Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.

BACKGROUND: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up. METHODS: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed. FINDINGS: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011). INTERPRETATION: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Case-mix adjustment to compare hospital performances regarding complications after cytoreductive surgery for ovarian cancer: a nationwide population-based study.

OBJECTIVE: Complication rates after cytoreductive surgery are important quality indicators for hospitals that treat patients with advanced-stage ovarian cancer. Case-mix factors are patient and tumor characteristics that may influence hospital outcomes such as the complication rates. Currently, no case-mix adjustment model exists for complications after cytoreductive surgery; therefore, it is unclear whether hospitals are being compared correctly. This study aims to develop the first case-mix adjustment model for complications after surgery for advanced-stage ovarian cancer, enabling an accurate comparison between hospitals. METHODS: This population-based study included all patients undergoing cytoreductive surgery for advanced-stage ovarian cancer registered in the Netherlands in 2017-2019. Case-mix variables were identified and assessed using logistic regressions. The primary outcome was the composite outcome measure 'complicated course'. Patients had a complicated course when at least one of the following criteria were met: (1) any complication combined with a prolonged length of hospital stay; (2) complication requiring reintervention; (3) any complication with a prolonged length of stay in the intensive care unit; or (4) 30-day mortality or in-hospital mortality during admission following surgery. Inter-hospital variation was analyzed using univariable and multivariable logistic regressions and visualized using funnel plots. RESULTS: A total of 1822 patients were included, of which 10.7% (n=195) had a complicated course. Comorbidity and tumor stage had a significant impact on complicated course rates in multivariable logistic regression. Inter-hospital variation was not significant for case-mix factors. Complicated course rates ranged between 2.2% and 29.1%, and case-mix adjusted observed/expected ratios ranged from 0.20 to 2.67 between hospitals. Three hospitals performed outside the confidence intervals for complicated course rates. These hospitals remained outliers after case-mix adjustment. CONCLUSION: There is variation between hospitals regarding complicated course rates after cytoreductive surgery for ovarian cancer in the Netherlands. While comorbidity and tumor stage significantly affected the complicated course rates, adjusting for case-mix factors did not significantly affect hospital outcomes. The limited impact of case-mix adjustment could be a result of the Dutch centralized healthcare model.

Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial.

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

Guideline adherence in ovarian cancer for surgical staging in the Netherlands.

OBJECTIVE: Previous studies have shown low adherence to surgical staging guidelines in patients with clinical early-stage ovarian carcinoma. The aim of this study was to identify guideline adherence for surgical staging and to show the distribution of each surgical item within the study population. In addition, we examined whether regional variation in the Netherlands exists for complete surgical staging. METHODS: Patients with ovarian cancer and surgical staging registered in the Dutch Gynecological Oncology Audit between January 1, 2015 and December 31, 2019 in the Netherlands were included. Complete surgical staging was defined according to the Dutch evidence-based guideline. Surgical items were ranked and illustrated. Variation in complete surgical staging for eight regional cancer networks was shown in funnel plots. Manual validation of registered data was performed in three gynecological oncology centers. RESULTS: 604 patients underwent surgical staging, 365 (60%) underwent an incomplete staging procedure, 295 (81%) were registered with early-stage disease (International Federation of Gynecology and Obstetrics I-IIA) and, of these patients, 115 (39%) received adjuvant chemotherapy. Patients with incomplete surgical staging were operated more often with minimal invasive techniques (laparoscopy or robot) compared with patients in the complete staging group (p<0.001). Sampling of cytology/ascites was the most frequently lacking factor (29%). Manual validation of data in three gynecological oncology centers identified reasons for incomplete staging, the most common being 'perioperative findings' such as dense adhesions between tumor and peritoneum, consistent with advanced stage disease (≥IIA). Regional variation for complete surgical staging showed two regions performing outside the confidence intervals (12.5% and 25.5%, mean 40%). CONCLUSION: Guideline adherence for staging was lower than expected and validation of data gave additional insights into the reasons that were contributing to incomplete surgical staging. Moreover, this analysis showed that regional variation for surgical staging exists, which forms a starting point to improve and harmonize staging procedures for these patients nationwide.

Neoadjuvant Chemotherapy Followed by Vaginal Radical Trachelectomy as Fertility-Preserving Treatment for Patients with FIGO 2018 Stage 1B2 Cervical Cancer.

