Explore the vast range of titles available.

Background The Acarbose Cardiovascular Evaluation (ACE) trial (ISRCTN91899513) evaluated the alpha‐glucosidase inhibitor acarbose, compared with placebo, in 6522 patients with coronary heart disease and impaired glucose tolerance in China and showed a reduced incidence of diabetes. We assessed the within‐trial medical resource use and costs, and quality‐adjusted life years (QALYs). Methods Resource use data were collected prospectively within the ACE trial. Hospitalizations, medications, and outpatient visits were valued using Chinese unit costs. Medication use was measured in drug days, with cardiovascular and diabetes drugs summed across the trial by participant. Health‐related quality of life was captured using the EuroQol‐5 Dimension‐3 Level questionnaire. Regression analyses were used to compare resource use, costs, and QALYs, accounting for regional variation. Costs and QALYs were discounted at 3% yearly. Results Hospitalizations were 6% higher in the acarbose arm during the trial (rate ratio 1.06, p = .009), but there were no significant differences in total inpatient days (rate ratio 1.04, p = .30). Total costs per participant, including study drug, were significantly higher for acarbose (¥ [Yuan] 56 480, £6213), compared with placebo (¥48 079, £5289; mean ratio 1.18, p < 0.001). QALYs reported by participants in the acarbose arm (3.96 QALYs) were marginally higher than in the placebo arm (3.95 QALYs), but the difference was not statistically significant (0.01 QALYs; p = .58). Conclusions Acarbose, compared with placebo, participants cost more due to study drug costs and reported no statistically significant difference in QALYs. These higher within‐trial costs could potentially be offset in future by savings from the acarbose‐related lower incidence of diabetes. Highlights The Acarbose Cardiovascular Evaluation trial compared quality adjusted life years (QALYs) and costs of acarbose relative to placebo in participants with coronary heart disease and impaired glucose tolerance in China. The acarbose group reported numerically higher QALYs than the placebo group. Total costs per participant, including study drug, were significantly higher for the acarbose group compared with placebo.

