Approximately 50% of patients diagnosed with non-small

ORIGINAL ARTICLE A Randomized Phase II Trial of Pemetrexed/Gemcitabine/ Bevacizumab or Pemetrexed/Carboplatin/Bevacizumab in the First-Line Treatment of Elderly Patients with Advanced Non-small Cell Lung Cancer David R. Spigel, MD,* John D. Hainsworth, MD,* Dianna L. Shipley, MD, Thomas J. Ervin, MD, Peter C. Kohler, MD, Eric T. Lubiner, DO, James D. Peyton, MD, David M. Waterhouse, MD, Howard A. Burris III, MD,* and F. Anthony Greco, MD* Purpose: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/ carboplatin/bevacizumab. Methods: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m 2 IV, gemcitabine 1500 mg/m 2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m 2 IV, carboplatin area under the concentration-time curve 5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/ responding patients continued bevacizumab until disease progression. Results: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage). *Sarah Cannon Research Institute, Nashville, Tennessee; Tennessee Oncology, PLLC, Nashville, Tennessee; Florida Cancer Specialists, Fort Myers, Florida; Munson Medical Center, Traverse City, Michigan; and Oncology Hematology Care, Inc., Cincinnati, Ohio. Disclosure: David R. Spigel, MD, has declared an uncompensated consultant/advisory role with Genentech and Eli Lilly and Co. F. Anthony Greco, MD, has declared an uncompensated consultant/advisory relationship with Eli Lilly and Co. All other investigators report no declarations of financial interest. Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203. E-mail: dspigel@tnonc.com Copyright 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0701-0196 Conclusions: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens. Key Words: Elderly, Pemetrexed, Bevacizumab, Non-small cell lung cancer. (J Thorac Oncol. 2012;7: 196 202) Approximately 50% of patients diagnosed with non-small cell lung cancer (NSCLC) are aged at least 70 years. 1,2 Nevertheless, elderly patients are consistently underrepresented in lung cancer clinical trials. 3 6 Many older patients are not eligible for trials because of comorbidities, concomitant medications, or poor performance status; and others may never be offered opportunities for trial participation because of physician concerns about toxicity. 1,7 Consequently, the safety and potential benefits of newer therapies have been understudied in a large subset of patients with advanced lung cancer. 8 Two recently approved therapies in NSCLC treatment are pemetrexed and bevacizumab. Pemetrexed is a novel multitargeted antifolate with proven efficacy and safety in prospective randomized trials with platinum therapy in the first-line nonsquamous NSCLC treatment setting 9 11 and as a single agent in maintenance and second-line settings. 12,13 Pemetrexed has also been studied in a biweekly schedule with gemcitabine in phase II trials at our center and by others and has been shown to be well tolerated and associated with overall response rates (ORRs) of approximately 20%. 14 16 Bevacizumab is a monoclonal antibody to vascular endothelial growth factor, which was shown to improve survival when combined with carboplatin and paclitaxel in the first-line treatment setting in patients with advanced nonsquamous NSCLC. 17 Eight-hundred seventy-five patients were enrolled in this randomized phase III trial, and 224 (26%) of these patients were aged at least 70 years. Nevertheless, in an unplanned retrospective analysis of the elderly cohort, 18 bevacizumab was associated with possible harm and no survival benefit. 196 Journal of Thoracic Oncology Volume 7, Number 1, January 2012

