Aspirin Use and Survival After Colon Cancer
Original Investigation Research
14. Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res. 2013;191:39-65.
22. Buskens CJ, Van Rees BP, Sivula A, et al. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology. 2002;122(7):1800-1807.
15. FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71(3):676-688.
23. de Jong AE, van Puijenbroek M, Hendriks Y, et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10(3):972-980.
16. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;69(6):1366-1372.
24. Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer. 2005;4(3):255-265.
in the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2012;26(4):e1-e13.
17. 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. 18. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal–like transition and promotes metastasis. Cancer Cell. 2011;20(5):576-590. 19. Placke T, Örgel M, Schaller M, et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012;72(2):440-448. 20. de Kruijf EM, van Nes JG, Sajet A, et al. The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res. 2010;16(4):1272-1280. 21. Chew SF, Kanaan C, Tait BD. HLA expression and cancer—14th IHIWS immunohistochemistry quality control exercise exchange results. Tissue Antigens. 2007;69(suppl 1):248-251.
25. van Eijk R, Stevens L, Morreau H, van Wezel T. Assessment of a fully automated high-throughput DNA extraction method from formalin-fixed, paraffin-embedded tissue for KRAS, and BRAF somatic mutation analysis. Exp Mol Pathol. 2013;94(1):121-125. 26. van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non–small-cell lung cancer using allele-specific qPCR. PLoS One. 2011;6(3):e17791. 27. Speetjens FM, de Bruin EC, Morreau H, et al. Clinical impact of HLA class I expression in rectal cancer. Cancer Immunol Immunother. 2008;57(5):601-609. 28. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer. 2006;118(1):6-10.
outcome in colorectal carcinoma. World J Gastroenterol. 2012;18(15):1793-1799. 30. Fariña Sarasqueta A, Zeestraten EC, van Wezel T, et al. PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. Cell Oncol (Dordr). 2011;34(6):523-531. 31. Domingo E, Church DN, Sieber O, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297-4305. 32. Akalay I, Janji B, Hasmim M, et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell–mediated lysis. Cancer Res. 2013;73(8):2418-2427. 33. Holmes MD, Chen WY, Schnitt SJ, et al. COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat. 2011;130(2):657-662. 34. Jonsson F, Yin L, Lundholm C, Smedby KE, Czene K, Pawitan Y. Low-dose aspirin use and cancer characteristics: a population-based cohort study. Br J Cancer. 2013;109(7):1921-1925. 35. Nishihara R, Lochhead P, Kuchiba A, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA. 2013;309(24): 2563-2571. 36. Yood MU, Campbell UB, Rothman KJ, et al. Using prescription claims data for drugs available over-the-counter (OTC). Pharmacoepidemiol Drug Saf. 2007;16(9):961-968.
29. Al-Maghrabi J, Buhmeida A, Emam E, et al. Cyclooxygenase-2 expression as a predictor of
Invited Commentary
Aspirin as Adjuvant Therapy for Stage III Colon Cancer Standard of Care? Alfred I. Neugut, MD, PhD
When one sees a patient newly diagnosed as having cancer, after finishing the initial discussion and treatment plan, it is almost inevitable that the patient or a family member will inquire, “What else should he [or she] do?” The implication is that, aside Related article page 732 from whatever benefits orthodox therapy—surgery, chemotherapy, radiotherapy—may confer, there are also additional benefits to be gained from lifestyle or behavioral changes, such as diet. I suppose that such beliefs stem from the remarkable benefits in this arena that one can see in cardiovascular disease, where diet, physical activity, and aspirin use are all routine, well accepted, and evidence-based parts of the post–myocardial infarction management landscape. It is no wonder that a patient with breast, colon, prostate, or lung cancer should not anticipate that similar recommendations would be forthcoming.1 Research on lifestyle and behavioral changes for cancer survivors has focused for the most part on how they can affect secjamainternalmedicine.com
ondary prevention, that is, risk of second malignant neoplasms. One notable success in this area is that strong evidence suggests that those with tobacco-related malignant diseases should discontinue smoking. But there are few circumstances where data support that such changes can have an impact on actual survival outcomes to the point where they have become standard of care for the therapy of a malignant disease. Perhaps that is about to change. In this issue of JAMA Internal Medicine, Reimers et al2 report the latest in a series of articles that have described the use and survival benefits of aspirin in patients with stage III colon cancer. This is a setting in which the recurrence and mortality rate, depending on the exact characteristics of the patient and the tumor, can range from 40% to 80% with surgery alone, and in which adjuvant chemotherapy can reduce these risks by 25% to 35%, that is, to 30% to 60%. Thus, the current standard of care for patients with stage III colon cancer is to recommend adjuvant chemotherapy with a fluoropyrimidine-based regimen. JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
739
Research Original Investigation
Aspirin Use and Survival After Colon Cancer
Table. Study Design and Results for 5 Observational Studies That Assessed the Impact of Postdiagnosis Aspirin Use on Colorectal Cancer Survival HR (95% CI) Deaths From Colorectal Cancer, No.
