FIGO Stage II-IV Research Articles

High prevalence of "non-pathogenic" POLE mutation with poor prognosis in a cohort of endometrial cancer from South India.

The Cancer Genome Atlas (TCGA) project identified favorable prognosis regarding the ultra-mutated endometrial cancer (EC) subtype linked to polymerase epsilon gene (POLE) mutations. This study investigated POLE mutations in EC of Indian patients. This retrospective analytical study was conducted between January 2016 and January 2023 at the Government Medical College, Kozhikode, and the MVR Cancer Center, Kozhikode, Kerala. Sanger sequencing of POLE gene exons 9 and 13 in 151 EC patients was carried out to analyze the relationship between mutations and epidemiological factors, clinicopathologic features, and treatment outcomes. Among 151 cases enrolled, 39 were unique POLE-mutated cases. Significant associations were high-grade tumors, myometrial invasion >50%, and Lymph-vascular space invasion (LVSI). The median follow-up was 40 months (95% confidence interval [CI], 34-46). A lower mean disease-specific survival (DSS) of 51.7 months (95% CI, 43.7-59.6) was noted in the POLE-mutated group compared with 72.11 months (95% CI, 67.60-76.62) for the POLE wild-type. A statistically significant hazard ratio (HR) of 2.683 for DSS in the POLE-mutated group was noted. In advanced stages (FIGO stages II-IV), a nine-fold HR for DSS and overall survival (OS) compared with POLE wild-type was identified. After controlling for treatment effects using Cox proportional HR, advanced-stage POLE-mutated tumors had a significantly higher HR of 8.67 for DSS compared with POLE-wild-type tumors of the same stage. This study identified a unique set of POLE mutations in Indian EC patients associated with poor prognosis, which were particularly pronounced in advanced stages. Advanced stage of presentation, type of POLE mutations, and possibly ethnicity are predictors of adverse outcomes in POLE-mutated EC. The present study highlights ethnicity as a determinant of phenotypic expression of genetic change.

Survival impact of bowel resection in patients with FIGO stage II-IV ovarian cancer.

To compare the effect of bowel resection vs stripping on the clinical outcomes of patients with FIGO II-IV ovarian cancer. We retrospectively analyzed patients with FIGO II-IV ovarian cancer who suffered from bowel involvement and underwent cytoreductive surgery between January 2014 and March 2022. Patients' survival was compared by Kaplan-Meier survival analysis and Cox proportional hazards models. Four hundred and twelve patients were included. 48 patients underwent bowel resection (BR), and 364 patients underwent bowel tumor stripping (BTS). The BR group had longer operative duration, hospital stay, time to post-operative chemotherapy, and more intraoperative bleeding. The median PFS was 37months (95% CI 12-62) in BTS compared to 25months (95% CI 10-40) in BR among patients who achieved R0 resection (p = 0.590). Among those with R1 resection, the median PFS in BST was 23months (95% CI 16-30) and that in BR was 15months (95% CI 12-18, p = 0.136); moreover, a favorable median PFS was observed in BTS with residual bowel lesions (23months, 95% CI 14-32), compared to BR (15months, 95% CI 12-18, p = 0.144). Multivariate analysis indicated that FIGO stage, PCI, cytoreduction time and residual lesions were independent prognostic factors of PFS. For patients with FIGO stage II-IV ovarian cancer with bowel implicated, bowel resection is necessary to achieve complete removal to improve the survival. If complete resection was judged unfeasible, cautious decision of bowel resection is required. Neoadjuvant chemotherapy might reduce the ratio of bowel resection for some with mesenteric involvement.

