Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor.

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. SIGNIFICANCE: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397.

Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Health system resource use among populations with complex social and behavioral needs in an urban, safety-net health system.

BACKGROUND: Costs incurred by health systems when caring for populations with social or behavioral complexity are poorly understood. We compared the frequency and costs of unreimbursed care among individuals with complexity factors (homelessness, a history of county jail incarceration, and/or substance use disorder or mental illness [SUD/MI]). METHODS: We conducted a cross-sectional analysis using electronic health record data for adults aged 18 and older between January 1, 2016 and December 31, 2017 from a Midwestern safety-net health system. Zero-inflated negative binomial regression models were used to assess risk-adjusted associations between complexity factors and care coordination encounters, missed appointments, and excess inpatient days. RESULTS: Our sample included 154,719 unique patients; 6.8% were identified as homeless, 7.8% had a history of county jail incarceration, and 20.6% had SUD/MI. Individuals with complexity factors were more likely to be African-American, Native American, or covered by Medicaid. In adjusted models, homelessness and SUD/MI were significantly associated with care coordination encounters (RR 1.8 [95% CI,1.7-2.0]; RR 1.9 [95% CI,1.8-2.0]), missed appointments (RR 1.5 [95% CI,1.4-1.6]; RR 1.7 [95% CI,1.7-1.8]), and excess inpatient days (RR 1.5 [95% CI,1.3-1.8]; RR 2.8 [95% CI,2.5-3.1]). County jail incarceration was associated with a significant increase in missed appointments. In 2017, SUD/MI accounted for 81.8% ($7,773,000/$9,502,000) of excess costs among those with social or behavioral complexity. CONCLUSIONS: Social and behavioral complexity are independently associated with high levels of unreimbursed health system resource use. IMPLICATIONS: Future payment models should account for the health system resources required to care for populations with complex social and behavioral needs. LEVEL OF EVIDENCE: IV.

Bevacizumab plus fosbretabulin in recurrent ovarian cancer: Overall survival and exploratory analyses of a randomized phase II NRG oncology/gynecologic oncology group study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Postoperative complications of epidural analgesia at hysterectomy for gynecologic malignancies: an analysis of the National Surgical Quality Improvement Program.

OBJECTIVE: The aim of this study was to identify the rate of 30-day postoperative complications after the use of epidural in women undergoing hysterectomy for gynecologic malignancy. Secondary outcome was the impact of epidural on hospital length of stay. METHODS: A retrospective cohort study was conducted using the American College of Surgeons' National Surgical Quality Improvement Program database. This large dataset includes perioperative risk factors and 30-day post-operative outcomes from more than 680 hospitals. Women who underwent abdominal hysterectomy for a gynecologic malignancy from January 2014 to December 2017 were included. Adult patients (18 years or older) who underwent abdominal hysterectomy were identified using common procedure terminology and international classification of diseases codes. Only laparotomy cases were included, and minimally invasive cases (laparoscopy, transvaginal) were excluded due to the small prevalence of epidural cases in this cohort. All patients received general anesthesia. If patients were noted to have "epidural anesthesia" they were included in the epidural cohort and those receiving other adjuvant techniques (regional blocks or spinal anesthesia) were excluded. The primary outcome of interest was the 30-day occurrence of a pulmonary embolism, deep-vein thrombosis, pneumonia, and urinary tract infection. Those who received epidural analgesia were matched in a 1:1 ratio with a similar group of patients who did not receive epidural analgesia using a calculated propensity score to control for confounding factors. RESULTS: A total of 2035 (13.8%) patients undergoing abdominal hysterectomy for a gynecologic malignancy received epidural analgesia. 1:1 propensity-matched samples included 2035 patients in both epidural and no-epidural groups. Patient characteristics between groups were similar. Overall 30-day complication rates were higher in the epidural group (75.9% vs 62.0%, P<0.01). Specific complications that were higher in the epidural group included: blood transfusion (28.9% vs 22.8%); wound disruption (2.0% vs 1.1%); surgical site infection (10.1% vs 7.2%); and delay in return of bowel function (12.3% vs 9.3%) (all P<0.05). Hospital length of stay was significantly longer in the epidural group as compared with the no-epidural group (5.69 days vs 4.79 days, P<0.01) and readmissions were higher in the epidural group (10.5% vs 9.7%, P<0.01), but there was no difference in 30-day mortality between the groups (P=0.62). DISCUSSION: The rate of 30-day complications and length of stay among women undergoing an abdominal hysterectomy for gynecologic malignancy was higher for those who received epidural analgesia, but there was no difference in 30-day mortality. Although epidural analgesia can provide a number of benefits when used for postoperative pain control, the possible association with increased 30-day morbidity and length of stay needs to be considered.

