An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study).

OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Staging with Unilateral Salpingo-Oophorectomy and Expert Pathological Review Result in No Recurrences in a Series of 81 Intestinal-Type Mucinous Borderline Ovarian Tumors.

OBJECTIVE: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors. METHODS: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors <10 cm and 2 blocks/cm diameter in tumors >10 cm) were performed in all cases. RESULTS: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months. CONCLUSIONS: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent.

Neoadjuvant Weekly Paclitaxel-Carboplatin Is Effective in Stage I-II Cervical Cancer.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by surgery in cervical cancer is widely studied with paclitaxel-ifosfamide-cisplatinum 3 weekly (TIP). Although the response rates with TIP are high, the toxicity is substantial. Therefore, this study evaluates dose-dense paclitaxel-carboplatin (TC) as an alternative. METHODS: In this prospective phase 2 study trial, we included 36 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IIB cervical cancer, who received 9 weeks' NACT dose-dense TC (median weekly dose paclitaxel 60 mg/m, carboplatinum area under the curve 2.7). Radiological response was evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Optimal pathologic response (OPT) was defined as complete disappearance of tumor (complete response [CR]) or residual disease with less than 3-mm stromal invasion (PR1). Suboptimal pathologic response consisted of persistent residual disease with more than 3-mm stromal invasion (PR2). RESULTS: Nine patients had a FIGO stage IB1 (25%), 7 had stage IB2(19%), 3 had stage IIA (8%), and 17 had stage IIB disease (47%). Evaluation by magnetic resonance imaging after NACT showed 32 RECIST responses (89%) (CR in 11, PR in 21). Patients who were inoperable had insufficient reduction of the tumor to be operable (4 patients), progressive disease (1 patient), or stable disease (1 patient). Thirty patients were suitable for surgery after NACT. Pathology showed OPT in 50% (CR in 10, PR1 in 5). Thirteen patients had pathologic lymph nodes on radiological evaluation before start of chemotherapy. After chemotherapy, the lymph nodes were negative in 6 (47%) of these patients (pathologic complete remission). Postoperative chemoradiotherapy was administered in 11 patients (2 because of close resection margins, 5 because of metastatic lymph node after surgery, 2 because of close resection margins and metastatic lymph nodes after surgery, and 1 tumor >4 cm after NACT). Hematologic toxicity was acceptable with no febrile neutropenia and a low nonhematologic toxicity. The estimated 5-year overall survival was 70.8%. CONCLUSIONS: Neoadjuvant TC dose-dense in cervical carcinoma has a high response rate, comparable with TIP, and an acceptable toxicity.

Use of PlasmaJet for Peritoneal Carcinomatosis in Ovarian Cancer.

OBJECTIVE: This study aimed to assess the role and complications of extensive cytoreduction with PlasmaJet (Plasma Surgical, Roswell, Ga) in ovarian cancer with peritoneal carcinomatosis. MATERIALS: All patients undergoing primary, secondary, or interval debulking surgery for ovarian cancer and treated with PlasmaJet between October 2013 and February 2015 were analyzed. RESULTS: Nineteen patients were enrolled. The median operative time was 270 minutes, median blood loss was 700 mL, and median length of stay was 9 days. In all patients, complete resection of all macroscopic disease was achieved.We used PlasmaJet to remove peritoneal carcinomatosis on the abdominal peritoneum, intestinal mesentery, bowel serosa, and diaphragmatic region. Overall, we treated 66 organs with PlasmaJet in our series. No bowel or urological fistulas were observed. According to the Clavien-Dindo classification, 13 adverse events were recorded at grade 2 or lesser. We observed only 1 grade 3 adverse event. No postoperative mortality was recorded. CONCLUSIONS: In our series, the PlasmaJet seems to be an efficient device for tumor ablation or dissection to obtain complete resection of all macroscopic disease in patients with peritoneal carcinomatosis.

Fertility Preservation Is Safe for Serous Borderline Ovarian Tumors.