Impact of adjuvant chemotherapy on the overall survival of patients with advanced stage low-grade serous ovarian carcinoma (130)

<b>Objectives:</b> Low-grade serous ovarian carcinoma (LGSOC) is a rare, relatively chemo-resistant histologic subtype of ovarian carcinoma. The impact of adjuvant chemotherapy on the survival of patients with the advanced-stage disease is not well defined. We aimed to utilize a large hospital-based database and investigate the survival of patients who did and did not receive adjuvant chemotherapy. <b>Methods:</b> Patients diagnosed between 2010-2015 with FIGO stage II-IV low-grade serous ovarian carcinoma who underwent primary debulking surgery with known residual disease status and had at least one month of follow-up were identified. Adjuvant chemotherapy or hormonal treatment was defined as receipt of chemotherapy or hormonal treatment within six months from surgery. Clinical-pathologic and demographic characteristics were compared with the Chi-square test. Overall survival was evaluated following the generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to control for a priori selected confounders. <b>Results:</b> A total of 618 patients with stage II-IV LGSOC were identified; 501 (81.1%) patients received adjuvant chemotherapy while 117 (18.9%) patients did not. In the present cohort, hormonal therapy was rarely administered (<i>n</i>=22, 3.6%). There were no differences between the two treatment groups in terms of age, presence of comorbid conditions, type of treatment facility, and insurance status. In the present cohort, the rate of CGR was 67.8%; 66.1%, and 75.2% among patients who did and did not receive adjuvant chemotherapy (p=0.057). The rate of adjuvant chemotherapy use was 67.4% for patients with stage II disease compared to 83.2% and 86.5% for those with stage III and IV disease, respectively. The median follow-up duration of the present cohort was 47.97 months. There was no difference in OS between patients who did and did not receive adjuvant chemotherapy (p=0.78); 4-year OS were 77.5% and 76.1%, respectively. Following stratification by residual disease status, adjuvant chemotherapy was not associated with a survival benefit for patients who achieved CGR (p=0.60; 4-year OS rates 85.5% and 79.5%, respectively) or had the gross residual disease (p=0.85; 4-year OS rates 63.1% and 66.3%, respectively). After controlling for patient age, presence of medical comorbid conditions, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR: 0.87, 95% CI: 0.55-1.38). On the contrary, the presence of gross residual disease (HR: 2.25, 95% CI: 1.58, 3.21) was associated with worse overall survival. <b>Conclusions:</b> Adjuvant chemotherapy may not be associated with an overall survival benefit for patients with advanced-stage LGSOC.

30-Year Experience With 22 Cases of Malignant Transformation Arising From Ovarian Mature Cystic Teratoma: A Rare Disease.

ObjectiveTo investigate the clinical characteristics and survival outcomes of patients with malignant transformation arising from ovarian mature cystic teratoma (MT-MCT).MethodsThis retrospective study included patients with ovarian MCTs at Peking Union Medical College Hospital (PUMCH) during 1990.01-2020.12. When the pathologic histology was MT-MCT, detailed information was collected.ResultsOverall, 7229 ovarian MCT patients and 22 patients with MT-MCT were enrolled. The rate of malignant transformation of all ovarian MCTs was 0.30%. Most patients with MT-MCT were 51 (21–75) years old, and the tumor mass size was 10 (3–30) cm. The typical clinical symptoms were mainly abdominal pain and distension. The levels of tumor markers were elevated on preoperative examination. Early diagnosis could be made by ultrasonic examination, pelvic enhanced MRI and CT. Most patients underwent debulking surgery and adjuvant chemotherapy. The most common histological type to exhibit malignant transformation was squamous cell carcinoma (59.1%), followed by adenocarcinoma (13.6%), carcinoid (9.1%), and borderline tumor (18.2%). The 5-year RFS and OS rates were 54.5% and 81.8%, respectively. Patients with FIGO stage I had the best RFS (P=0.047) and OS (P=0.018), followed by those with FIGO stage II-IV.ConclusionMT-MCTs mainly occur in elderly females, are rare and have a poor prognosis. Advanced FIGO stage is a risk factor for survival. Although there is no standard treatment, cytoreductive debulking surgery and adjuvant chemotherapy could be considered. Perimenopausal and menopausal women with MCT should receive surgical treatment.

Survival and reproductive outcomes after fertility-sparing surgery performed for borderline epithelial ovarian tumor in Japanese adolescents and young adults: Results of a retrospective nationwide study.