Second primary anal and oropharyngeal cancers in cervical cancer survivors.

BACKGROUND: Human papilloma virus infection is responsible for approximately 31,500 new cancers in the United States annually. Almost all cervical cancers are linked to human papilloma virus infection. As early identification and treatment of cervical cancer improve, the incidence of cervical cancer has decreased and survival has improved. However, survivors continue to remain at risk for other human papilloma virus-related malignancies. The purpose of this study was to assess the risk of primary anal and oropharyngeal cancers among women with a history of squamous cell carcinoma of the cervix. STUDY DESIGN: A population-based cohort of 21,060 women diagnosed with cervical squamous cell carcinoma from 1973 through 2014 was identified from the Surveillance, Epidemiology, and End Results Program-9 data. Standardized incidence ratios for anal and oropharyngeal cancers were calculated to estimate the risk of a second primary human papilloma virus-related malignancy based on incidence in the general population. Results were further stratified by age (20-53, 54 years old or older) and latency period (2-11, 12-59, 60-119, 120 months or longer). The number needed to screen for oropharyngeal and anal cancers was estimated using study results and Centers for Disease Control and Prevention-reported incidence rates. RESULTS: Cervical squamous cell cancer survivors had a higher risk of being diagnosed with oropharyngeal cancer (standardized incidence ratio, 4.36, 95% confidence interval, 1.19-11.15) and anal cancer (standardized incidence ratio, 2.20, 95% confidence interval, 1.28-3.52). Patients diagnosed with cervical cancer between ages 20 and 53 years had an increased risk of anal cancer (standardized incidence ratio, 3.53, 95% confidence interval, 1.15-8.23). Age 54 years or older at cervical cancer diagnosis was associated with increased oropharyngeal cancer risk only (standardized incidence ratio, 5.04, 95% confidence interval, 1.37-12.91). Latency stratification was significant for increased OPC risk between 2-11 months and 12-59 months after diagnosis. At 120 months or longer, there was an increased risk of both oropharyngeal cancer (standardized incidence ratio, 7.97, 95% confidence interval, 2.17-20.42) and anal cancer (standardized incidence ratio, 2.60, 95% confidence interval, 1.34-4.54). The estimated number needed to screen for oropharyngeal cancer (number needed to screen for oropharyngeal cancer, 282) and anal cancer (number needed to screen for anal cancer, 1272) is significantly less than the number needed to screen for cervical cancer. CONCLUSION: Squamous cell cervical cancer survivors have a substantially increased risk of anal and oropharyngeal cancers. This increased risk is significant 10 or more years after the cervical cancer diagnosis. Health care providers and survivors should be aware of this increased risk. The development of effective and economical surveillance methods for anal and oropharyngeal cancers in cervical cancer survivors is urgently needed.

Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy Plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.

PURPOSE: To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma. METHODS: Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22. RESULTS: A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm. CONCLUSION: Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.

Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial.

The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival (EFS) in adults with de novo acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with de novo AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m2/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results [August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided P=0.006], corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at clinicaltrials.gov; identifier: 00927498).

A preoperative risk score to predict red blood cell transfusion in patients undergoing hysterectomy for ovarian cancer.

