Clinical trial NCT01351415: A Study of Bevacizumab in Combination With Standard of Care Treatment in Participants With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC)
Official title: An Open-label, Randomized, Phase IIIb Trial Evaluating the Efficacy and Safety of Standard of Care +/- Continuous Bevacizumab Treatment Beyond Progression of Disease (PD) in Patients With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC) After First Line Treatment With Bevacizumab Plus a Platinum Doublet-containing Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Squamous Non-Small Cell Lung Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-05-10
Enrollment: 485
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This open-label, randomized, multicenter study will evaluate the efficacy and safety of bevacizumab (Avastin) in combination with standard of care (SOC) treatment in participants with advanced non-squamous NSCLC. Participants will be enrolled at documentation of progression of disease (PD) after 4-6 cycles of first-line treatment with bevacizumab plus a platinum doublet-containing therapy and a minimum of two cycles of bevacizumab maintenance treatment prior to PD. Participants will be randomly assigned to one of two treatment arms to receive either bevacizumab plus SOC treatment or SOC treatment alone.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed non-squamous NSCLC
* Documented progression of disease (locally recurrent or metastatic) per investigator assessment following first-line treatment with 4-6 cycles of Bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of 2 cycles of Bevacizumab (monotherapy) maintenance treatment prior to first progression of disease
* No treatment interruption of Bevacizumab treatment greater than 2 consecutive cycles (42 days) between the start of first-line treatment to start of Cycle 1 of second line treatment
* Randomization within 4 weeks of progression of disease
* At least one unidimensionally measurable lesion meeting RECIST v1.1 criteria
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Participants with adequate hematological, liver, and renal function
* Female participants must not be pregnant or breast-feeding. Female participants of childbearing potential and fertile male participants must agree to use a highly effective contraceptive during the trial and for a period of at least 6 months following the last administration of trial drug(s)

Exclusion Criteria:

* Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component
* Epidermal growth factor receptor (EGFR)-mutation-positive disease according to local laboratory testing
* History of hemoptysis greater than or equal to (\>/=) grade 2 within 3 months of randomization
* History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding and active gastrointestinal bleeding
* Major cardiac disease
* Treatment with any other investigational agent within 28 days prior to randomization
* Known hypersensitivity to bevacizumab or any of its excipients, or any SOC drugs foreseen
* Malignancy other than NSCLC within 5 years prior to randomization and evidence of any other disease that contraindicates the use of an investigational or SOC drug

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
Secondary outcomes:
measure: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Percentage of Participants With Objective Response According to RECIST v1.1
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Percentage of Participants With Disease Control According to RECIST v1.1
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Duration of Response (DoR) According to RECIST v1.1
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Time to Progression (TTP) According to RECIST v1.1
timeFrame: Up to data cut-off date 24 June 2016 (approximately 5 years)
measure: Percentage of Participants Who Are Alive at Month 6, 12, and 18
timeFrame: Month 6, 12, 18
Other outcomes:
Locations:
city: Mobile
country: United States
facility: USA Mitchell Cancer Institute
state: Alabama
city: Glendale
country: United States
facility: Palo Verde Hema/Onc
state: Arizona
city: Glendale
country: United States
facility: Arizona Center for Cancer Care
state: Arizona
city: Jonesboro
country: United States
facility: Clopton Clinic
state: Arkansas
city: Burbank
country: United States
facility: East Valley Hematology ; Oncology Medical Group
state: California
city: Encinitas
country: United States
facility: California Cancer Associates for Research & Excellence, Inc.
state: California
city: La Jolla
country: United States
facility: Scripps Clinic; Hematology & Oncology
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center
state: California
city: San Luis Obispo
country: United States
facility: Coastal Integrative Cancer Care
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: New Britain
country: United States
facility: The Hospital of Central CT
state: Connecticut
city: Norwich
country: United States
facility: Eastern Ct Hema/Onco Assoc; Dept of Oncology
state: Connecticut
city: Boca Raton
country: United States
facility: Lynn Cancer Institute - West
state: Florida
city: Jacksonville
country: United States
facility: Baptist - MD Anderson Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Rockledge
country: United States
facility: Cancer Care Centers of Brevard
state: Florida
city: Atlanta
country: United States
facility: Emory Univ Winship Cancer Inst
state: Georgia
city: Savannah
country: United States
facility: Summit Cancer Care PC
state: Georgia
city: Post Falls
country: United States
facility: Kootenai Cancer Center
state: Idaho
city: Elk Grove Village
country: United States
facility: Alexian Brothers Neurosci Inst
state: Illinois
city: Evanston
country: United States
facility: Oncology-Evanston Nthwest Healthcare Kellogg Cancer Care Ctr
state: Illinois
city: Joliet
country: United States
facility: Joliet Oncology Hematology Associates, Ltd.