Epithelial borderline ovarian tumor (BOT) frequently occurs in young women. Because progression-free survival, overall survival, and reproductive function are important outcomes, BOT is often treated by fertility-sparing surgery (FSS). We conducted a Japan-wide study to understand post-FSS prognosis in relation to clinical characteristics and types of FSS performed. We analyzed clinical and outcome data pertaining to 531 adolescent and young adult (AYA) patients (aged 15-39 years) who underwent FSS for BOT between 2009 and 2013. Median (range) age was 30 (15-39) years, and median observation time was 70 (2-120) months. The disease was of FIGO stage I in 492 (93%) patients. Histopathologically, tumors were of the mucinous (n=372, 70%), serous (n=120, 23%), seromucinous (n=23, 4%), and other (n=16, 3%) types. Five-year overall survival was 99.5% among patients with stage I and 100% among those with stage II-IV. Five-year progression-free survival was 96.7% and 69.3%, respectively. Multivariate analysis in cases of stage I showed a positive peritoneal cytology to be a significant risk factor for recurrence (HR, 5.199; p=0.0188). The post-FSS pregnancy rate was relatively low for patients aged ≥30 years (OR, 0.868; 95% CI, 1.16-3.00; p=0.0090). Post-FFS outcomes in terms of overall and progression-free survival are favorable, especially for AYA patients with stage I BOT. However, the relapse rate is high for patients with FIGO stage II-IV and for those with stage I but a positive peritoneal cytology. A long-term prospective observation is needed before reproductive outcomes can be fully established.

ENGOT-ov54/Swiss-GO-2/MATAO including LOGOS (Low-Grade Ovarian cancer Sub-study): MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer—A randomized, double-blinded, placebo-controlled, multicenter phase III Trial.

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

A multiplex biomarker assay improves the diagnostic performance of HE4 and CA125 in ovarian tumor patients.

ObjectiveSurvival in epithelial ovarian cancer (EOC) remains poor. Most patients are diagnosed in late stages. Early diagnosis increases the chance of survival. We used the proximity extension assay from Olink Proteomics to search for new protein biomarkers with the potential to improve the diagnostic performance of CA125 and HE4 in patients with ovarian tumors.Material and methodsPlasma samples were obtained from 180 women with ovarian tumors; 30 cases of benign tumor, 28 cases with borderline tumors, 25 early EOC cases (FIGO stage I) and 97 advanced EOC cases (FIGO stages II-IV). Proteins were measured using the Olink® Oncology II and Inflammation panels. For statistical analyses, patients were categorized into benign tumors versus cancer and benign tumors versus borderline + cancer, respectively.ResultsWe analyzed 177 biomarkers. Thirty-four proteins had ROC AUC > 0.7 for discrimination between benign tumors and cancer. Fifteen proteins had ROC AUC > 0.7 for discrimination between benign tumors and borderline tumors + cancer. HE4 ranked highest for both comparisons. A reference model with HE4, CA125 and age (AUC 0.838 for benign tumors vs. cancer and AUC 0.770 for benign tumors vs. borderline tumors + cancer) was compared to the reference model with the addition of each of the remaining proteins with AUC > 0.7. ITGAV was the only individual biomarker found to improve diagnostic performance of the reference model, to AUC 0.874 for benign tumors vs. cancer and AUC 0.818 for benign tumors vs. borderline tumors + cancer (p < 0.05). Cross-validation and LASSO regression was combined to select multiple biomarker combinations. The best performing model for discrimination between benign tumors and borderline tumors + cancer was a 6-biomarker combination (HE4, CA125, ITGAV, CXCL1, CEACAM1, IL-10RB) and age (AUC 0.868, sensitivity 0.86 and specificity 0.82, p = 0.016 for comparison with the reference model).ConclusionHE4 was the best performing individual biomarker for discrimination between benign ovarian tumors and EOC including borderline tumors. The addition of other carcinogenesis-related biomarkers in a multiplex biomarker panel can improve the diagnostic performance of the established biomarkers HE4 and CA125.

