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To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1–3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91–1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82–1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86–1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86–1.38; p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75–1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062. • Topotecan plus paclitaxel is not superior to cisplatin plus paclitaxel for recurrent/metastatic cervical cancer. • Topotecan-paclitaxel plus bevacizumab is not superior to cisplatin-paclitaxel plus bevacizumab for cervical cancer. • The non‑platinum doublet, topotecan-paclitaxel, should not be routinely used for recurrent/metastatic cervical cancer. [ABSTRACT FROM AUTHOR]

• All women with ovarian cancer should be offered germline testing for BRCA mutations and other cancer susceptibility genes • Patients with deleterious BRCA mutations should be offered frontline maintenance therapy with a PARP inhibitor • Assays for homologous recombination deficiency may guide treatment options in patients without a deleterious BRCA mutation • Tumor molecular profiling may identify targeted therapies for off-label use in patients with limited treatment options Advances in next generation sequencing have allowed for rapid and economical germline and tumor genomic profiling. Targeted therapies based on molecular tumor profiling are now integrated into treatment guidelines for many solid tumors. In epithelial ovarian cancer, 50% of tumors possess damaging mutations in homologous recombination repair genes (aka homologous recombination deficiency or HRD) which includes the BRCA genes. Deleterious BRCA mutations and HRD have recently emerged as predictive biomarkers for the use of PARP inhibitors in ovarian cancer. Every patient with ovarian cancer must be referred for genetic counseling and germline testing for BRCA mutations. Multigene panel genetic testing may be more informative and cost-effective than limited testing of cancer susceptibility genes. Patients without a germline deleterious BRCA mutation must be assessed for a somatic BRCA mutation. Assays for HRD may help guide treatment options in women who do not have a BRCA mutation. Currently, all patients with a germline or somatic BRCA mutation should be offered upfront maintenance therapy with a PARP inhibitor. During May 2020, options for maintenance therapy with a PARP inhibitor were expanded to patients with HRD and HR-proficient tumors. [ABSTRACT FROM AUTHOR]

To explore the relationship between tumor size and response to combined anti-vascular targeted therapy using the anti-angiogenesis inhibitor, bevacizumab, and the tubulin-binding vascular disrupting agent, fosbretabulin. An exploratory, post-hoc analysis of the randomized phase II trial, Gynecologic Oncology Group-0186I, was performed. One hundred and seven patients with recurrent ovarian carcinoma, treated with up to 3 prior regimens, were randomized to bevacizumab 15 mg/kg body weight with or without intravenous fosbretabulin 60 mg/m2 body surface area every 21 days until progression or unacceptable toxicity. The primary analysis favored the combination (HR 0.69; 95% CI, 0.47–1.00; p =.049) [Monk BJ, et al. J Clin Oncol 2016;34:2279–86]. The Cox proportional hazards model was used to estimate the treatment effect in various subpopulations. With extended follow-up, the median PFS for bevacizumab plus fosbretabulin was 7.6 months as compared to 4.8 months with bevacizumab alone (HR 0.74; 90% CI, 0.54–1.02). Overall survival was similar in the experimental and control arms (25.2 vs 24.4 mos, respectively, HR 0.85; 90% CI, 0.59–1.22; p =.461). Eighty-one patients had measurable disease and median tumor size was 5.7 cm. In the ≤5.7 cm subgroup, the HR for progression or death was 0.77 (90% CI 0.45–1.31). Patients with tumors >5.7 cm (n = 40) had a HR for progression or death of 0.55; 90% CI, 0.32–0.96; p =.075). Although no significant survival benefit was observed , the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study. • Tumor vascular disrupting agents represent a novel anti-vascular strategy • Combined vascular disrupting agent plus anti-angiogenesis therapy may have activity in bulky, recurrent ovarian carcinoma • The combination appears to be tolerable in the subpopulations studied. [ABSTRACT FROM AUTHOR]