state: Illinois
city: Niles
country: United States
facility: Cancer Care & Hematology; Specialists of Chicagoland
state: Illinois
city: River Forest
country: United States
facility: W. Suburban Ctr for Cncer Care
state: Illinois
city: Indianapolis
country: United States
facility: St. Francis Medical Group
state: Indiana
city: Newburgh
country: United States
facility: Oncology Hematology Associates of Southwest Indiana
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic
state: Iowa
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Jewish Cancer Care
state: Kentucky
city: Baton Rouge
country: United States
facility: Hematology/Oncology Clinic, LLP
state: Louisiana
city: Lafayette
country: United States
facility: Louisiana Oncology Associates
state: Louisiana
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: York
country: United States
facility: York Hospital
state: Maine
city: Annapolis
country: United States
facility: Anne Arundel Health System Research Instit-Annapolis Oncology Ctr
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center; Neely Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Ann Arbor Hematology Oncology
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital; Hematology Oncology
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer & Hematology Center of West Michigan
state: Michigan
city: Saint Louis Park
country: United States
facility: Metro-Minnesota CCOP
state: Minnesota
city: Saint Joseph
country: United States
facility: St Joseph Oncology
state: Missouri
city: Saint Louis
country: United States
facility: Heartland CCOP/Missouri Baptist Medical Center
state: Missouri
city: Stony Brook
country: United States
facility: Stony Brook Univ Cancer Ctr; Medical Oncology Clinic
state: New York
city: Hickory
country: United States
facility: Carolina Oncology Specialists, PA - Hickory
state: North Carolina
city: Canton
country: United States
facility: Aultman Hospital
state: Ohio
city: Columbus
country: United States
facility: Mid Ohio Onc Hematology Inc
state: Ohio
city: Dayton
country: United States
facility: Dayton Clinical Oncology Prog
state: Ohio
city: Middletown
country: United States
facility: Signal Point Clinical; Research Center, LLC
state: Ohio
city: Toledo
country: United States
facility: Toledo Hospital; CCOP Toledo
state: Ohio
city: Coos Bay
country: United States
facility: Bay Area Hospital
state: Oregon
city: Bethlehem
country: United States
facility: St. Lukes Hospital and Health Network
state: Pennsylvania
city: Dunmore
country: United States
facility: Hematology & Oncology Assoc; North Eastern Pennsylvania
state: Pennsylvania
city: Langhorne
country: United States
facility: St. Mary Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania; Radiation Oncology
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Hospital
state: Pennsylvania
city: Pawtucket
country: United States
facility: Memorial Hospital of Rhode Island
state: Rhode Island
city: Germantown
country: United States
facility: West Clinic
state: Tennessee
city: Knoxville
country: United States
facility: University of Tennessee Medical Center Cancer Institute
state: Tennessee
city: Dallas
country: United States
facility: Unv of TX SW Med Cntr; Hematology/Onc
state: Texas
city: Portsmouth
country: United States
facility: Delta Hematology/ Oncology Associates
state: Virginia
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care - Roanoke
state: Virginia
city: Spokane
country: United States
facility: Medical Oncology Associates
state: Washington
city: Appleton
country: United States
facility: Fox Valley Hema and Onc SC
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran
state: Wisconsin
city: Madison
country: United States
facility: UNI OF WISCONSIN SCHOOL OF MEDICINE; GI Oncology Research Group, Paul P Carbone Cancer Center
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Inst. Alexander Fleming; Oncology Dept
city: La Pampa
country: Argentina
facility: Centro Oncologico Infinito; Oncologia
city: Mar Del Plata
country: Argentina
facility: Hospital Privado de Comunidad; Oncology
city: Rosario
country: Argentina
facility: Sanatorio Parque de Rosario
city: Santa Fe
country: Argentina
facility: ISIS Clinica Especializada
city: Viedma, Rio Negro
country: Argentina
facility: Clínica Viedma
city: Hohenems
country: Austria
facility: LKH Hohenems; Abteilung für Pulmologie
city: Innsbruck
country: Austria
facility: Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie
city: Natters
country: Austria
facility: Lkh Natters; Abt. Für Atemwegs- & Lungenkrankheiten
city: Steyr
country: Austria
facility: A.Ö. LKH; Abt. für Lungenkrankheiten
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen; Lungenabt.
city: Wien
country: Austria
facility: Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie
city: Wien
country: Austria
facility: Krankenhaus Der Stadt Wien Lainz; V. Medizinische Abt.