Colorectal Cancer Mortality
Colorectal Cancer Mortality Without Prior Aspirin Use 0.53 (0.33-0.86)
Source
Design
Country
Chan et al,4 2009
Cohort
United States
222
0.71 (0.53-0.95)
Bastiaannet et al,6 2012
Cohort
Netherlands
656
0.47 (0.26-0.80)
NS
McGowan et al,5 2013
Cohort
Scotland
1021
NS
0.58 (0.45-0.75)
Domingo et al,7 2013
Cohort
United Kingdom
173
0.11 (0.001-0.832) In those with PIK3CA mutations 0.94 (0.59-1.49) for PIK3CA wild-typea
NS
Reimers et al,2 2014
Cohort
Netherlands
465
0.53 (0.38-0.74) For those with tumors that express HLA class I antigen 1.03 (0.66-1.61) for nonexpressors
NS
Abbreviations: HR, hazard ratio; NS, not stated. a
The HR here is for recurrence-free survival.
Aspirin has long been known to reduce the incidence of colorectal cancer.3 However, use in the therapeutic setting was first raised in an article4 in JAMA in 2009 in which it was suggested that those with stage III colon cancer who used aspirin had a 29% improvement in survival outcomes, while those who initiated the use of aspirin (ie, had not used aspirin prediagnosis) obtained a 47% improvement in mortality outcomes. Most important, this mortality benefit was restricted to those whose tumor overexpressed cyclooxygenase-2 (COX-2), the putative mechanism by which aspirin was hypothesized to exert its beneficial effects. While extremely intriguing, this single study remained too uncertain on which to base a change in treatment or standard of care. Nonetheless, it did precipitate 2 randomized clinical trials, 1 in Asia and 1 an Intergroup randomized trial in the United States (using celecoxib rather than aspirin as the COX-2 inhibitor). However, given the sample size requirements and follow-up times for survival in these trials, it will be many years before either study provides data for conclusive recommendations. In the meantime, several recent observational studies5-7 have confirmed the therapeutic benefits of aspirin in improving survival for patient with stage III colon cancer, including the article by Reimers et al2 in this issue of JAMA Internal Medicine. For the most part, the benefits are similar to those described in the 2009 article4 and are strongest if aspirin use is initiated after colon cancer diagnosis (Table); prior aspirin use does not improve survival and may reduce subsequent survival benefit.8 Most of the studies attribute its benefit to survival as a COX-2 inhibitor, although evidence has also been adduced for its anticancer effect through an antimetastatic mechanism, or through some as-yet unknown pathway. Furthermore, these survival benefits are nontrivial: almost across the board, their magnitude parallels or even exceeds the benefits adduced by normative cytotoxic chemotherapy. Certainly, if one just simplistically does a back-of-the-envelope risk-benefit analysis of aspirin use vs chemotherapy, one must begin to wonder whether it is not time to make aspirin a part of the conventional standard of care for this disease, given the relatively low risk profile of aspirin. We live in an era of evidence-based medicine, and, in oncology, more than in most medical specialties, we tend to await 740
randomized data before creating a new standard of care. But is this really so? And is it always essential? How many treatments in oncology are premised on phase 2 trial data that are also fundamentally nonrandomized uncontrolled data? Indeed, one could argue that the treatment of stage II colon cancer, while controversial, has less clear-cut evidence to support it than now exists for aspirin in the context of stage III colon cancer. For while the evidence is observational, the evidence is bolstered by the specificity derived from the linkage to biomarker data—for example, the demonstration that aspirin prolonged survival only in those with tumors with COX-2 overexpression4 or in those with the PIK3CA mutation associated with COX-2,7 or, as in the article by Reimers et al,2 in those who expressed HLA class I antigen. For my own patients, I have so far not recommended aspirin. But I think, based on current evidence, that if I personally had a stage III tumor, I would add aspirin to my FOLFOX (folinic acid–fluorouracil–oxaliplatin) adjuvant therapy. And if I feel that way for myself, should I not convey that to my patients? We need to have the guideline reviews that make these things official, for example, Cochrane Review, American Society of Clinical Oncology, National Comprehensive Cancer Network. While aspirin has significant data demonstrating its benefits as a chemopreventive agent for colon cancer, its adverse effects (gastrointestinal tract bleeding, intracranial hemorrhage, gastritis) outweigh its benefits in the prevention setting (eg, giving aspirin to 2000 average-risk adults might prevent 1 colorectal cancer at the expense of multiple cases of gastrointestinal tract bleeding, stroke). However, in the setting of patients with stage III colon cancer, who have significant risks for mortality, the risks of a daily aspirin seem minor relative to the putative gains in mortality observed in the studies described herein. Thus, this risk-benefit ratio would justify, until further studies are forthcoming, that tissue biomarker studies are not necessary to define a subgroup to treat. Clearly, though, that will be an important area for further research. But for now, as far as I am concerned, when a patient or patient’s spouse asks, “What else should he be doing, Doctor?”—I will have a ready response.
JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
jamainternalmedicine.com
Aspirin Use and Survival After Colon Cancer
ARTICLE INFORMATION Author Affiliation: Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeon, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. Corresponding Author: Alfred I. Neugut, MD, PhD, Columbia University Medical Center, 722 W 168th St, Room 725, New York NY 10032 (ain1@cumc .columbia.edu). Published Online: March 31, 2014. doi:10.1001/jamainternmed.2013.14544. Conflict of Interest Disclosures: None reported. REFERENCES 1. Neugut AI. Preventive oncology: lessons from preventive cardiology. Lancet. 2004;363(9414): 1004-1005.
jamainternalmedicine.com
Original Investigation Research
2. Reimers MS, Bastiaannet E, Langley RE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer [published online March 31, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.511. 3. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet. 2010;376(9754):17411750. 4. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649-658.
6. Bastiaannet E, Swampier K, Dekker’s OM, et al. Use of aspirin post diagnosis improves survival for colon cancer patients. Br J Cancer. 2012;106(9):1564-1570. 7. Domingo E, Church DN, Siebel O, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297-4305. 8. Din FV, Theodoratos E, Farrington SM, et al. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut. 2010;59(12):16701679.
5. McGowan C, Munro AJ, Donna PT, Steele RJ. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Ear J Cancer. 2013;49(5):1049-1057.
JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
741
Original Investigation Research
14. Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res. 2013;191:39-65.
22. Buskens CJ, Van Rees BP, Sivula A, et al. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology. 2002;122(7):1800-1807.
15. FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71(3):676-688.
23. de Jong AE, van Puijenbroek M, Hendriks Y, et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10(3):972-980.
16. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;69(6):1366-1372.
24. Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer. 2005;4(3):255-265.
in the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2012;26(4):e1-e13.
17. 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. 18. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal–like transition and promotes metastasis. Cancer Cell. 2011;20(5):576-590. 19. Placke T, Örgel M, Schaller M, et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012;72(2):440-448. 20. de Kruijf EM, van Nes JG, Sajet A, et al. The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res. 2010;16(4):1272-1280. 21. Chew SF, Kanaan C, Tait BD. HLA expression and cancer—14th IHIWS immunohistochemistry quality control exercise exchange results. Tissue Antigens. 2007;69(suppl 1):248-251.
25. van Eijk R, Stevens L, Morreau H, van Wezel T. Assessment of a fully automated high-throughput DNA extraction method from formalin-fixed, paraffin-embedded tissue for KRAS, and BRAF somatic mutation analysis. Exp Mol Pathol. 2013;94(1):121-125. 26. van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non–small-cell lung cancer using allele-specific qPCR. PLoS One. 2011;6(3):e17791. 27. Speetjens FM, de Bruin EC, Morreau H, et al. Clinical impact of HLA class I expression in rectal cancer. Cancer Immunol Immunother. 2008;57(5):601-609. 28. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer. 2006;118(1):6-10.
outcome in colorectal carcinoma. World J Gastroenterol. 2012;18(15):1793-1799. 30. Fariña Sarasqueta A, Zeestraten EC, van Wezel T, et al. PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. Cell Oncol (Dordr). 2011;34(6):523-531. 31. Domingo E, Church DN, Sieber O, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297-4305. 32. Akalay I, Janji B, Hasmim M, et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell–mediated lysis. Cancer Res. 2013;73(8):2418-2427. 33. Holmes MD, Chen WY, Schnitt SJ, et al. COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat. 2011;130(2):657-662. 34. Jonsson F, Yin L, Lundholm C, Smedby KE, Czene K, Pawitan Y. Low-dose aspirin use and cancer characteristics: a population-based cohort study. Br J Cancer. 2013;109(7):1921-1925. 35. Nishihara R, Lochhead P, Kuchiba A, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA. 2013;309(24): 2563-2571. 36. Yood MU, Campbell UB, Rothman KJ, et al. Using prescription claims data for drugs available over-the-counter (OTC). Pharmacoepidemiol Drug Saf. 2007;16(9):961-968.