OBJECTIVES: This study aimed to determine the overall survival (OS) and progression-free interval and the influence of fertility-preserving surgery (FPS) versus radical surgery (RS) in patients with serous borderline ovarian tumor (BOT). METHODS: Clinical parameters of patients with serous BOT treated between 1993 and 2013 in one institution were retrospectively investigated. All tumors were examined by one pathologist with experience in gynecological pathology. RESULTS: One hundred thirty-two patients with serous BOT (inclusive 16 microinvasive) were analyzed (45% were ≤40 years), with a median follow-up of 6 years. Thirty-two percent (42/132) of the patients received FPS; 14% (18/132) relapsed (invasive or borderline). The 5-year progression-free survival was 89%. The risk of recurrence was higher in patients 40 years or younger (P = 0.019), after FPS (P = 0.002), in patients with a higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.016), for bilateral BOT (P = 0.0132), and for the micropapillary variant (P = 0.067). The OS at 5 years was 97%. There was no statistically significant difference in OS between FPS and RS [all (6 of 90) patients, except for 1, with RS died]. One patient died of relapsed BOT. Among the recurrences, low-grade invasive carcinoma was diagnosed in 4 patients. Three of these 4 patients were originally operated radically, 2 had a micropapillary variant FIGO stage III, and 1 had a papillary pattern FIGO stage II with microinvasion; all 3 had noninvasive implants and are alive. One patient with a micropapillary variant, FIGO stage IIIC with microinvasion and invasive implants, received FPS and died of disease. CONCLUSIONS: The risk of recurrence is higher after FPS compared with RS; however, no influence on OS was observed. This was because most of the patients relapsed as BOT. Fertility preservation is justified in young patients with serous borderline tumors.

Common germline polymorphisms associated with breast cancer-specific survival.

INTRODUCTION: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. METHODS: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. RESULTS: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. CONCLUSIONS: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.

Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer.

BACKGROUND: Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. METHODS: In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel-ifosfamide-carboplatin or a combination of paclitaxel-carboplatin was used as neoadjuvant chemotherapy. RESULTS: Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58months with all patients alive and no evidence of disease until now. CONCLUSIONS: Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data.

Para-aortic lymph node metastases in locally advanced cervical cancer: Comparison between surgical staging and imaging.

OBJECTIVE: Compare surgical staging with imaging (PET-CT, PET or CT) of the para-aortic lymph nodes (PAOLN) in locally advanced cervical cancer (LACC). METHODS: Monocentric retrospective study of 336 patients with cervical cancer FIGO stage IB2-IVA. All patients underwent staging of the PAOLN using imaging by PET-CT, PET or CT. Two hundred and four patients with normal or not overtly malignant PAOLN on imaging underwent surgical PAOLN staging up to the inferior mesenteric artery (189 endoscopy and 15 laparotomy). RESULTS: The patients were divided into 4 groups: 16 with positive surgical staging and negative PAOLN imaging (sPAOLN+), 172 negative surgical staging (sPAOLN-), 20 positive imaging without surgical staging (iPAOLN+) and 128 negative imaging without surgical staging (iPAOLN-). Median operative time of staging was 70 (40-160) min and median number of removed PAOLN was 5 (0-24). Operative complications were 10 peroperative bleedings, 2 ureteral traumas, 1 carbon dioxide retention and 1 retroperitoneal abscess. The median follow-up was 31 (1-218) months. Overall survival at 2 years was for sPAOLN+, sPAOLN-, iPAOLN+, and iPAOLN- 40%, 83%, 58%, and 69%, respectively (p<0.001 for sPAOLN+ and iPAOLN+ versus sPAOLN- and iPAOLN-). The most frequent site of recurrence was distant LN metastases (outside the pelvic and PAO area) (36%) for sPAOLN+. For sPAOLN-, iPAOLN+, and iPAOLN- the most frequent site of recurrence was the cervix (27%, 66% and 26%, respectively). CONCLUSION: Despite negative imaging, PAOLN metastases were present in 8% at surgical staging. Overall survival is significantly influenced by the presence of PAOLN metastases.

Phase II study of weekly paclitaxel/carboplatin in combination with prophylactic G-CSF in the treatment of gynecologic cancers: A study in 108 patients by the Belgian Gynaecological Oncology Group.