Impact of provider volume on front-line chemotherapy guideline compliance and overall survival in elderly patients with advanced ovarian cancer

PurposeWe sought to evaluate whether provider volume or other factors are associated with chemotherapy guideline compliance in elderly patients with epithelial ovarian cancer (EOC). MethodsWe queried the SEER-Medicare database for patients ≥66 years, diagnosed with FIGO stage II-IV EOC from 2004 to 2013 who underwent surgery and received chemotherapy within 7 months of diagnosis. We compared NCCN guideline compliance (6 cycles of platinum-based doublet) and chemotherapy-related toxicities across provider volume tertiles. Factors associated with guideline compliance and chemotherapy-related toxicities were assessed using logistic regression. Overall survival (OS) was compared across volume tertiles and Cox proportional-hazards model was created to adjust for case-mix. Results1924 patients met inclusion criteria. The overall rate of guideline compliance was 70.3% with a significant association between provider volume and compliance (64.5% for low-volume, 72.2% for medium-volume, 71.7% for high-volume, p = .02). In the multivariate model, treatment by low-volume providers and patient age ≥ 80 years were independently associated with worse chemotherapy-guideline compliance. In the survival analysis, there was a significant difference in median OS across provider volume tertiles with median survival of 32.8 months (95%CI 29.6, 36.4) low-volume, 41.9 months (95%CI 37.5, 46.7) medium-volume, 42.1 months (95%CI 38.8, 44.2) high-volume providers, respectively (p < .01). After adjusting for case-mix, low-volume providers were independently associated with higher rates of mortality (aHR 1.25, 95%CI: 1.08, 1.43). ConclusionsIn a modern cohort of elderly Medicare patients with advanced EOC, we found higher rates of non-compliant care and worse survival associated with treatment by low-volume Medicare providers. Urgent efforts are needed to address this volume-outcomes disparity.

Fertility-sparing surgery and reproductive-outcomes in patients with borderline ovarian tumors

BackgroundBorderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS. MethodsPatients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary. ResultsAmong 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7–95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1–102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9–47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported. ConclusionFSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses.

Relation between type of hysterectomy and survival rate in patients with ovarian cancer - single-center study.

Aim of the studyTo evaluate the survival rate of patients with advanced ovarian carcinoma in relation to the type of surgical intervention – total abdominal hysterectomy with bilateral adnexectomy and omentectomy as a minimal standard compared to extended hysterectomy with a retroperitoneal approach.Material and methodsThe study was implemented based on retrospectively obtained data from 104 patients operated on for advanced epithelial ovarian carcinoma (FIGO stages II-IV) in the period from 2004 to 2012. Total abdominal hysterectomy, bilateral adnexectomy, and omentectomy were performed on 23 patients. Extended hysterectomy with a retroperitoneal approach and varying degrees of peritonectomy, omentectomy, and appendectomy were performed on 74 patients. Seven patients were treated with adnexectomy or biopsy alone. We divided the patients into two groups according to the mode of surgery. The first one comprised the patients who underwent radical hysterectomy and the second one comprised total abdominal hysterectomy plus bilateral adnexectomy. The two groups were examined for their overall survival rate, relapse-free survival rate, and 5-year survival rate.ResultsMean overall survival rate, relapse-free survival rate, and 5-year survival rate in the group with extended hysterectomy were higher compared to the group with total abdominal hysterectomy.ConclusionsThe extended hysterectomy with a retroperitoneal approach with or without systematic lymph node dissection seems to be more appropriate in the surgical treatment of advanced ovarian carcinoma. The procedure is related to the improvement of survival rate as a result of the inclusion of macroscopically invisible lesions in the surgical removal.

Removal of the entire internal iliac vessel system is a feasible surgical procedure for locally advanced ovarian carcinoma adhered firmly to the pelvic sidewall.

