Summary Background GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and ...progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. Methods Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0–1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m2 intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m2 intravenously over 24 h or 175 mg/m2 intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m2 over 3 h on day 1) and topotecan (0·75 mg/m2 for 30 min on days 1–3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov , number NCT00803062. Findings Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI −4·1 to 1·7; p=0·30). Interpretation Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit. Funding National Institutes of Health.
Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent ...activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.
Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important.
Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).
The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).
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.
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.
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.
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.
National Cancer Institute.
In Teaching Literature in a Second Language, Brian Parkinson and Helen Reid Thomas focus on the relationship of language and literature in the context of the classroom. They examine both the language ...of literature as it occurs in a variety of texts from different genres and the language of the classroom as teachers and learners respond in speech and writing to those texts. While giving specific examples from the main literary genres of poetry, short stories, novels and drama, the authors are also concerned with the wider issues that affect all teachers such as assessment, evaluation, planning and working with a syllabus, and teacher development. Exercises and suggestions for further work are included for each section.The book is addressed primarily to students of applied linguistics and practising teachers, and is relevant both to teachers of EFL or ESL and to those who come from a background of literature teaching.Features*Selective review of relevant work in the field*Covers the teaching of poetry, drama, short stories and novels*Full bibliography of literary texts used*Exercises and suggestions for further work.
We show that a higher incidence of campylobacteriosis is found in young children (age, <5 years) living in rural, compared with urban, areas. Association of this difference with particular animal ...sources was evaluated using multilocus sequence typing. This evaluation was achieved by comparing Campylobacter isolates originating from these children, retail poultry, and a range of animal sources by use of source attribution and phylogenetic analysis methods. The results indicate that chicken is a major source of infection in young urban children, although not in their rural counterparts, for which ruminant and other avian sources are more important
Organisms can modify their surrounding environment, but whether these changes are large enough to feed back and alter their evolutionary trajectories is not well understood, particularly in wild ...populations. Here we show that nutrient pulses from decomposing Atlantic salmon (Salmo salar) parents alter selection pressures on their offspring with important consequences for their phenotypic and genetic diversity. We found a strong survival advantage to larger eggs and faster juvenile metabolic rates in streams lacking carcasses but not in streams containing this parental nutrient input. Differences in selection intensities led to significant phenotypic divergence in these two traits among stream types. Stronger selection in streams with low parental nutrient input also decreased the number of surviving families compared to streams with high parental nutrient levels. Observed effects of parent‐derived nutrients on selection pressures provide experimental evidence for key components of eco‐evolutionary feedbacks in wild populations.
To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma.
Gynecologic Oncology Group protocol 240 is a phase ...3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1–3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS.
At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91–1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82–1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86–1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86–1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75–1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones.
Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.
•Topotecan plus paclitaxel is not superior to cisplatin plus paclitaxel for recurrent/metastatic cervical cancer.•Topotecan-paclitaxel plus bevacizumab is not superior to cisplatin-paclitaxel plus bevacizumab for cervical cancer.•The non‑platinum doublet, topotecan-paclitaxel, should not be routinely used for recurrent/metastatic cervical cancer.
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