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Clin Trials. 2009 Jun;6(3):272-87. doi: 10.1177/1740774509105380.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

Collaborators (879)

Thürlimann B, Aebi S, Blacher L, Castiglione M, Coates AS, Cufer T, Forbes JF, Gelber RD, Giobbie-Hurder A, Goldhirsch A, Hiltbrunner A, Holmberg SB, Maibach R, Martoni A, Mauriac L, McGrogan G, Mouridsen HT, Paridaens R, Price KN, Rabaglio M, Rasmussen BB, Regan MM, Santoro A, Smith IE, Wardley A, Vantongelen K, Viale G, Vantongelen K, Chaudri-Ross HA, Emanuel D, Evans DB, Sguotti C, Trostmann U, Goldhirsch A, Gelber RD, Gusterson BA, Hiltbrunner A, Hürny C, Murray E, Price K, Rabaglio M, Studer R, Viale G, Wallgren A, Aebi A, Coates AS, Colleoni M, Cortés Funes H, Gelber RD, Goldhirsch A, Green M, Hiltbrunner S, Holmberg SB, Karlsson P, Kössler I, Láng I, Lindtner J, Paganetti F, de Stoppani M, Rudenstam CM, Senn HJ, Stahel R, Thürlimann B, Veronesi A, Hiltbrunner A, Rabaglio M, Egli G, Cliffe B, Ribeli-Hofmann S, Munarini F, Kammler R, Studer R, Ruepp R, Maibach R, Munarini V, Castiglione M, Gelber RD, Price KN, Giobbie-Hurder A, Keshaviah A, Litman H, Regan MM, Sun Z, Huang H, Somos LJ, Timmers B, Nickerson L, Blacher L, Heckman Scolese T, Belisle M, Caporale M, Celano J, Dalfonso L, Dooley L, Fischer S, Galloway K, Gould J, Hinkle R, Hinkle M, Jones G, Kral R, Lippert S, Meshulam J, Mundy L, Pavlov-Shapiro A, Scott K, Scott M, Shepard S, Swick J, Swick L, Weinbaum D, Westby C, Zielinski T, Gusterson BA, Mallon E, Viale G, Dell'Orto P, Mastropasqua M, Del Curto B, Garber JE, Gradishar W, Lagakos SW, Lindgren I, Waldie E, van Hoomissen I, De Smet M, Trostmann U, Schmidt W, Bolton A, Hackl W, Snyder RS, Forbes JF, Coates AS, Lindsay D, Preece D, Cowell J, Talbot D, Whipp A, Abell F, Basser R, Bell R, Brady B, Blakey D, Briggs P, Burns I, Campbell P, Chao M, Chirgwin J, Chua B, Clarke K, Collins J, De Boer R, Din JC, Doig R, Dowling A, Drummond R, Efe N, Fan ST, Francis M, Francis P, Ganju V, Gibbs P, Goss G, Green M, Gregory P, Griffiths J, Haines I, Henderson M, Holmes R, James P, Kiffler J, Lehman M, Leyden M, Lim L, Lindeman G, Lynch R, Mann B, McKendrick J, McLachlan S, McLennan R, Mitchell G, Mitra S, Murphy C, Parker I, Phillips K, Porter I, Richardson G, Scarlet J, Sewak S, Shapiro J, Snyder R, Stanley R, Steer C, Stoney D, Strickland A, Toner G, Underhill C, White K, White M, Wirth A, Wong S, Byram D, Byard I, Della-Fiorentina S, Goldrick A, Hovey E, Moylan E, Segelov E, Chan A, Buck M, Hastrich D, Ingram D, Van Hazel G, Willsher P, Wilcken N, Crombie C, Forbes JF, Abell F, Ackland S, Bonaventura A, Cox S, Denham J, Gourlay R, Jackson D, Sillar R, Stewart J, Lewis C, Brigham B, Goldstein D, Friedlander M, Walpole E, Thompson D, Gill PG, Bochner M, Coventry J, Kollias J, Malycha P, Olver I, Colosimo M, Cheuk R, Kenny L, McCarthy N, Wyld D, Young R, Harrup R, Kimber R, Lowenthal R, Trotter J, Bayliss E, Chan A, Ransom D, Byrne M, Buck M, Dewar J, Nowak A, Powell A, Van Hazel G, Abdi EA, Brodribb R, Volobueva Z, Harnett P, Gurney H, Wilcken N, Harvey VJ, EvansQ B, Jones W, McCrystal M, Porter D, Thompson P, Vaughan M, Gibbs D, Atkinson C, Burcombe R, Fitzharris B, Hickey B, Jeffery M, Robinson B, McLaren B, Costello S, North J, Perez D, Campbell ID, Gilbert L, Gannaway R, Jameson M, Kennedy I, Long J, Round G, Spellman L, Whittle D, Woolerton D, Menke C, Biazús J, Cericatto R, Cavalheiro J, Xavier N, Bittelbrunn A, Rabin E, Gutiérrez J, Arriagada R, Bronfman L, Zuñiga M, Gutiérrez