Marco Colleoni1, Kathryn P Gray2, Shari Gelber2, István Láng2, Beat Thürlimann2, Lorenzo Gianni2, Ehtesham A Abdi2, Henry L Gomez2, Barbro K Linderholm2, Fabio Puglisi2, Carlo Tondini2, Elena Kralidis2, Alexandru Eniu2, Katia Cagossi2, Daniel Rauch2, Jacquie Chirgwin2, Richard D Gelber2, Meredith M Regan2, Alan S Coates2, Karen N Price2, Giuseppe Viale2, Aron Goldhirsch2. 1. Marco Colleoni, Giuseppe Viale, and Aron Goldhirsch, European Institute of Oncology; Giuseppe Viale, University of Milan, Milan; Lorenzo Gianni, Ospedale degli Infermi, Rimini; Fabio Puglisi, University Hospital of Udine, University of Udine, Udine; Carlo Tondini, Osp. Papa Giovanni XXIII, Bergamo; Katia Cagossi, Ospedale di Carpi, Carpi, Italy; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, Meredith M. Regan, and Karen N. Price, International Breast Cancer Study Group Statistical Center; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, and Meredith M. Regan, Dana-Farber Cancer Institute; Kathryn P. Gray and Richard D. Gelber, Harvard T.H. Chan School of Public Health; Richard D. Gelber and Meredith M. Regan, Harvard Medical School; Richard D. Gelber and Karen N. Price, Frontier Science and Technology Foundation, Boston, MA; István Láng, National Institute of Oncology, Budapest, Hungary; Beat Thürlimann, Kantonsspital, St Gallen; Beat Thürlimann, Elena Kralidis, and Daniel Rauch, Swiss Group for Clinical Cancer Research, Bern; Elena Kralidis, Kantonsspital Aarau, Aarau; Daniel Rauch, Spital Thun, Thun, Switzerland; Ehtesham A. Abdi, The Tweed Head Hospital, Tweed Heads, New South Wales and Griffith University, Southport, Queensland; Ehtesham A. Abdi and Jacquie Chirgwin, Australia and New Zealand Breast Cancer Trials Group; Jacquie Chirgwin, Box Hill and Maroondah Hospitals and Monash University, Melbourne, Victoria; Alan S. Coates, International Breast Cancer Study Group and University of Sydney School of Public Health, Sydney, New South Wales, Australia; Henry L. Gomez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Barbro K. Linderholm, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden; and Alexandru Eniu, Cancer Institute Ion Chiricuta, Cluj, Romania. marco.colleoni@ieo.it. 2. Marco Colleoni, Giuseppe Viale, and Aron Goldhirsch, European Institute of Oncology; Giuseppe Viale, University of Milan, Milan; Lorenzo Gianni, Ospedale degli Infermi, Rimini; Fabio Puglisi, University Hospital of Udine, University of Udine, Udine; Carlo Tondini, Osp. Papa Giovanni XXIII, Bergamo; Katia Cagossi, Ospedale di Carpi, Carpi, Italy; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, Meredith M. Regan, and Karen N. Price, International Breast Cancer Study Group Statistical Center; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, and Meredith M. Regan, Dana-Farber Cancer Institute; Kathryn P. Gray and Richard D. Gelber, Harvard T.H. Chan School of Public Health; Richard D. Gelber and Meredith M. Regan, Harvard Medical School; Richard D. Gelber and Karen N. Price, Frontier Science and Technology Foundation, Boston, MA; István Láng, National Institute of Oncology, Budapest, Hungary; Beat Thürlimann, Kantonsspital, St Gallen; Beat Thürlimann, Elena Kralidis, and Daniel Rauch, Swiss Group for Clinical Cancer Research, Bern; Elena Kralidis, Kantonsspital Aarau, Aarau; Daniel Rauch, Spital Thun, Thun, Switzerland; Ehtesham A. Abdi, The Tweed Head Hospital, Tweed Heads, New South Wales and Griffith University, Southport, Queensland; Ehtesham A. Abdi and Jacquie Chirgwin, Australia and New Zealand Breast Cancer Trials Group; Jacquie Chirgwin, Box Hill and Maroondah Hospitals and Monash University, Melbourne, Victoria; Alan S. Coates, International Breast Cancer Study Group and University of Sydney School of Public Health, Sydney, New South Wales, Australia; Henry L. Gomez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Barbro K. Linderholm, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden; and Alexandru Eniu, Cancer Institute Ion Chiricuta, Cluj, Romania.
Abstract
PURPOSE: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. PATIENTS AND METHODS: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. RESULTS: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). CONCLUSION: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.
RCT Entities:
PURPOSE: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. PATIENTS AND METHODS: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and humanepidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. RESULTS: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). CONCLUSION:CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.
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