OBJECTIVE: To investigate the addition of prophylactic G-CSF to each weekly paclitaxel/carboplatin course in patients with recurrent platinum-resistant ovarian (OC), or recurrent or advanced endometrial (EC) or cervical carcinoma (CC). METHODS: 108 patients were enrolled i.e. 36 in each cohort. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatin (AUC 2.7) were administered weekly. G-CSF (filgrastim) was given to all patients on day 5 (and if needed on day 6). RESULTS: For patients with OC, 91% had platinum-resistant and 9% platinum-refractory disease. Median number of prior chemotherapy lines was 3 for OC, 1 for EC, and 1 for CC. Grade 3-4 neutropenia was observed in 34% of patients (95% CI: 26%-44%, P<0,0001) (OC 29%, EC 36%, CC 38%). This is lower compared to historical data in all cohorts (84%). Confirmed sepsis was observed in 5%, grade 3-4 thrombocytopenia in 41%, grade 2-3 peripheral neuropathy in 17% of patients. In 71% of patients dose was delayed. Dose reduction was necessary for carboplatin in 47% and paclitaxel in 18% of patients. ORR was 51% (OC 48%, EC 45%, CC 58%). Median (95% CI) PFS and OS was 7.1 (5.1-8.1) and 12.7 (10.2-16.3) months, respectively (OC 7 and 13, EC 6 and 19, CC 6 and 14). CONCLUSION: Weekly paclitaxel/carboplatin with G-CSF is an effective treatment with acceptable toxicity in patients with platinum-resistant or platinum-refractory OC, advanced or recurrent EC and CC. The incidence of grade 3-4 neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without routine use of prophylactic G-CSF.

Robot-Assisted Radical Hysterectomy in Cervical Carcinoma: The Belgian Experience.

OBJECTIVE: The purpose of this study was to report the experience and oncological outcome of robot-assisted radical hysterectomies (RRHs) for cervical cancer performed in Belgium. METHODS: Patients undergoing RRH for cervical cancer (n = 109) were prospectively collected between July 2007 and April 2014 in the 5 Belgian centers performing RRH for cervical cancer. RESULTS: The median age of the patients was 46 years (range, 31-80 years). Histological types included squamous cell carcinoma in 61 patients, adenocarcinoma in 22 patients, adenosquamous in 8 patients, endometrioid carcinoma in 2 patients, and other types (n = 16). The International Federation of Gynecology and Obstetrics stage distribution was IA (n = 9), stage IB1 (n = 71), stage IB2 (n = 4), stage II (n = 24), and unknown (n = 1). Twenty-four patients received adjuvant therapy, 17 patients underwent radiochemotherapy, and 7 underwent adjuvant radiation. Eighteen patients relapsed, and 5 died of disease. The median follow-up was 27.5 months (range, 3-82 months). The 2- and 5-year overall survivals were 96% and 89%, respectively. The 2- and 5-year disease-free survivals (DFSs) were 88% and 72%, respectively. The 2-year DFS per stage was 100% for IA, 88% for IB1, 100% for IB2, and 83% for II. The 5-year DFS per stage was 100% for stage IA and 75% for IB1. The complications were as expected for radical hysterectomy. CONCLUSIONS: This series confirms the feasibility and safety of RRH not only in cervical cancer stage IA to IB1, but also after neoadjuvant chemotherapy in stage IB2 to IIB.

Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer.

OBJECTIVE: Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. METHODS: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). RESULTS: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26). CONCLUSIONS: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.

Whole-body MRI with diffusion-weighted sequence for staging of patients with suspected ovarian cancer: a clinical feasibility study in comparison to CT and FDG-PET/CT.

