JNCI J Natl Cancer Inst (2015) 107(8): djv149 doi: 10.1093/jnci/djv149 First published online June 05, 2015 Correspondence
correspondence RE: Aspirin and COX-2 Inhibitor Use in Patients With Stage III Colon Cancer
Correspondence to: Margaret Lee, MBBS, BMedSci, Walter and Eliza Hall Institute of Medical Research (PG), Department of Medical Oncology (ML), The Royal Melbourne Hospital, 9 Darcy Lane, Kensington, Vic, Australia (e-mail: [email protected]).
There continues to be interest in the potential for aspirin and COX-2 inhibitors to prevent recurrence and/or death in patients with early-stage colon cancer, with the study by Ng et al. (1) providing further support. Unfortunately this study only adds to a confusing literature, with minimal data on agents provided and no contribution to the emerging evidence that tumor molecular determinants have a major impact on treatment benefit. The study by Ng et al. (1) retrieved quite limited available data related to aspirin and COX-2 inhibitor use from a cohort of patients with colon cancer enrolled in an adjuvant chemotherapy study. Data was collected from self-administered questionnaires, midway through and six months after chemotherapy completion. There was no data on prediagnosis use, dosages administered, or duration of use, an obvious concern as previous studies of aspirin in colorectal cancer prevention indicate both a dose and duration effect (2). For unclear reasons “consistent” aspirin use was defined as use at both timepoints, whereas “consistent” COX-2 inhibitor use was based only on usage at the second timepoint. Such apparently arbitrary definitions are notable in a study where the 95% confidence intervals on most of the reported data approach or indeed exceed 1. Further, the standard way of reporting the latter is to say there is no association, rather than to include these statistically non-significant results alongside the statistically significant associations, which the authors have chosen to do in the abstract. Multiple biomarkers have been reported for aspirin and COX-2 inhibitor benefit in the prevention and treatment of colorectal cancer (CRC) recurrence. Liao et al. (3) reported a marked reduction in death (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.06 to 0.61, P < .001) from aspirin use in patients with a PIK3CA mutation, which occurs in approximately 15% of CRC, and no benefit in wild-type tumors. Contrastingly, Reimers et al. reported the opposite: no benefit in patients with a PIK3CA mutation (HR = 0.73, 95% CI = 0.33 to 1.63, P = .44) and an overall
survival benefit in patients with wild-type tumors (HR = 0.55, 95% CI = 0.40 to 0.74, P < .001) (4). A more consistent impact of COX-2 expression has been seen on benefit from COX-2 inhibitors, including a prospective randomized phase III trial (5) where prevention of CRC recurrence by rofecoxib was observed in the first year of follow-up. While this study was terminated early, it is surprising that these results were not alluded to by Ng et al. While the findings of Ng et al. (1) support the overall literature, they arguably add little to our understanding of how to use these agents to help our patients, particularly given the borderline or non-significant nature of their results. The contradictory nature of studies in this area, particularly regarding the potentially major impact of tumor PI3KCA mutations, highlights the unreliable nature of these post hoc analyses. Rather than further such analyses, which will continue to leave the clinical community wondering how to advise their patients, the focus should be on large prospective studies that will provide reliable information, and data from these are urgently awaited.
Notes References 1. Ng K, Meyerhardt JA, Chan AT, et al. Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst. 2015;107(1):dju345 doi:10.1093/jnci/dju345. 2. Flossmann E, Rothwell PM. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Lancet. 2007;369(9573):1603–1613. 3. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596–1606. 4. Reimers MS, Bastiaannet E, Langley RE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med. 2014;174(5):732–739. 5. Midgley RS, McConkey CC, Johnstone EC, et al. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of VICTOR trial. J Clin Oncol. 2010;28(30):4575–4580.
Received: March 29, 2015; Accepted: May 5, 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 1
correspondence
Affiliations of authors: Walter and Eliza Hall Institute of Medical Research (PG), Department of Medical Oncology (ML), The Royal Melbourne Hospital, Kensington, Vic, Australia.