Journal of Thoracic Oncology Volume 7, Number 1, January 2012 Bevacizumab in Elderly Patients with NSCLC We sought to prospectively assess the roles of two modern chemotherapy regimens in elderly patients with NSCLC. The favorable therapeutic index of pemetrexed in patients with nonsquamous NSCLC made it a promising platform therapy to combine with bevacizumab in these patients. In this randomized phase II trial, we concurrently evaluated two pemetrexed/bevacizumab regimens, one with biweekly gemcitabine and a second with carboplatin, as first-line regimens in elderly patients with advanced disease. PATIENTS AND METHODS This randomized, open-label, multicenter, phase II study was initiated in March 2007 and completed enrollment in December 2009. It was performed at selected sites in the Sarah Cannon Research Institute Oncology Research Consortium, a community-based clinical trial organization (Appendix). This study was approved by the institutional review boards of all participating sites before patient enrollment. Eligibility Patients aged 70 years or older with histologically confirmed nonsquamous NSCLC were enrolled. Patients had measurable disease by radiologic evaluation per RECIST (version 1.0). 19 Patients had unresectable stage III or IV disease; had not received prior systemic therapy for advanced disease (including erlotinib or gefitinib); had adequate organ function (as defined by an absolute neutrophil count 1500/ l; platelets 100,000/ l; hemoglobin 8 g/dl; serum creatinine of 1.5 mg/dl or creatinine clearance 50 ml/min; urine protein/ creatinine ratio of 1.0 or urine dipstick 2 for protein; bilirubin 1.5 the upper limit of normal); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Exclusion criteria included the following: any hemoptysis within 4 weeks before enrollment; untreated central nervous system (CNS) metastases (patients with CNS metastases treated with radiation or surgery were eligible if there was no evidence of CNS disease progression after treatment); or significant cardiovascular disease including unstable angina, myocardial infarction, or stroke within 6 months of enrollment or uncontrolled hypertension (defined as systolic blood pressure 150 mm Hg and/or diastolic blood pressure 100 mm Hg despite antihypertensive therapy). Therapeutic anticoagulation was not allowed, however, patients could receive prophylactic anticoagulation (e.g., port prophylaxis). All patients provided written informed consent before study entry. Pretreatment Evaluation Patients underwent a medical history and physical examination before starting treatment. Complete blood counts and comprehensive metabolic profiles were also assessed. Evaluations for proteinuria, hypertension, and cardiac function by electrocardiogram were performed. Baseline tumor measurements were established by computed tomography (CT) of the chest, abdomen, and pelvis, position emission tomography, and CT or magnetic resonance imaging of the brain. Treatment Patients were randomized 1:1 to cohorts A or B. Patients randomized to cohort A received bevacizumab 10 mg/kg, pemetrexed 500 mg/m 2, and gemcitabine 1500 mg/m 2 intravenously on days 1 and 15 of each 28-day cycle. Patients randomized to cohort B received bevacizumab 15 mg/kg, pemetrexed 500 mg/m 2, and carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 mg/ml/min intravenously on day 1 of each 21-day cycle. Patients were restaged with CT scans every two cycles (8 weeks) in cohort A or every three cycles (9 weeks) in cohort B. Patients received a maximum of six cycles of chemotherapy followed by maintenance bevacizumab if there was no evidence of progressive disease (PD) or unacceptable toxicity. Patients received folic acid 350 to 1000 g orally daily and intramuscular injections of 1000 g vitamin B 12 before starting therapy and administered continuously (B 12 every 9 weeks) until 3 weeks after the last dose of pemetrexed. Routine antiemetics and dexamethasone were administered as premedication in each cohort. Leucovorin could be used as a rescue agent for cytopenias if necessary. Eli Lilly (Indianapolis, IN) supplied the pemetrexed and gemcitabine for the study, and Genentech (San Francisco, CA) supplied the bevacizumab. Carboplatin was obtained from commercial