Aspirin Use Improves Established Colorectal Cancer Survival
Aspirin Use Improves Established Colorectal Cancer Survival
The current meta-analysis summarised the results of eleven studies, including seven studies on aspirin use after CRC diagnosis and seven studies on aspirin use before CRC diagnosis. The results indicated that use of aspirin postdiagnosis was inversely associated with the overall mortality of CRC. This association appeared to be slightly stronger among patients with colon cancer than among patients with rectal cancer (HR=0.78 for colon cancer and 0.90 for rectal cancer). Besides, the present meta-analysis further suggested that increased expression of PTGS2 (COX-2) and the presence of mutated PIK3CA in the primary tumours served as predictive molecular biomarkers for adjuvant aspirin therapy.
There has been high-quality evidence showing a benefit of aspirin use in sporadic adenomatous polyps prevention, and observational studies have suggested aspirin to be associated with a reduction in CRC risk and mortality. In addition to the well-recognised chemoprevention effect against CRC, recent data also suggest a role of aspirin as an adjuvant agent for patients with CRC. However, the precise molecular mechanisms underlying the effects of aspirin against CRC are still unclear. Reimers et al speculated that the effects of aspirin on CRC survival might result from an effect on circulating tumour cells and their ability to develop into metastatic cancer. This is also supported by the pervious evidence from RCTs, which indicated that aspirin use reduced the risk of cancer metastasis. As suggested by a previous study, direct platelet–tumour cell contacts may activate the tumour growth factor-β/SMAD and nuclear factor-κB (NFκB) pathways in cancer cells, resulting in an invasive mesenchymal-like phenotype with metastatic potential. Moreover, a molecular study indicated that acquisition of an epithelial–mesenchymal phenotype markedly reduced inhibition of cytotoxic T-lymphocytes-mediated tumour cell lysis. Thus, aspirin may prevent cancer metastasis through inhibiting platelet–tumour cell signalling and epithelial–mesenchymal transition in circulating tumour cells.
The anticancer effect of aspirin has also been attributed to direct inhibition of PTGS (COX) family of enzymes involved in prostaglandin synthesis. Previous studies have investigated the interaction between aspirin and tumour PTGS2 expression and tumour PIK3CA mutation. These molecular pathological epidemiology (MPE) studies were well-designed cohort studies and provided further evidence for the role of PIK3CA and PTGS2 (COX-2) in CRC progression, while they were all conducted in European countries and in the USA, and the PIK3CA mutation and PTGS2 overexpression rate differed across the studies. Thus, further studies, especially prospective cohorts or RCTs with large sample size, are still warranted to validate the findings and to investigate this issue in other ethnic groups such as Asians. Though there are some limitations in MPE studies such as selection bias, confounding and causal inference, this evolving field of epidemiology could provide new insights into the pathogenic processes and optimise personalised prevention or treatment of CRC. PTGS2 (COX-2) was indicated to promote inflammation and cell proliferation, and overexpression of PTGS2 (COX-2) has been observed to be associated with poor prognosis of CRC. The phosphatidylinositol 3-kinase (PI3K) signalling pathway plays a vital role in carcinogenesis, and upregulation of PI3K enhances PTGS2 (COX-2) activity and prostaglandin E2 (PGE2) synthesis. These findings might partially explain why the effect of aspirin on survival among patients with muted PIK3CA and PTGS2 (COX-2)-positive tumours differs from those patients with wild-type PIK3CA and PTGS2 (COX-2)-negative tumours. Aspirin also has a broader range of downstream effect, including inhibition of NFκB, induction of apoptosis by activation of p38 kinase and catabolism of polyamines.
There are still some confusing problems unresolved, including when aspirin should be used and what is the optimal dose and duration for aspirin adjuvant therapy. Our analysis further supported aspirin use after diagnosis but not prior diagnosis improved survival of CRC. While significant data suggested that aspirin has a benefit as a chemoprevention agent for CRC, we should consider whether its adverse effect such as GI tract bleeding outweighs its benefit. Thus, it is critical to identify the lowest dose of aspirin that can achieve sufficient antitumour effect because of the potential toxicities of aspirin. The included observational studies adopted dosages between 75 and more than 300 mg daily. Pharmacological data indicated that low-dose aspirin use at 75–100 mg daily was sufficient to completely inhibit PTGS1 in platelets, and 81 mg aspirin is sufficient to inhibit rectal mucosal PGE2 production. Several studies have suggested that regular aspirin use may be associated with improved survival. An ongoing randomised study is conducted in high-risk Dukes B and C patients with CRC to evaluate the survival benefit for a dose of 200 mg aspirin daily (ASCOLT). Because of limited data, dose–response analysis for the association between aspirin use and CRC survival could not be conducted and the optimal duration of aspirin therapy is still unclear.
