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Aspirin as a Treatment for Cancer
Clinical Oncology 25 (2013) 333e335 Contents lists available at SciVerse ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Aspirin as a Treatment for Cancer I. Phillips *, R. Langley y, D. Gilbert *, A. Ring z * Sussex
Cancer Centre, Royal Sussex County Hospital, Brighton, UK MRC Clinical Trials Unit, London, UK z Brighton and Sussex Medical School, Brighton, UK y
Received 14 February 2013; accepted 18 February 2013
Over the last 2 years, data from prospective trials have consolidated the pre-existing evidence from epidemiological and observational studies that suggest that aspirin has clinically relevant anticancer properties [1]. Specifically, it has been suggested that aspirin may prove to be a useful adjuvant therapy in the treatment of cancer, and a large trial (Add-Aspirin) is planned to investigate this [2]. Although aspirin was originally synthesised over 100 years ago, its mechanisms of action, and the realisation that these could translate into anticancer activity in humans, have only recently become apparent. Aspirin has two broad biological effects: cyclo-oxygenase (COX)-dependent effects, in which aspirin inhibits the pro-inflammatory enzymes COX-1 and COX-2, and COX-independent effects. Both have putative anticancer roles. The COX signalling pathway leads to the formation of biologically active prostaglandins involved in processes critical to the growth and development of cancers, including angiogenesis, apoptosis, cell proliferation and migration. Aspirin irreversibly binds platelet COX-1 thereby preventing platelet aggregation. It has been shown that platelets play an important role in invasion and metastases [3]; by reducing platelet aggregation, aspirin may exert an anti-metastasis effect. Alternatively, COX-2 is expressed in many cancers, and it has been hypothesised that COX-2derived prostaglandins inhibit apoptosis, modulate the immune system and regulate tumour-associated angiogenesis [4]. Intriguingly, recent data suggest that the beneficial adjuvant role of aspirin in colorectal cancer may be limited to patients whose tumour shows mutations in PIK3CA, a downstream component of the COX-2 signalling and an integral part of the epidermal growth factor receptor pathway [5]. Author for correspondence: A. Ring, Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton, Sussex BN2 5BE, UK. Tel: þ441273-696955; Fax: þ44-1273-623312. E-mail address: [email protected] (A. Ring).
In vitro studies have suggested that aspirin also works independently of COX-1 and -2 to decrease tumorigenesis, prevent angiogenesis and increase apoptosis [6]. Potential pathways and molecules that have been implicated include inhibition of nuclear factor kB, wnt signalling, B-catenin, tumour necrosis factor, down-regulation of survivin, caspase 9, p38 MAP kinase, mitochondrial cytochrome c and the ceramide pathway [1,7]. In particular, nuclear factor kB inhibition both in vitro and in vivo leads to selective inhibition of the growth of neoplastic cells [8]. Thus, COX-dependent and -independent effects of aspirin provide a biologically plausible rationale through which aspirin may have anticancer effects and are supported by the emerging clinical data from both the primary and secondary prevention setting.