The ACE trial is examining whether acarbose, an insulin-sparing postprandial glucose-lowering agent, can reduce cardiovascular (CV) events in patients who have coronary heart disease (CHD) and impaired glucose tolerance (IGT), with prevention of type 2 diabetes (T2D) as a secondary outcome.1,2 This update report evaluates the impact of the protocol-driven 4-week CV risk management optimization strategy during the run-in period, lists participant baseline characteristics, and examines whether temporal differences occurred during the 7-year recruitment period.Materials and methods Design The ACE trial is a randomized, double-blind, placebo-controlled, secondary-prevention study evaluating whether acarbose, added to fully optimized usual care for CV disease, is superior to placebo with respect to CV outcomes in participants who have CHD and IGT.Mean (SD) age was 64.2 (8.1) years; body mass index (BMI), 25.4 (3.1) kg/m2; systolic blood pressure, 130 (14) mm Hg; diastolic blood pressure, 78 (9) mm Hg; HbA1c, 5.9% (0.7%); low-density lipoprotein (LDL) cholesterol, 2.3 (0.8) mmol/L; and geometric mean (±1SD) triglycerides, 1.40 (0.53; 3.72) mmol/L.Fewer participants remained smokers or continued consuming alcohol, and there were statistically significant lower mean values for BMI, systolic blood pressure, diastolic blood pressure, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides.Temporal differences in baseline characteristics Table III lists key baseline characteristics at enrollment by each calendar year from 2009 to 2015.N=6526 Age (y) 64.2±8.1 Male 4764 (73.0%) Current smoker 812 (12.6%) Consuming alcohol 597 (9.3%) Race Han 6331 (97.0%) Hui 74 (1.1%) Asian or Asian British 15 (0.2%) Mongolian 13 (0.2%) Wei 7 (0.11%) Miao 3 (0.05%) Tibetan 1 (0.02%) White 1 (0.02%) Other 81 (1.2%) BMI (kg/m2) 25.4±3.1 Waist circumference (cm)⁎ 91 (85, 97) Systolic blood pressure (mm Hg) 130 (14) Diastolic blood pressure (mm Hg 78 (9) Fasting plasma glucose (mmol/L) 5.4 (5.0, 5.9) 2-h plasma glucose (mmol/L) 9.1 (8.3, 10.1) HbA1c (%) 5.9±0.7 HbA1c (mmol/mol) 41±8 LDL cholesterol (mmol/L) 2.3 (0.8) HDL cholesterol (mmol/L) 1.18 (0.31) Triglycerides (mmol/L)† 1.40 (0.53, 3.72) Plasma creatinine (μmol/L) 77 (66, 89) Plasma alanine aminotransferase (U/L) 22 (17, 31) Hemoglobin (g/dL) 14.0±1.8 Mean red cell corpuscular volume (fL) 91.2±7.7 White blood cell count (×109/L) 6.3±1.8 Platelet count (×109/L) 199±58 eGFR (mL/min per 1.73 m2)⁎ 89 (75, 103) Male 89 (76, 104) Female 86 (71, 101) eGFR ≥90 3085 (47.3%) eGFR 60-89 2956 (45.3%) eGFR <60 482 (7.4%) CV risk factors Previous MI 685 (10.5%) Unstable angina 948 (14.5%) Current stable angina 727 (11.1%) Hypertension 4277 (65.5%) Previous stroke 428 (6.6%) Atrial fibrillation 255 (3.9%) Previous heart failure 243 (3.7%) Table I ACE participant baseline characteristics N=6526 At recruitment At randomization Difference P⁎ Lipid-lowering therapy Statin 91.3% 93.2% +1.9% <.0001 Fibrate 1.0% 1.0% 0% .86 Niacin 0.3% 0.3% 0% .75 Antithrombotic therapy Acetylsalicylic acid 93.2% 94.1% +0.9% .026 Clopidogrel 64.1% 61.1% −3.0% .0002 Other 1.3% 1.2% −0.1% .39 Antihypertensive therapy β-Blocker 66.0% 66.0% 0% .95 Angiotensin-converting enzyme inhibitor (ACEi) 34.5% 34.8% +0.3% .64 Angiotensin receptor blocker (ARB) 24.9% 25.8% +0.9% .25 ACEi or ARB 58.1% 59.1% +1.0% .22 Aldosterone antagonist 3.3% 2.6% −0.7% .029 Calcium-channel blocker 29.4% 29.1% −0.3% .74 Thiazide diuretic 3.2% 2.9% −0.3% .37 Nonthiazide diuretic 2.7% 2.2% −0.5% .06 Other 2.5% 1.5% −1.0% <.0001 Antianginal therapy Nitrates 38.8% 37.1% −1.7% .038 Other 6.6% 5.5% −1.1% .0042 Other CV therapy Digitalis 1.4% 1.1% −0.3% .088 Antiarrhythmics 1.6% 1.5% −0.1% .36 Glucose-lowering therapy Metformin 0.3% 0.3% 0% .75 Other <0.1% <0.1% 0% – CV risk factor values Current smoker 14.0% 12.6% −1.4% <.0001 Consuming alcohol 11.4% 9.3% −2.1% <.0001 BMI (kg/m2) 25.5 (3.1) 25.4 (3.1) −0.072 <.0001 Systolic blood pressure (mm Hg) 131 (16) 130 (14) −1.52 <.0001 Diastolic blood pressure (mm Hg) 79 (10) 78 (9) −0.43 .0003 LDL cholesterol (mmol/L) 2.4 (0.9) 2.3 (0.8) −0.12 <.0001 HDL cholesterol (mmol/L) 1.17 (0.33) 1.18 (0.31) +0.021 .0002 Triglycerides (mmol/L)† 1.45 (0.52, 3.99) 1.40 (0.53, 3.72) −0.041 .0002 Table II Cardiovascular risk factor management therapies and risk factor values, before and after the 4-week single-blind placebo run-in period 2009(n=474) 2010(n=1475) 2011(n=1787) 2012(n=1194) 2013(n=782) 2014(n=428) 2015(n=382) Women⁎ 22.4% 24.8% 27.9% 28.0% 30.1% 25.2% 29.6% Han race 97.9% 97.2% 97.2% 96.9% 97.2% 95.6% 96.1% Current smoker 13.3% 12.3% 12.2% 10.4% 13.9% 13.8% 14.2% Lipid-lowering therapy 92.6% 93.2% 94.3% 94.6% 92.3% 91.9% 93.6% ACE or ARB therapy⁎ 62.4% 61.8% 60.3% 58.2% 58.4% 50.9% 51.2% β-Blocker therapy⁎ 72.6% 67.7% 66.8% 65.2% 62.4% 61.3% 62.1% Calcium-channel blocker therapy⁎ 34.0% 30.6% 30.4% 27.5% 25.9% 28.5% 25.6% Antiplatelet therapy 98.5% 98.6% 98.4% 97.9% 96.6% 96.9% 96.8% BMI (kg/m2) 25.6 (23.7, 27.7) 25.4 (23.5, 27.3) 25.1 (23.1, 27.1) 25.1 (23.3, 27.3) 25.4 23.4, 27.5) 25.4 (23.5, 27.3) 25.3 (23.4, 27.6) HbA1c (%) 5.8 (5.5, 6.2) 5.9 (5.6, 6.3) 5.9 (5.6, 6.3) 5.9 (5.5, 6.2) 5.9 (5.6, 6.2) 5.9 (5.6, 6.2) 5.9 (5.7, 6.2) Systolic blood pressure (mm Hg) 130 (120, 140) 130 (120, 140) 130 (120, 140) 130 (120, 40) 130 (120, 140) 130 (120, 140) 130 (120, 140) LDL cholesterol (mmol/L) 2.3 (1.8, 2.8) 2.2 (1.8, 2.8) 2.1 (1.7, 2.7) 2.1 (1.7, 2.6) 2.1 (1.6, 2.8) 2.1 (1.7, 2.8) 2.1 (1.7, 2.6) eGFR (mL/min per 1.73 m2) 89 (74, 104) 88 (74, 102) 87 (74, 102) 89 (75, 103) 90 (76, 105) 90 (77, 105) 90 (75, 104) Table III Temporal changes in key baseline characteristics for participants randomized within each calendar year STOP-NIDDM4,5 DREAM6 NAVIGATOR7,8 ORIGIN9 Full cohort (N=1368) Full cohort (N=5269) Secondary prevention cohort (N=2266) Nondiabetic cohort (N=1456) Glucose-lowering Intervention Acarbose 100 mg tds Rosiglitazone 8 mg/d Nateglinide 60 mg tds Insulin glargine Entry criteria IGT IGT or IFG without known CV disease IGT and age >50 y with a prior CV event IGT or IFG with a prior CV event Male 49.0% 40.8% 69.8% 65.2% White race 97.5% 53.6% 86.5% 64.8% Age (y) 54.5 (7.9) 54.7 (10.9) 64 (57, 70) 63.5 (7.8) BMI (kg/m2) 31.0 (4.3) 30.9 (5.6) 29.76 (26.8, 33.5) 29.8 (5.2) Fasting plasma glucose (mmol/L) 6.2 (0.5) 5.8 (0.7) 6.10 (5.7, 6.5) 6.9 (6.1, 8.2) 2-h plasma glucose (mmol/L) 9.3 (1.0) 8.7 (1.4) 9.10 (8.4, 9.9) N/A Systolic blood pressure (mm Hg) 131.1 (16.3) 136.1 (18.4) 136.5 (124, 149) 146 (124, 168) LDL cholesterol (mmol/L) 3.6 (0.9) N/A 2.84 (2.29, 3.52) 2.92 (1.88, 3.96) Triglycerides (mmol/L) 2.07 (1.2) N/A 1.73 (1.23, 2.39) 1.58 (0.65, 2.23) Median follow-up for study (y) 3.3 3.0 5.0 6.2 Relative impact on risk of new-onset diabetes −25% (P=.0015) −62% (P<.0001) +7% (P=.05) −28% (P=.006) Relative impact on CV risk⁎ 49% (P=.03) +37% (P= .08) Core CV: −6% (P=.43) Extended CV: −7% (P=.16) Core CV: +2% (P=.63) Extended CV: +4% (P=.27) Table IV Cardiovascular outcome trials conducted in people with IGT, showing data only for glucose-lowering interventions