Cancer complicates 1 in 1000 pregnancies. Multidisciplinary consensus comprised of Gynecologic Oncology, Pathology, Neonatology, Radiology, Anesthesiology, Maternal Fetal Medicine, and Social Work should be convened. Pregnancy provides an opportunity for cervical cancer screening, with deliberate delays in treatment permissible for early stage carcinoma. Vaginal delivery is contraindicated in the presence of gross lesion(s) and radical hysterectomy with lymphadenectomy at cesarean delivery is recommended. Women with locally advanced and metastatic/recurrent disease should commence treatment at diagnosis with chemoradiation and systemic therapy, respectively; neoadjuvant chemotherapy to permit gestational advancement may be considered in select cases. Most adnexal masses are benign and resolve by the second trimester. Persistent, asymptomatic, benign-appearing masses can be managed conservatively; surgery, if indicated, is best deferred to 15–20 weeks, with laparoscopy preferable over laparotomy whenever possible. Benign and malignant germ cell tumors and borderline tumors are occasionally encountered, with unilateral adnexectomy and preservation of the uterus and contralateral ovary being the rule. Epithelial ovarian cancer is exceedingly rare. Ultrasonography and magnetic resonance imaging lack ionizing radiation and can be employed to evaluate disease extent. Tumor markers, including CA-125, AFP, LDH, inhibin-B, and even CEA and ßhCG may be informative. If required, chemotherapy can be administered following organogenesis during the second and third trimesters. Because platinum and other anti-neoplastic agents cross the placenta, chemotherapy should be withheld after 34 weeks to avoid neonatal myelosuppression. Bevacizumab, immune checkpoint inhibitors, and PARP inhibitors should be avoided throughout pregnancy. Although antenatal glucocorticoids to facilitate fetal pulmonary maturation and amniotic fluid index assessment can be considered, there is no demonstrable benefit of tocolytics, antepartum fetal heart rate monitoring, and/or amniocentesis. Endometrial, vulvar, and vaginal cancer in pregnancy are curiosities, although leiomyosarcoma and the dreaded twin fetus/hydatidiform mole have been reported. For gynecologic malignancies, pregnancy does not impart aggressive clinical behavior and/or worse prognosis • Cancer affects 1 in 1000 pregnancies. • Diagnostic workup for cancer must be carefully selected and interpreted in pregnancy. • Cervical cancer is the most common gynecologic malignancy diagnosed in pregnancy. • Surgery and chemotherapy can be appropriately used with preservation of pregnancy. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54–0.95; p = .004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3 months; HR 0.77; 95% CI, 0.62–9.95; p = .007. Post-progression survival was not significantly different between the arms in GOG 240. Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone. Methods: A post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival >18weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count <1000mm3. The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS. Results: Neutropenic data was available for 3447 patients. Neutropenic (n=3196) and non-neutropenic groups (n=251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74–0.99; p=0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN. Conclusion: These data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations. [Copyright &y& Elsevier]

Abstract: Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous–intraperitoneal (IV–IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether the number of positive pelvic nodes (PPN), cervical stromal involvement (CSI), and/or lymphovascular space involvement (LVSI) were prognostic factors among women with advanced endometrial carcinoma treated with adriamycin plus cisplatin (AP) or whole abdominal irradiation (WAI). Methods: Data were abstracted from records of patients treated with adjuvant WAI or AP in a GOG randomized trial. Cox proportional hazards models were used to estimate the association of CSI and PPN with differences in PFS and OS while adjusting for treatment and previously studied factors. Results: WAI was randomly allocated to 202 and AP to 194 eligible patients. CSI (n=93 total) was associated with a 44% increase in risk of progression and a 33% increase in risk of death. There was a trend for increasing number PPN being associated with a 7% per positive node increase in risk of progression/death. For CSI, the estimated unadjusted treatment hazard ratios (HRs) were: PFS 0.85 (0.53, 1.38); OS 0.81 (0.50, 1.33). For metastatic disease limited to a single PPN (n=25), the unadjusted HRs were: PFS 0.96 (0.34, 2.74); OS 0.73 (0.24, 2.18). The test of homogeneity of treatment effect (ie., AP vs WAI) across subgroups (CSI, number of positive pelvic nodes) was not statistically significant for either endpoint, thus supporting the superiority of chemotherapy as reported in the original manuscript. Conclusions: The presence of CSI and increasing number of PPN were associated with poor prognosis. On average, patients with CSI experienced improved PFS and OS when treated with AP relative to WAI. [Copyright &y& Elsevier]