Downloaded from http://jnci.oxfordjournals.org/ at University of Alabama at Birmingham on July 28, 2015
Margaret Lee, Peter Gibbs
correspondence RE: Aspirin and COX-2 Inhibitor Use in Patients With Stage III Colon Cancer
Correspondence to: Margaret Lee, MBBS, BMedSci, Walter and Eliza Hall Institute of Medical Research (PG), Department of Medical Oncology (ML), The Royal Melbourne Hospital, 9 Darcy Lane, Kensington, Vic, Australia (e-mail: [email protected]).
There continues to be interest in the potential for aspirin and COX-2 inhibitors to prevent recurrence and/or death in patients with early-stage colon cancer, with the study by Ng et al. (1) providing further support. Unfortunately this study only adds to a confusing literature, with minimal data on agents provided and no contribution to the emerging evidence that tumor molecular determinants have a major impact on treatment benefit. The study by Ng et al. (1) retrieved quite limited available data related to aspirin and COX-2 inhibitor use from a cohort of patients with colon cancer enrolled in an adjuvant chemotherapy study. Data was collected from self-administered questionnaires, midway through and six months after chemotherapy completion. There was no data on prediagnosis use, dosages administered, or duration of use, an obvious concern as previous studies of aspirin in colorectal cancer prevention indicate both a dose and duration effect (2). For unclear reasons “consistent” aspirin use was defined as use at both timepoints, whereas “consistent” COX-2 inhibitor use was based only on usage at the second timepoint. Such apparently arbitrary definitions are notable in a study where the 95% confidence intervals on most of the reported data approach or indeed exceed 1. Further, the standard way of reporting the latter is to say there is no association, rather than to include these statistically non-significant results alongside the statistically significant associations, which the authors have chosen to do in the abstract. Multiple biomarkers have been reported for aspirin and COX-2 inhibitor benefit in the prevention and treatment of colorectal cancer (CRC) recurrence. Liao et al. (3) reported a marked reduction in death (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.06 to 0.61, P < .001) from aspirin use in patients with a PIK3CA mutation, which occurs in approximately 15% of CRC, and no benefit in wild-type tumors. Contrastingly, Reimers et al. reported the opposite: no benefit in patients with a PIK3CA mutation (HR = 0.73, 95% CI = 0.33 to 1.63, P = .44) and an overall
survival benefit in patients with wild-type tumors (HR = 0.55, 95% CI = 0.40 to 0.74, P < .001) (4). A more consistent impact of COX-2 expression has been seen on benefit from COX-2 inhibitors, including a prospective randomized phase III trial (5) where prevention of CRC recurrence by rofecoxib was observed in the first year of follow-up. While this study was terminated early, it is surprising that these results were not alluded to by Ng et al. While the findings of Ng et al. (1) support the overall literature, they arguably add little to our understanding of how to use these agents to help our patients, particularly given the borderline or non-significant nature of their results. The contradictory nature of studies in this area, particularly regarding the potentially major impact of tumor PI3KCA mutations, highlights the unreliable nature of these post hoc analyses. Rather than further such analyses, which will continue to leave the clinical community wondering how to advise their patients, the focus should be on large prospective studies that will provide reliable information, and data from these are urgently awaited.
Notes References 1. Ng K, Meyerhardt JA, Chan AT, et al. Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst. 2015;107(1):dju345 doi:10.1093/jnci/dju345. 2. Flossmann E, Rothwell PM. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Lancet. 2007;369(9573):1603–1613. 3. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596–1606. 4. Reimers MS, Bastiaannet E, Langley RE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med. 2014;174(5):732–739. 5. Midgley RS, McConkey CC, Johnstone EC, et al. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of VICTOR trial. J Clin Oncol. 2010;28(30):4575–4580.
Received: March 29, 2015; Accepted: May 5, 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 1
correspondence
Affiliations of authors: Walter and Eliza Hall Institute of Medical Research (PG), Department of Medical Oncology (ML), The Royal Melbourne Hospital, Kensington, Vic, Australia.
Downloaded from http://jnci.oxfordjournals.org/ at University of Alabama at Birmingham on July 28, 2015
Margaret Lee, Peter Gibbs