BACKGROUND: Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (i.e., tumor size between 2 and 4 cm) is a radical hysterectomy (RH) with pelvic lymph node dissection (PLND). We evaluated the oncological and fertility outcomes treatment in patients receiving a fertility-sparing alternative consisting of neoadjuvant chemotherapy (NACT) followed by vaginal radical trachelectomy (VRT). METHODS: Patients with stage 1B2 cervical cancer who wished to preserve fertility were included from September 2009 to September 2018. NACT consisted of 6-week cycles of cisplatin or carboplatin with paclitaxel. If tumor size decreased to 2 cm or smaller, NACT was followed by a robot-assisted PLND and VRT. RESULTS: Eighteen patients were included. Median follow-up time was 49.7 months (range 11.4-110.8). Median tumor size was 32 mm (range 22-40 mm). Complete remission after NACT occurred in seven women. Four women had a poor response on NACT. Three underwent RH with PLND; one received chemoradiation after PLND instead of VRT because of positive lymph nodes. The remaining 14 patients received VRT 3-4 weeks after NACT. Four recurrences occurred: three after NACT and VRT and one after NACT and RH. Median time to recurrence was 20.8 months (range 17.0-105.7). Three recurrences occurred in women with adenocarcinoma with lymph vascular space invasion (LVSI). In four women fertility could not be preserved. To date, four women had six pregnancies, including three live births born at term, two first trimester miscarriages, and one currently ongoing pregnancy. CONCLUSION: NACT and VRT in women with stage 1B2 cervical cancer showed promising results. In 78% fertility was preserved. However, patients with poor response on NACT and with adenocarcinoma and/or LVSI were possibly at risk for recurrence. Long-term results in relation to fertility and oncological outcome are needed to corroborate these findings. IMPLICATIONS FOR PRACTICE: Standard treatment for women with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (tumor size 2-4 cm) is a radical hysterectomy and pelvic lymph node dissection (PLND). However, many of these women are young and wish to preserve fertility. Data on fertility-sparing treatment options are sparse, but neoadjuvant chemotherapy followed by a vaginal radical trachelectomy and PLND could be an alternative. Since 2009 we performed an observational cohort study in which 18 women opted for this treatment in our center. In 14 women fertility could be preserved. In four patients the tumor recurred. In four women six pregnancies occurred. After careful selection this treatment could be a good fertility-sparing treatment option.

Central radiology assessment of the randomized phase III open-label OVHIPEC-1 trial in ovarian cancer.

INTRODUCTION: Hyperthermic intraperitoneal chemotherapy (HIPEC) improved investigator-assessed recurrence-free survival and overall survival in patients with stage III ovarian cancer in the phase III OVHIPEC-1 trial. We analyzed whether an open-label design affected the results of the trial by central blinded assessment of recurrence-free survival, and tested whether HIPEC specifically targets the peritoneal surface by analyzing the site of disease recurrence. METHODS: OVHIPEC-1 was an open-label, multicenter, phase III trial that randomized 245 patients after three cycles of neoadjuvant chemotherapy to interval cytoreduction with or without HIPEC using cisplatin (100 mg/m2). Patients received three additional cycles of chemotherapy after surgery. Computed tomography (CT) scans and serum cancer antigen 125 (CA125) measurements were performed during chemotherapy, and during follow-up. Two expert radiologists reviewed all available CT scans. They were blinded for treatment allocation and clinical outcome. Central revision included Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurements and peritoneal cancer index scorings at baseline, during treatment, and during follow-up. Time to centrally-revised recurrence was compared between study arms using Cox proportional hazard models. Subdistribution models compared time to peritoneal recurrence between arms, accounting for competing risks. RESULTS: CT scans for central revision were available for 231 patients (94%) during neoadjuvant treatment and 212 patients (87%) during follow-up. Centrally-assessed median recurrence-free survival was 9.9 months in the surgery group and 13.2 months in the surgery+HIPEC group (HR for disease recurrence or death 0.72, 95% CI 0.55 to 0.94; p=0.015). The improved recurrence-free survival and overall survival associated with HIPEC were irrespective of response to neoadjuvant chemotherapy and baseline peritoneal cancer index. Cumulative incidence of peritoneal recurrence was lower after surgery+HIPEC, but there was no difference in extraperitoneal recurrences. CONCLUSION: Centrally-assessed recurrence-free survival analysis confirms the benefit of adding HIPEC to interval cytoreductive surgery in patients with stage III ovarian cancer, with fewer peritoneal recurrences. These results rule out radiological bias caused by the open-label nature of the study.