Abstract: Objectives: Topotecan improves response rate (RR), progression-free survival (PFS) and overall survival (OS) when added to cisplatin in treating metastatic and recurrent cervical cancer. The objective of this study was to assess the feasibility of adding weekly topotecan to cisplatin in patients with primary, locally advanced carcinoma of the cervix receiving pelvic irradiation. Methods: Patients with primary, previously untreated, histologically confirmed invasive squamous cell, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IB2–IVA were treated with external beam pelvic radiotherapy (45 Gy), intracavitary low dose rate brachytherapy (40 Gy) and a parametrial boost (5.4–9 Gy) with overall treatment time not to exceed 8 weeks. Concurrent chemotherapy was IV cisplatin 40 mg/m2 plus IV topotecan 2 mg/m2 on days 1, 8, 15, 22, 29 and once during parametrial boost for 6 cycles. Patients were monitored with history, physical examination, tumor measurement and laboratory evaluation before entering the study, before each cycle of chemotherapy, at study termination and every three months thereafter. Results: The study met its accrual goal of 12 patients. With a median follow-up of 22 months, eleven patients completed treatment and ten are in long term follow up without evidence of recurrent disease. The 12th patient developed progressive disease during therapy. All patients completed at least 4 cycles of chemotherapy, with the majority (82%) completing 5 or more. Grade 2 or higher neutropenia delayed treatment in 54% of cycles. The median treatment delay was 1.5 cycles (range: 1 to 5 cycles). Median treatment time was 59 days (range 46 to 81 days). The complete RR was 92% (95% confidence interval, 55%–100%). Conclusions: The addition of weekly topotecan to cisplatin at this dose and schedule during pelvic irradiation for locally advanced cervical cancer appears to be feasible. Based on this primary treatment data and the activity of cisplatin–topotecan in the recurrent disease setting, phase II and III studies of this combination are warranted. [Copyright &y& Elsevier]

Abstract: Purpose. : To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay. Methods. : Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy). Results. : For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient. Conclusions. : For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis. [Copyright &y& Elsevier]

: BackgroundMalignant granular cell tumors are among the rarest of soft tissue cancers, currently understood to be of Schwann cell origin. As with their benign counterparts, malignant granular cell tumors (MGCTs) have a wide anatomic distribution and carry a poor prognosis, with recurrence and metastasis typically within 1 year of diagnosis. Only a handful of MGCTs have been described in the pelvis.: CaseWe describe a case of malignant granular cell tumor that presented as a pararectal mass associated with severe rectal pain. The patient underwent pelvic exenteration and postoperative radiation therapy. She recurred with evidence of liver metastases on imaging studies 8 months following her exenteration.: ConclusionWe discuss the diagnosis and prognosis of malignant granular cell tumors arising in the pelvis. [Copyright &y& Elsevier]

Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group. From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed). Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/ BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [ p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [ p < 0.001]. g BRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); s BRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to g BRCA was 35% vs 31% (p = 0.36). HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of g BRCA was excluded; rates of s BRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications. [Display omitted] • 48% of high grade serous ovarian cancers (HGSC) in older patients are homologous recombination deficient (HRD). • Somatic or germline BRCA1/2 pathogenic variants (PVs) contribute to almost half of HGSC tumors with HRD. • Excluding the contribution of germline BRCA PVs, the frequency of HRD is similar in younger vs older patients with HGSC. • The frequency of somatic BRCA1/2 PVs is independent of age (8% younger v 10% older participants). • HRD testing should not be restricted by patient age. [ABSTRACT FROM AUTHOR]

Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer. This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004–2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria. A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57–1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52–23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49–1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42–0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy. Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually. • Stage IVA CC presents with distinctly poor outcomes compared to other stages of LACC. • Standard of care for stage IVA has remained chemoradiotherapy for the last 20 years. • Racial minorities have poor survival outcomes and highest incidence of stage IV CC. • Ongoing clinical trials are likely to lead to changing the standard of care for LACC. • Improving outcomes for the highest risk group (stage IVA) will continue to be important. [ABSTRACT FROM AUTHOR]

Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 μg/ml (range 0.4–3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46–1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors. [Display omitted] • Platinum resistance in gynecologic cancer correlates with metabolic signatures measured by quantitative mass spectrometry. • Metabolic signatures predict clinical outcome following carboplatin plus Paclitaxel chemotherapy. • Altered amino acid and lipid profiles characterize a state of tumor cellular quiescence associated with immune dysfunction. [ABSTRACT FROM AUTHOR]