Our meta-analysis comprehensively analysed observational data on the survival benefit of aspirin therapy for established patients with CRC, and the results further suggested that aspirin use after diagnosis improved CRC survival. This may be important for clinical practice of CRC; however, the current analysis is restricted by several limitations. First, the number of studies involved in this meta-analysis was relatively small, and thus some of the subgroup analyses were difficult to conduct and might be less reliable. Second, the dose and duration of aspirin usage differed among studies and related data of individuals were not available from each study, which may possibly result in less accurate estimates of survival benefit for aspirin therapy.
Third, the heterogeneity across studies could not be fully explained. The sensitivity analysis indicated that the meta-analyses were influenced by individual study. After excluding the study with case–control design, heterogeneity decreased for meta-analyses of both all-cause mortality and CRC-specific mortality. Other factors, including aspirin dose, duration, sample size and distribution of tumour stages, may also be the source of heterogeneity. Therefore, further analysis should be conducted if individual participant data are available. Fourth, the available studies involved in the current analysis were mostly observational studies, which are vulnerable to selection bias, information bias and confounding. Thus, inadequate control of the confounders might lead to exaggeration or underestimation of survival benefit estimates. Besides, all the studies were performed in the USA or in European countries.
In conclusion, the results from this meta-analysis demonstrated that aspirin use after diagnosis was inversely associated with CRC overall mortality, particular among individuals with positive PTGS2 (COX-2) expression and mutated PIK3CA tumours. This highlights that PTGS2 (COX-2) and PIK3CA are potential markers to tailor aspirin use for patients with CRC. The findings have considerable clinical and health policy importance since aspirin is cheap and may provide a cost-effective approach to improve CRC survival. If finally proved to be effective, aspirin might challenge the paradigm of adjuvant therapy for CRC. Future research, especially RCT, is desirable to confirm this low-cost and easily administered, relatively safe therapy to reduce CRC mortality and to enable a better understanding of the role of aspirin adjuvant therapy for CRC survival.
Discussion
The current meta-analysis summarised the results of eleven studies, including seven studies on aspirin use after CRC diagnosis and seven studies on aspirin use before CRC diagnosis. The results indicated that use of aspirin postdiagnosis was inversely associated with the overall mortality of CRC. This association appeared to be slightly stronger among patients with colon cancer than among patients with rectal cancer (HR=0.78 for colon cancer and 0.90 for rectal cancer). Besides, the present meta-analysis further suggested that increased expression of PTGS2 (COX-2) and the presence of mutated PIK3CA in the primary tumours served as predictive molecular biomarkers for adjuvant aspirin therapy.
There has been high-quality evidence showing a benefit of aspirin use in sporadic adenomatous polyps prevention, and observational studies have suggested aspirin to be associated with a reduction in CRC risk and mortality. In addition to the well-recognised chemoprevention effect against CRC, recent data also suggest a role of aspirin as an adjuvant agent for patients with CRC. However, the precise molecular mechanisms underlying the effects of aspirin against CRC are still unclear. Reimers et al speculated that the effects of aspirin on CRC survival might result from an effect on circulating tumour cells and their ability to develop into metastatic cancer. This is also supported by the pervious evidence from RCTs, which indicated that aspirin use reduced the risk of cancer metastasis. As suggested by a previous study, direct platelet–tumour cell contacts may activate the tumour growth factor-β/SMAD and nuclear factor-κB (NFκB) pathways in cancer cells, resulting in an invasive mesenchymal-like phenotype with metastatic potential. Moreover, a molecular study indicated that acquisition of an epithelial–mesenchymal phenotype markedly reduced inhibition of cytotoxic T-lymphocytes-mediated tumour cell lysis. Thus, aspirin may prevent cancer metastasis through inhibiting platelet–tumour cell signalling and epithelial–mesenchymal transition in circulating tumour cells.
