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Aspirin as Adjuvant Therapy
for Colorectal Cancer
A Promising New Twist for an Old Drug
greater among patients who initiated aspirin use aftercancer diagnosis than among those who used it before, and the benefit was limited to those with tumors that VEN BEFORE THE TIME OF HIPPOCRATES, WILLOW EX-tracts, which contain salicylates, were used in medi- cine as analgesic, anti-inflammatory, and antipy- Although these findings are based on an observational retic agents. Acetylsalicylic acid was isolated in the study rather than an intervention trial, they meet many of mid-19th century, and since 1899 when it was patented, as- the usual criteria for acceptance as valid and causal. In a pirin has enjoyed global popularity. The relatively recent previous observational study of stage III colon cancer discovery of its antiplatelet activity has also led to the wide- patients treated in a randomized chemotherapy trial, spread use of aspirin as an antistroke and cardioprotective Fuchs et al12 found similar survival benefits among con- agent, but the list of its medical applications continues to sistent aspirin users. The finding that former aspirin users derived less benefit from subsequent aspirin use More than 30 years ago, Sporn et al2 coined the term than former nonusers did is biologically plausible, con- chemoprevention to describe and propose the use of oral sidering the tumors that developed in former users were drugs, chemicals, or supplements to reduce the risk of can- not prevented by aspirin use. Furthermore, the results cer. In the ensuing decades, chemoprevention research has were consistent across a variety of strata such as age, sex, generated high hopes and enormous increases in funding, and cancer site (colon vs rectum). Most compelling, the although only a few agents have shown efficacy in clinical benefits of aspirin use were observed only among patients trials, and of those few, most are too toxic for use by who had COX-2–expressing tumors, enhancing the bio- average-risk individuals. In addition to its other effects, logical plausibility of the findings.
aspirin has been shown to be a potentially effective chemo- In the study by Chan et al,11 the survival benefits of aspi- preventive agent for a number of cancers, but most clearly rin were similar in patients who received standard adju- for colorectal neoplasia.3 Numerous observational studies vant chemotherapy and those who did not, and in patients and randomized trials have demonstrated the efficacy of with stage I and stage II disease as well as those who had aspirin against the development of colorectal adenomas stage III disease at diagnosis. Thus, aspirin may have the and cancer through its actions as an inhibitor of the potential to be useful as adjuvant therapy not just for cyclooxygenase 2 (COX-2) pathway, which is overex- locally advanced disease but for early stage patients as pressed in 80% to 85% of colorectal cancers.4,5 Nonethe- well. Further studies are needed to confirm and extend less, aspirin is not recommended as a colorectal cancer these findings, and should also investigate the use of aspi- chemopreventive agent because of its adverse effects— rin as an agent in individuals with metastatic disease. One notably gastrointestinal irritation and bleeding.6 Specific such study is the Bolus, Infusional, or Capecitabine with COX-2 inhibitors, such as rofecoxib or celecoxib, which Camptosar-Celecoxib (BICC-C) study, which started in have less gastrointestinal toxicity than aspirin, also have 2003 and randomized patients with untreated metastatic failed to come into widespread use because of their unex- colorectal cancer to 1 of 3 chemotherapy regimens, and in addition randomized them to either a COX-2 inhibitor However, aspirin may now have yet another new role (celecoxib) or placebo.13 The COX-2 inhibitor portion of as a cancer treatment agent, at least in the adjuvant set- the study was discontinued in 2005 because the cardiovas- ting. In this issue of JAMA, Chan and colleagues11 report cular toxicity of the agent became apparent14 and initial that, among patients with colorectal cancer participating results of the trial indicated no survival benefit for the in a large cohort study, aspirin users had a 29% lower cancer-specific mortality and a 21% lower overall mortal- Author Affiliations: Department of Medicine and Herbert Irving Comprehensive
ity than nonusers. The reduction in mortality was even Cancer Center, College of Physicians and Surgeons, and the Department of Epi-demiology, Mailman School of Public Health, Columbia University, New York, NewYork.
See also p 649.
Corresponding Author: Alfred I. Neugut, MD, PhD, Columbia University Medical
Center, 630 W 168th St, New York, NY 10032 (ain1@columbia.edu).
688 JAMA, August 12, 2009—Vol 302, No. 6 (Reprinted)
2009 American Medical Association. All rights reserved.
A major recent priority in clinical oncology has been to de- REFERENCES
velop biomarkers for prognosis and to predict response to spe- 1. Vonkeman HE, van de Laar MA. Nonsteroidal anti-inflammatory drugs: ad-
cific interventions. This quest for so-called personalized medi- verse effects and their prevention [published online ahead of print September 27,2008]. Semin Arthritis Rheum. doi:10.1016/j.semarthrit.2008.08.001.
cine reflects the serious toxicity of most cancer drugs with the 2. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carci-
concomitant low response; better definition of who is likely nogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35(6):1332-1338.
to respond would identify a smaller subgroup that is much 3. Cuzick J, Otto F, Baron JA, et al. Aspirin and non-steroidal anti-inflammatory
more likely to benefit and spare other patients the toxicity.
drugs for cancer prevention: an international consensus statement. Lancet Oncol.
Such biomarkers reflect the longstanding success of hor- 2009;10(5):501-507.
4. Ogino S, Kirkner GJ, Nosho K, et al. Cyclooxygenase-2 expression is an inde-
mone receptors and ERBB2 status in breast cancer to deter- pendent predictor of poor prognosis in colon cancer. Clin Cancer Res. 2008; mine use of hormonal therapy and trastuzumab. In colorec- 14(24):8221-8227.
5. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN.
tal cancer, KRAS mutations have recently attained similar status Up-regulation of cyclooxygenase 2 gene expression in human colorectal adeno- as predictors of response to cetuximab and panitumumab,16 mas and adenocarcinomas. Gastroenterology. 1994;107(4):1183-1188.
6. Dube´ C, Rostom A, Lewin G, et al; US Preventive Services Task Force. The use
and BRAF mutations are likely to achieve similar status soon.17 of aspirin for primary prevention of colorectal cancer: a systematic review pre- The specificity of the response of colorectal cancers to aspi- pared for the US Preventive Services Task Force. Ann Intern Med. 2007;146 rin for patients in whom tumors overexpressed COX-211 sug- (5):365-375.
7. Bertagnolli MM, Eagle CJ, Zauber AG, et al; APC Study Investigators. Cele-
gests that this potential future treatment comes with its own coxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006; 355(9):873-884.
8. Arber N, Eagle CJ, Spicak J, et al; PreSAP Trial Investigators. Celecoxib for the
Cardiologists have made post–myocardial infarction pa- prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355(9): tients acutely aware of the need to alter their lifestyle, use 885-895.
9. Solomon SD, Wittes J, Finn PV, et al; Cross Trial Safety Assessment Group. Car-
aspirin prophylaxis, and stop smoking, even as patients re- diovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross ceive the standard cardiac treatments, such as stents and ␤- trial safety analysis. Circulation. 2008;117(16):2104-2113.
10. Baron JA, Sandler RS, Bresalier RS, et al; APPROVe Trial Investigators. A ran-
blockers. By recommending such behavior changes, cardi- domized trial of rofecoxib for the chemoprevention of colorectal adenomas.
ologists have empowered patients and their families to Gastroenterology. 2006;131(6):1674-1682.
participate more actively in their own healing. Similar be- 11. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of co-
lorectal cancer. JAMA. 2009;302(6):649-659.
havioral and lifestyle changes in cardiology also may be ap- 12. Fuchs CS, Meyerhardt JA, Heseltine DS, et al. Influence of regular aspirin use
propriate in oncology18 as oncology patients and their fami- on survival for patients with stage III colon cancer: findings from Intergroup TrialCALGB 89803. J Clin Oncol. 2005;23(16s):3530.
lies often seek similar means of controlling their outcomes.
13. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irino-
Only the rare cancer patient or next of kin does not ask at tecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of meta-static colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007; some time during the first encounter, after hearing the di- agnosis, stage, prognosis, and plans for chemotherapy, “What 14. Solomon SD, McMurray JJ, Pfeffer MA, et al; Adenoma Prevention with Cele-
else should be done doctor? What should be eaten?” coxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib ina clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352(11): To date, few studies have assessed the effects of such life- style factors on survival among colorectal cancer patients.
15. Fuchs C, Marshall J, Mitchell E, et al. Updated results of BICC-C study com-
paring first-line irinotecan/fluoropyrimidine combinations with or without cele-
Fuchs, Meyerhardt, and Chan have led the way with a series coxib in mCRC: updated efficacy data. J Clin Oncol. 2007;25(18S):4027.
of elegant observational studies on diet,19 physical activ- 16. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit
from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):
ity,20,21 obesity and weight loss,22,23 cigarette smoking,24 and now aspirin use.11 Although most of these findings require con- 17. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for
response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol.
firmation in further observational studies or clinical trials, and some of the results may represent confounding—the current 18. Neugut AI. Preventive oncology–lessons from preventive cardiology. Lancet.
study on aspirin use in nonmetastatic colorectal cancer,11 in 2004;363(9414):1004-1005.
19. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns
conjunction with the wealth of data in the precancerous set- with cancer recurrence and survival in patients with stage III colon cancer. JAMA.
ting, the similar findings in the prior study in the Cancer and 2007;298(7):754-764.
20. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and sur-
Leukemia Group B (CALGB) trial,12 and the extraordinarily vival after colorectal cancer diagnosis. J Clin Oncol. 2006;24(22):3527-3534.
specific COX-2 biomarker findings bring an observational study 21. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact of physical activity
on cancer recurrence and survival in patients with stage III colon cancer: findings
as close as it can to offering patients a way to help them- from CALGB 89803. J Clin Oncol. 2006;24(22):3535-3541.
selves. An ongoing randomized trial sponsored by the Na- 22. Meyerhardt JA, Niedzwiecki D, Hollis D, et al; Cancer and Leukemia Group B
tional Cancer Center of Singapore will potentially confirm these 89803. Impact of body mass index and weight change after treatment on cancerrecurrence and survival in patients with stage III colon cancer: findings from Can- findings. Moreover, in the near future, COX-2 expression may cer and Leukemia Group B 89803. J Clin Oncol. 2008;26(25):4109-4115.
well join KRAS mutation analysis as a standard predictive 23. Meyerhardt JA, Tepper JE, Niedzwiecki D, et al. Impact of body mass index
on outcomes and treatment-related toxicity in patients with stage II and III rectal
marker and aspirin may become standard adjuvant therapy cancer: findings from Intergroup Trial 0114. J Clin Oncol. 2004;22(4):648- in the management of colorectal cancer.
657.
24. Jackson NA, Fuchs CS, Niedzwiecki D, et al. The impact of smoking on cancer
recurrence and survival in patients with stage III colon cancer: findings from in-
Financial Disclosures: None reported.
tergroup trial CALGB 89803. J Clin Oncol. 2008;26(15s):4039.
2009 American Medical Association. All rights reserved.
(Reprinted) JAMA, August 12, 2009—Vol 302, No. 6 689

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