Introduction/BackgroundMaintenance therapy for recurrent ovarian cancer is intended to extend progression-free survival (PFS) without compromising patient quality of life; therefore, the clinical benefits of prolonged PFS should be evaluated in the context of toxicities that may compromise patients‘ wellbeing. In ARIEL3 (CO-338-014; NCT01968213), rucaparib significantly improved PFS vs placebo in all predefined patient cohorts regardless of biomarker status (Coleman et al. Lancet. 2017;390:1949-61) or age (Ledermann et al. Presented at SGO 2019; abst 4). This post hoc exploratory analysis examined quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in patients from ARIEL3, including the subgroup of patients with a BRCA mutation and subgroups based on patient age.MethodologyPatients were randomised 2:1 to oral rucaparib (600 mg BID) or placebo. QA-PFS and Q-TWiST were analysed in patients with a BRCA mutation (germline, somatic, or origin unknown), the ITT population (ie, all randomised patients), and subgroups of the ITT population defined by patient age at baseline (<65, 65–74, or ≥75 years). Q-TWiST was performed using 2 sets of treatment-emergent adverse events (TEAEs): all grade ≥3 TEAEs and grade ≥2 TEAEs of nausea, vomiting, fatigue, and asthenia only.ResultsThe visit cutoff date for these analyses was 15 April 2017. QA-PFS, Q-TWiST considering grade ≥3 TEAEs, and Q-TWiST considering select grade ≥2 TEAEs were significantly longer with rucaparib than placebo in patients with a BRCA mutation and in the ITT population (table). Across all age subgroups, QA-PFS and Q-TWiST (both analyses) were significantly longer with rucaparib than placebo (table 1).Abstract – Table 1ConclusionIn the ITT population, BRCA-mutant subgroup, and age subgroups analysed, the quality-adjusted analyses, which incorporated patient-centred perspectives, confirmed the benefit of rucaparib vs placebo.DisclosureNC: Clovis, Advaxis, AstraZeneca, BIOCAD, MSD, Pfizer, PharmaMar, Roche, Takeda, Tesaro AMO: Clovis, Amgen, Immunovaccine, Verastem, AstraZeneca, WebRx DL: Clovis, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, Tesaro CA: Clovis, Mateon, Bayer, Cerulean, Tesaro, VentiRx AO: Clovis, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, Tesaro AD: Precision Oncology Australia, Shire, Specialised Therapeutics Australia JIW: AbbVie, AstraZeneca ARC: AstraZeneca, Roche, Clovis GS: Clovis, AstraZeneca, PharmaMar, Roche, Tesaro AL: Clovis, Pfizer, PharmaMar, GamaMabs, Merus, AstraZeneca RWH: Clovis, AstraZeneca, Tesaro MAG: Clovis, AstraZeneca, PharmaMar, Roche PCF: Clovis, AstraZeneca JCG: AstraZeneca, BMS, Janssen, Ipsen, MSD, Astellas DMO’M: Clovis, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, Tesaro, Amgen, ImmunoGen, AbbVie, Ambry, Health Analytics, Agenus, Ajinomoto, Array, BMS, ERGOMED Clinical Research, Exelixis, Genentech, GSK, INC Research, inVentiv Health Clinical, Ludwig Institute for Cancer Research, Novartis, PRA International, Regeneron, Serono, Stemcentrx, TRACON DKA: Morphotek, Clovis, Advaxis, AstraZeneca, Pfizer, Syndax, Tesaro SB: Clovis, AstraZeneca, ImmunoGen, GamaMabs, Merck Serono, PharmaMar, Roche, Seattle Genetics, Tesaro JG-D: AstraZeneca, Clovis, Genentech/Roche, Janssen EMS: nothing to disclose JM: Modus Outcomes TC, LM, SG, JB: Clovis RLC: Clovis, AbbVie, AstraZeneca, Esperance, Janssen, Merck, Millennium, OncoMed, Roche/Genentech, Bayer, GamaMabs, Genmab, Gradalis, Millennium, Pfizer, Tesaro JAL: Clovis, AstraZeneca, Pfizer, Artios Pharma, Cristal Therapeutics, Merck/MSD, Regeneron, Roche, Seattle Genetics, Tesaro.