A Patient With a Low-grade Mucinous Neoplasm Involving the Ovary and Pseudomyxoma Peritonei Originating in an Isolated Intestinal Duplication.

A considerable number of mucinous ovarian tumors are metastatic from other primary tumors, mainly from the gastrointestinal tract, and primary malignant mucinous ovarian tumors are considered rare. Mucinous ovarian tumors occurring within the clinical syndrome of pseudomyxoma peritonei are assumed to almost always originate from the appendix. We describe a patient with a low-grade mucinous tumor involving the ovary in coexistence with pseudomyxoma peritonei, who underwent appendectomy 25 yr earlier. The tumor originated from a rare cystic gastrointestinal duplication found in the mesenteric fat showing adenomatous changes. This illustrates that even in absence of the appendix, mucinous ovarian tumors occurring with pseudomyoma peritonei rarely arise from the ovary.

Vaginal Radical Trachelectomy for Early-Stage Cervical Cancer: Increased Recurrence Risk for Adenocarcinoma.

OBJECTIVE: To evaluate consecutive vaginal radical trachelectomies (VRTs) in early-stage cervical cancer in the 2 main referral centers for fertility-preserving surgery in the Netherlands. MATERIALS AND METHODS: Oncology, fertility, and obstetrical data were recorded in a regional database of all VRTs without neoadjuvant chemotherapy performed in 2 major referral centers between 2000 and 2015. RESULTS: Most of the patients (91.7%) had stage IB1 disease. In 72.0%, squamous cell carcinoma was the histologic diagnosis; in 24.2%, adenocarcinoma; and in 3.8%, adenosquamous carcinoma. The median follow-up was 51 months.Nine (6.8%) recurrences occurred, 4 resulting in death of disease (death rate, 3.0%). Recurrence rates were 12.5% for adenocarcinoma, 20% for adenosquamous carcinoma, and 4.2% for squamous cell carcinoma (P < 0.01).From 117 women, data about fertility and obstetrical outcome were obtained. Almost 60% of women attempted to conceive after a VRT. Of these women, 40% needed fertility treatment. A total of 47 pregnancies were established, and a total of 37 children were born of which 30 (81.1%) were delivered after 32 weeks of gestational age. CONCLUSIONS: Nonsquamous cell histology and high-grade disease are associated with a significantly higher risk of recurrence in the univariate and multivariate analyses. Women with both these histology features should be counseled reticently for VRT.Pregnancies after VRT must be regarded as high-risk pregnancies with a high prematurity rate.

Neuropathic Pain Components in Patients with Cancer: Prevalence, Treatment, and Interference with Daily Activities.

BACKGROUND: Pain and neuropathic symptoms impact quality of life of patients with cancer. To obtain more insight in the prevalence, severity, and treatment of neuropathic symptoms in patients with cancer and their interference with daily activities, we conducted a cross-sectional study at the outpatient clinic of a Dutch university hospital. METHODS: A cross-sectional study among outpatients with cancer. To identify pain, its intensity, quality, and interference with daily activities, the Brief Pain Inventory (BPI) was used. Neuropathic symptoms were identified with the Douleur Neuropathique (DN4) interview and pain characteristics with the McGill Pain Questionnaire (MPQ). Pain medication and adjuvant analgesics were also collected with a prestructured questionnaire. Descriptives, chi-squared tests, t-tests, and a logistic regression analysis were conducted. RESULTS: 892 patients completed the questionnaires. Twenty-three percent (n = 204) reported moderate to severe pain, and 19% (n = 170) scored positive on neuropathic symptoms (DN4 ≥ 3). Particularly in patients with a rating on a numeric rating scale (NRS) < 5, existence of neuropathic symptoms significantly increased interference with daily activities. Of patients with neuropathic symptoms, 8% received adjuvant pain treatment. Receiving curative treatment, using a systemic drug with neurotoxicity, having had an operation, and having had a lymph node dissection independently contributed to having neuropathic symptoms. CONCLUSIONS: This study shows that over 40% of the patients with moderate to severe pain also have neuropathic symptoms, causing increased interference with daily activities. Most of these patients do not receive adjuvant analgesics. There is a need to improve management of neuropathic symptoms in patients with cancer.