BACKGROUND: Patients with ovarian cancer experience a high rate of anemia throughout their treatment course, with rates that range from 19-95%. Blood transfusions offer symptom relief but may be costly, are limited in supply, and have been associated with worse 30-day surgical morbidity and mortality rates. OBJECTIVE: The purpose of this study was to identify risk factors for blood transfusion with packed red blood cell and to develop a transfusion risk score to identify patients who undergo surgery for ovarian cancer and who are at lowest risk for a blood transfusion. Our aim was to help clinicians identify those patients who may not require a crossmatch to encourage resource use and cost-savings. STUDY DESIGN: This is a retrospective database cohort study of 3470 patients who underwent hysterectomy for ovarian cancer with the use the National Surgical Quality Improvement Program database from 2014-2016. The association between risk factors with respect to 30-day postoperative blood transfusion was modeled with the use of logistic regression. A risk score to predict blood transfusion was created. RESULTS: Eight hundred ninety-one (25.7%) patients received a blood transfusion. In multivariate analysis, blood transfusion was associated independently with age (odds ratio, 1.90, P<.01), African American race (odds ratio, 2.30; P<.01), ascites (odds ratio, 1.89; P=.02), preoperative hematocrit level <30% (odds ratio, 10.70; P<.01), preoperative platelet count >400×109/L (odds ratio, 1.75; P<.01), occurrence of disseminated cancer (odds ratio, 1.71; P<.01), open surgical approach (odds ratio, 7.88; P<.01), operative time >3 hours (odds ratio, 2.19; P<.01), and additional surgical procedures that included large bowel resection (odds ratio, 4.23; P<.01), bladder/ureter resection (odds ratio, 1.69; P=.02), and pelvic exenteration (P=.02). A preoperative risk score that used age, race, ascites, preoperative hematocrit level, platelets, presence of disseminated cancer, planned hysterectomy approach, and procedures accurately predicted blood transfusion with good discriminatory ability (C-statistic=0.80 [P<.001]; C-statistic=0.69 [P<.001] for derivation and validation datasets, respectively) and calibration (Hosmer-Lemeshow goodness-of-fit, P=.081; P=.56 for derivation and validation datasets, respectively). CONCLUSION: Patients who undergo hysterectomy for ovarian cancer experience a high incidence of blood transfusions in the perioperative period. Preoperative risk factors and planned surgical procedures can be used in our transfusion risk score to help predict anticipated blood requirements.

Correlation between Surgeon's assessment and radiographic evaluation of residual disease in women with advanced stage ovarian cancer reported to have undergone optimal surgical cytoreduction: An NRG Oncology/Gynecologic Oncology Group study.

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≤1cm) 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 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm 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 >1cm 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.

Preoperative predictors that impact the survival and outcome of patients undergoing secondary cytoreduction for ovarian cancer.

This study aimed to examine the factors affecting feasibility of optimal and complete secondary cytoreductive surgery (SCRS) and to characterise the prognostic factors that correlate with improved survival in patients who underwent SCRS. This is a retrospective single-institutional cohort study of patients who underwent SCRS for recurrent epithelial ovarian cancer (EOC). One hundred and forty-eight patients met inclusion criteria. Platinum sensitivity was associated with complete cytoreduction at SCRS. Factors associated with suboptimal cytoreduction (SOC) were age >55 years, serous histology, largest tumour implant size >4 cm, and SOC at primary surgery. Overall survival analysis showed significantly longer survival with complete cytoreduction compared to optimal and SOC. Surgical outcome of SCRS was an independent predictor of survival regardless of the outcome of primary cytoreduction. Location of the largest implant, DFI and timing of chemotherapy also impact on survival.

Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study.

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57-0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66-0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40-0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777-83. ©2017 AACR.

Increased sediment load during a large-scale dam removal changes nearshore subtidal communities.

The coastal marine ecosystem near the Elwha River was altered by a massive sediment influx-over 10 million tonnes-during the staged three-year removal of two hydropower dams. We used time series of bathymetry, substrate grain size, remotely sensed turbidity, scuba dive surveys, and towed video observations collected before and during dam removal to assess responses of the nearshore subtidal community (3 m to 17 m depth). Biological changes were primarily driven by sediment deposition and elevated suspended sediment concentrations. Macroalgae, predominantly kelp and foliose red algae, were abundant before dam removal with combined cover levels greater than 50%. Where persistent sediment deposits formed, macroalgae decreased greatly or were eliminated. In areas lacking deposition, macroalgae cover decreased inversely to suspended sediment concentration, suggesting impacts from light reduction or scour. Densities of most invertebrate and fish taxa decreased in areas with persistent sediment deposition; however, bivalve densities increased where mud deposited over sand, and flatfish and Pacific sand lance densities increased where sand deposited over gravel. In areas without sediment deposition, most invertebrate and fish taxa were unaffected by increased suspended sediment or the loss of algae cover associated with it; however, densities of tubeworms and flatfish, and primary cover of sessile invertebrates increased suggesting benefits of increased particulate matter or relaxed competition with macroalgae for space. As dam removal neared completion, we saw evidence of macroalgal recovery that likely owed to water column clearing, indicating that long-term recovery from dam removal effects may be starting. Our results are relevant to future dam removal projects in coastal areas and more generally to understanding effects of increased sedimentation on nearshore subtidal benthic communities.

