Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016.

INTRODUCTION: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.

Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Mixed clear cell/endometrioid and clear cell/serous carcinoma of the uterus are clinicopathologically similar to pure clear cell carcinoma: An NRG Oncology/Gynecologic Oncology Group (GOG-210) study of 311 women.

OBJECTIVES: Clear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. METHODS: The term "mixed" was applied to tumors with multiple identifiable components, and "indeterminate" was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. RESULTS: One hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. CONCLUSION: In clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032).

OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

Abdominopelvic MR to CT registration using a synthetic CT intermediate.

Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods.

The presence of an endometrioid component does not alter the clinicopathologic profile or survival of patients with uterine serous cancer: A gynecologic oncology group (GOG/NRG) study of 934 women.

OBJECTIVE: While most cases of endometrial cancer can readily be classified as pure endometrioid, pure serous, or another type, others show an apparent mixture of serous and endometrioid components, or indeterminate serous versus endometrioid features. Since serous histology carries a worse prognosis than endometrioid, Gynecologic Oncology Group protocol GOG-8032 was established to examine whether the presence of a non-serous component is a favorable feature in an otherwise serous cancer. METHODS: 934 women with serous cancer were prospectively identified among a larger group enrolled in GOG-0210. Six expert gynecologic pathologists classified each case as pure serous (SER, n=663), mixed serous and endometrioid (SER-EM-M, n=138), or indeterminate serous v. endometrioid (SER-EM-I, n=133) by H&E morphology. Follow-up data from GOG-0210 were analyzed. RESULTS: The subgroups did not differ on BMI, race, ethnicity, lymphovascular invasion, cervical invasion, ovary involvement, peritoneal involvement, omental involvement, FIGO stage, or planned adjuvant treatment. SER-EM-M patients were younger (p=0.0001) and less likely to have nodal involvement (p=0.0287). SER patients were less likely to have myoinvasion (p=0.0002), and more likely to have adnexal involvement (p=0.0108). On univariate analysis, age, serous subtype, race, and components of FIGO staging predicted both progression-free and overall survival. On multiple regression, however, serous subtype (SER, SER-EM-M, or SER-EM-I) did not significantly predict survival. CONCLUSIONS: There were few clinicopathologic differences between cases classified as SER, SER-EM-M, and SER-EM-I. Cases with a mixture of serous and endometrioid morphology, as well as cases with morphology indeterminate for serous v. endometrioid type, had the same survival as pure serous cases. NCT#: NCT00340808.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adjusting to the new reality: Evaluation of early practice pattern adaptations to the COVID-19 pandemic.

OBJECTIVE: We aim to define national practice patterns to assess current clinical practice, anticipated delays and areas of concern that potentially could lead to deviations from the normal standard of care. METHODS: Anonymous surveys were emailed to members of the Society of Gynecologic Oncology (SGO). The spread of COVID-19 and its impact on gynecologic oncology care in terms of alterations to normal treatment patterns and anticipated challenges were assessed. The Wilcoxon rank sum test was performed to determine risk factors for COVID-19 infection. RESULTS: We analyzed the responses of 331 gynecologic oncology providers. COVID-19 is present in 99.1% of surveyed communities with 99.7% reporting mitigation efforts in effect. The infection rate differs significantly between regions (p≪0.001) with the Northeast reporting the highest number of COVID-19 cases. Practice volume has dropped by 61.6% since the start of the pandemic with most cancellations being provider initiated. A majority of responders (52.8%) believed that ovarian cancer will be the most affected cancer by COVID-19. >94% of responders are proceeding with gynecologic cancer surgeries with exception of grade 1, endometrioid endometrial adenocarcinoma (36.3%). Surgical backlog (58.6%), delayed cancer diagnosis (43.2%) and re-establishing normal care with delayed patient (37.8%) were identified as the top 3 challenges after COVID-19 has abated. CONCLUSIONS: COVID-19 is widespread and has radically altered normal practice patterns. Despite COVID-19 related concerns, most gynecologic oncology care is proceeding. However, the steep decline in clinical volume shows there is a large group of patients who are not being diagnosed or are deferring care.

Sleep, quality of life, and depression in endometrial cancer survivors with obesity seeking weight loss.

PURPOSE: Incidence and mortality rates of uterine cancer are increasing and, obesity, which is also rising, has been associated with uterine cancer development and mortality. A recent study found that poor sleep quality is common among endometrial cancer survivors and those with obesity had more sleep disturbances than those having normal weight. However, it is unclear if higher levels of obesity (Class III, BMI ≥ 40 kg/m2), which are rising rapidly, are differentially associated with sleep as well as depression and quality of life in endometrial cancer survivors. METHODS: We evaluated sleep, depression, and quality of life in 100 Stage I endometrial cancer survivors with obesity seeking weight loss enrolled in a lifestyle intervention (NCT01870947) at baseline. RESULTS: The average age was 60 years and mean BMI was 42.1 kg/m2 with 58% having a BMI ≥ 40 kg/m2. Most survivors (72.3%) had poor sleep quality and most (71.2%) reported sleeping < 7 h/night. Survivors with class III compared with class I obesity had significantly more sleep disturbances and daytime dysfunction; and, those with poor sleep had higher depression and lower quality of life. Survivors with a BMI ≥ 50 kg/m2 (~ 25%) had the highest levels of depression and lowest physical and emotional well-being. CONCLUSIONS: Our results reveal that endometrial cancer survivors with class III compared with class I obesity have poorer sleep quality, higher depression, and lower quality of life. Given the rising rates of obesity and uterine cancer mortality, interventions to combat both obesity and poor sleep are needed.

Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study.

OBJECTIVE: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVES: The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients. METHODS: Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated. RESULTS: 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables. CONCLUSION: SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol.

OBJECTIVE: To report clinical and pathologic relationships with disease spread in endometrial cancer patients. METHODS: Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003-2007, open eligibility enrollment was conducted, and from 2007-2011, eligibility was restricted to enrich underrepresented patients or those at high risk. RESULTS: This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease. CONCLUSIONS: This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.

A phase I study of IV doxorubicin plus intraperitoneal (IP) paclitaxel and IV or IP cisplatin in endometrial cancer patients at high risk for peritoneal failure (GOG 9920): an NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of a modified paclitaxel/doxorubicin/cisplatin (TAP) regimen which incorporated intraperitoneal (IP) paclitaxel or IP paclitaxel/cisplatin in advanced endometrial cancer. METHODS: Patients (pts) with FIGO (1998) Stage IIIA/IIIC with positive cytologic washings/ascites, adnexa, or serosa or Stage IV (intraperitoneal disease spread), histologically confirmed endometrial cancer were eligible. The study was designed as a phase I, 3+3 dose escalation study evaluating 5 dose levels (DL). All pts received cycles 1-2 with IV TAP, and cycles 3-6 with IV/IP therapy, on a 21day schedule. Adverse events were evaluated on cycles 3-4 for dose limiting toxicity (DLT) and dose escalation decisions. RESULTS: Twenty-one pts were enrolled, of which 17 were evaluable for DLT. Most pts had Stage IV disease (76%) and serous/clear cell histology (59%). The MTD was determined to be DL 3 (cycles 3-6 including paclitaxel 90mg/m(2) IP, doxorubicin 45mg/m(2) IV, cisplatin 50mg/m(2)). Three DLT events occurred and were related to grades 3-4 metabolic toxicities. There was one grade 2 sensory neuropathy event and myelosupression was tolerable without the use of G-CSF. 88% of evaluable pts completed 6cycles of therapy. With a median follow-up of 22months, 46% of patients remain progression-free at 2years. CONCLUSION: We described an IV/IP based modification of a standard TAP regimen in endometrial cancer. Based on the high rate of completing 6cycles of therapy, low rates of neuropathy, and promising PFS, further study of IP therapy in endometrial cancer is warranted.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study.

OBJECTIVES: To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS: Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION: In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.

Adjuvant vaginal brachytherapy decreases the risk of vaginal recurrence in patients with stage I non-invasive uterine papillary serous carcinoma. A multi-institutional study.

OBJECTIVES: To investigate the impact of adjuvant vaginal brachytherapy on vaginal recurrence in stage I non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a retrospective multi-institutional study from 2000-2012. 103 patients who underwent surgical treatment with non-invasive stage IA UPSC were included. RESULTS: 85% and 55% underwent staging lymphadenectomy and omentectomy respectively. 28.2% (29/103) developed recurrence. Vaginal, pelvic and extra-pelvic recurrences developed in 7.8% (8/103), 3.9% (4/103) and 16.5% (17/103) respectively. Among patients who were observed or received only chemotherapy, the rate of vaginal recurrence was 10.9% (7/64) compared to 2.6% (1/39) among those who received vaginal brachytherapy +/- chemotherapy (p=0.035). The rate of vaginal recurrence was not different between those who were observed and those who received only chemotherapy (9.3% vs. 14.3%, p=0.27). The 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 88.3% and 90.6%. Patients who underwent surgical staging had longer PFS (p=0.001) and OS (p=0.0005) compared to those who did not. In multivariable analysis controlling for age, histology, chemotherapy, brachytherapy, and staging lymphadenectomy, only lymphadenectomy was an independent predictor of PFS (HR 0.28, 95% CI 0.11-0.71, p=0.0037) and OS (HR 0.27, 95% CI 0.10-0.71, p=0.0035). Neither chemotherapy nor brachytherapy were predictors of PFS or OS. CONCLUSIONS: This is the largest study reported in stage I non-invasive UPSC. The majority of recurrences were extra-pelvic. Vaginal brachytherapy has a significant role in reducing the risk of vaginal recurrence and surgical staging was the only predictor of outcome. Therefore, both should be considered in these patients.

Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer. METHODS: After pathology review, only endometrioid tumors with high neoplastic cellularity (≥70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. RESULTS: A total of 475 eligible cases were identified. Of 368 MSI+ cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI+) (12.9%, p<0.001) and were associated with higher tumor grade (p=0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58-2.32; p=0.68) or DFS (HR 0.61; 95% CI, 0.25-1.50; p=0.28). CONCLUSION: Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer.

Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer.

BACKGROUND/PURPOSE: This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). METHODS: Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. RESULTS: Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. CONCLUSION: Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.

Radiation Therapy With or Without Cisplatin for Local Recurrences of Endometrial Cancer: Results From an NRG Oncology/GOG Prospective Randomized Multicenter Clinical Trial.

PURPOSE: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION: Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.