Satellite lymphovascular space invasion: An independent risk factor in early stage cervical cancer.

OBJECTIVE: This study was performed to determine whether satellite LVSI in women with early stage cervical carcinoma is an independent prognostic factor for recurrence and survival. METHODS: A total of 210 eligible patients with FIGO stages IA2 and IB1 cervical carcinoma, who underwent radical hysterectomy or radical trachelectomy with pelvic lymphadenectomy between January 2000 and December 2012, were included. Variables studied included age, histology type, differentiation grade, tumor size (TS), depth of invasion (DI), lymph node metastasis (LNM), conjoined lymphovascular space invasion (LVSI) and satellite LVSI. Univariate and multivariate analyses were performed to define variables that best predict recurrence and survival. RESULTS: Univariate analysis showed that differentiation grade, depth of invasion, tumor size, lymph node metastasis, and both conjoined LVSI and satellite LVSI were significantly associated with recurrence and survival. Using multivariate analysis, differentiation grade (HR 3.63, 95%-CI 1.51-8.72), conjoined LVSI (HR 5.95, 95%-CI 1.57-22.53) and satellite LVSI (HR 7.45, 95%-CI 3.03-18.27) were independent prognostic factors for recurrence; LNM (HR 5.55, 95%-CI 1.52-20.26) and satellite LVSI (HR 8.94, 95%-CI 2.43-32.95) were prognostic factors for overall survival. For patients with low-risk cervical cancer without LNM only satellite LVSI correlated significantly with disease-free and overall survival. CONCLUSION: Differentiation grade, DI, TS, LNM, and conjoined LVSI as well as satellite LVSI were prognostic factors for DFS and OS. Satellite LVSI is the most important factor predicting DFS and OS in early stage cervical cancer, especially when lymph nodes are negative.

Self-reported distress in patients with ovarian cancer: is it related to disease status?

OBJECTIVE: Patients with epithelial ovarian cancer have a poor prognosis and often undergo intensive treatment. These patients are therefore at risk for experiencing distress and reduced quality of life. The aim of this study was to explore the self-reported distress severity, experienced problems, and quality of life in relation to their disease status. METHODS: This cross-sectional study was conducted in 2011 at a University Medical Center. Women with ovarian cancer (n = 273), both during and after treatment, were asked by mail to fill in self-report questionnaires. Distress was measured using with the Distress Thermometer (DT), Hospital Anxiety and Depression Scale, and Impact of Event Scale. Problems and quality of life were assessed with the problem list of the DT, and European Organization for Research and Treatment of Cancer Quality of Life C-30 and OV28. RESULTS: The questionnaire data of 104 patients were analyzed. Screening with the DT revealed distress in 32% [mean (SD), 3.1 (2.6)]. Distress was found with the Hospital Anxiety and Depression Scale in 14% [8.6 (5.9)] and with the Impact of Event Scale in 18% of the patients [17.5 (15.5)]. No significant differences were found in distress severity and self-reported problems between patients with and without recurrence. In both groups, the problems fatigue, condition, and neuropathy were most reported. Patients with distress (DT ≥ 5) experienced significantly worse functioning, more problems, and lower quality of life than patients without distress (P < 0.01). CONCLUSIONS: This study showed that disease status in patients with ovarian cancer seems to have no influence on distress, quality of life, and the problems encountered. However, distressed patients experienced more problems, with physical and emotional functioning, and had lower quality of life. The problems fatigue, physical condition, and neuropathy are the most prevailing.

Müllerian precursor lesions in serous ovarian cancer patients: using the SEE-Fim and SEE-End protocol.