Primary Prevention Randomised trials assessing aspirin’s effects on the cardiovascular system and disease have collected data on cancer incidence. In a pooled analysis by Rothwell and colleagues [9] of six primary prevention studies of daily low-dose aspirin allocation, aspirin reduced the risk of a cancer diagnosis with a hazard ratio of 0.88 (95% confidence interval 0.80e0.98, P ¼ 0.017); the effect was greater in those scheduled to receive treatment for at least 5 years (hazard ratio 0.83, 0.70e0.93, P ¼ 0.003) [9]. Moreover, in a further analysis of cancers diagnosed in patients on these trials, it was found that aspirin also reduced the risk of cancer with definite distant metastasis (hazard ratio 0.64, 0.48e0.84, P ¼ 0.001) [10] and the risk of metastasis on subsequent follow-up in patients without metastasis at diagnosis (hazard ratio 0.45, 0.28e0.72, P ¼ 0.0009) [10]. This observation is consistent with the previous finding that aspirin use in patients on these trials was associated with a lower risk of cancer-related death [11]. Overall, pooled data from caseecontrol and cohort studies suggest that aspirin
0936-6555/$36.00 Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2013.03.001
334
I. Phillips et al. / Clinical Oncology 25 (2013) 333e335
reduces the risk of a diagnosis of several common cancers: colorectal cancer (relative risk 0.73, 0.67e0.79, P < 0.001), gastric cancer (relative risk 0.67, 0.54e0.83, P < 0.001), breast cancer (relative risk 0.90, 0.85e0.95, P < 0.001), lung cancer (relative risk 0.91, 0.84e0.99, P ¼ 0.001) and prostate cancer (relative risk 0.90, 0.85e0.96, P < 0.001) [12]. Although there is compelling evidence that daily aspirin exposure decreases the risk of developing several common cancers, the absolute risk of developing cancer in, for example, a 5 year time period in the general population is low. As a result, the benefits of aspirin as a primary prevention measure in the general population may be limited owing to the large numbers needed to treat and the potential risk of complications. These may include gastric bleeding and haemorrhagic stroke: in a meta-analysis of 24 randomised controlled trials (almost 66 000 participants) gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68, 95% confidence interval 1.51e1.88, P < 0.0001) [13]. By contrast, if one takes a population where the absolute risk of developing a cancer is high, the balance of benefits against risks may favour aspirin as a primary prevention strategy. In the CAPP-2 study, 861 patients with Lynch syndrome were randomised to receive aspirin 600 mg, starch or placebo daily in a 2 2 factorial design. Patients who received aspirin for 25 months had a decreased risk of developing colorectal cancer, with a hazard ratio of 0.41 (0.19e0.86, P ¼ 0.02) [14]. It is notable in this study that the benefits of aspirin did not become apparent until at least 5 years after randomisation, illustrating the need for longterm follow-up in studies of aspirin as an anticancer intervention. The ASPECT trial is a phase III trial that is currently aiming to identify the benefit of esomeprazole and aspirin in patients with Barrett’s oesophagus [15].
Secondary Prevention A number of reports have described lower rates of cancer recurrence and death in patients who reported using aspirin after a diagnosis of an early solid tumour, compared with those who did not report aspirin use. Colorectal Cancer In an analysis of two large prospective cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study) the influence of pre- and post-diagnosis aspirin use on the survival of patients with stage IeIII colorectal cancer was examined. Reported aspirin use after a diagnosis of colorectal cancer reduced cancer-specific mortality (hazard ratio 0.71, 0.53e0.95, P ¼ 0.02) and prolonged overall survival (hazard ratio 0.79, 0.65e0.97, P ¼ 0.03). Among those patients who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate hazard ratio for colorectal cancer-specific mortality of 0.53 (0.33e0.86) [16]. These findings are supported by data from Dutch (adjusted rate
