Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial
2017; Elsevier BV; Volume: 19; Issue: 1 Linguagem: Inglês
10.1016/s1470-2045(17)30715-5
ISSN1474-5488
AutoresMarco Colleoni, Weixiu Luo, Per Karlsson, Jacquie Chirgwin, Stefan Aebi, Guy Jérusalem, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair M. Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Séamus O’Reilly, Vincenzo Di Lauro, Andrea Gombos, Thomas Ruhstaller, Harold J. Burstein, Karin Ribi, Jürg Bernhard, Giuseppe Viale, Rudolf Maibach, Manuela Rabaglio, Richard D. Gelber, Alan S. Coates, Angelo Di Leo, Meredith M. Regan, Aron Goldhirsch, A. Vandebroek, Martine Berlière, C. Mitine, Peter Vuylsteke, Marleen Borms, Randal D’hondt, Philippe Glorieux, Jeroen Mebis, Didier Verhoeven, Michael Coibion, Frédéric Forget, Lionel Duck, Didier Verhoeven, Wim Wyendaele, Annelore Barbeaux, Jean-Paul Salmon, Patrick Berteloot, Joanna Vermeij, Vincent R. Richard, Saverio Cinieri, Lorenzo Gianni, Mario Clerico, Graziella Pinotti, Antônio Bernardo, Laura Biganzoli, Alessandra Gennari, Claudio Graiff, Dino Amadori, Rodolfo Passalacqua, John Forbes, Prudence A. Francis, Serene S. Foo, Frances Boyle, Andrew Redfern, André van der Westhuizen, Craig Lewis, Sharad Sharma, Philip Beale, Ian Byard, Stephen Begbie, Frank Sardelic, Ehtesham Abdi, D.D. Clark, Aaron Chindewere, Stephen Della‐Fiorentina, Ray Asghari, Mohammed Islam, Lee Na Teo, Shane White, Linda Gilbert, Katherine Gardner, Catarina Uhlmann, Daniel Rauch, Meinrad Mannhart, Katharina Buser, Konstantin J. Dedes, Andreas Mueller, Christoph Rageth, Stephanie von Orelli, Hans Joerg Senn, Olivia Pagani, A Pedrazzini, Christoph Rochlitz, Alexandre Bodmer, Sandro Anchisi, Khalil Zaman, Roger von Moos, Daniel Betticher, Elena Kralidas, Răzvan Popescu, Mathias K. Fehr, Per Olof Nyman, Anja Jungquist, Chaido Chamalidou, Theodoros Foukakis, Charlotta Dabrosin, Antonis Valachis, Istvan Lang, Zsuzsanna Kahán, Javier Retamales, Ulloa Roberto Torres, Marcela Fritis, Sebastián Solé, Soledad Torres, Jaime Letzkus, Paula Escobar, Ines Vigneaux, Jorge Arancibia, Juana Bernardita Cardemil, Patricio Huidobro, Henry Gómez, Julie Wetter, Daniel Vorobiof, G. B. McMichael, Justus Apffelstaedt, И. К. Воротников, Joel Schwartz, Thomas H. Openshaw, Hervé Bonnefoi, Jean-Philippe Jacquin, Natalie Bonichon-Lamichhane, Simona Borstner, Ashwini Budrukkar, Marianne Ewertz, Oscar Zambrano Quispe, Peter Michael Vestlev, Hella Danø, Ditte Nielsen, Erik Jakobsen, Inger Hoejris, Jurij Bogovic, Britta Bjerregaard Jensen, Knud Aage Møller, Eric Lars Stenbygaard, Ravi Sharma, C. Bedi, Maria Bews-Hair, Glyn Neades, Mike McKirdy, Matthew Barber, Abdulla Alhasso, Diana Ritchie, Judith Fraser, Lucy Scott, Frances Yuille, Alison Lannigan, Dermot Murphy, Mike Shere, Christian Jackisch, Oliver Tomé, S Steer, Doris Augustin, Kristina Lübbe, Christian Jackisch, Heike Köcker-Korus, Jörg-Uwe Deuker, Andrea Stefek, Marianne Just, Uwe Rhein, Christina Bechtner, Dirk-Toralf Baerens, Iris Schrader, Eva‐Maria Grischke, Ralf Lorenz, Wolfgang Dietz, Jörg Thomalla, Jörg Schilling, A. Rempen, Heiko Graf, Gabriele Doering, Steffi Busch, Georg Heinrich, Hans Tesch, Christoph Uleer, Petra Krabisch, Siegfried Rösel, Christian M. Kurbacher, Horst Ostertag, Klaus-M Josten, Carsten Hielscher, Isolde Gröll, Ute Marie Mattner, A. Prechtl, Tilmann Lantzsch, Eva Ciruelos, Isabel Garau, Meritxell Bellet, Miguel Ángel Climent, Rafael López‐López, Juan Antonio Virizuela, Begoña Bermejo, Noelia Martínez-Jáñez, Kepa Amillano, Raúl Márquez, Joan Dorca, María José Godes, Santiago González, Shinji Ohno, Tomoyuki Aruga, Daisuke Yotsumoto, Yutaka Yamamoto, Tomohiko Aihara, Takashi Morimoto, Hiroko Bando, Norikazu Masuda, Masakazu Toi, Kenjiro Aogi, Nobuaki Sato, Morihito Okada, Masato Takahashi, Eriko Tokunaga, Hiroji Iwata, Takashi Fujita, Michael Fridrik, Gunda Pristauz, Claudia Hackl, Christian F. Singer, V. Wette, Michael Gnant, Josef Thaler, Richard Greil, Burghard Abendstein, Dietmar Heck, D. Manfreda, P. Sevelda, I. Thiel, F Tuttlies, Herbert Stöger, W. Neunteufel, John Crown, John Kennedy, Arnold Hill, John McCaffrey, Conleth G. Murphy, Linda Coate, Maccon Keane, Michael J. Martin, Miriam O’Connor, Karen Duffy, Barbara Ruepp, Martine Piccart, Dimitrios Zardavas,
Tópico(s)Advanced Breast Cancer Therapies
ResumoBackground In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. Methods We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4–6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1–4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. Findings Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53–72), disease-free survival was 85·8% (95% CI 84·2–87·2) in the intermittent letrozole group compared with 87·5% (86·0–88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93–1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3–5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3–5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3–5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3–5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). Interpretation In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. Funding Novartis and the International Breast Cancer Study Group.
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