supplies. Dose Modifications Toxicity was assessed using the common terminology criteria for adverse events (version 3.0) of the National Cancer Institute. Administration of hematopoietic growth factors was at the discretion of the treating physician in accordance with the American Society of Clinical Oncologists guidelines. Dose reductions for gemcitabine (1200 mg/m 2 and 900 mg/m 2 ), carboplatin (AUC 4 and AUC 3) or pemetrexed (400 mg/m 2 and 300 mg/m 2 ) were based on the worst grade of toxicity observed in the previous cycle and on day 1 blood counts of each cycle. Dose reductions were made if the absolute neutrophil count was 1500/ L, platelets 100,000/ L, or if febrile neutropenia occurred. Nonhematologic grade 3 or 4 toxicity dose reductions were at physician discretion. A maximum of two dose reductions were allowed from the planned treatment and were permanent. The patient was removed from the study if the toxicity remained unresolved after a 2-week delay. Bevacizumab was discontinued for grade 2 pulmonary or CNS hemorrhage, any grade 4 hemorrhage, grade 4 proteinuria, grade 4 congestive heart failure, fistula development, thromboemboli, wound dehiscence, or reversible posterior leukoencephalopathy. Bevacizumab was held for surgical procedures, other proteinuria, hypertension, other hemorrhage, or other congestive heart failure for up to 4 weeks, or the bevacizumab was discontinued. Patients could continue with chemotherapy if bevacizumab was discontinued. Definition of Response All patients were evaluated for response by RECIST v1.0. The best response was obtained from evaluations recorded from the start of treatment until the end of study treatment. Statistical Considerations This primary end point of this randomized phase II trial was to evaluate the time to progression (TTP) of each Copyright 2011 by the International Association for the Study of Lung Cancer 197

Spigel et al. Journal of Thoracic Oncology Volume 7, Number 1, January 2012 cohort independently. This trial was not designed to compare cohorts. TTP was defined as the interval between the date of treatment initiation and the date of PD. The patient was considered assessable but classified as a treatment failure if there was discontinuation of treatment because of toxicity. Historically, the median TTP for elderly patients with advanced NSCLC is 6 to 8 months. Bevacizumab administration was hypothesized to improve TTP by 40% (in each cohort). To detect a 40% prolongation in TTP with 90% power at a two-sided alpha of 5%, a total of 55 patients per cohort (110 total) were enrolled. Secondary end points included assessments of ORR, toxicity, and overall survival (OS). OS was measured from the date of study entry until the date of death and was estimated using the method of Kaplan and Meier. 20 The safety data were summarized based on treatment received. RESULTS Patient Characteristics One-hundred ten patients were enrolled and randomized, 55 per cohort. Baseline patient characteristics were similar in both cohorts (Table 1). Patients had predominantly stage IV disease, adenocarcinomas, and median ages of 76 (cohort A) and 77 (cohort B). Treatment Received The median number of treatment cycles administered in cohorts A and B were 2.5 cycles (2.5 months; range, 0.5 11 months) and 6 cycles (4.5 months; range, 0.75 9 months), respectively. Only three patients (5%) in cohort A started maintenance bevacizumab therapy (median number of maintenance cycles 6; range, 2.3 5.5 months). Forty-nine percent of patients in cohort B started maintenance bevacizumab TABLE 1. Characteristic Patient Characteristics No. of Patients (%) Cohort A, (n 55) Cohort B, (n 55) Median age, range (yr) 76 (70 89) 77 (70 88) Sex, n (%) Male 29 (53) 26 (47) Female 26 (47) 29 (53) ECOG performance status, n (%) 0 25 (45) 21 (38) 1 30 (55) 34 (62) Race, n (%) Caucasian 53 (96) 52 (95) African-American 2 (4) 3 (5) Stage, n (%) IIIB 5 (9) 8 (14) IV 50 (91) 47 (86) Histology, n (%) Adenocarcinoma 43 (78) 44 (80) Large cell 2 (4) 4 (7) Not otherwise specified 10 (18) 7 (13) (median number of maintenance cycles 5; range, 1.4 15.4 months). One patient in cohort A and seven patients in cohort B are still receiving maintenance bevacizumab at the time of this analysis. Dose reductions occurred in both cohorts. Eighteen patients (33%) in cohort A and 23 patients (42%) in cohort B experienced at least 1 chemotherapy dose reduction. The most common reasons for gemcitabine/pemetrexed dose reductions were neutropenia and fatigue. The most common reasons for carboplatin/pemetrexed dose reductions were neutropenia and thrombocytopenia. Bevacizumab was held at least once in 28 patients (51%) in cohort A and in 5 patients (9%) in cohort B. These holds were primarily because of hospitalizations or toxicities such as infections, thromboembolic events, proteinuria, and bleeding. Growth factor support was common in both cohorts. Granulocyte colony-stimulating factor was administered in 18% and 38% (cohorts A and B, respectively), and erythropoietin was administered in 38% and 36% (cohorts A and B, respectively). Approximately 20% of patients in each cohort received red blood cell transfusions. Efficacy Best responses for all patients are summarized by cohort (Table 2). All patients were included in the efficacy analyses. One patient had a complete response (2%) and 18 patients had a partial response (33%) for an ORR of 35% (95% confidence interval [CI], 23 49%) in cohort A. Eighteen patients (33%) had stable disease, whereas seven patients had PD (13%). Nineteen patients in cohort B had a partial response (35%; 95% CI, 23 49%) in cohort B. Twenty-five patients had stable disease (45%) and six patients had PD (11%). Eleven patients in cohort A and five patients in cohort B were not evaluable for response. The reasons included the following: (cohort A) toxicities (rash, cytopenias, diarrhea, and fatigue; 1 patient each), physician discretion (5), infection (1), and patient decision (1); (cohort B) patient decision (2), hyponatremia (1), and myocardial infarction and cardiopulmonary arrest (both unrelated; 1 patient each). Thirty-six percent of patients in cohort A are alive with a median follow-up of 11.4 months. Fifty-eight percent of patients in cohort B are alive with a median follow-up of 13.8 months. The median TTP in cohort A was 4.7 months (95% CI, 3.8 5.8 months), and 10.2 months (95% CI, 6.3 12.7 months) in cohort B (Figure 1). The median overall survivals for cohorts A and B were 7.5 months (95% CI, 5.6 11.3 months) and 14.8 months (95% CI, 10.25 upper limit not TABLE 2. Best Response Rates Cohort A, (n 55) Cohort B, (n 55) Response, n (%) Complete response 1 (2) 0 Partial response* 18 (33) 19 (35) Stable disease 18 (33) 25 (45) Progressive disease 7 (13) 6 (11) Not evaluable 11 (20) 5 (9) *Nine confirmed (A) and 12 confirmed (B). 198 Copyright 2011 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 1, January 2012 Bevacizumab in Elderly Patients with NSCLC FIGURE 1. Time to progression (TTP). TABLE 3. Cohort A Gemcitabine/Pemetrexed Treatment- Related Toxicity* (n 55) No. of Patients (%) Grade 3 Grade 4 Grade 5 Total Hematologic Anemia 11 (20) 1 (2) 0 12 (22) Leukopenia 17 (31) 5 (9) 0 22 (40) Neutropenia 13 (24) 15 (27) 0 28 (51) Febrile neutropenia 3 (5) 1 (2) 0 4 (7) Thrombocytopenia 5 (9) 1 (2) 0 6 (11) Nonhematologic Anorexia 3 (5) 0 0 3 (5) Cardiac arrhythmia 2 (4) 1 (2) 0 3 (5) Dehydration 4 (7) 0 4 (7) Dyspnea 10 (18) 0 1 (2) 11 (20) Fatigue 19 (35) 1 (2) 0 20 (36) Hypertension 1 (2) 0 0 1 (2) Hyponatremia 0 4 (7) 0 4 (7) Infection 12 (22) 0 2 (4) 14 (25) Muscle pain 4 (7) 0 0 4 (7) Proteinuria 1 (2) 0 0 1 (2) Respiratory failure 1 (2) 1 (2) 1 (2) 3 (5) Thrombosis/embolism 2 (4) 2 (4) 0 4 (7) *In greater than 5% of total patients. FIGURE 2. Overall survival probability. reached), respectively (Figure 2). One-year survivals for cohorts A and B were 33% and 