Objective. To determine whether a non-platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. Methods. Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m(2) plus topotecan 0.75 mg/m(2) days 1-3 (n = 223) vs cisplatin 50 mg/m(2) plus paclitaxel 135 or 175 mg/m(2) (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. Results. 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, re-spectively (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. Conclusions. 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.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

The Figure Legend for the Supplemental Figure 1 describes the content of the 3 panels that make up this Supplemental Figure.

Abstract To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45− cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0–18) and, at 36 days posttreatment, was 4 (range, 0–17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79–0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32–1.03) and PFS (HR, 0.59; 95% CI, 0.36–0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

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/m(2) on day 1 or 2) plus paclitaxel (135 mg/m(2) or 175 mg/m(2) on day 1) or topotecan (0.75 mg/m(2) on days 1-3) plus paclitaxel (175 mg/m(2) 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.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

Objectives: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Results: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. Conclusions: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.

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-HI 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. (C) 2016 Published by Elsevier Inc.

Introduction/Background Endometrial cancer (EC) is the most common cancer of the female reproductive organs. More than 54,000 women in the United States are expected to be diagnosed with this disease in 2015 and over 10,000 women will die as a result [1]. The majority of women with EC will be cured after hysterectomy with or without adjuvant therapies. However, approximately 10%–15% of women with early-stage EC will experience tumor recurrence [2,3]. The chances of developing recurrence are greatest in those women with an advanced International Federation of Gynecology and Obstetrics (FIGO) stage tumor [4,5].

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

Objectives: To evaluate chemotoxicity and quality of life (QOL) in older patients undergoing treatment for recurrent and advanced endometrial cancers within GOG phase III chemotherapy trials.

5604 Background: To evaluate chemotoxicity and quality of life (QOL) in older women undergoing treatment for recurrent and advanced cervical cancer within Gynecologic Oncology Group (GOG) phase III chemotherapy trials. Methods: 5 trials (GOG 110, 149, 169, 179, 204) were used to characterize chemotoxicity profiles by age. ‘Older’ was defined as age ≥ 65. Toxicity was based on GOG or CTC scales. Concordant chemotherapy arms between trials were pooled: Cisplatin (C), cisplatin/ifosfamide (CI); cisplatin/topotecan (CT); cisplatin/paclitaxel (CP). Categorical variables were compared using the Pearson chi-square test. The Cox PH model was used to evaluate prognostic factors (at baseline or before a landmark) and to estimate the adjusted effects on survival. Poisson models of toxicity as a function of age were examined. Associations between age and QOL using Fact-G and Fact-Cx (GOG 169,179, 204) were assessed with linear mixed models. Results: 1201 women were evaluated (C: 407; CI: 288; CT: 255; CP: 251). Median age was 65 (IQR 58–71) and 107 were age ≥ 65. Being older was associated with improved PFS for C (HR 0.99, 95%CI .98-1.00) and CT (HR 0.98, 95%CI 0.96-0.99); and improved OS in CP (HR0.98, 95CI 0.97-1.00) and CT (HR 0.98, 95%CI0.97-0.99) in adjusted models. The most frequent grade ≥ 3 toxicities in those age ≥ 65 were leukopenia (85% for CP; 80% for CT; 92% for CI), anemia (40% for CT) and thrombocytopenia (40% in CT). Neuropathy and neurologic toxicity did not differ by age for any regimen. Grade ≥ 3 toxicities that differed significantly by age and were most frequent in older women included leukopenia (85%, p = 0.058) for CP; nausea-vomiting (30%, p = 0.03) and metabolic (25%, p = 0.04) for CT. However, age was not associated with overall toxicity for any regimen in the adjusted models. Toxicity did not confound age-dependent outcomes on PFS or OS. QOL did not differ by age group for any regimen. Conclusions: Older age was not associated with severe toxicity or poorer quality of life in women who underwent chemotherapy for advanced or recurrent cervical cancer in phase III national consortia trials. Older patients should be encouraged to participate in cervical cancer trials.

Introduction/Background Vulvar carcinoma is a rare gynecologic malignancy in the United States, estimated to have approximately 5150 new cases and to result in 1080 deaths in 2015 [1]. Approximately 80% of vulvar cancer patients are diagnosed at an early stage, when the disease is still confined to the perineum without nodal metastases [2]. The mainstay of management for these localized cases of vulvar cancer is surgical resection and lymph node assessment, which entail a good prognosis. However, in cases with surgical margins that are close or positive or in cases found to have positive nodes, the patient’s prognosis is compromised [3-5]. In these less favorable situations, there is an overall survival (OS) benefit with adjuvant therapy [6,7]. Margin and nodal status are the 2 most common indications for adjuvant therapy [4,8]. Adjuvant therapy would also be considered in the presence of other pathologic risk factors, including lymph vascular space invasion (LVSI), deep invasion of the primary, or a large primary [4].