Ovarian carcinomas sometimes grow in the pelvic cavity, adhering firmly to the pelvic sidewall. These cases are often considered as inoperable or result in the incomplete resection because the tumors are not mobile. We performed en bloc resection of the tumors along with the entire internal iliac vessel system to achieve complete resection. Twenty of 237 consecutive patients with FIGO stage II-IV ovarian, fallopian tubal, or primary peritoneal carcinoma who underwent cytoreductive surgery at Chiba University Hospital between January 2008 and December 2016 had locally advanced tumors adhered firmly to the pelvic sidewall. We performed isolation of the tumors from the pelvic sidewall using the following procedure: the trunk of internal iliac vessels, the obturator vessels, the inferior gluteal and internal pudendal vessels were isolated and divided. The tumor together with the entire internal iliac vessel system was isolated from the sacral nerve plexus and piriform muscle. We examined the surgical outcomes, perioperative complications, and prognosis for the patients who underwent this procedure. All patients successfully underwent complete resection, resulting in no gross residual disease in the pelvic cavity. There was no mortality within 90 days postoperatively. Two patients had Grade IIIb complications, comprising wound dehiscence and vesicovaginal fistula. Recurrence occurred in nine of the patients. However, no recurrence was observed in the pelvic sidewall. The median progression-free survival was 43 months. Removal of the entire internal iliac vessel system is feasible for the complete resection of locally advanced ovarian carcinomas adhered firmly to the pelvic sidewall.

937PD - PD-L1 expression and prognosis significance in advanced ovarian cancer

Background: Recent data suggest that programmed death ligand 1 (PD-L1) expression may predict response to anti–programmed death 1 (PD-1) therapy. This retrospective observational study evaluated the prognostic effect of PD-L1+ expression in patients with histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube cancer (OCa). Methods: Patients diagnosed with FIGO stages II-IV OCa from 2004-2012, at Aarhus University Hospital and Rigshospitalet, Copenhagen, Denmark, were included. PD-L1 expression was measured in tissue collected at OCa surgery, using immunohistochemistry with anti–PD-L1 22C3 antibody. PD-L1+ expression was defined as staining in ≥ 1% of tumor or inflammatory cells. Patients partially sensitive (PPS; treatment-free interval [TFI] of 6-12 mo) or fully sensitive (FPS; TFI >12 mo) to platinum therapy were considered platinum sensitive, whereas those refractory (TFI <3 mo) or resistant (TFI of 3-6 mo) to platinum were platinum insensitive. Data were analyzed using Cox proportional hazard model, adjusting for age, stage, histology, residual tumor, surgery type, performance status, and/or TFI. Results: Median age of the 376 patients at diagnosis was 63 years (range, 26-86). 77% had histologic grade 2/3 serous adenocarcinoma, 46% had residual tumor after surgery, and 9%, 70%, and 21% had FIGO stages II, III, and IV disease, respectively. FPS, PPS, platinum-resistant, and platinum-refractory disease comprised 49%, 27%, 15%, and 9% of patients, respectively. 50.5% of patients were PD-L1+, with prevalence increasing with increased platinum sensitivity (P for linear trend <0.05). Median overall survival (OS) was 43 mo (50.4 mo in PD-L1+ vs 38.3 mo in PD-L1– patients). A statistically significant association was seen between PD-L1+ tumors and longer OS (adjusted hazard ratio [aHR], 0.71 [95% CI, 0.55-0.91]). The association was not significant in platinum-insensitive patients (aHR, 0.82 [0.50-1.36]), but there was a tendency towards significance in platinum-sensitive patients (0.77 [0.57-1.06]), driven by those with a TFI of 6-12 mo. Conclusions: PD-L1 was frequently expressed in advanced OCa patients, and expression may be prognostic, particularly in those with partially platinum-sensitive OCa. Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: T.T. Vo: Employed by, own stock in, and have received research grants from Merck & Co., Inc. W. Zhou, M. Busch-Sørensen, D. Chappell: Employed by and own stock in Merck & Co., Inc. T. Steiniche: Received research funding from and have been reimbursed for travel and accommodation expenses by Merck & Co., Inc. All other authors have declared no conflicts of interest.

Diffusion-weighted MRI of epithelial ovarian cancers: Correlation of apparent diffusion coefficient values with histologic grade and surgical stage