city: Wien
country: Austria
facility: SMZ - Baumgartner Hohe, Pavilion Leopold; 1.Interne Lungenabteilung, Onkologische Tagesklinik
city: Bruxelles
country: Belgium
facility: Clin. Europe (Ste Elisabeth)
city: Salvador, Bahia
country: Brazil
facility: Nucleo de Oncologia da Bahia - NOB
state: BA
city: Fortaleza
country: Brazil
facility: Centro de Pesquisa Clínica- Instituto do Câncer do Ceará- ICC
state: CE
city: Brasilia
country: Brazil
facility: Sociedade beneficente de senhoras Hospital Sirio Libanes
state: DF
city: Brasilia
country: Brazil
facility: Centro de Estudos e Pesquisas Oncologicas - CESPO
state: DF
city: Taguatinga
country: Brazil
facility: Instituto de Câncer de Brasília
state: DF
city: Rio de Janeiro
country: Brazil
facility: Clinicas Oncologicas Integradas - COI
state: RJ
city: Ijui
country: Brazil
facility: Hospital de Caridade de Ijui; Oncologia
state: RS
city: Itajai
country: Brazil
facility: Clinica de Neoplasias Litoral
state: SC
city: Sao Paulo
country: Brazil
facility: Hospital A. C. Camargo; Oncologia
state: SP
city: São Paulo
country: Brazil
facility: Hospital Sao Jose
state: SP
city: Hillerod
country: Denmark
facility: Nordsjællands Hospital, Hillerød, Onkologisk Afdeling
city: Aix En Provence
country: France
facility: Poly Parc Rambot La Provencale; Chimiotherapie Ambulatoire
city: Caen
country: France
facility: Centre Francois Baclesse; Oncologie
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal; Service de Pneumologie
city: Gleize
country: France
facility: Hopital Nord Ouest;Unite 2c
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: Hopital Calmette; Pneumologie
city: Lyon
country: France
facility: Hopital Louis Pradel; Cardiologie B
city: Marseille
country: France
facility: Hôpital Saint Joseph; Oncologie Medicale
city: Marseille
country: France
facility: Hopital Nord; Service d'Oncologie Multidisciplinaire et Innovation Thérapeutique
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Pierre Benite
country: France
facility: Ch Lyon Sud; Chir Onc Gyne Sct Jules Courmont
city: Pontoise
country: France
facility: CH Rene Dubos; Oncologie
city: Saint Herblain
country: France
facility: Ico Rene Gauducheau; Oncologie
city: St-Priest-En-Jarez
country: France
facility: Institut de Cancérologie de Loire
city: Strasbourg
country: France
facility: Centre Paul Strauss; Oncologie Medicale
city: Toulon
country: France
facility: Hia Sainte Anne; Pneumologie
city: Toulon
country: France
facility: Hopital Sainte Musse; Pneumologie
city: Toulouse
country: France
facility: Clinique Pasteur; Pneumologie
city: Vesoul
country: France
facility: Chi De La Haute Saone De Vesoul; Pneumologie
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka GmbH; Pneumologie
city: Bergisch Gladbach
country: Germany
facility: Praxis Dr. med. David Borquez
city: Esslingen
country: Germany
facility: Klinikum Esslingen; Klinik für Kardiologie, Angiologie und Pneumologie
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest; Klinik f. Onkologie und Hämatologie
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie
city: Großhansdorf
country: Germany
facility: LungenClinic Großhansdorf
city: Halle (Saale)
country: Germany
facility: Krankenhaus Martha-Maria Halle-Doelau gGmbH; Klinik fuer Innere Medizin I
city: Homburg/Saar
country: Germany
facility: Universitaetsklinikum des Saarlandes; Innere Medizin V
city: Immenhausen
country: Germany
facility: Fachklinik für Lungenerkrankungen
city: Karlsruhe
country: Germany
facility: St. Vincentius Kliniken Karlsruhe; Abteilung Hämatologie / Onkologie
city: Leipzig
country: Germany
facility: Robert-Koch-Klinik; Pneumologie
city: Leipzig
country: Germany
facility: Praxis Christian Geßner
city: Minden
country: Germany
facility: Johannes-Wesling-Klinikum Minden; Onkologische Ambulanz / Tagesklinik
city: Muenchen
country: Germany
facility: Ludwig-Maximilians Uni Klinik Innenstadt; Medizinische Klinik
city: Oldenburg
country: Germany
facility: Pius-Hospital; Klinik fuer Haematologie und Onkologie
city: Athens
country: Greece
facility: Sotiria Hospital
city: Piraeus
country: Greece
facility: Metropolitan Hospital; 2Nd Oncology Clinic
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki Papanikolaou; Uni Pneumonology Dept.