The anticancer effect of aspirin has also been attributed to direct inhibition of PTGS (COX) family of enzymes involved in prostaglandin synthesis. Previous studies have investigated the interaction between aspirin and tumour PTGS2 expression and tumour PIK3CA mutation. These molecular pathological epidemiology (MPE) studies were well-designed cohort studies and provided further evidence for the role of PIK3CA and PTGS2 (COX-2) in CRC progression, while they were all conducted in European countries and in the USA, and the PIK3CA mutation and PTGS2 overexpression rate differed across the studies. Thus, further studies, especially prospective cohorts or RCTs with large sample size, are still warranted to validate the findings and to investigate this issue in other ethnic groups such as Asians. Though there are some limitations in MPE studies such as selection bias, confounding and causal inference, this evolving field of epidemiology could provide new insights into the pathogenic processes and optimise personalised prevention or treatment of CRC. PTGS2 (COX-2) was indicated to promote inflammation and cell proliferation, and overexpression of PTGS2 (COX-2) has been observed to be associated with poor prognosis of CRC. The phosphatidylinositol 3-kinase (PI3K) signalling pathway plays a vital role in carcinogenesis, and upregulation of PI3K enhances PTGS2 (COX-2) activity and prostaglandin E2 (PGE2) synthesis. These findings might partially explain why the effect of aspirin on survival among patients with muted PIK3CA and PTGS2 (COX-2)-positive tumours differs from those patients with wild-type PIK3CA and PTGS2 (COX-2)-negative tumours. Aspirin also has a broader range of downstream effect, including inhibition of NFκB, induction of apoptosis by activation of p38 kinase and catabolism of polyamines.
There are still some confusing problems unresolved, including when aspirin should be used and what is the optimal dose and duration for aspirin adjuvant therapy. Our analysis further supported aspirin use after diagnosis but not prior diagnosis improved survival of CRC. While significant data suggested that aspirin has a benefit as a chemoprevention agent for CRC, we should consider whether its adverse effect such as GI tract bleeding outweighs its benefit. Thus, it is critical to identify the lowest dose of aspirin that can achieve sufficient antitumour effect because of the potential toxicities of aspirin. The included observational studies adopted dosages between 75 and more than 300 mg daily. Pharmacological data indicated that low-dose aspirin use at 75–100 mg daily was sufficient to completely inhibit PTGS1 in platelets, and 81 mg aspirin is sufficient to inhibit rectal mucosal PGE2 production. Several studies have suggested that regular aspirin use may be associated with improved survival. An ongoing randomised study is conducted in high-risk Dukes B and C patients with CRC to evaluate the survival benefit for a dose of 200 mg aspirin daily (ASCOLT). Because of limited data, dose–response analysis for the association between aspirin use and CRC survival could not be conducted and the optimal duration of aspirin therapy is still unclear.
Our meta-analysis comprehensively analysed observational data on the survival benefit of aspirin therapy for established patients with CRC, and the results further suggested that aspirin use after diagnosis improved CRC survival. This may be important for clinical practice of CRC; however, the current analysis is restricted by several limitations. First, the number of studies involved in this meta-analysis was relatively small, and thus some of the subgroup analyses were difficult to conduct and might be less reliable. Second, the dose and duration of aspirin usage differed among studies and related data of individuals were not available from each study, which may possibly result in less accurate estimates of survival benefit for aspirin therapy.
Third, the heterogeneity across studies could not be fully explained. The sensitivity analysis indicated that the meta-analyses were influenced by individual study. After excluding the study with case–control design, heterogeneity decreased for meta-analyses of both all-cause mortality and CRC-specific mortality. Other factors, including aspirin dose, duration, sample size and distribution of tumour stages, may also be the source of heterogeneity. Therefore, further analysis should be conducted if individual participant data are available. Fourth, the available studies involved in the current analysis were mostly observational studies, which are vulnerable to selection bias, information bias and confounding. Thus, inadequate control of the confounders might lead to exaggeration or underestimation of survival benefit estimates. Besides, all the studies were performed in the USA or in European countries.
In conclusion, the results from this meta-analysis demonstrated that aspirin use after diagnosis was inversely associated with CRC overall mortality, particular among individuals with positive PTGS2 (COX-2) expression and mutated PIK3CA tumours. This highlights that PTGS2 (COX-2) and PIK3CA are potential markers to tailor aspirin use for patients with CRC. The findings have considerable clinical and health policy importance since aspirin is cheap and may provide a cost-effective approach to improve CRC survival. If finally proved to be effective, aspirin might challenge the paradigm of adjuvant therapy for CRC. Future research, especially RCT, is desirable to confirm this low-cost and easily administered, relatively safe therapy to reduce CRC mortality and to enable a better understanding of the role of aspirin adjuvant therapy for CRC survival.
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