ratio 0.77, 0.63e0.95, P ¼ 0.015) [17] and Scottish cohort studies (hazard ratio 0.67, 0.57e0.79, P < 0.001) [18]. In a recent paper [5], patients with colorectal cancer containing a PI3 kinase mutation had a significant improvement in survival after adjuvant aspirin: cancer-specific survival hazard ratio 0.18 (0.06e0.61, P ¼ 0.001) and overall survival hazard ratio 0.54 (0.31e0.94, P ¼ 0.001). By contrast, there was no effect in patients with wild-type PIK3CA. Breast Cancer The Nurses’ Health Study recruited 4164 female US nurses who had been diagnosed with stage IeIII breast cancer between 1976 and 2002 and followed the women until death or June 2006. Aspirin use was assessed every 2 years as part of a predetermined questionnaire. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks for 1, 2e5 and 6e7 days of aspirin use per week compared with no use were 1.07 (95% confidence interval 0.70e1.63), 0.29 (95% confidence interval 0.16e0.52) and 0.36 (95% confidence interval 0.24e0.54), respectively (test for linear trend, P < 0.001). This association did not differ appreciably by stage, menopausal status, body mass index or oestrogen receptor status. Prostate Cancer In the Cancer of the Prostate Strategic Urologic Research Endeavor database, 5955 men with localised adenocarcinoma of the prostate treated with radical prostatectomy or radiotherapy have been followed up for a median of 70 months. Multivariate analysis suggests that aspirin use was independently associated with a lower risk of prostate cancer-specific mortality (adjusted hazard ratio 0.43, 95% confidence interval 0.21e0.87; P ¼ 0.02). Ten year mortality was found to be significantly different, 3% versus 8% (P < 0.01) for those taking aspirin compared with aspirinnaive patients [19]. Oesophago-gastric Cancer In a study of 1716 patients in China who had undergone an oesophagectomy for cancer, patients who were randomised to a ward where they received aspirin had a superior survival compared with those who were randomised to wards where they received placebo or no tablet. The 5 year survival for all patients on aspirin (445) was 51.2%, placebo (658) 41% and no tablet (495) 42.3% (P ¼ 0.04 for the difference between treatments) [20]. The suggestion that aspirin may reduce the risk of recurrence of these tumours with such impressive hazard ratios for an adjuvant treatment is provocative. However, as the data are largely derived from cohort studies and retrospective analyses, it is not possible to derive accurate toxicity data to allow the risk: benefit calculations to be made with accuracy. In addition, it is not possible to correct for all relevant confounding variables. Reports of aspirin use may be subject to bias and the question of dose and schedule is not addressed. For these reasons, a definitive,
I. Phillips et al. / Clinical Oncology 25 (2013) 333e335
randomised trial evaluating the role of aspirin in the adjuvant setting is warranted. The proposed Add-Aspirin trial will aim to recruit 10 000 patients who have had radical treatment for early colorectal cancer, oesophago-gastric, prostate and breast cancer. Participants will receive standard adjuvant therapy according to local protocols, and then be randomised to aspirin 100 or 300 mg or placebo daily for 5 years with a primary outcome measure based on survival. Only then may the prospect of aspirin as an adjuvant therapy for cancer be fulfilled.
References [1] Langley R, Tierney J, Cafferty F, Parmar M, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer 2011;105:1107e1112. [2] Add-aspirin trial. MRC Clinical Trials Unit. E-mail. [email protected]. [3] Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative hostetumor cell interactions during hematogenous dissemination. Cancer Discov 2012;2(12):1091e1099. [4] Cha YI, DuBois RN. NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 2007;58:239e252. [5] Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367(17):1596e1606. [6] Ferrario A, Xu F, Luna M, et al. Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib. Cancer Lett 2011;304(1):33e40. [7] Thun M, Jacob E, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9(5):259e267. [8] Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 2004;91(2):381e388. [9] Rothwell P, Fowkes F, Zanchetti A, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379(9826):1602e1612.