59%, respectively. Treatment-Related Toxicity Treatment-related toxicities for all patients are summarized in Tables 3 and 4. Thirteen patients on cohort A (23%) were removed from study treatment because of toxicities such as severe infection, hematologic toxicity, and fatigue. Of the patients in cohort B, only five (9%) were removed from study treatment because of toxicity, ranging from thromboembolic episodes, proteinuria, and hematologic toxicity. Randomization to treatment arms and subsequent reasons for treatment discontinuation are illustrated in Figure 3. The most frequent grade 3/4 toxicity associated with both treatment regimens was hematologic. Hematologic toxicities included the following: neutropenia (cohort A, 51%/B, 45%), leukopenia (A, 40%/B, 27%), anemia (A, 22%/B, 7%), and thrombocytopenia (A, 11%/B, 31%). Severe and life-threatening febrile neutropenia was limited to four patients in cohort A (7%). Twelve patients in cohort A (22%) and 11 patients (20%) in cohort B received packed red blood cell transfusions with a median of two transfusions administered per cohort. Platelet TABLE 4. Cohort B Carboplatin/Pemetrexed Treatment- Related Toxicity* (n 55) No. of Patients (%) Grade 3 Grade 4 Grade 5 Total Hematologic Anemia 4 (7) 0 0 4 (7) Leukopenia 14 (25) 1 (2) 0 15 (27) Neutropenia 19 (35) 6 (11) 0 25 (45) Febrile neutropenia 0 0 0 0 Thrombocytopenia 12 (22) 5 (9) 0 17 (31) Nonhematologic Anorexia 0 0 0 0 Cardiac arrhythmia 0 0 0 0 Dehydration 4 (7) 0 0 4 (7) Dyspnea 5 (9) 1 (2) 0 6 (11) Fatigue 10 (18) 0 0 10 (18) Hypertension 3 (5) 1 (2) 0 4 (7) Hyponatremia 0 1 (2) 0 1 (2) Infection 4 (7) 0 0 4 (7) Myalgia 6 (11) 0 0 6 (11) Proteinuria 2 (4) 1 (2) 0 3 (5) Respiratory failure 0 0 1 (2) 1 (2) Thrombosis/embolism 3 (5) 1 (2) 0 4 (7) *In 5% of total patients. transfusions were infrequent, with no patients in cohort A and only three patients (5%) in cohort B undergoing transfusions. Fatigue (36%), dyspnea (20%), and infection (25%, including pneumonia, cellulitis, and sepsis) were notable Copyright 2011 by the International Association for the Study of Lung Cancer 199

Spigel et al. Journal of Thoracic Oncology Volume 7, Number 1, January 2012 FIGURE 3. CONSORT diagram. severe nonhematologic toxicities in cohort A. The significant severe nonhematologic toxicities in cohort B were dyspnea (11%), fatigue (18%), and myalgias (11%). There were 42 hospitalizations in cohort A and 25 hospitalizations in cohort B. Eight deaths on study in cohort A were noted within the safety reporting window, three of these were possibly related to study treatment (sepsis, thrombocytopenia, and myocardial infarction). Six deaths on study were noted in cohort B. Of these, two (4%) were possibly related to treatment (sepsis and pulmonary hemorrhage). DISCUSSION Elderly patients represent a large and growing proportion of the NSCLC population but are still frequently undertreated and underrepresented in clinical trials. 1,3,21 23 Coexisting medical conditions, polypharmacy, and poor performance status are common barriers to trial enrollment and treatment. 24 Physician and family perceptions are important barriers in older patients as well. 6,25 Therapies used routinely in younger patients are often viewed as more toxic and relatively ineffective in elderly patients with life-threatening disease. Nevertheless, national guidelines discourage the use of age as a factor in treatment selection as mounting evidence from randomized trials supports the role of chemotherapy in older patients with advanced NSCLC. 26 31 This trial was designed to assess two pemetrexed/ bevacizumab-based first-line NSCLC regimens. The favorable therapeutic index of pemetrexed made it an ideal agent to use in combination with bevacizumab, an agent with broad activity in multiple tumor settings, but uncommon severe toxicity. Biweekly pemetrexed and gemcitabine had been previously studied at our center and by others and found to be generally well tolerated with modest activity. 