ObjectiveThe purpose of this article is to correlate the apparent diffusion coefficient (ADC) values of epithelial ovarian cancers with histologic grade and surgical stage. Materials and methodsWe enrolled 43 patients with pathologically proven epithelial ovarian cancers for this retrospective study. All patients underwent preoperative pelvic magnetic resonance imaging (MRI) including diffusion-weighted images with b value of 0 and 1000s/mm2 at 3.0-T unit. The mean ADC values of the solid portion of the tumor were measured and compared among different histologic grades and surgical stages. ResultsThe mean ADC values of epithelial ovarian cancers differed significantly between grade 1 (well-differentiated) and grade 2 (moderately-differentiated) (P=0.013) as well as between grade 1 and grade 3 (poorly-differentiated) (P=0.01); however, no statistically significant difference existed between grade 2 and grade 3 (P=0.737). The receiver-operating characteristic analysis indicated that a cutoff ADC value of less than or equal to 1.09×10−3mm2/s was associated with 94.4% sensitivity and 85.7% specificity in distinguishing grade 1 and grade 2/3 cancer. The difference in mean ADC values was statistically significant for early stage (FIGO stage I) and advanced stage (FIGO stage II-IV) cancer (P=0.011). The interobserver agreement for the mean ADC values of epithelial ovarian cancers was excellent. ConclusionThe mean ADC values of the solid portion of epithelial ovarian cancers negatively correlated to histologic grade and surgical stage. The mean ADC values may be useful imaging biomarkers for assessment of tumor grade of epithelial ovarian cancer.

880PD - Pazopanib Versus Placebo in Women Without Progression After First-Line Chemotherapy for Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (Aeoc): Second Interim Overall Survival Analysis from the Ago-Ovar16 Trial

ABSTRACT Aim: We previously reported results from AGO-OVAR16 (NCT00866697), a randomized, double-blind, placebo-controlled phase 3 trial that evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients without disease progression after first-line chemotherapy for AEOC (du Bois et al, ASCO 2013; abstract LBA5503). Patients in the pazopanib arm had longer progression-free survival (PFS) versus those in the placebo arm (HR = 0.766; 95% CI: 0.643, 0.911; P = .0021; medians 17.9 vs 12.3 months, respectively). The first interim analysis for overall survival (OS) after 190 deaths (20% of the study population) revealed no difference between arms (HR = 0.994; 95% CI: 0.747, 1.321). In this report we present updated results from the planned second interim OS analysis after 335 events (36% of the study population; 61% of events required for the final OS analysis, which will be performed after 551 events). Methods: Eligible patients had histologically confirmed AEOC, FIGO stage II-IV, and no evidence of disease progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy. Patients were randomized 1:1 to receive pazopanib 800 mg once daily or placebo for up to 24 months. The primary endpoint was PFS by RECIST. Secondary endpoints included OS, safety, and quality of life. Results: A total of 940 patients were randomized. At this second interim analysis of OS, 172 patients (36%) in the pazopanib arm and 163 patients (35%) in the placebo arm had died (HR = 1.076; 95% CI: 0.868, 1.333; P = .4985). The majority of deaths in each arm were attributed to the cancer under study. Additional subgroup analyses are ongoing and will be presented. Conclusions: Results from this updated OS analysis are consistent with the first interim analysis. Although maintenance therapy with pazopanib in AEOC significantly prolonged PFS in the overall study population, no difference in OS was observed in the planned second interim OS analysis. Disclosure: J.A. Arranz Arija: I have received honorarium for participating in advisory boards organized by GSK. I have received honorarium for participating as speaker in meetings organized by GSK. I do not have other economic relationships nor interest with GSK; N. Colombo: I have to declare participation in advisory boards; B.J. Monk: I have received honoraria for Advisory Boards. GSK supports research done at my institution and the payments do not go to me; T. Herzog: Consultant via advisory boards: Az, Roche, merk, morphotek No other as no speaker bureaus stock etc; C. Barrett and M. Jobanputra: I am employed by GlaxoSmithKline and hold GSK stock; Q. Wang: I'm a GSK employee and own GSK stocks. I do not have anything else to disclose; A. Du Bois: Consultant/advisor for Roche, Pharmamar, Amgen, and MSD Honoraria received from Roche, Johnson & Johnson, Pharmamar and MSD. All other authors have declared no conflicts of interest.