To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)—a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. AUC statistics (range, 0.52–0.64) showed log(CrCl Jelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%–15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials. • The formula used to estimate CrCl affects carboplatin dosing. • Estimated creatinine clearance (CrCl) <60 mL/min (by Jelliffe) did not accurately predict adverse events. • Our data do not support a minimum threshold CrCl <60 mL/min as exclusion criteria from clinical trials. [ABSTRACT FROM AUTHOR]

Purpose We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer. Methods This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging. Results Of 1873 enrolled patients, surgical outcome was described as optimal (RD ≤ 1 cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26 days (range: 1–109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD > 1 cm in size. RD > 1 cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD > 1.5 cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD > 1 cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08–1.56; p = 0.0059). Conclusions Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1 cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon. [ABSTRACT FROM AUTHOR]

To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared. We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09–1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04–1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00–3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00–1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov : NCT00011986 • Age ≥ 70 years was associated with an increased risk of both cancer-related and non-cancer related death. • Carboplatin and paclitaxel administration is well tolerated regardless of age. • Older age was associated with higher rates of grade 2 or higher peripheral neuropathy. • Risks of other chemotherapy related toxicities were equal between older compared to younger patients. [ABSTRACT FROM AUTHOR]

Abstract: Infection with the human papillomavirus (HPV) is the most common sexually transmitted disease afflicting approximately 80% of the population. HPV infection is an essential factor in cervical carcinogenesis and cervical carcinoma is the second most common cause of cancer among women worldwide. In addition to cervical cancer, other malignancies in both men and women such as esophageal, oropharyngeal, and anal cancer have been causally associated with this virus. Other gender-specific HPV-related cancers include penile, vulvar and vaginal cancer. HPV-16 is the most common HPV type associated with a malignant phenotype regardless of organ of origin. HPV-16 together with HPV-18 accounts for approximately 70% of cervical cancers. Other non-oncogenic HPV types including HPV types 6 and 11 are associated with over 90% of benign HPV-related lesions such as genital warts and juvenile respiratory papillomatosis. [Copyright &y& Elsevier]

To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31–129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0–10 vs. 11–35 U/mL) were not predictive of outcome (p = 0.4). Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients. • Normal baseline CA125 prior to chemotherapy is associated with better survival in high-risk early-stage ovarian cancer. • Normalization of CA125 after the first cycle of chemotherapy is associated improved survival in early-stage ovarian cancer. • Percent decline and absolute nadir normal value of CA125 were not predictive of outcome in early-stage ovarian cancer. [ABSTRACT FROM AUTHOR]

Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS. Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS. Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23–28%) and LTDFS ≥10 years was 18% (95% CI, 16–20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p < 0.001). Younger age (p < 0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis. Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes. • Long term survivors with advanced ovarian cancer are uncommon and include patients alive with or without disease recurrence • Clinical trials don't report the patients who are long term disease free survivors (LTDFS ≥10 years) and likely cured • Almost 20% of patients were LTDFS ≥10 years in GOG trials of intravenous vs intraperitoneal chemotherapy • Apart from younger patient age at diagnosis there were no other factors associated with LTDFS ≥10 years [ABSTRACT FROM AUTHOR]

In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (g BRCA) status. Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and g BRCA status. 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCA wt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between g BRCA m (n = 211) and g BRCA wt (n = 902) subgroups. DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and g BRCA wt groups, versus Q3W. g BRCA status did not impact safety. • Weekly (compared to every 3 weeks) paclitaxel was associated with longer PFS in HRP and BRCA wt cohorts • PFS was improved with veliparib compared with control regardless of paclitaxel dosing schedule • In general, grade 3/4 adverse events were more common in dose-dense paclitaxel groups compared with every-3-week paclitaxel • Germline BRCA status showed no impact on incidences of adverse events across arms [ABSTRACT FROM AUTHOR]

Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein. QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale. At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change. PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials. Trial registration: NCT00942357 • Radiation/chemotherapy caused more QOL and GI symptoms versus chemotherapy; the differences were not clinically meaningful. • Both treatment groups experienced neuropathy, especially in the chemotherapy group. • The differing toxicities of the 2 arms can assist clinicians in counseling patients given the efficacy equivalence. [ABSTRACT FROM AUTHOR]

Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants. One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16–1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26–0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59–0.90). Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups. • Non-Hispanic black women had a decreased risk of death with upfront and maintenance bevacizumab. • Women of Asian ancestry had a decreased risk of death when compared to white women. • Native Asian women had a longer median overall survival rate when compared to American women of Asian ancestry. [ABSTRACT FROM AUTHOR]

The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment. We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk. We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12–2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67–4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81–10.26; deep 1/3, HR 7.05, CI 2.99–16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25–17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI. Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer. • Adenocarcinoma is a distinct cervical cancer subtype and treatment should be based on data specific to this subtype. • Risk factors for recurrence differ for squamous cell carcinoma and adenocarcinoma of the cervix. • For adenocarcinoma of the cervix, tumor size is the risk factor associated with the highest risk of recurrence. • For squamous cell carcinoma, depth of invasion is the risk factor associated with the highest risk of recurrence. • Histology-specific nomograms accurately and linearly represent risk of recurrence for squamous cell and adenocarcinoma. [ABSTRACT FROM AUTHOR]

Increasing measures of adiposity have been correlated with poor oncologic outcomes and a lack of response to anti-angiogenic therapies. Limited data exists on the impact of subcutaneous fat density (SFD) and visceral fat density (VFD) on oncologic outcomes. This ancillary analysis of GOG-218, evaluates whether imaging markers of adiposity were predictive biomarkers for bevacizumab (bev) use in epithelial ovarian cancer (EOC). There were 1249 patients (67%) from GOG-218 with imaging measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between SFD and VFD with overall survival (OS). Increased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05–1.19 p = 0.0009 and 1.13, 95% CI: 1.05–1.20 p = 0.0006 respectively). In the predictive analysis for response to bev, high VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09–1.37; p = 0.025). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90–1.14) Median OS was 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD high groups on placebo versus bev, respectively. High VFD and SFD have a negative prognostic impact on patients with EOC. High VFD appears to be a predictive marker of bev response and patients with high VFD may be more likely to benefit from initial treatment with bev. • Subcutaneous fat density (SFD) and visceral fat density (VFD) appear to be prognostic biomarkers for EOC. • High VFD may also be a predictive biomarker for use of bevacizumab in this patient population. • There was no correlation between IL-6 and VFD as predictive biomarkers for use of bevacizumab. [ABSTRACT FROM AUTHOR]

Report the results from a preplanned interim analysis of a phase III, double blind, randomized controlled study of ofranergene obadenovec (VB-111), a targeted anti-cancer gene therapy, in combination with paclitaxel in patients with platinum resistant ovarian cancer (PROC). The OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m2 with VB-111 or placebo. The protocol specifies a pre-planned unblinded futility interim analysis of CA-125 response per GCIG criteria in the first 60 evaluable patients. The futility rule determined for this analysis was that the response rate of VB-111 must be greater than the response rate of placebo by at least 10% in order to continue the study. Coincident with the interim analysis, the blinded CA-125 response rate was estimated as a proportion of the first 60 evaluable patients with CA-125 response per GCIG criteria. Post-treatment fever is provided as a possible surrogate marker of VB-111 therapy activity. The median age of the evaluable patients was 62 years (range 41–82); 97% had high-grade serous cancer; 58% had been treated with 3 or more previous lines of therapy, 70% received prior anti-angiogenic treatment, 43% received prior PARP inhibitors. CA-125 response in the VB-111 and weekly paclitaxel treated arm met the pre-specified interim criterion of an absolute advantage of 10% or higher compared to the control. Blinded results show a 53% CA-125 response rate (32/60) with 15% complete response (n=9). Assuming balanced randomization and an absolute advantage of 10% or higher to the VB-111 arm, it may be deducted that the response in the VB-111 treatment arm is 58% or higher. Among patients with post-treatment fever, the CA-125 response rate was 69%. At the time of the interim analysis, response rate findings are comparable to the responses seen in a similar patient population in the phase I/II study. The independent data and safety monitoring committee (iDSMC) recommended continuing the OVAL trial as planned. No new safety signals were identified. • OVAL is a Phase III trial using paclitaxel and VB-111 in recurrent ovarian cancer • VB-111 has a dual mechanism targeting tumor vasculature and anti-tumor immunity • CA-125 response in the VB-111 treated arm met the pre-specified interim criterion • Assuming balanced randomization, the response in the VB-111 arm was at least 58% • The OVAL study has been recommended to continue enrollment as planned [ABSTRACT FROM AUTHOR]

Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53 , the most commonly mutated gene in cancer, with outcomes on GOG-86P. TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov : NCT00977574. • In previous analyses of GOG-86P, the addition of upfront bevacizumab to chemotherapy did not improve outcomes overall. • We now report that cases with mutations in the tumor suppressor TP53 experienced longer PFS and OS with bevacizumab. • OS with bevacizumab versus temsirolimus + chemotherapy doubled for cases with mutated TP53 (30 versus 14.4 months). • A mutation in TP53 is a potential biomarker for sensitivity to bevacizumab when added to chemotherapy upfront. [ABSTRACT FROM AUTHOR]

Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2 -mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. Non‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3–3.5× times greater than intravenous non‑platinum-based regimens. High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care. • Non‑platinum therapies are more cost-effective in comparison to bevacizumab and PARPi for platinum-resistant ovarian cancer. • Even when adjusting for quality of life, the non‑platinum chemotherapy proved to be the most cost-effective. • Primary expense of novel therapies lies in high developmental costs, rather than costs of infusions and complications. [ABSTRACT FROM AUTHOR]

Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity. From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity. Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71–1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively. Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches. NCT00857545. • Polyvalent vaccine with adjuvant OPT-821 compared to adjuvant alone was modestly immunogenic and did not prolong survival. • The vaccine with adjuvant OPT-821 was well tolerated, with mild toxicity largely confined to the injection site reactions. • Multi-remission patients are a distinct population in which to explore innovative consolidation/maintenance approaches. [ABSTRACT FROM AUTHOR]

Abstract Purpose Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). Patients and methods Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1–3 prior regimens, performance status (PS) 0–2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. Results 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28–92), PS (0: 73%, 1–2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66–1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72–1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. Conclusion The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone. Highlights • Bevacizumab monotherapy is active therapy for recurrent ovarian cancer, but resistance is common. • BV + EV combination had a higher measurable response (22% vs 12%) compared to BV alone. • BV + EV combination had higher toxicity and study removal (29% vs 12%) compared to BV alone. • BV + EV combination did not improve progression free or overall survival. [ABSTRACT FROM AUTHOR]

Objective Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy. Methods In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety. Results Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63–1.02), 1.22 (0.96–1.55) and 0.87 (0.68–1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55–0.91), 0.99 (0.78–1.26), and 0.97 (0.77–1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified. Conclusion PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P. [ABSTRACT FROM AUTHOR]

Objective Microscopic residual disease following complete cytoreduction (R0) is associated with a significant survival benefit for patients with advanced epithelial ovarian cancer (EOC). Our objective was to develop a prediction model for R0 to support surgeons in their clinical care decisions. Methods Demographic, pathologic, surgical, and CA125 data were collected from GOG 182 records. Patients enrolled prior to September 1, 2003 were used for the training model while those enrolled after constituted the validation data set. Univariate analysis was performed to identify significant predictors of R0 and these variables were subsequently analyzed using multivariable regression. The regression model was reduced using backward selection and predictive accuracy was quantified using area under the receiver operating characteristic area under the curve (AUC) in both the training and the validation data sets. Results Of the 3882 patients enrolled in GOG 182, 1480 had complete clinical data available for the analysis. The training data set consisted of 1007 patients (234 with R0) while the validation set was comprised of 473 patients (122 with R0). The reduced multivariable regression model demonstrated several variables predictive of R0 at cytoreduction: Disease Score (DS) ( p < 0.001), stage ( p = 0.009), CA125 ( p < 0.001), ascites ( p < 0.001), and stage-age interaction ( p = 0.01). Applying the prediction model to the validation data resulted in an AUC of 0.73 (0.67 to 0.78, 95% CI). Inclusion of DS enhanced the model performance to an AUC of 0.83 (0.79 to 0.88, 95% CI). Conclusions We developed and validated a prediction model for R0 that offers improved performance over previously reported models for prediction of residual disease. The performance of the prediction model suggests additional factors (i.e. imaging, molecular profiling, etc.) should be explored in the future for a more clinically actionable tool. [ABSTRACT FROM AUTHOR]