14 16 Similarly, carboplatin and pemetrexed has proven to be safe and com- 200 Copyright 2011 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 7, Number 1, January 2012 Bevacizumab in Elderly Patients with NSCLC parable with other platinum doublets in the first-line setting. 9 More recently, carboplatin, pemetrexed, and bevacizumab has emerged as a promising active regimen and is currently in phase III testing. 30,32 Our trial was designed to assess pemetrexed/gemcitabine/bevacizumab and pemetrexed/carboplatin/bevacizumab for preliminary efficacy and safety in elderly patients in the first-line setting. Patient age ranged from 70 to 89 years and most had a PS of 1. Overall, each regimen was found to be well tolerated, although cytopenias and fatigue were notable in each cohort, and potential treatment-related deaths were seen in 5% and 4% of patients in cohorts A and B, respectively. Serious infection was relatively common in the gemcitabine group (25%), but only observed in 7% with carboplatin. Among all patients, two patients (2%) may have died because of treatment-related infection. Serious bleeding or thromboembolic events were rare. In terms of efficacy, each regimen was associated with response and disease-control rates expected of modern doublet regimens in relatively younger patients treated in the first-line setting. The 35% response rates for each cohort compare favorably with the 35% response rate seen in the pivotal randomized trial with carboplatin, paclitaxel, and bevacizumab where 57% of the participants were aged 64 years or younger. 17 Nevertheless, such comparisons should also include the higher 55% rate seen in the Patel et al. 30 trial with carboplatin, pemetrexed, and bevacizumab. A notable finding in our trial was the prolonged TTP (10.2 months) and overall survival (14.8 months) in the carboplatin cohort. These rates are among the highest reported from our center in the first-line NSCLC setting in any population. In contrast, patients in the gemcitabine cohort had an overall survival of 7.5 months, more consistent with previous results in this patient group. This trial has several limitations. The size of the patient cohorts in this randomized phase II study results in wide confidence limits around the efficacy end points and prevents definitive comparison of these two regimens. All patients in this trial were considered to be candidates for bevacizumab treatment and therefore may not truly reflect the overall population of elderly patients seen in practice. The different assessment intervals for the two treatment cohorts (8 weeks versus 9 weeks) may also have affected the progression free survival determinations. In summary, this trial demonstrates that pemetrexed/ bevacizumab-based regimens are active and tolerable as first-line therapies for elderly patients with advanced NSCLC. The carboplatin/pemetrexed/bevacizumab regimen in particular was associated with long TTP and overall survival. This regimen is the experimental arm of an ongoing large randomized trial versus carboplatin/paclitaxel/bevacizumab in the first-line setting not limited to elderly patients. 32 Hopefully, enough elderly patients will be included to permit a subset analysis for safety and efficacy. These trials offer potential important opportunities to advance care for our elderly patients. ACKNOWLEDGMENT Supported, in part, by grants from Eli Lilly and Co., Indianapolis, IN, and Genentech, Inc., San Francisco, CA. APPENDIX TABLE A1. Sarah Cannon Oncology Research Consortium Participating Sites Tennessee Oncology, PLLC Florida Cancer Specialists Oncology Hematology Care, Inc. Grand Rapids Oncology Program Nebraska Methodist Cancer Care Consultants in Blood Disorders and Cancer Cancer Care of Western North Carolina Associates in Hematology and Oncology Chattanooga Oncology Hematology Associates Mercy Hospital Nashville, TN Ft. 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