29. Al-Maghrabi J, Buhmeida A, Emam E, et al. Cyclooxygenase-2 expression as a predictor of
Invited Commentary
Aspirin as Adjuvant Therapy for Stage III Colon Cancer Standard of Care? Alfred I. Neugut, MD, PhD
When one sees a patient newly diagnosed as having cancer, after finishing the initial discussion and treatment plan, it is almost inevitable that the patient or a family member will inquire, “What else should he [or she] do?” The implication is that, aside Related article page 732 from whatever benefits orthodox therapy—surgery, chemotherapy, radiotherapy—may confer, there are also additional benefits to be gained from lifestyle or behavioral changes, such as diet. I suppose that such beliefs stem from the remarkable benefits in this arena that one can see in cardiovascular disease, where diet, physical activity, and aspirin use are all routine, well accepted, and evidence-based parts of the post–myocardial infarction management landscape. It is no wonder that a patient with breast, colon, prostate, or lung cancer should not anticipate that similar recommendations would be forthcoming.1 Research on lifestyle and behavioral changes for cancer survivors has focused for the most part on how they can affect secjamainternalmedicine.com
ondary prevention, that is, risk of second malignant neoplasms. One notable success in this area is that strong evidence suggests that those with tobacco-related malignant diseases should discontinue smoking. But there are few circumstances where data support that such changes can have an impact on actual survival outcomes to the point where they have become standard of care for the therapy of a malignant disease. Perhaps that is about to change. In this issue of JAMA Internal Medicine, Reimers et al2 report the latest in a series of articles that have described the use and survival benefits of aspirin in patients with stage III colon cancer. This is a setting in which the recurrence and mortality rate, depending on the exact characteristics of the patient and the tumor, can range from 40% to 80% with surgery alone, and in which adjuvant chemotherapy can reduce these risks by 25% to 35%, that is, to 30% to 60%. Thus, the current standard of care for patients with stage III colon cancer is to recommend adjuvant chemotherapy with a fluoropyrimidine-based regimen. JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
739
Research Original Investigation
Aspirin Use and Survival After Colon Cancer
Table. Study Design and Results for 5 Observational Studies That Assessed the Impact of Postdiagnosis Aspirin Use on Colorectal Cancer Survival HR (95% CI) Deaths From Colorectal Cancer, No.
Colorectal Cancer Mortality
Colorectal Cancer Mortality Without Prior Aspirin Use 0.53 (0.33-0.86)
Source
Design
Country
Chan et al,4 2009
Cohort
United States
222
0.71 (0.53-0.95)
Bastiaannet et al,6 2012
Cohort
Netherlands
656
0.47 (0.26-0.80)
NS
McGowan et al,5 2013
Cohort
Scotland
1021
NS
0.58 (0.45-0.75)
Domingo et al,7 2013
Cohort
United Kingdom
173
0.11 (0.001-0.832) In those with PIK3CA mutations 0.94 (0.59-1.49) for PIK3CA wild-typea
NS
Reimers et al,2 2014
Cohort
Netherlands
465
0.53 (0.38-0.74) For those with tumors that express HLA class I antigen 1.03 (0.66-1.61) for nonexpressors
NS
Abbreviations: HR, hazard ratio; NS, not stated. a
The HR here is for recurrence-free survival.
