65 years. Cardiovascular disease and diabetes were more frequent in the older age group (p < 0.001 and p = 0.001). Haematological and cardiovascular grade III/IV toxicities were more often seen in patients above 65 years, while non-haematological toxicity was not (p = 0.03, odds ratio [OR] 1.35; p = 0.04, OR 1.83; and p = 0.90, OR 0.98, respectively). There was no difference in prior discontinuation of treatment in multivariate analysis. Cox regression showed a trend towards poorer progression-free survival (p = 0.053, hazard ratio 1.143) in the older age group., Conclusion: Haematological and cardiovascular toxicities are more frequent in elderly patients. However, this did not influence prior discontinuation of therapy. Elderly patients should not be deprived of adequate chemotherapy or excluded from clinical studies just because of their age. Thorough geriatric assessment and monitoring is mandatory., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: The main goal of the current study was to compare survival differences among subgroups of primary ovarian cancer patients in International Federation of Gynecology and Obstetrics (FIGO) stages IIIC and IIIA1 after complete tumor debulking surgery., Methods: A total of 218 patients with primary ovarian cancer who received complete cytoreductive surgery were included in the current retrospective analysis of the validated Tumor Bank Ovarian Cancer Network Database, which covers the periods January 2002 until December 2012. According to their tumor spread pattern, patients were divided into three groups: Group A (peritoneum only), Group B (peritoneum and lymph nodes), and Group C (lymph nodes only). Associations between groups and clinicopathological factors were analyzed using standard statistical procedures., Results: The vast majority of patients were classified into Group B. Lymph node involvement was detected in 70.5 % of the cases where peritoneal implants presented ≥2 cm beyond the pelvis (Group A + B). The estimated 5-year overall survival (OS) rates were 47.4 % in Group A, 45.1 % in Group B, and 91.7 % in Group C (p < 0.01). In the subgroup analysis of Group B, both pelvic and para-aortic lymph node involvement was found in 57 % of patients. Patients in Group B who had para-aortic lymph node involvement only had better median progression-free survival (PFS) compared with patients with pelvic lymph node involvement only and pelvic and para-aortic lymph node involvement (28, 16, and 18 months, respectively; p = 0.02). The median OS differed significantly between patients with para-aortic lymph node involvement only versus patients with both pelvic and para-aortic involvement (68.5 vs. 46.7 months; p = 0.02). Three-year PFS was 90.0 % in FIGO IIIA1(i) and 62.6 % in FIGO IIIA1(ii) (hazard ratio 2.30, 95 % confidence interval 0.45-11.58)., Conclusions: Patients with FIGO stage IIIC with lymph node involvement only had the best clinical outcome compared with patients in the same stage with peritoneal involvement only. Furthermore, involvement of both pelvic and para-aortic lymph nodes were of the same infrequency, and involvement of only para-aortic lymph nodes in this stage resulted in a better chance of survival than involvement of pelvic lymph nodes only or both pelvic and para-aortic lymph nodes simultaneously. In accordance with the revised FIGO classification of 2013, our study revealed that FIGO IIIA1(i) is prognostically better compared with FIGO IIIA1(ii).