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    Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Schwartzberg Lee S,Tauer Kurt W,Hermann Robert C,Makari-Judson Grace,Isaacs Claudine,Beck J Thaddeus,Kaklamani Virginia,Stepanski Edward J,Rugo Hope S,Wang Wei,Bell-McGuinn Katherine,Kirshner Jeffrey J,Eisenberg Peter,Emanuelson Richard,Keaton Mark,Levine Ellis,Medgyesy Diana C,Qamar Rubina,Starr Alexander,Ro Sunhee Kwon,Lokker Nathalie A,Hudis Clifford A Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. EXPERIMENTAL DESIGN:This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). RESULTS:One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). CONCLUSION:The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. 10.1158/1078-0432.CCR-12-3177
    Efficacy of bevacizumab combined with chemotherapy in the treatment of HER2-negative metastatic breast cancer: a network meta-analysis. Sun Zhengwu,Lan Xiaoyan,Xu Shizhao,Li Shen,Xi Yalin BMC cancer BACKGROUND:It is not known what combination of bevacizumab and chemotherapy agents is the best therapeutic regimen. Comparative study results among the efficacies of bevacizumab plus chemotherapy remain controversial in patients with HER2-negative metastatic breast cancer. METHODS:We searched Pubmed, Embase, and Cochrane Library Central Resister of Controlled Trials through were July 2019 for randomized controlled trials that evaluated the efficacy of bevacizumab plus chemotherapy in HER2-negative metastatic breast cancer. Data on included study characteristics, outcomes, and risk of bias were abstracted by two reviewers. RESULTS:A total of 16 RCT studies involving 5689 patients were included. The results showed that bevacizumab (Bev) - taxanes (Tax) - capecitabine (Cap) has highest-ranking and is probably more effective for prolonging progression-free survival (PFS) than Tax, Cap, Bev-Tax and Bev-Cap, which was no convincing differences among Bev-Cap-vinorelbine, Bev-Tax-everolimus, Bev-Tax-trebananib, Bev-exemestane, Bev-Cap-cyclophosphamide in Bev-containing regimens. For overall response rate (ORR), Bev-Tax-Cap is superior to Tax, Cap and Bev-Cap, while Bev-Tax-trebananib is superior to Cap. The cumulative probability ranking showed that Bev-Tax-Cap or Bev-Tax-trebananib may have best pathological response rate in HER2-negative metastatic breast cancer. CONCLUSION:Our results provide moderate quality evidence that bevacizumab-taxanes-capecitabine maybe the most effective bevacizumab plus chemotherapy on PFS and ORR in HER2-negative metastatic breast cancer, however it should be also considered that bevacizumab may add toxicity to chemotherapy and whether improve overall survival (OS) or not. 10.1186/s12885-020-6674-1
    Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial. Brufsky Adam,Valero Vicente,Tiangco Beatrice,Dakhil Shaker,Brize Arija,Rugo Hope S,Rivera Ragene,Duenne Anja,Bousfoul Naima,Yardley Denise A Breast cancer research and treatment Patients with metastatic triple-negative breast cancer (TNBC) typically have a poor prognosis and limited treatment options. To determine the impact of combining bevacizumab with second-line chemotherapy in patients with metastatic TNBC, we performed an exploratory subgroup analysis of the randomized phase 3 RIBBON-2 trial. RIBBON-2 enrolled patients with metastatic breast cancer that had progressed on first-line non-bevacizumab-containing chemotherapy. After selection of chemotherapy (taxane, gemcitabine, capecitabine, or vinorelbine), patients were randomized 2:1 to receive chemotherapy with either bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Of 684 patients treated in RIBBON-2, 159 (23%) had TNBC. Baseline characteristics were reasonably balanced in the two treatment groups. The majority received taxane chemotherapy. The hazard ratio (HR) for PFS was 0.494 [95% confidence interval (CI) 0.33-0.74; P = 0.0006]. Median PFS was 6.0 months with bevacizumab-chemotherapy versus 2.7 months with chemotherapy alone. Median OS was 17.9 versus 12.6 months, respectively (HR 0.624, 95% CI 0.39-1.007; P = 0.0534). ORR was 41 versus 18%, respectively (P = 0.0078). The safety profile was consistent with the overall study population and previous phase 3 trials of bevacizumab. Patients with metastatic TNBC derived significant PFS and response benefits from the combination of bevacizumab with second-line chemotherapy. Despite the small sample size and immature data, there was a trend toward improved OS. 10.1007/s10549-012-2008-6
    Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses. Brodowicz T,Lang I,Kahan Z,Greil R,Beslija S,Stemmer S M,Kaufman B,Petruzelka L,Eniu A,Anghel R,Koynov K,Vrbanec D,Pienkowski T,Melichar B,Spanik S,Ahlers S,Messinger D,Inbar M J,Zielinski C British journal of cancer BACKGROUND:The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS:Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS:The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS:A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340). 10.1038/bjc.2014.504
    Bevacizumab added to neoadjuvant chemotherapy for breast cancer. Bear Harry D,Tang Gong,Rastogi Priya,Geyer Charles E,Robidoux André,Atkins James N,Baez-Diaz Luis,Brufsky Adam M,Mehta Rita S,Fehrenbacher Louis,Young James A,Senecal Francis M,Gaur Rakesh,Margolese Richard G,Adams Paul T,Gross Howard M,Costantino Joseph P,Swain Sandra M,Mamounas Eleftherios P,Wolmark Norman The New England journal of medicine BACKGROUND:Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS:We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. RESULTS:The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. CONCLUSIONS:The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.). 10.1056/NEJMoa1111097
    Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lang Istvan,Brodowicz Thomas,Ryvo Larisa,Kahan Zsuzsanna,Greil Richard,Beslija Semir,Stemmer Salomon M,Kaufman Bella,Zvirbule Zanete,Steger Günther G,Melichar Bohuslav,Pienkowski Tadeusz,Sirbu Daniela,Messinger Diethelm,Zielinski Christoph, The Lancet. Oncology BACKGROUND:Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. METHODS:In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS:Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. INTERPRETATION:In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. FUNDING:Central European Cooperative Oncology Group; Roche. 10.1016/S1470-2045(12)70566-1
    Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer. Lang I,Inbar M J,Kahán Z,Greil R,Beslija S,Stemmer S M,Kaufman B,Zvirbule Z,Steger G G,Messinger D,Brodowicz T,Zielinski C European journal of cancer (Oxford, England : 1990) BACKGROUND:We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. PATIENTS AND METHODS:Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal. RESULTS:A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. CONCLUSION:These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials. 10.1016/j.ejca.2012.04.022
    Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Zielinski Christoph,Láng István,Inbar Moshe,Kahán Zsuzsanna,Greil Richard,Beslija Semir,Stemmer Salomon M,Zvirbule Zanete,Steger Günther G,Melichar Bohuslav,Pienkowski Tadeusz,Sirbu Daniela,Petruzelka Luboš,Eniu Alexandru,Nisenbaum Bella,Dank Magdalena,Anghel Rodica,Messinger Diethelm,Brodowicz Thomas, The Lancet. Oncology BACKGROUND:The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS:In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS:Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION:Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING:Roche. 10.1016/S1470-2045(16)30154-1
    Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients' preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer. Decker Thomas,Söling Ulrike,Hahn Antje,Maintz Christoph,Kurbacher Christian Martin,Vehling-Kaiser Ursula,Sent Dagmar,Klare Peter,Hagen Volker,Chiabudini Marco,Falkenstein Julia,Indorf Martin,Runkel Eva,Potthoff Karin BMC cancer BACKGROUND:The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. METHODS:In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). RESULTS:61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first-/second-line, Cap+Bev) and 54.1% and 52.9% (first-/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines. CONCLUSIONS:Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians' preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported. TRIAL REGISTRATION:EudraCT No: 2013-005329-22. Registered on 19 August 20. 10.1186/s12885-020-06747-y