Introduction/BackgroundIn ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all patient populations, regardless of biomarker status (Coleman et al. Lancet. 2017;390:1949–61). This subgroup analysis examined the effect of the stratification factor PFI following penultimate platinum-based chemotherapy (also a prognostic factor in ovarian cancer) on primary and secondary endpoints of investigator-assessed and blinded independent central review (BICR)-assessed PFS in ARIEL3.MethodologyPatients were randomised 2:1 to oral rucaparib (600 mg BID) or placebo. Analysis was based on the randomisation stratification factor of PFI following penultimate platinum-based regimen: 6–12 months or >12 months. PFS was assessed in 3 predefined cohorts: BRCA mutant; BRCA mutant + BRCA wild type/high loss of heterozygosity (LOH high); and intent-to-treat (ITT) population. Safety was assessed in all patients who received ≥1 dose of rucaparib.ResultsVisit cutoff dates for efficacy and safety were 15 April 2017 and 31 December 2017, respectively. For all predefined cohorts, investigator and BICR assessments showed a significant PFS improvement with rucaparib vs placebo in both PFI subgroups (figure 1).Abstract – Figure 1As expected, patients receiving placebo with a PFI 6–12 months had a shorter median PFS than those with a PFI >12 months. The treatment by PFI subgroup interaction was not significant, indicating that the treatment benefit was similar in both PFI subgroups. Safety data in the PFI subgroups were consistent with the overall study population, as previously reported.ConclusionIn ARIEL3, rucaparib maintenance treatment significantly improved PFS vs placebo in all cohorts, irrespective of PFI subgroup. The magnitude of treatment effect was similar for both PFI subgroups.DisclosureARC: AstraZeneca, Roche, Clovis AMO: Clovis, Amgen, Immunovaccine, Verastem, AstraZeneca, WebRx DL: Clovis, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, Tesaro CA: Clovis, Mateon, Bayer, Cerulean, Tesaro, VentiRx AO: Clovis, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, Tesaro AD: Precision Oncology Australia, Shire Pharmaceuticals, Specialised Therapeutics Australia NC: Clovis, Advaxis, AstraZeneca, BIOCAD, MSD, Pfizer, PharmaMar, Roche, Takeda, Tesaro JIW: AbbVie, AstraZeneca GS: Clovis, AstraZeneca, PharmaMar, Roche, Tesaro AL: Clovis, Pfizer, PharmaMar, GamaMabs, Merus, AstraZeneca RWH: Clovis, AstraZeneca, Tesaro MAG: Clovis, AstraZeneca, PharmaMar, Roche PCF: Clovis, AstraZeneca JCG: AstraZeneca, BMS, Janssen, Ipsen, MSD, Astellas DMO’M: Clovis, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, Tesaro, Amgen, ImmunoGen, AbbVie, Ambry, Health Analytics, Agenus, Ajinomoto, Array BioPharma, BMS, ERGOMED Clinical Research, Exelixis, Genentech, GSK, INC Research, inVentiv Health Clinical, Ludwig Institute for Cancer Research, Novartis, PRA International, Regeneron, Serono, Stemcentrx, TRACON DKA: Morphotek, Clovis, Advaxis, AstraZeneca, Pfizer, Syndax, Tesaro SB: Clovis, AstraZeneca, ImmunoGen, GamaMabs, Merck Serono, PharmaMar, Roche, Seattle Genetics, Tesaro JG-D: AstraZeneca, Clovis, Genentech/Roche, Janssen EMS: nothing to disclose TC, LM, SG: Clovis RLC: Clovis, AbbVie, AstraZeneca, Esperance, Janssen, Merck, Millennium, OncoMed, Roche/Genentech, Bayer, GamaMabs, Genmab, Gradalis, Pfizer, Tesaro JAL: Clovis, AstraZeneca, Pfizer, Artios Pharma, Cristal Therapeutics, MSD, Regeneron, Roche, Seattle Genetics, Tesaro.