Aspirin has long been known to reduce the incidence of colorectal cancer.3 However, use in the therapeutic setting was first raised in an article4 in JAMA in 2009 in which it was suggested that those with stage III colon cancer who used aspirin had a 29% improvement in survival outcomes, while those who initiated the use of aspirin (ie, had not used aspirin prediagnosis) obtained a 47% improvement in mortality outcomes. Most important, this mortality benefit was restricted to those whose tumor overexpressed cyclooxygenase-2 (COX-2), the putative mechanism by which aspirin was hypothesized to exert its beneficial effects. While extremely intriguing, this single study remained too uncertain on which to base a change in treatment or standard of care. Nonetheless, it did precipitate 2 randomized clinical trials, 1 in Asia and 1 an Intergroup randomized trial in the United States (using celecoxib rather than aspirin as the COX-2 inhibitor). However, given the sample size requirements and follow-up times for survival in these trials, it will be many years before either study provides data for conclusive recommendations. In the meantime, several recent observational studies5-7 have confirmed the therapeutic benefits of aspirin in improving survival for patient with stage III colon cancer, including the article by Reimers et al2 in this issue of JAMA Internal Medicine. For the most part, the benefits are similar to those described in the 2009 article4 and are strongest if aspirin use is initiated after colon cancer diagnosis (Table); prior aspirin use does not improve survival and may reduce subsequent survival benefit.8 Most of the studies attribute its benefit to survival as a COX-2 inhibitor, although evidence has also been adduced for its anticancer effect through an antimetastatic mechanism, or through some as-yet unknown pathway. Furthermore, these survival benefits are nontrivial: almost across the board, their magnitude parallels or even exceeds the benefits adduced by normative cytotoxic chemotherapy. Certainly, if one just simplistically does a back-of-the-envelope risk-benefit analysis of aspirin use vs chemotherapy, one must begin to wonder whether it is not time to make aspirin a part of the conventional standard of care for this disease, given the relatively low risk profile of aspirin. We live in an era of evidence-based medicine, and, in oncology, more than in most medical specialties, we tend to await 740
randomized data before creating a new standard of care. But is this really so? And is it always essential? How many treatments in oncology are premised on phase 2 trial data that are also fundamentally nonrandomized uncontrolled data? Indeed, one could argue that the treatment of stage II colon cancer, while controversial, has less clear-cut evidence to support it than now exists for aspirin in the context of stage III colon cancer. For while the evidence is observational, the evidence is bolstered by the specificity derived from the linkage to biomarker data—for example, the demonstration that aspirin prolonged survival only in those with tumors with COX-2 overexpression4 or in those with the PIK3CA mutation associated with COX-2,7 or, as in the article by Reimers et al,2 in those who expressed HLA class I antigen. For my own patients, I have so far not recommended aspirin. But I think, based on current evidence, that if I personally had a stage III tumor, I would add aspirin to my FOLFOX (folinic acid–fluorouracil–oxaliplatin) adjuvant therapy. And if I feel that way for myself, should I not convey that to my patients? We need to have the guideline reviews that make these things official, for example, Cochrane Review, American Society of Clinical Oncology, National Comprehensive Cancer Network. While aspirin has significant data demonstrating its benefits as a chemopreventive agent for colon cancer, its adverse effects (gastrointestinal tract bleeding, intracranial hemorrhage, gastritis) outweigh its benefits in the prevention setting (eg, giving aspirin to 2000 average-risk adults might prevent 1 colorectal cancer at the expense of multiple cases of gastrointestinal tract bleeding, stroke). However, in the setting of patients with stage III colon cancer, who have significant risks for mortality, the risks of a daily aspirin seem minor relative to the putative gains in mortality observed in the studies described herein. Thus, this risk-benefit ratio would justify, until further studies are forthcoming, that tissue biomarker studies are not necessary to define a subgroup to treat. Clearly, though, that will be an important area for further research. But for now, as far as I am concerned, when a patient or patient’s spouse asks, “What else should he be doing, Doctor?”—I will have a ready response.
JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
jamainternalmedicine.com
Aspirin Use and Survival After Colon Cancer
ARTICLE INFORMATION Author Affiliation: Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeon, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. Corresponding Author: Alfred I. Neugut, MD, PhD, Columbia University Medical Center, 722 W 168th St, Room 725, New York NY 10032 (ain1@cumc .columbia.edu). Published Online: March 31, 2014. doi:10.1001/jamainternmed.2013.14544. Conflict of Interest Disclosures: None reported. REFERENCES 1. Neugut AI. Preventive oncology: lessons from preventive cardiology. Lancet. 2004;363(9414): 1004-1005.
jamainternalmedicine.com
Original Investigation Research
2. Reimers MS, Bastiaannet E, Langley RE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer [published online March 31, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.511. 3. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet. 2010;376(9754):17411750. 4. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649-658.
6. Bastiaannet E, Swampier K, Dekker’s OM, et al. Use of aspirin post diagnosis improves survival for colon cancer patients. Br J Cancer. 2012;106(9):1564-1570. 7. Domingo E, Church DN, Siebel O, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297-4305. 8. Din FV, Theodoratos E, Farrington SM, et al. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut. 2010;59(12):16701679.
5. McGowan C, Munro AJ, Donna PT, Steele RJ. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Ear J Cancer. 2013;49(5):1049-1057.
JAMA Internal Medicine May 2014 Volume 174, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/16/2015
741