Objective This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC. Methods Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency > 0.05 and genotyping rate > 0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p -values with genomic control adjustment. Results The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e − 08 . No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p -2.144e − 08 ) (rs6256 p -9.774e − 07 ) for PFS and 2 different SNPs were identified (rs295315 p -7.536e − 07 ; rs17693104 p -7.734e − 07 ) which were close to significance for OS. Conclusions Using the pre-specified level of significance of 1 × 10 − 08 , we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers. [ABSTRACT FROM AUTHOR]

Background Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. Methods Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800 mg was administered orally every day (1 cycle = 28 days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) > 6 months and objective tumor response. Results Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had > 2 cycles of brivanib with 4 (14%) receiving > 10 cycles (range: 1–20). Seven (25%) patients had PFS > 6 months (90% CI: 7.3%–33.9%). Two (7%) (90% CI: 1.3%–20.8%) patients had partial tumor response with duration of 8 and 22 months and 12 (43%) had stable disease. The median PFS was 3.2 months (90% CI: 2.1–4.4). The median overall survival was 7.9 months (90% CI: 6.1–11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. Conclusions Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability. [ABSTRACT FROM AUTHOR]

Objective Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. Methods We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. Results We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. Conclusions Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases. [ABSTRACT FROM AUTHOR]

Objectives To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. Methods Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. Results The median TSIC was 62.5 days (interquartile range 28–83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26 days, p < 0.001). TSIC was significantly associated (p = 0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R 2 − 0.141, 95%CI − 0.217, − 0.064, p < 0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. Conclusions In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further. [ABSTRACT FROM AUTHOR]

Objectives We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. Methods This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p < 0.001) and were more likely to have positive peritoneal cytology (p < 0.001), positive lymph nodes (p = 0.05) and higher disease stage on final pathology (p < 0.001). With a median follow-up time of 60 months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p < 0.001), extra-pelvic recurrences (p < 0.001) and poorer PFS (p < 0.001) and OS (p < 0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p = 0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. Conclusions Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach. [ABSTRACT FROM AUTHOR]

Objective To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I–III trials. Methods An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths. Results One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60–70 years and an additional 5% were > 70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p = 0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p = 0.022 and p < 0.001 respectively). Only all grade lymphatic (p = 0.006) and grade ≥ 3 cardiovascular toxicities (p = 0.019) were found to vary with age. A 2% increase in the risk of death for every year increase > 50 for all-cause mortality (HR 1.02; 95% CI, 1.01–1.04) was found, but no association between age and disease specific mortality was found. Conclusion This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were > 60 years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities. [ABSTRACT FROM AUTHOR]

Background Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA). Methods Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400 mg orally BID with one cycle being 28 days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha = 10% (at a 10% assumed null response probability). Results The median age of the 50 eligible patients was 57 years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n = 3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events > 10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18 months. Conclusions The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Objective To evaluate the cost-effectiveness of bevacizumab in recurrent/persistent and metastatic cervical cancer using recently reported updated survival and toxicology data. Methods A Markov decision tree based on the Gynecologic Oncology Group 240 randomized trial was created. The 2013 MediCare Services Drug Payment Table and Physician Fee Schedule provided costs. In the 5-year model subjects transitioned through the following states: response, progression, minor complications, severe complications, and death. Patients experiencing a health utility per month according to treatment effectiveness were calculated. Because cervical cancer survival is measured in months rather than years, results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY), adjusted from a baseline of having advanced cervical cancer during a month. Results The estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, adding $73,791 per 3.5 months (0.29 year) of life gained, resulting in an incremental cost-effectiveness ratio (ICER) of $21.083 per month of added life. The ICER increased to $5775 per month of added life and $24,597/QALmonth ($295,164/QALY) due to the smaller difference in QALmonths. With 75% bevacizumab cost reduction, the ICER is $6737/QALmonth ($80,844/QALY), which translates to $23,580 for the 3.5 month (0.29 year) gain in OS. Conclusions Increased costs are primarily related to the cost of drug and not the management of bevacizumab-induced complications. Cost reductions in bevacizumab result in dramatic declines in the ICER, suggesting that cost reconciliation in advanced cervical cancer may be possible through the availability of biosimilars, and/or less expensive, equally efficacious anti-angiogenesis agents. [ABSTRACT FROM AUTHOR]