Treatment reality in elderly patients with advanced ovarian cancer: a prospective analysis of the OVCAD consortium

BackgroundApproximately one third of women diagnosed with ovarian cancer is 70 years or older. Information on the treatment reality of these elderly patients is limited.Methods275 patients with primary epithelial ovarian cancer FIGO stage II-IV undergoing cytoreductive surgery and platinum-based chemotherapy were prospectively included in this European multicenter study. Patients <70 and ≥70 years were compared regarding clinicopathological variables and prognosis.ResultsMedian age was 58 years (18–85); 47 patients (17.1%) were 70 years or older. The postoperative 60-day-mortality rate was 2.1% for elderly and 0.4% for younger patients (p < 0.001). Elderly patients were less likely to receive optimal therapy (no residual disease after surgery and platinum combination chemotherapy) compared to patients <70 years (40.4% vs. 70.1%, p < 0.001) and their outcome was less favorable regarding median PFS (12 vs. 20 months, p = 0.022) and OS (30 vs. 64 months, p < 0.001). However, in multivariate analysis age itself was not a prognostic factor for PFS while the ECOG performance status had prognostic significance in elderly patients.ConclusionsElderly patients with ovarian cancer are often treated less radically. Their outcome is impaired despite no consistent prognostic effect of age itself. Biological age and functional status should be considered before individualized treatment plans are defined.

Clinical Significance of the Maximal Standardized Uptake Value for F-18 Fluorodeoxyglucose in Primary Cervical Cancer as an Indicator of Prognosis

We evaluated the prognostic significance of tumor metabolic activity on pretreatment positron emission tomography using the glucose analog F-18 fluorodeoxyglucose (FDG-PET) in patients with FIGO stage II-IV cervical cancer.

Primary treatment patterns in women recruited to the Australian Ovarian Cancer Study

Associations between clinical outcome and patient characteristics, such as tumour gene expression, and inherited variation (single nucleotide polymorphisms) can be difficult to reproduce between ovarian cancer cohorts. Sources of variation include the size and composition of patient cohorts and treatment, which has varied over time and can vary between countries. We have undertaken a review of treatment in patients recruited to the Australian Ovarian Cancer Study (AOCS) to determine the primary treatment patterns and levels of consistency across the cohort. Australian clinical practice guidelines for the management of women with epithelial ovarian cancer were published in 2004 [1] and AOCS recruited women with suspected ovarian, fallopian tube or primary peritoneal cancer from 2002-2006. AOCS collected fresh tissue, blood, epidemiological/dietary questionnaires and clinical follow-up data for women aged 18-79 diagnosed with invasive (n=1476) and borderline (n=352) cancer, and material and data are available for research, by application. Clinical data was collected through a national research nurse network at pre-specified intervals: at diagnosis, completion of primary treatment and then at 6-monthly intervals. At the end of Feb 2011 primary treatment data was complete on 99% of eligible cases and the median follow-up time was 5.1 years. Most patients with invasive cancer underwent surgery prior to chemotherapy (n=1190, 82%) and a small proportion had an interval debulk (surgery following ~3 cycles of chemotherapy, 12%) or other procedure (<10%). The vast majority of women with advanced stage cancer (FIGO stage II-IV) received chemotherapy (1116/1167, 96%) and of these, over 99% (1110/1116) received a platin-based regimen. The most common regimens were carboplatin/paclitaxel (77%) and carboplatin alone (9%), most women (86%) received 6-8 cycles and 95% of women who received adjuvant chemotherapy began treatment within 6 weeks of surgery. In conclusion, the majority of women in AOCS were treated according to national guidelines, enabling the selection of cases with uniform treatment for projects investigating associations of genomic and genetic features with clinical outcome.

Prediction of Chemotherapy Response With Platinum and Taxane in the Advanced Stage of Ovarian and Uterine Carcinosarcoma