335
[10] Rothwell P, WIlson M, Price J, Belch J, Meade T, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591e1601. [11] Rothwell P, Belch J, Ogawa H, Warlow C, Meade T. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31e41. [12] Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol 2012;23(6):1403e1415. [13] Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. Br Med J 2000;321(7270):1183e1187. [14] Burn J, Gerdes A, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011;378(9809):2081e2087. [15] Thiagarajan P, Jankowski J. Aspirin and NSAIDs; benefits and harms for the gut. Best Pract Res Clin Gastroenterol 2012; 26(2):197e206. [16] Chan AT, Ogino S, Fuchs C. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302(6):649e658. [17] Bastiaannet E, Dekkers O, de Craen A, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012;106(9):1564e1570. [18] McCowan C, Donnan P, Steele R. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 2013;49(5):1049e1057. [19] Choe K, Cowan J, Chan J, Carroll P, D'Amico A, Liauw S. Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol 2012;30(28): 3540e3544. [20] Liu J, Jamieson G, Wu T, Zhu G, Drew P. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol 2009;16(5): 1397e1402.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Aspirin as a Treatment for Cancer I. Phillips *, R. Langley y, D. Gilbert *, A. Ring z * Sussex
Cancer Centre, Royal Sussex County Hospital, Brighton, UK MRC Clinical Trials Unit, London, UK z Brighton and Sussex Medical School, Brighton, UK y
Received 14 February 2013; accepted 18 February 2013
Over the last 2 years, data from prospective trials have consolidated the pre-existing evidence from epidemiological and observational studies that suggest that aspirin has clinically relevant anticancer properties [1]. Specifically, it has been suggested that aspirin may prove to be a useful adjuvant therapy in the treatment of cancer, and a large trial (Add-Aspirin) is planned to investigate this [2]. Although aspirin was originally synthesised over 100 years ago, its mechanisms of action, and the realisation that these could translate into anticancer activity in humans, have only recently become apparent. Aspirin has two broad biological effects: cyclo-oxygenase (COX)-dependent effects, in which aspirin inhibits the pro-inflammatory enzymes COX-1 and COX-2, and COX-independent effects. Both have putative anticancer roles. The COX signalling pathway leads to the formation of biologically active prostaglandins involved in processes critical to the growth and development of cancers, including angiogenesis, apoptosis, cell proliferation and migration. Aspirin irreversibly binds platelet COX-1 thereby preventing platelet aggregation. It has been shown that platelets play an important role in invasion and metastases [3]; by reducing platelet aggregation, aspirin may exert an anti-metastasis effect. Alternatively, COX-2 is expressed in many cancers, and it has been hypothesised that COX-2derived prostaglandins inhibit apoptosis, modulate the immune system and regulate tumour-associated angiogenesis [4]. Intriguingly, recent data suggest that the beneficial adjuvant role of aspirin in colorectal cancer may be limited to patients whose tumour shows mutations in PIK3CA, a downstream component of the COX-2 signalling and an integral part of the epidermal growth factor receptor pathway [5]. Author for correspondence: A. Ring, Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton, Sussex BN2 5BE, UK. Tel: þ441273-696955; Fax: þ44-1273-623312. E-mail address: [email protected] (A. Ring).
In vitro studies have suggested that aspirin also works independently of COX-1 and -2 to decrease tumorigenesis, prevent angiogenesis and increase apoptosis [6]. Potential pathways and molecules that have been implicated include inhibition of nuclear factor kB, wnt signalling, B-catenin, tumour necrosis factor, down-regulation of survivin, caspase 9, p38 MAP kinase, mitochondrial cytochrome c and the ceramide pathway [1,7]. In particular, nuclear factor kB inhibition both in vitro and in vivo leads to selective inhibition of the growth of neoplastic cells [8]. Thus, COX-dependent and -independent effects of aspirin provide a biologically plausible rationale through which aspirin may have anticancer effects and are supported by the emerging clinical data from both the primary and secondary prevention setting.