Objective Palliative care is recognized as an important component of oncologic care. We sought to assess the quality/quantity of palliative care education in gynecologic oncology fellowship. Methods A self-administered on-line questionnaire was distributed to current gynecologic oncology fellow and candidate members during the 2013 academic year. Descriptive statistics, bivariate and multivariate analyses were performed. Results Of 201 fellow and candidate members, 74.1% (n = 149) responded. Respondents were primarily women (75%) and white (76%). Only 11% of respondents participated in a palliative care rotation. Respondents rated the overall quality of teaching received on management of ovarian cancer significantly higher than management of patients at end of life (EOL), independent of level of training (8.25 vs. 6.23; p < 0.0005). Forty-six percent reported never being observed discussing transition of care from curative to palliative with a patient, and 56% never received feedback about technique regarding discussions on EOL care. When asked to recall their most recent patient who had died, 83% reported enrollment in hospice within 4 weeks of death. Fellows reporting higher quality EOL education were significantly more likely to feel prepared to care for patients at EOL (p < 0.0005). Mean ranking of preparedness increased with the number of times a fellow reported discussing changing goals from curative to palliative and the number of times he/she received feedback from an attending (p < 0.0005). Conclusions Gynecologic oncology fellow/candidate members reported insufficient palliative care education. Those respondents reporting higher quality EOL training felt more prepared to care for dying patients and to address complications commonly encountered in this setting. [ABSTRACT FROM AUTHOR]

Abstract: During progression of cervical cancer, human papillomavirus genomes and cellular tumor suppressor genes can become methylated. Toward a better understanding of these biomarkers, we studied 104 samples with HPV16, 18, 31, and 45 representing five pathological categories from asymptomatic infection to cancer. We grouped all samples by HPV type and pathology and measured the overall methylation of informative amplicons of HPV late genes and the cellular DAPK gene. Methylation of all four HPV types as well as of the DAPK gene is lowest in asymptomatic infection and increases successively in all four pathological categories during progression to cancer. 27 out of 28 cancer samples showed methylation both in the L2/L1 genes as well as in DAPK, but a much lower fraction in all other pathological categories. We discuss the problem to develop diagnostic tests based on complex methylation patterns that make it difficult to classify amplicons as “methylated” or “unmethylated”. [Copyright &y& Elsevier]

Abstract: Background: A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer. Methods: Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined. Results: Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed. Conclusions: This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation. [Copyright &y& Elsevier]

Abstract: Purpose: To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC). Methods: Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400mg or tamoxifen 20mg orally twice daily for up to 1year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum. Results: Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR=1.31, 95% confidence interval [CI]=0.93–1.85), an increased risk of death (HR=1.76, 95% CI=1.16–2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS. Conclusion: Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort. [Copyright &y& Elsevier]

Abstract: Objective.: To identify patient characteristics which predict receipt of neoadjuvant chemotherapy (NCT) versus standard therapy (ST) in metastatic ovarian cancer. Methods.: A retrospective matched case control study was conducted of 52 women treated with NCT compared to 104 women who received standard treatment from 1996 to 2007. The t test was used for comparison of means between the groups, and the χ 2 test was used for categorical data. Multivariable analysis was performed with logistic regression models and only two-tailed analyses with a P value <0.05 were considered statistically significant. Results.: Age, employment and marital status, and insurance alone did not affect treatment allocation (P =NS). However, non-Hispanic White (NHW) patients were more as likely to receive ST (P <0.05). When insurance was stratified by ethnicity, NHW patients were twice as likely to have private insurance (OR=2.29, CI=1.16–4.53). Furthermore, medically compromised (MC) patients who were NHW were almost three times more likely to receive ST (OR=2.72, CI=1.02–5.00). In multivariate analysis, only MC and publically funded women were more likely to receive NCT (OR 3.83 CI=1.35–11.11); P =0.01). During surgery, patients receiving NCT were found to have smaller tumors and less ascites, and were more likely to be optimally debulked with lower estimated blood loss and shorter hospital stays. The median survival for ST was 55.8 months versus 26 months for NCT (P <0.001). Conclusions.: Non-clinical factors such as publically funded status and non-Hispanic White race may influence the allocation of NCT for women with metastatic ovarian cancer. [Copyright &y& Elsevier]