J, Acevedo JC, Torres S, León A, Salazar E, Soto Diaz L, Duval R, Oddeshede N, Venti MC, Peña K, Puente L, Maidana V, Baeza R, Arriagada R, Olfos P, Solé J, Vinés E, Mariani C, Láng I, Hitre E, Szabó E, Horváth Z, Ganofszky E, Juhos E, Veronesi A, Crivellari D, Magri MD, Buonadonna A, Coran F, Borsatti E, Candiani E, Massarut S, Roncadin M, Arcicasa M, Carbone A, Perin T, Gloghini A, Tondini C, Labianca R, Poletti P, Bettini A, Clerico M, Vincenti M, Malossi A, Seles E, Perfetti E, Sartorello B, Simoncini E, Marini G, Marpicati P, Farfaglia R, Bianchi AM, Grigolato P, Lucini L, Frata P, Huscher A, Micheletti E, Fogazzi C, Artioli F, Cagossi K, Scaltriti L, Bandieri E, Botticelli L, Ravaioli A, Pasquini E, Rudnas B, Foghin L, Visini M, Zavallone L, Ucci G, Colleoni M, Viale G, Veronesi P, Peruzzotti G, Corsetto L, Ghisini R, Renne G, Luini A, Orlando L, Torrisi R, Rocca A, De Pas T, Munzone A, alimberti V, Zurrida S, Intra M, Nolé F, Orecchia R, Martinelli G, de Braud F, Goldhirsch A, Ravaioli A, Gianni L, Gome H, Cufer T, Pajk B, Cervek J, Werner ID, Murray E, Govender D, Dalvie S, Erasmus T, Robertson B, Read B, Nel E, Toop J, Nedeva N, Panieri E, Vorobiof D, Chasen D, McMichael G, Mohammed C, Holmberg SB, Holmberg SB, Mattsson J, Sellström H, Lindberg B, Goldhirsch A, Herrmann R, Schönenberger A, Mingrone W, Honegger Ch, Bärtschi E, Neter M, Rederer G, Schär G, Rochlitz C, Herrmann R, Oertli D, Wight E, Moch H, Bernier J, Bronz L, Cavalli F, Gallerani E, Richetti A, Franzetti A, Conti-Beltraminelli M, Ghielmini M, Gyr T, Mauri S, Saletti PC, Goldhirsch A, Pagani O, Graffeo R, Locatelli M, Longhi S, Rey PC, Ruggeri M, Zucca E, Wyss D, Mazzucchelli L, Pedrinis E, Rusca T, Aebi S, Fey MF, Castiglione M, Rabaglio M, Aebi S, Fey MF, Zuber M, Beck G, Aebi S, Fey MF, Schönenberger R, Lüthi JM, Rauch D, Bonnefoi H, Egli F, Steiner R, Fehr P, Perey L, de Grandi P, Jeanneret W, Leyvraz S, Delaloye JF, Thürlimann B, Köberle D, Weisser F, Mattmann S, Müller A, Cerny T, Späti B, Höfliger M, Fürstenberger G, Bolliger B, Ohlschlegel C, Lorenz U, Bamert M, Kehl-Blank J, Vogel E, Thürlimann B, Hess D, Senn I, Köberle D, Ehrsam A, Nauer C, Ohlschlegel C, Kehl-Blank J, Vogel E, Widmer L, Häfner M, Pestalozzi BC, Fehr M, Caduff R, Varga Z, Trüb R, Fink D, Bättig BA, Buser K, Bürki N, Dieterle A, Hasler L, Mannhart-Harms M, Rageth C, Richner J, Spataro V, Umbricht M, Ellis P, Harris S, Akbar N, McVicars H, Lees C, Raman R, Crane G, Mouridsen HT, Mouridsen HT, Jakobsen E, Cold S, Kamby C, Ewertz M, Vestlev PM, Andersen J, Grundtvig P, Sandberg E, Philip P, Madsen EL, Moeller KA, Haahr V, Johansson J, Mauriac L, Debled M, Campo P, Larregain-Fournier D, Remy S, Auvray H, De Gislain C, Delille F, Porteret MC, Servent V, Chapoutier M, Tubiana-Mathieu N, Lavau-Denes S, Bosc P, Guastalla JP, Bachelot T, Arbault C, Netter-Pinon G, Perrin V, Monnier A, Hammoud Y, Romieu G, Culine L, Pinosa V, Cany L, Maguire C, Daban A, Le Saux M, Grandon C, Kerbrat P, Catheline C, Veyret C, Jugieau E, Talon V, Le Mevel A, Maury S, Gladieff L, Lignon N, Dodwell D, Dodwell D, Joffe J, Drew P, Nejim A, Horgan K, Lansdown M, Perren T, Coleman RE, Campos D, Cóppola F, Martinez J, Freue M, Wainstein C, Zori Comba A, Cazap E, Mickiewicz E, Balbiani L, Osuna A, Palazzo E, de Romedis M, Cagnolati S, Delfino CA, Caccia G, de Angelis RL, Fein L, Sala R, Nassurdi C, Colombo Berra A, Viroglio R, Blajman C, Requejo H, Silberman L, Birrell S, Eaton M, Hoffman C, Humeniuk V, Craft P, Stuart-Harris R, Yip D, Bell R, Abell F, Francis