city: Thessaloniki
country: Greece
facility: Diavalkaniko Hospital
city: Avellino
country: Italy
facility: Citta Ospedaliera; Divisione Oncologia Medica
state: Campania
city: Napoli
country: Italy
facility: IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A
state: Campania
city: Roma
country: Italy
facility: Policlinico Universitario Campus Biomedico; Uoc Oncologia Medica
state: Lazio
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini; U.O.C. Pneumologia Ad Indirizzo Oncologico 1
state: Lazio
city: Genova
country: Italy
facility: IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A
state: Liguria
city: Saronno
country: Italy
facility: Az. Osp. Di Busto P.O. Di Saronno; U.O. Di Oncologia Medica
state: Lombardia
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana-Ospedale Cisanello; Dipartimento Cardio Toracico-Pneumologia Ii
state: Toscana
city: Aichi
country: Japan
facility: Aichi Cancer Center Hospital; Respiratory Medicine
city: Chiba
country: Japan
facility: National Cancer Center Hospital East; Thoracic Oncology
city: Ehime
country: Japan
facility: National Hospital Organization Shikoku Cancer Center; Thoracic Oncology
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center, Thoracic Oncology
city: Hyogo
country: Japan
facility: Hyogo Cancer Center; Thoracic Oncology
city: Kanagawa
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center; Respiratory Medicine
city: Kanagawa
country: Japan
facility: Yokohama Municipal Citizen'S Hospital; Respiratory
city: Miyagi
country: Japan
facility: Miyagi Cancer Center; Respiratory Medicine
city: Okayama
country: Japan
facility: Okayama University Hospital; Respiratory and Allergy Medicine
city: Osaka
country: Japan
facility: OSAKA CITY GENERAL HOSPITAL;Medical Oncology
city: Osaka
country: Japan
facility: Osaka International Cancer Institute; Thoracic Oncology
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center; Thoracic Oncology
city: Tokyo
country: Japan
facility: National Cancer Center Hospital; Thoracic Medical Oncology
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR, Respiratory Medicine
city: Beirut
country: Lebanon
facility: American University of Beirut - Medical Center
city: Beirut
country: Lebanon
facility: Hotel Dieu de France; Oncology
city: Beirut
country: Lebanon
facility: Middle East Inst. of Health; Oncology
city: Aguascalientes
country: Mexico
facility: Centenario Hospital Miguel Hidalgo
city: Mexico City
country: Mexico
facility: Hospital Central Sur de Alta Especialidad Petróleos Mexicanos
city: Mexico City
country: Mexico
facility: Centro Médico Abc the American British Cowdray Medical Center, I.A.P. - Centro de Cáncer
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis; Afdeling Longziekten
city: Den Haag
country: Netherlands
facility: Leyenburg Hospital; Pulmonology
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis; Dept of Lung Diseases
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St Jansdal; Dept of Lung Diseases
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nieuwegein
country: Netherlands
facility: Antonius Ziekenhuis; Dept of Lung Diseases
city: Muscat
country: Oman
facility: College of Medicine & Sciences, Sultan Qaboos University Hospital
city: Banska Bystrica
country: Slovakia
facility: Fnsp Fdr Banska Bystrica; Dep of Pneumology&Ftizeology
city: Bratislava
country: Slovakia
facility: FNsP Bratislava, Nemocnica Ruzinov
city: Kosice
country: Slovakia
facility: Vychodoslovensky onkologicky ustav
city: Nitra
country: Slovakia
facility: Inst. of Tb & Respiratory Diseases; Dep. of Oncology
city: Barakaldo
country: Spain
facility: Hospital de Cruces; Servicio de Oncologia
state: Vizcaya
city: Alicante
country: Spain
facility: Hospital General Univ. de Alicante; Servicio de Oncologia
city: Madrid
country: Spain
facility: Centro Oncologico MD Anderson International Espana
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz; Servicio de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset; Servicio de Oncologia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet; Servicio Oncologia
city: Al Ain
country: United Arab Emirates
facility: Tawam Hospital; Medical Oncology Department
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. doi: 10.1001/jamaoncol.2018.3486. Epub 2018 Dec 13.
citation: Takeda M, Yamanaka T, Seto T, Hayashi H, Azuma K, Okada M, Sugawara S, Daga H, Hirashima T, Yonesaka K, Urata Y, Murakami H, Saito H, Kubo A, Sawa T, Miyahara E, Nogami N, Nakagawa K, Nakanishi Y, Okamoto I. Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial. Cancer. 2016 Apr 1;122(7):1050-9. doi: 10.1002/cncr.29893. Epub 2016 Feb 1.
citation: Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. doi: 10.1016/j.cllc.2011.05.002. Epub 2011 Jun 25.