To evaluate the role of an in vitro drug resistance assay to predict the response to platinum and taxane combination chemotherapy in advanced ovarian and uterine carcinosarcoma. We evaluated all patients with FIGO stage II-IV ovarian and FIGO stage III-IV uterine carcinosarcoma, who received platinum and taxane chemotherapy after initial cytoreductive surgery between January 1, 1995 and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics, clinicopathologic data, response to chemotherapy, and follow-up outcomes were abstracted from the medical records. In vitro drug resistance assay results (Extreme Drug Resistance [EDR] Assay, Oncotech Inc, Tustin, CA) were evaluated. Response to chemotherapy was then compared with the assay results. There were 51 cases in which in vitro drug resistance assay results were available, of which 17 (33.3%) received combination chemotherapy with platinum and taxane. For these 17 cases, the primary site of disease was ovary in 12 cases and uterus in the other 5 cases. Overall response rate for these 17 cases was 70.6%. Chemotherapy response in the presence of EDR to at least 1 of the 2 drugs (EDR-PT) was significantly lower than non-EDR-PT (37.5% vs. 100%, P = 0.009). Sensitivity, specificity, positive predictive value, and negative predictive value for chemotherapy response in non-EDR-PT were 75%, 100%, 100%, and 62.5%, respectively. EDR-PT showed a significantly lower progression-free survival (1-year progression-free survival rate, 28.6% vs. 100%, P = 0.01) and overall survival (5-year overall survival rate, 26.9% vs. 57.1%, P = 0.033). Use of an in vitro drug resistance assay was a feasible test to predict the chemotherapy response and survival outcome in advanced ovarian and uterine carcinosarcoma.

Multicenter randomized phase III trial of 3-weekly paclitaxel/platinum (PC3w) versus weekly paclitaxel/platinum (PCw) induction therapy followed by PC3w maintenance therapy in advanced epithelial ovarian cancer (EOC)

5538 Background: Response rates (RR) up to 50% were found with PCw in platinum resistant EOC. We compared the efficacy of first-line PCw induction therapy to PC3w. Methods: 270 patients (pts) with FIGO stage II-IV, Performance status (PS) 0–2 were randomly assigned to 3 x PC3w (P 175mg/m2 with either cisplatin [Cis] 75mg/m2 or carboplatin [Car] AUC 6) or 6 x PCw (P 90mg/m2 with either Cis 70mg/m2 or Car AUC 4, day 1,8,15 and day 29,36,43) followed by up to 6 cycles PC3w in both arms. Pts were stratified for FIGO stage, PS, tumor size and center. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were RR and toxicity. A total of 225 events were needed to detect a 10–13% absolute difference in PFS/OS with a power of 84% (one-sided). Results: 267 pts (134 TC-3w and 133 TCw) were eligible (3 pts wrong tumor type). Pt characteristics were well balanced; median age 58 years, serous 62%, residual disease &gt;1cm 66%, FIGO stage II 7%, III 64%, IV 29%. Median dose-intensity for PC3w was: P 58(47–58) and Cis 25(22.5–25) mg/m2/w, Car 2(1.6–2) AUC/w, for PCw: P 60(36–60) and Cis 44.7(30–44.7) mg/m2/w and for Car 2.7(1,6–2,7) AUC/w. After a median follow-up of 39 months (m) (range 0.03 - 93.3m) 206 pts (77%) had progressed and 164 pts (61%) had died. Median PFS was 18m for TC3w and 19m for TCw, 5-year PFS was 20% and 18%, respectively (logrank test: p = 0.63). Median OS was 44m for TC3w and 45m for TCw, 5-year OS was 36% and 37%, respectively (logrank test: p = 0.87). RR after induction therapy in 176 pts with measurable disease was 72% for TC3w and 74% for TCw (p = 0.68). TCw was well tolerated. Grade 3/4 toxicity for TC3w vs. TCw was respectively, platelets 1.75% vs.1.55% (ns), WBC 5.5% vs. 8.7 (p = &lt;0.0001), granulocytes 16.7% vs. 11.7% (p = &lt;0.001) and delay 3% vs. 9% of the cycles. TCw induced less grade 2/3 muscular and joint pain (TC3w 6.3% and 3.5% vs. TCw 0.3% and 0.8% of the cycles) and less neurotoxicity (TC3w 6% vs. 1.6% of the pts in TCw). The other toxicities were similar in frequency and severity in both arms. Conclusions: TCw was well tolerated and had less granulocytopenia, neurotoxicity, and muscular and joint pain but did not yield benefit in terms of OS, PFS or RR. No significant financial relationships to disclose.

Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors)

The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial. To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP and > or =5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58% > or = 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma. The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes. The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.