OBJECTIVES: To evaluate whole-body MRI with diffusion-weighted sequence (WB-DWI/MRI) for staging and assessing operability compared with CT and FDG-PET/CT in patients with suspected ovarian cancer. METHODS: Thirty-two patients underwent 3-T WB-DWI/MRI, (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and CT before diagnostic open laparoscopy (DOL). Imaging findings for tumour characterisation, peritoneal and retroperitoneal staging were correlated with histopathology after DOL and/or open surgery. For distant metastases, FDG-PET/CT or image-guided biopsies were the reference standards. For tumour characterisation and peritoneal staging, WB-DWI/MRI was compared with CT and FDG-PET/CT. Interobserver agreement for WB-DWI/MRI was determined. RESULTS: WB-DWI/MRI showed 94 % accuracy for primary tumour characterisation compared with 88 % for CT and 94 % for FDG-PET/CT. WB-DWI/MRI showed higher accuracy of 91 % for peritoneal staging compared with CT (75 %) and FDG-PET/CT (71 %). WB-DWI/MRI and FDG-PET/CT showed higher accuracy of 87 % for detecting retroperitoneal lymphadenopathies compared with CT (71 %). WB-DWI/MRI showed excellent correlation with FDG-PET/CT (κ = 1.00) for detecting distant metastases compared with CT (κ = 0.34). Interobserver agreement was moderate to almost perfect (κ = 0.58-0.91). CONCLUSIONS: WB-DWI/MRI shows high accuracy for characterising primary tumours, peritoneal and distant staging compared with CT and FDG-PET/CT and may be valuable for assessing operability in ovarian cancer patients. KEY POINTS: • Whole-body MRI with diffusion weighting (WB-DWI/MRI) helps to assess the operability of suspected ovarian cancer. • Interobserver agreement is good for primary tumour characterisation, peritoneal and distant staging. • WB-DWI/MRI improves mesenteric/serosal metastatic spread assessment compared with CT and FDG-PET/CT. • Retroperitoneal/cervical-thoracic nodal staging using qualitative DWI criteria was reasonably accurate. • WB-DWI/MRI and FDG-PET/CT showed the highest diagnostic impact for detecting thoracic metastases.

Epithelial ovarian cancer: rationale for changing the one-fits-all standard treatment regimen to subtype-specific treatment.

OBJECTIVE: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs. METHODS: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY. RESULTS: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%). CONCLUSIONS: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

The "Leuven" paclitaxel/carboplatin weekly regimen in patients with recurrent ovarian cancer, a retrospective study.

OBJECTIVE: To evaluate the "Leuven" weekly paclitaxel/carboplatinum (TC) regimen in recurrent ovarian cancer in a retrospective study. METHODS: Eighteen courses of paclitaxel (60mg/m(2)) and carboplatinum (AUC 2.7) were administered weekly. Platinum-resistance was defined as progression during or within 6months after platinum-based chemotherapy. RESULTS: Sixty-three patients were included with a median number of prior treatment regimens of 4 (range 0-10). Forty-three patients were platinum resistant and 20 were platinum sensitive (14 intermediate sensitive and 5 sensitive). One patient in the platinum resistant group and 2 patients in the platinum sensitive group achieved complete remission, 15 patients in the platinum resistant and 5 patients in the platinum sensitive group achieved partial remission according to RECIST. In the entire patient population evaluable for response (n=62), the median progression free survival (PFS) was 6.7months; the median overall survival (OS) was 9.7months. Median PFS was 6months for the platinum resistant and 8months for the platinum sensitive group. The median OS was 9months in the platinum resistant and 11months in the platinum sensitive group. Toxicity was mostly bone marrow related with neutropenia grade 3/4 in 67% and neutropenic fever in 6% of patients. Dose reduction was necessary in 24% of patients. Nausea, vomiting and fatigue were the most frequent non-hematological side effects. CONCLUSION: Weekly paclitaxel and carboplatin is an effective regimen for patients with recurrence of ovarian cancer with a response rate of 37% in platinum resistant disease and a manageable toxicity profile.

Multi-center experience of robot-assisted laparoscopic para-aortic lymphadenectomy for staging of locally advanced cervical carcinoma.

OBJECTIVES: FIGO classification is commonly used for staging of locally advanced cervical cancer. Laparoscopic para-aortic lymphadenectomy is currently used as a diagnostic tool, since we know that presence of para-aortic lymph node metastases identifies patients with poor prognosis. The application of robotics during this procedure needs to be investigated. DESIGN: Retrospective multi-center study. SETTING: Three centers participated in building one database. POPULATION: Thirty-seven patients with locally advanced cervical cancer underwent a robot-assisted laparoscopic para-aortic lymphadenectomy. METHODS: Patients were prospectively enrolled in one register. Retrospective analysis of the whole database was performed. MAIN OUTCOME MEASURES: Surgical outcomes of the robot-assisted procedure and follow-up data. RESULTS: Median number of lymph nodes collected was 27.5 (1-54) per patient. Five of 37 patients had para-aortic node metastases. The false negative rate for PET-CT diagnosing para-aortic node metastases was 11.4% (4/35). Two major intra-operative complications occurred (5.4%). Postoperative morbidity was low (13.5%). Median follow-up was 27 months [95% confidence interval (95% CI) was 24-30]. Median disease-free survival was 16 months (95% CI 2.4-29.6). Patients with negative nodes had a median disease-free survival of 24 months (not assessable), although patients with positive nodes had a median disease-free survival of 9 months (95% CI 6.9-11.9). CONCLUSIONS: In this series we report that robot-assisted laparoscopic para-aortic lymphadencetomy provided the surgeon with useful information, diagnosing 11.4% of occult para-aortic lymph node metastases in women with locally advanced cervical cancer. Intra-operative and postoperative morbidity were low. The presence of para-aortic lymph node metastases correlated with shorter disease-free survival.