Serous ovarian cancer is suggested to develop from epithelium embryologically derived from the Müllerian ducts. The aim of the current study is to thoroughly, analyze the epithelium derived from the Müllerian ducts (cervix, endometrium and fallopian tubes) in serous ovarian cancer patients. Sixty women diagnosed with serous ovarian carcinoma were included in this multicentre, observational study. Tissues were embedded completely for histological assessment, in accordance with the SEE-Fim and SEE-End protocol (Sectioning and Extensively Examining of the Fimbriated end; and-Endometrium), and prevalence of cervical, as well as endometrial and tubal pathology was analyzed. In 31 (52%) cases, a pathologic lesion was identified, and in 16 (27%) of these cases coexistence of pathologic lesions. In 1 case, severe dysplasia was found in the cervix, in 9 (15%) cases endometrial intraepithelial carcinoma, in 19 (32%) cases atypical hyperplasia, and in 23 (43%) cases serous tubal intraepithelial carcinoma. Serous tubal intraepithelial carcinoma was seen significantly more often concurrent with endometrial atypical hyperplasia or endometrial intraepithelial carcinoma than with benign endometrium (64 vs 28%; P=0.01). To conclude, histological assessment of epithelium derived from Müllerian ducts of serous ovarian cancer patients resulted in the identification of endometrial intraepithelial carcinoma, serous tubal intraepithelial carcinoma and/or endometrial atypical hyperplasia in more than half of cases. Coexistence of these pathologic lesions was common, and might represent an effect of field carcinogenesis or tumor implantation of migrating cells.

Feasibility of Introducing a Prehabilitation Program into the Care of Gynecological Oncology Patients-A Single Institution Experience.

Prehabilitation is an upcoming strategy to optimize patient's functional capacity, nutritional status, and psychosocial well-being in order to reduce surgical complications and enhance recovery. This study aims to assess the feasibility of implementing a multimodal prehabilitation program into the standard care of gynecological oncology patients at an academic hospital in terms of recruitment, adherence, and safety, which were assessed by the number of patients eligible, recruitment rate, participation rate, and adherence to individual modalities. Data were derived from the F4S PREHAB trial, a single-center stepped-wedge trial implementing a multimodal prehabilitation program among various surgical specialties. All patients undergoing elective surgery as part of treatment for ovarian, uterine, and vulvar cancer at the Radboudumc, an academic hospital in The Netherlands, between May 2022 and September 2023 were considered eligible for the F4S PREHAB trial and, consequently, were included in this cohort study. The multimodal prehabilitation program comprised a physical exercise intervention, nutritional intervention, psychological intervention, and an intoxication cessation program. A total of 152 patients were eligible and approached for participation of which 111 consented to participate, resulting in a recruitment rate of 73%. Participants attended an average of six exercise sessions and adhered to 85% of possible training sessions. Respectively, 93% and 98% of participants adhered to the prescribed daily protein and vitamin suppletion. Ten participants were referred to a psychologist and completed consultations. Out of nine active smokers, two managed to quit smoking. A total of 59% adhered to alcohol cessation advice. No adverse events were reported. This study demonstrates that introducing a multimodal prehabilitation program into the standard care of gynecological oncology patients is feasible in terms of recruitment and adherence, with no serious adverse events.

Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients: The STAPOVER study protocol.

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype-guided targeted therapy to improve survival without compromising quality of life. Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.

Cervical cytology in serous and endometrioid endometrial cancer.

The aim of this study was to determine the frequency of abnormal cervical cytology in preoperative cervical cytology of patients diagnosed with uterine papillary serous carcinoma (UPSC) and endometrioid endometrial carcinoma (EEC). In addition, associations between abnormal cervical cytology and clinicopathologic factors were evaluated. In this multicentre study, EEC patients diagnosed at two hospitals from 1999 to 2009 and UPSC patients diagnosed at five hospitals from 1992 to 2009, were included. Revision of the histologic slides was performed systematically and independently by 3 gynecopathologists. Cervical cytology within six months before histopathologic diagnosis of endometrial carcinoma was available for 267 EEC and 80 UPSC patients. Cervical cytology with atypical, malignant, or normal endometrial cells in postmenopausal women was considered as abnormal cytology, specific for endometrial pathology. Abnormal cervical cytology was found in 87.5% of UPSC patients, compared with 37.8% in EEC patients. In UPSC, abnormal cytology was associated with extrauterine spread of disease (P=0.043). In EEC, abnormal cytology was associated with cervical involvement (P=0.034). In both EEC and UPSC patients, abnormal cervical cytology was not associated with survival. In conclusion, abnormal cervical cytology was more frequently found in UPSC patients. It was associated with extrauterine disease in UPSC patients, and with cervical involvement in EEC patients. More prospective research should be performed to assess the true clinical value of preoperative cervical cytology in endometrial cancer patients.

Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls.