M, Kiffer J, Lynch R, McLennan R, White K, Green M, Basser R, Collins J, De Boer R, Din JC, Efe N, Fan ST, Lindeman G, Wong S, Green M, Basser R, Collins J, De Boer R, Din JC, Efe N, Fan ST, Lindeman G, Wong S, Stewart J, Abell F, Ackland S, Bonaventura A, Trotter J, Bayliss E, Chan A, Ransom D, Redfern A, de Souza P, Links M, Dalley D, Grygiel J, Ward R, Underhill C, Clarkek K, Steer C, Walpole E, Thompson D, Nogaret JM, Christiaens MR, Neven P, Paridaens R, Smeets A, Vergote I, Weltens C, Wildiers H, Focan C, Marcelis L, Kains JP, Canon JL, André Vèsale CH, Brohèe D, Gowing J, Yelle L, Dubé P, Vogel C, León Prieto M, Petrakova K, Palacova M, Demlova R, Siffnerova H, Fischer J, Bustova I, Kankova H, Pintova M, Vitek P, Abrahamova J, Kordikova D, Petruzelka L, Sedlackova E, Honova H, Heinrich B, Wischnik A, Oberhoff C, Schindler AE, Münstedt K, Meyer D, Grosse R, Kölbl H, Schmidt W, Mink D, Lück HJ, Dornoff W, Hoffmann G, Hackmann J, Bader W, Kahan Z, Pajkos G, Kristo K, Dank M, Nagykalnai T, Landherr L, Kner E, Kispál M, Dani A, Martoni A, Zamagni C, Giaquinta S, Piana E, Mattioli R, Imperatori L, Santoro A, Carnaghi C, Rimassa L, Gasparini G, Sciarretta G, Morabito A, Barni S, Cazzaniga M, Cabiddu M, Puglisi F, Cellerino R, Antognoli S, Freddari F, Mantovani G, Massa E, Astara G, Segati R, Rosso R, Del Mastro L, VenturiniF M, Bighin C, Bajetta E, Zilembo N, Paleari D, Procopio G, Salvagni S, Perrone MA, Franciosi V, Catalano G, Luzi Fedeli S, Pinotti G, Giardina G, Vallini I, Massidda B, Ionta MT, Deidda MC, Nalli G, Sit G, Carreca I, Cucciarré S, Burgio D, Lombardo M, Pandoli G, Di Stefano P, Boni C, Bisagni G, Banzi MC, Linarello P, Colosini G, Spasiano A, Caldonazzo A, Pacquola MG, Sleeboom HP, Rutten HJ, Luiten EJ, Roerdink HT, Roumen RH, McLaren B, Costello S, North J, Perez D, Bayston K, Pfieffer M, Kennedy I, Campbell ID, Gilbert L, Gannaway R, Jameson M, Long J, Round G, Spellman L, Whittle D, Woolerton D, Jassem J, Welnicka-Jaskiewicz M, Senkus-Konefka E, Matuszewska K, Koralewski P, Pernal J, Pienkowski T, Brewczynska E, Bauer-Kosinska B, Sienkiewicz-Kozlowska R, Jagiello-Gruszfeld A, Sudol K, Tujakowski J, Zurawski B, Pawlega J, Jablonska E, Zygulska A, Górnasiowa A, Filypczyk-Cisarz E, Pajak K, Albano JQ, da Costa B, Henriques A, Amaral H, Marques F, Komov DV, Polikarpova SB, Makhson AN, Zabaznyi NV, Vozny EK, Dobrovolskaya NY, Bolshakova S, Yurgina OV, Korman DB, Maslova IA, Semiglazov V, Ivanov V, Manikhas G, Dolmatov G, Apffelstaedt J, Eedes D, Slabber C, Coccia-Portugal MA, Maart K, Alés Martinez JE, Aramburo P, Sánchez R, Rifa J, Martin J, Pérez-Carrión R, González Larriba JL, Cubillo A, Jiménez MM, Casado A, Fra J, Vieitez JM, Esteban E, Lacave AJ, Wight E, Bartens S, Decio R, Güth U, Breitenstein U, Icli F, Dincol D, Baltali E, Ozisik Y, Topuz E, Basaran M, Aydiner A, Ozdedeli E, Harmancioglu O, Yilmaz AU, Smith IE, Thompson AM, Wardley A, Hickish T, Neave F, Sabini G.

Abstract

BACKGROUND:

Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer.

PURPOSE:

To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting.

METHODS:

From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent.

RESULTS:

The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization.

LIMITATIONS:

Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole.

CONCLUSIONS:

BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

PMID:
19528136
PMCID:
PMC2893024
DOI:
10.1177/1740774509105380
[Indexed for MEDLINE]
Free PMC Article

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