Treatment of high-risk gestational trophoblastic neoplasia with weekly high-dose methotrexate-etoposide.

OBJECTIVE: To assess toxicity and efficacy of weekly high-dose methotrexate-etoposide (HD MTX-ETO) in high-risk gestational trophoblastic neoplasia (GTN). METHODS: Retrospective chart review of high-risk GTN patients treated with HD MTX-ETO (methotrexate 1000 mg/m² day 1, etoposide 100 mg/m² days 1 and 2, q 1 wk). RESULTS: 134 cycles of HD MTX-ETO were administered to twelve patients; median number of cycles was 8 (range 2-39 cycles). Median follow up was 25.5 months (range 11-69). 7 of these patients switched due to ototoxicity from EP-EMA (etoposide 150 mg/m², cisplatin 75 mg/m² i.v. day 1; etoposide 100 mg/m², methotrexate 300 mg/m², dactinomycin 0.5 mg i.v. day 8, q 14 d) to HD MTX-ETO, after an average of 7 cycles of EP-EMA. Six achieved complete remission without disease recurrence. One patient with a placental site trophoblastic tumour died due to progressive disease. Five patients received HD MTX-ETO primarily; 1 patient with choriocarcinoma presenting with metastases to the brain and liver (WHO score 19) was switched to EP-EMA and died due to complications under EP-EMA. The other 4 achieved complete remission without disease recurrence. HD MTX-ETO was well tolerated; non-haematological toxicity was low except for alopecia and fatigue. Nine patients had grade 2-4 anaemia and received packed cells. Eight patients had grade 3-4 neutropenia and received G-CSF. Two patients developed febrile neutropenia without sepsis. CONCLUSIONS: These preliminary results show a better toxicity profile with HD MTX-ETO than EP-EMA and encouraging efficacy. HD MTX-ETO might be a treatment option for some patients with high-risk GTN and needs further investigation.

EP-EMA regimen (etoposide and cisplatin with etoposide, methotrexate, and dactinomycin) in a series of 18 women with gestational trophoblastic neoplasia.

OBJECTIVE: Evaluation of toxicity and outcome of high-risk gestational trophoblastic neoplasia when treated with EP-EMA (etoposide, 150 mg/m; cisplatin, 75 mg/m, intravenous, day 1; etoposide, 100 mg/m; methotrexate, 300 mg/m; dactinomycin, 0.5 mg, intravenous, day 8, every two weeks). MATERIALS AND METHODS: We conducted a retrospective chart review of the period 2004-2010. The first-line chemotherapy regimen for high-risk gestational tropholdastic neoplasia was EP-EMA. RESULTS: Eighteen patients were treated with EP-EMA, either as first-line chemotherapy for high-risk gestational trophoblastic neoplasia (n = 6), placental site trophoblastic tumor (n = 1), or as salvage chemotherapy for gestational trophoblastic neoplasia after single-agent methotrexate (methotrexate, 1 mg/kg, on days 1, 3, 5, and 7 every two weeks) (n = 10) or high-dose methotrexate-etoposide: methotrexate, 1000 mg/m, on day 1; etoposide, 100 mg/m, on days 1 to 2, every week) (n = 1). Median number of cycles of EP-EMA was 8 (range, 3-11). Median follow-up was 19 months (range, 7-77 months). Concerning response rate, 16 patients (89%) achieved complete remission without disease recurrence.Two patients (11%) died: One patient with placental site trophoblastic tumor died of progressive disease; the second patient presented with choriocarcinoma, primarily metastasized to liver, lung, skin, kidney, and brain. She died of sepsis and endocarditis after adding intrathecal methotrexate and switching cisplatin to carboplatin in the EP-EMA regimen. Toxicity was significant. Eight treatment changes were made owing to grade 2 to grade 3 ototoxicity: 7 to high-dose methotrexate-etoposide, 1 change of cisplatin to carboplatin. Fifteen patients (83%) experienced grade 3/4 neutropenia.