OBJECTIVE: A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential. METHODS: Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma. RESULTS: Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p=0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p=0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p=0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization. CONCLUSIONS: Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae.

Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion?

OBJECTIVE: The pathogenesis of serous ovarian carcinoma (SOC) is still unknown. Recently, endometrial intraepithelial carcinoma (EIC) was proposed to be the precursor lesion of SOC. This study examines the model of EIC as precursor for SOC. METHODS: Cases of SOC with a noninvasive or superficially invasive serous lesion, a hyperplastic lesion with/without atypia, or EIC in the endometrium were selected for inclusion in this study. Tissue sections from both ovaries, the fallopian tubes, and the uterus were extensively reviewed by an expert gynecopathologist. For both EIC and SOC, immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor; TP53 mutation analysis; and in situ ploidy analysis were performed. RESULTS: Nine cases of SOC with concurrent EIC in the endometrium were identified. Immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor revealed almost identical expression patterns and similar intensities in each pair of EIC and coincident SOC. Identical TP53 mutations were found in SOC and coinciding EIC in 33% of the cases, suggesting a clonal origin. DNA ploidy analysis, as a marker for neoplastic progression, demonstrated an increased number of aneuploid nuclei in SOC compared to their corresponding EIC (P = 0.039). In addition, the mean amount of DNA per nucleus in SOC was higher (ie, more aneuploid) compared to EIC (P = 0.039). CONCLUSION: This study provides a first indication of EIC as possible precursor lesion for SOC. This finding could have major clinical implications for future ovarian cancer management and underscores EIC as a possible target for early SOC detection and prevention.

Prehabilitation to Improve Outcomes of Patients with Gynaecological Cancer: A New Window of Opportunity?

The literature evaluating the effect of prehabilitation programmes on postoperative outcomes and quality of life of patients with gynaecological cancer undergoing surgery was reviewed. Databases including Pubmed, Medline, EMBASE (Ovid) and PsycINFO were systematically searched to identify studies evaluating the effect of prehabilitation programmes on patients with gynaecological cancer. Both unimodal and multimodal prehabilitation programmes were included encompassing physical exercise and nutritional and psychological support. Primary outcomes were surgical complications and quality of life. Secondary outcomes were anthropometric changes and adherence to the prehabilitation programme. Seven studies fulfilled the inclusion criteria, comprising 580 patients. Included studies were nonrandomised prospective studies (n = 4), retrospective studies (n = 2) and one case report. Unimodal programmes and multimodal programmes were included. In patients with ovarian cancer, multimodal prehabilitation resulted in significantly reduced hospital stay and time to chemotherapy. In patients with endometrial and cervical cancer, prehabilitation was associated with significant weight loss, but had no significant effects on surgical complications or mortality. No adverse events of the programmes were reported. Evidence on the effect of prehabilitation for patients with gynaecological cancer is limited. Future studies are needed to determine the effects on postoperative complications and quality of life.

High prevalence of atypical hyperplasia in the endometrium of patients with epithelial ovarian cancer.

OBJECTIVES: The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). METHODS: Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. RESULTS: In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P=.001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. CONCLUSIONS: Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC.

Histopathologic assessment of the entire endometrium in asymptomatic women.

Knowledge on the nature of the endometrium in women without symptoms of endometrial disease is poor. Therefore, the aim of this prospective study was to describe the endometrium of a cohort of asymptomatic women. The entire endometrium of premenopausal and postmenopausal women was embedded for histologic examination. All included patients underwent a hysterectomy on indication of uterovaginal prolapse, from July 2011 to October 2012, in 3 hospitals in the South of the Netherlands. Exclusion criteria were symptoms of postmenopausal vaginal blood loss or premenopausal disordered vaginal bleeding. As a result, 68 women were included in the study, 48 women were postmenopausal and 20 were premenopausal. In the endometrium of 10 women, simple hyperplasia was found (15%); 1, complex hyperplasia (2%); 2, simple atypical hyperplasia (3%); 2, complex atypical hyperplasia (3%); and 2, a small focus of intramucosal endometrioid endometrial carcinoma (3%). In general, the endometrium was heterogeneous, and most lesions were not present in the entire endometrium. In conclusion, after examining the entire endometrium, a remarkable high prevalence of endometrial pathology was found in asymptomatic women. The clinical meaning of these lesions is not yet clear, but endometrial pathology may frequently exist without symptoms.