National Cancer Database Report of Lymphadenectomy Trends in Endometrial Cancer.

OBJECTIVES: Lymph node involvement has a significant impact on prognosis that may direct adjuvant therapy. The role of routine lymph node staging (LNS) is controversial given conflicting results in multiple studies. Our aims are to describe treatment patterns of LNS, identify factors impacting LNS, and quantify the contemporary trends. METHODS/MATERIALS: The National Cancer Data Base was queried for patients undergoing hysterectomy for endometrioid and serous uterine carcinomas from 2003 to 2012. For endometrioid tumors, LNS was considered indicated if at least 1 of 4 criteria was met. Multivariate logistic regression and Cox proportional hazards model were used. RESULTS: A total of 161,683 patients were identified who received hysterectomy for 155,893 (96.4%) endometrioid and 5790 (3.6%) serous carcinomas. Receipt of LNS was significantly associated with greater than 50% myometrial invasion (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.55-1.73), grades 3 to 4 (OR, 3.03; 95% CI, 2.83-3.25), and tumor size greater than 2 cm (OR, 1.17; 95% CI, 1.28-1.26). Of the 97,152 patients with endometrioid carcinoma who met criteria for comprehensive staging, 73,268 (75.4%) underwent LNS. Patients with endometrioid carcinoma meeting criteria for LNS were less likely to receive LNS if they were of African American race (OR, 0.92; 95% CI, 0.86-0.98), had Medicaid insurance status (OR, 0.75; 95% CI, 0.69-0.81), had Medicare insurance (OR, 0.82; 95% CI, 0.79-0.86), or received care at a community program (OR, 0.39; 95% CI, 0.33-0.46). CONCLUSIONS: Nationally, most patients with greater than 50% myometrial invasion, grades 3 to 4, and/or tumor size greater than 2 cm receive LNS, but this was significantly impacted by insurance status, demographic characteristics, and facility location/type.

Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. METHODS: The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851. FINDINGS: Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1]). INTERPRETATION: The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. FUNDING: National Cancer Institute and Genentech.

CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study.

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3-6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684-91. ©2017 AACR.

Survival Outcomes Improved in Contemporary Cohort of Patients With Pelvic or Abdominal Recurrence After Treatment for Stage I/II Endometrial Carcinoma.

OBJECTIVES: Pelvic and abdominal recurrences in stage I/II endometrial carcinoma are associated with poor outcomes, yet prognostic factors for survival after recurrence are not well described. Herein, we identify patients with pelvic or abdominal recurrence after surgery for stage I/II endometrial carcinoma and describe symptoms at presentation, prognostic factors, and salvage treatment toxicity. MATERIALS AND METHODS: This is a retrospective cohort of 20 consecutively treated patients with recurrence after treatment for stage I/II endometrial carcinoma followed by our Institution's Radiation Oncology Department from 1998 to 2015. RESULTS: The median time to pelvic or abdominal recurrence was 18.1 months (range, 4.2 to 59.6 mo), with 50% of recurrences at extranodal locations. Two-year progression-free survival (PFS) was 44% and 2-year overall survival (OS) was 82%. Salvage treatments varied widely, including chemotherapy and radiotherapy (RT) (7), surgery and RT (3), and surgery, chemotherapy, and RT (3). On univariate analysis of PFS, symptoms at recurrence (P=0.04) and extranodal recurrences (P<0.01) were found to be statistically significant negative prognosticators for PFS. On univariate analysis of OS, increasing age at recurrence and presence of symptoms were found to have a trend toward statistically significant association with negative OS outcomes (P=0.08 and P=0.10, respectively). CONCLUSIONS: Our study demonstrates that long-term survival for pelvic or abdominal recurrences is possible with curative salvage therapy. The presence of symptoms is a negative prognostic factor in treatment outcome, and imaging may be effective for diagnosis in symptomatic and asymptomatic patients. Larger studies need to be performed to confirm these findings.