Role of neoadjuvant chemotherapy in the management of stage IIIC-IV ovarian cancer: survey results from the members of the European Society of Gynecological Oncology.

OBJECTIVE: The aim of this study is to evaluate the current opinion of the members of the European Society of Gynecological Oncology (ESGO) on the use of neoadjuvant chemotherapy (NACT) in stage IIIC and IV ovarian cancer. METHODS: A link to a 21-item questionnaire, with questions about the management of patients with stage IIIC and IV ovarian cancer, was sent 3 times to the ESGO members (N = 1177). RESULTS: Of the 469 (40%) responding members, 70.2% believe there is sufficient evidence to use NACT followed by interval debulking for the treatment of stage IIIC and IV ovarian cancer. On the basis of a multivariable logistic regression analysis, no relationships between the belief in evidence for NACT and practice type (P = 0.15) or level of experience (P = 0.41) were observed. Only 5.3% of respondents never use NACT, and 30% uses NACT in less than 10% of their patients. Optimal debulking, defined as "no macroscopic residual tumor," is reported in more than 60% of the patients by 20% of the respondents at primary debulking, and by 34.6% of the respondents when interval debulking is performed. Whether a patient can be optimally primarily debulked is impossible to determine preoperatively according to 51.1% of the respondents. Computed tomographic scan (79.4%) and clinical examination (72.5%) are regarded as the most important modalities to predict operability. Diagnostic laparoscopy is used by 46.3% of the respondents. The most important reasons for choosing NACT are bulky disease in the upper abdomen (64.7%) and stage IV disease (58.7%). CONCLUSIONS: Of the responding ESGO members, 70% believe there is sufficient evidence to treat patients with stage IIIC-IV ovarian cancer with NACT, and 30% uses NACT in less than 10% of their patients.

Pelvic exenterations for gynecological malignancies: a study of 36 cases.

OBJECTIVE: Evaluation of surgical outcomes, survival, and morbidity associated with pelvic exenteration (PE) performed for gynecologic malignancies. METHODS: Review of 36 consecutive patients who underwent PE between June 1999 and April 2010. RESULTS: Pelvic exenteration was performed for cancer of the cervix (n = 18), endometrium (n = 9), vagina/vulva (n = 8), and ovary (n = 1). Four patients underwent PE as primary treatment and 32 patients for recurrent disease after pelvic radiotherapy. Median age was 57 years (range, 35-81 years). Bricker (n = 17), Mainz pouch (n = 10), and augmentation after bladder resection (n = 6) were used as urinary derivations. J-pouch coloanal anastomosis was performed in 14, colostomy in 13, and side-to-end anastomosis in 4 patients. There was no operative mortality. The most important postoperative complications were rectovaginal fistula (5), urinary leakage (2), vesicovaginal fistula (1), and sepsis (3). One of the 6 patients with a partial cystectomy developed a vesicovaginal fistula, which was successfully treated with a Martius flap. With a median follow-up of 78 months (range, 2-131) months, the 5-year overall and disease-specific survival (DSS) rates were 44% and 52%, respectively. Five-year DSS for cervical, endometrial, and vaginal/vulvar cancer was 44%, 80%, and 57%, respectively. Combined operative and radiotherapeutic treatment (CORT) was performed in 3 patients with pelvic side wall relapse. Of the 15 patients 65 years or older, a 5-year DSS of 71% was observed in comparison with 42% in the younger subgroup, and their complication rates were similar to the younger patient group. Thirteen patients (36%) reported to have psychological disturbances associated with stoma-related problems. Only 3 patients requested a vaginal reconstruction during follow-up. CONCLUSIONS: Pelvic exenteration offers a sustained survival with an acceptable morbidity in patients with advanced or recurrent gynecologic cancer. Older age was not associated with higher morbidity/mortality in this series.