Primary Prevention Randomised trials assessing aspirin’s effects on the cardiovascular system and disease have collected data on cancer incidence. In a pooled analysis by Rothwell and colleagues [9] of six primary prevention studies of daily low-dose aspirin allocation, aspirin reduced the risk of a cancer diagnosis with a hazard ratio of 0.88 (95% confidence interval 0.80e0.98, P ¼ 0.017); the effect was greater in those scheduled to receive treatment for at least 5 years (hazard ratio 0.83, 0.70e0.93, P ¼ 0.003) [9]. Moreover, in a further analysis of cancers diagnosed in patients on these trials, it was found that aspirin also reduced the risk of cancer with definite distant metastasis (hazard ratio 0.64, 0.48e0.84, P ¼ 0.001) [10] and the risk of metastasis on subsequent follow-up in patients without metastasis at diagnosis (hazard ratio 0.45, 0.28e0.72, P ¼ 0.0009) [10]. This observation is consistent with the previous finding that aspirin use in patients on these trials was associated with a lower risk of cancer-related death [11]. Overall, pooled data from caseecontrol and cohort studies suggest that aspirin
0936-6555/$36.00 Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2013.03.001
334
I. Phillips et al. / Clinical Oncology 25 (2013) 333e335
reduces the risk of a diagnosis of several common cancers: colorectal cancer (relative risk 0.73, 0.67e0.79, P < 0.001), gastric cancer (relative risk 0.67, 0.54e0.83, P < 0.001), breast cancer (relative risk 0.90, 0.85e0.95, P < 0.001), lung cancer (relative risk 0.91, 0.84e0.99, P ¼ 0.001) and prostate cancer (relative risk 0.90, 0.85e0.96, P < 0.001) [12]. Although there is compelling evidence that daily aspirin exposure decreases the risk of developing several common cancers, the absolute risk of developing cancer in, for example, a 5 year time period in the general population is low. As a result, the benefits of aspirin as a primary prevention measure in the general population may be limited owing to the large numbers needed to treat and the potential risk of complications. These may include gastric bleeding and haemorrhagic stroke: in a meta-analysis of 24 randomised controlled trials (almost 66 000 participants) gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68, 95% confidence interval 1.51e1.88, P < 0.0001) [13]. By contrast, if one takes a population where the absolute risk of developing a cancer is high, the balance of benefits against risks may favour aspirin as a primary prevention strategy. In the CAPP-2 study, 861 patients with Lynch syndrome were randomised to receive aspirin 600 mg, starch or placebo daily in a 2 2 factorial design. Patients who received aspirin for 25 months had a decreased risk of developing colorectal cancer, with a hazard ratio of 0.41 (0.19e0.86, P ¼ 0.02) [14]. It is notable in this study that the benefits of aspirin did not become apparent until at least 5 years after randomisation, illustrating the need for longterm follow-up in studies of aspirin as an anticancer intervention. The ASPECT trial is a phase III trial that is currently aiming to identify the benefit of esomeprazole and aspirin in patients with Barrett’s oesophagus [15].
Secondary Prevention A number of reports have described lower rates of cancer recurrence and death in patients who reported using aspirin after a diagnosis of an early solid tumour, compared with those who did not report aspirin use. Colorectal Cancer In an analysis of two large prospective cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study) the influence of pre- and post-diagnosis aspirin use on the survival of patients with stage IeIII colorectal cancer was examined. Reported aspirin use after a diagnosis of colorectal cancer reduced cancer-specific mortality (hazard ratio 0.71, 0.53e0.95, P ¼ 0.02) and prolonged overall survival (hazard ratio 0.79, 0.65e0.97, P ¼ 0.03). Among those patients who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate hazard ratio for colorectal cancer-specific mortality of 0.53 (0.33e0.86) [16]. These findings are supported by data from Dutch (adjusted rate
ratio 0.77, 0.63e0.95, P ¼ 0.015) [17] and Scottish cohort studies (hazard ratio 0.67, 0.57e0.79, P < 0.001) [18]. In a recent paper [5], patients with colorectal cancer containing a PI3 kinase mutation had a significant improvement in survival after adjuvant aspirin: cancer-specific survival hazard ratio 0.18 (0.06e0.61, P ¼ 0.001) and overall survival hazard ratio 0.54 (0.31e0.94, P ¼ 0.001). By contrast, there was no effect in patients with wild-type PIK3CA. Breast Cancer The Nurses’ Health Study recruited 4164 female US nurses who had been diagnosed with stage IeIII breast cancer between 1976 and 2002 and followed the women until death or June 2006. Aspirin use was assessed every 2 years as part of a predetermined questionnaire. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks for 1, 2e5 and 6e7 days of aspirin use per week compared with no use were 1.07 (95% confidence interval 0.70e1.63), 0.29 (95% confidence interval 0.16e0.52) and 0.36 (95% confidence interval 0.24e0.54), respectively (test for linear trend, P < 0.001). This association did not differ appreciably by stage, menopausal status, body mass index or oestrogen receptor status. Prostate Cancer In the Cancer of the Prostate Strategic Urologic Research Endeavor database, 5955 men with localised adenocarcinoma of the prostate treated with radical prostatectomy or radiotherapy have been followed up for a median of 70 months. Multivariate analysis suggests that aspirin use was independently associated with a lower risk of prostate cancer-specific mortality (adjusted hazard ratio 0.43, 95% confidence interval 0.21e0.87; P ¼ 0.02). Ten year mortality was found to be significantly different, 3% versus 8% (P < 0.01) for those taking aspirin compared with aspirinnaive patients [19]. Oesophago-gastric Cancer In a study of 1716 patients in China who had undergone an oesophagectomy for cancer, patients who were randomised to a ward where they received aspirin had a superior survival compared with those who were randomised to wards where they received placebo or no tablet. The 5 year survival for all patients on aspirin (445) was 51.2%, placebo (658) 41% and no tablet (495) 42.3% (P ¼ 0.04 for the difference between treatments) [20]. The suggestion that aspirin may reduce the risk of recurrence of these tumours with such impressive hazard ratios for an adjuvant treatment is provocative. However, as the data are largely derived from cohort studies and retrospective analyses, it is not possible to derive accurate toxicity data to allow the risk: benefit calculations to be made with accuracy. In addition, it is not possible to correct for all relevant confounding variables. Reports of aspirin use may be subject to bias and the question of dose and schedule is not addressed. For these reasons, a definitive,
I. Phillips et al. / Clinical Oncology 25 (2013) 333e335
randomised trial evaluating the role of aspirin in the adjuvant setting is warranted. The proposed Add-Aspirin trial will aim to recruit 10 000 patients who have had radical treatment for early colorectal cancer, oesophago-gastric, prostate and breast cancer. Participants will receive standard adjuvant therapy according to local protocols, and then be randomised to aspirin 100 or 300 mg or placebo daily for 5 years with a primary outcome measure based on survival. Only then may the prospect of aspirin as an adjuvant therapy for cancer be fulfilled.
References [1] Langley R, Tierney J, Cafferty F, Parmar M, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer 2011;105:1107e1112. [2] Add-aspirin trial. MRC Clinical Trials Unit. E-mail. [email protected]. [3] Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative hostetumor cell interactions during hematogenous dissemination. Cancer Discov 2012;2(12):1091e1099. [4] Cha YI, DuBois RN. NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 2007;58:239e252. [5] Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367(17):1596e1606. [6] Ferrario A, Xu F, Luna M, et al. Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib. Cancer Lett 2011;304(1):33e40. [7] Thun M, Jacob E, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9(5):259e267. [8] Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 2004;91(2):381e388. [9] Rothwell P, Fowkes F, Zanchetti A, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379(9826):1602e1612.
335
[10] Rothwell P, WIlson M, Price J, Belch J, Meade T, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591e1601. [11] Rothwell P, Belch J, Ogawa H, Warlow C, Meade T. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31e41. [12] Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol 2012;23(6):1403e1415. [13] Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. Br Med J 2000;321(7270):1183e1187. [14] Burn J, Gerdes A, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011;378(9809):2081e2087. [15] Thiagarajan P, Jankowski J. Aspirin and NSAIDs; benefits and harms for the gut. Best Pract Res Clin Gastroenterol 2012; 26(2):197e206. [16] Chan AT, Ogino S, Fuchs C. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302(6):649e658. [17] Bastiaannet E, Dekkers O, de Craen A, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012;106(9):1564e1570. [18] McCowan C, Donnan P, Steele R. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 2013;49(5):1049e1057. [19] Choe K, Cowan J, Chan J, Carroll P, D'Amico A, Liauw S. Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol 2012;30(28): 3540e3544. [20] Liu J, Jamieson G, Wu T, Zhu G, Drew P. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol 2009;16(5): 1397e1402.