The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years. 5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan–Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837. Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3–26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2–17; p=0·015) for death from any cause, 17% (6–26; p=0·002) for myocardial infarction, and 26% (14–36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5–32; p=0·010) for death from any cause and 31% (12–46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy. Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible. University of Oxford Nuffield Department of Population Health Pump Priming.

To determine which hydration (saline, saline + mannitol, or saline + furosemide) is associated with least cisplatin nephrotoxicity. We randomized 49 women who received cisplatin (75 mg/m(2) every 3 weeks) into one of the three hydration arms. The 24-h creatinine clearance was measured before and on day 6 after cisplatin infusion. The patients of each arm received 2 l of saline hydration. In the saline + furosemide arm, 40 mg of furosemide was given after hydration. In the saline + mannitol arm, 50 g of mannitol was mixed with the cisplatin. For the first cycle of chemotherapy, 15 women were randomized to saline, 17 to saline + furosemide, and 17 to saline + mannitol. For each group, the creatinine clearances before cisplatin infusion were (means+/-SD, milliliters per minute) 84.5+/-26.8, 82.5+/-24.0 and 87.4+/-25.6, and after cisplatin infusion were 79.1+/-31.9, 68.7+/-21.5, and 56.4+/-22.9, respectively. The decreases in creatinine clearance were similar between the saline group and the saline + furosemide group ( P=0.66), but different between the saline + mannitol group and the saline group ( P=0.02) or the saline + furosemide group ( P=0.02). As each woman received multiple courses of cisplatin, 15 who received saline contributed 41 paired datasets, 17 who received saline + furosemide contributed 49 paired datasets, and 17 who received saline + mannitol contributed 36 paired datasets showed similar patterns. Hydration with saline or saline + furosemide appears to be associated with less cisplatin nephrotoxicity than saline + mannitol.

In this prospective randomized trial, minimally invasive radical hysterectomy resulted in lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. A prospective randomized trial and an epidemiologic study that used large cancer databases (National Cancer Database and SEER) both showed that minimally invasive radical hysterectomy was associated with shorter survival in early cervical cancer than open abdominal radical hysterectomy.

Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting. Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths. Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma. NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.

A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% with placebo.

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Clovis Oncology.