Group-based trajectory modeling of fear of disease recurrence among women recently diagnosed with gynecological cancers.

OBJECTIVE: Fear of cancer recurrence is an important clinical phenomenon and is associated with decrements in life domains. The study goals were to characterize patterns of global fear of recurrence (FOR) and 4 domains of fear (health, role, womanhood, and death worry) over time in women who were diagnosed with gynecological cancer and to identify demographic, medical, and psychological predictors of FOR. METHOD: One hundred eighteen women participating in the usual care arm of a randomized trial completed the Concerns about Recurrence scale as well as measures of depressive symptoms, cancer-specific distress, coping, coping efficacy, and social network responses at 4 time points. The majority of the sample was diagnosed with stage 3 ovarian cancer. RESULTS: Group-based trajectory modeling identified subgroups of women with high-stable (49.1%), high-decreasing (25.3%), and low-stable (25.5%) trajectories for global FOR. For role worries, 3 similar group trajectories were identified. For health worries, modeling identified subgroups with high-decreasing (19.1%) and low-increasing (80.9%) trajectories. For womanhood worries, modeling identified subgroups with high-increasing (15.7%) and low-decreasing (84.2%) trajectories. Young age, metastatic cancer, depression, cancer distress, holding back, and lower coping efficacy were associated with the high-stable global FOR and at least 1 domain of FOR. CONCLUSION: Almost half of the women recently diagnosed with gynecological cancer evidence persistently elevated FOR over the 6-month period postdiagnosis. Psychological interventions to reduce FOR may be more effective if they focus on teaching patients coping skills, as well as greater comfort expressing cancer-specific concerns to others.

The role of adjuvant radiation in lymph node positive endometrial adenocarcinoma.

OBJECTIVES: The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer. METHODS: We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS. RESULTS: The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS. CONCLUSIONS: In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings.

Disparities in the management and outcome of cervical cancer in the United States according to health insurance status.

INTRODUCTION: Our study sought to characterize the presentation, local management and outcomes of invasive cervical cancer with regard to patient insurance status. METHODS: We queried the NCI-SEER database for invasive cervical cancer cases in patients aged 18-64 from 2007 to 2011. We analyzed clinical and socioeconomic data with regard insurance status (insured, Medicaid, or uninsured). We tested for associations between patient insurance status and treatment with definitive surgery for FIGO IA2-IB1 patients, and treatment with suboptimal radiation therapy (RT) for FIGO IB2-IVA patients (other than combination external beam and brachytherapy). We evaluated overall and cause specific survival according to insurance status. RESULTS: 11,714 cases were analyzed: 60% insured, 31% Medicaid, and 9% uninsured. FIGO III/IV stage at presentation was more frequent with Medicaid (40%) and uninsured (42%) compared to insured patients (28%) (p<0.001). For FIGO IA2-IB1 patients, receipt of definitive surgery was inversely associated with uninsured status (OR [95%CI]=0.65 [0.47-0.90], p<0.001) in univariable analysis; however the relationship lost significance after multivariable adjustment. For FIGO IB2-IVA patients, the use of suboptimal RT was associated with uninsured status (OR [95%CI]=1.33 [1.07-1.65], p=0.011) in adjusted analyses. Among all patients, overall mortality was increased with Medicaid (HR [95%CI]=1.16 [1.05-1.28], p=0.003) and uninsured status (HR [95%CI]=1.17 [1.01-1.34], p=0.031) in multivariable analysis. Cancer specific mortality survival trended towards significance in multivariable analyses for both Medicaid (HR [95%CI]=1.11 [1.00-1.24] and uninsured status (HR [95%CI]=1.14 [0.98-1.33]). CONCLUSIONS: Disparities in cervical cancer treatment with regard to insurance status are apparent in a recent cohort of American patients. Later stage at presentation and differences in management partially account for the inferior prognostic outcomes associated with Medicaid and uninsured status.