Objectives: In GOG 240, the incorporation of bevacizumab significantly increased overall survival (OS). In this study, we also reported that the topotecan–paclitaxel (TP) backbone was found to be neither superior nor inferior to cisplatin–paclitaxel (CP) for efficacy. The National Comprehensive Cancer Network recently listed the cisplatin–paclitaxel–bevacizumab triplet for cervix cancer. A principal objective of GOG 240 was to prospectively validate previously identified pooled clinical prognostic factors (Moore criteria) and use them to study the chemotherapy backbones.

Expert Panel on Radiation Oncology–Gynecology: Larissa J. Lee, MD; Anuja Jhingran, MD; Elizabeth Kidd, MD; David K. Gaffney, MD, PhD; Higinia Rosa Cardenes, MD, PhD; Mohamed A. Elshaikh, MD; Beth Erickson, MD; Nina A. Mayr, MD; David Moore, MD; Ajmel A. Puthawala, MD; Gautam G. Rao, MD; William Small Jr, MD; Mahesh A. Varia, MD; Andrew O. Wahl, MD; Aaron H. Wolfson, MD; Catheryn M. Yashar, MD; William Yuh, MD.

Among the myriad variations of the Hippocratic Oath echoed a universal theme: “I will use my power to help the sick to the best of my ability and judgment; I will abstain from harming or wronging any man by it [ [1] Lloyd G.E.R. Hippocratic writings. Penguin Books, New York1978: 67 Google Scholar ].” Nowhere else in medicine is the dictum to do no harm more poignant than in the practice of surgery, whereby the very nature of the intervention strikes a balance between an intentional tissue injury and an intended better outcome. Within the specialty of gynecologic oncology we have witnessed the advent of minimally-invasive surgery, fertility-conserving operations, and a number of less radical procedures designed to preserve the curative potential of the parent treatment and yet lead to less morbidity and a better quality of life.

Objectives: Locoregionally advanced vulvar cancer (LRAVC) is a rare disease that presents many challenging medical decisions. An expert panel was convened to reach consensus on the most appropriate pretreatment assessment and therapeutic interventions in LRAVC patients. Methods: The American College of Radiology Appropriateness Criteria are evidenced-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journal and the application of a well-established consensus methodology (modified Delphi) to rate appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to formulate recommendations. Results: Three clinical variants were developed to address common scenarios in the management of LRAVC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches, with numerical ratings and descriptive commentary. Conclusions: In combining available medical literature and expert opinion, this manuscript may serve as an aid for other practitioners in the appropriate management of patients with LRAVC.

PURPOSE:To determine associations between pretreatment health-related quality of life subscales with progression-free (PFS) and overall survival (OS) in advanced and recurrent cervical cancer. PATIENTS AND METHODS:Patients included those participating in Gynecologic Oncology Group advanced or recurrent cervical cancer phase III treatment trials who completed the Functional Assessment of Cancer Therapy for patients with cervical cancer (FACT-Cx) and a single-item pain scale at study entry. The FACT-Cx includes five domains: physical (PWB), emotional (EWB), social (SWB), functional well being (FWB), and cervix cancer subscale (CCS). A high quality of life (QoL) score reflects better QoL. After stratifying by protocol and adjusting for patient and disease characteristics, a Cox proportional hazards model was fitted for each subscale as a continuous variable. If statistically significant, (p<0.05), an analysis on mean item scores (MIS) was performed. RESULTS:Nine-hundred-ninety-one patients were enrolled from 1997 to 2007. The majority (87%) had recurrent disease. After adjustment for covariates and predictors, only the PWB domain (better physical QoL) was associated with improved OS [HR 0.96 95% CI 0.95-0.98; p<0.001]. When classifying patients based on the MIS of each subscale, the patients with the lowest risk of death were likely to report less compromised QoL (MIS>3) for PWB [HR 0.44 (0.33-0.58) P<0.001], FWB [0.49 (0.38-0.62) P<0.001], and CCS [0.48 (0.38-0.61) P<0.001]. CONCLUSION:The pretreatment patient-reported PWB as measured by the PWB subscale of the FACT-Cx, is significantly associated with survival in advanced cervical cancer trials, even after controlling for known prognostic factors.