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Aspirin as a Treatment for Cancer
... interestingly, recent trials demonstrated the benefits of low-dose aspirin for VTE prophylaxis in patients with multiple myeloma treated with thalidomide or lenalidomide. [26] Although evidence for the promising anticancer activity of aspirin has been reported, [27] the underlying mechanisms are still unclear even though AMPK activation, and NF-κB and mTOR inhibition have been confirmed in pancreatic and colorectal cancer cells, [28,29] www.wjpps.com │ Vol 10, ...
In drug development, drug repositioning is gaining growing interest because it represents a clever way to exploit new molecular targets of a known drug or target promiscuity among various diseases for different medical uses than the one originally considered. We concentrate on known non-oncological drugs with new therapeutic applications in oncology in this study, describing the reasoning behind this approach and presenting practical evidence.
... Generally, drug repurposing, which is otherwise known as drug repositioning, refers to the identification of new therapeutic applications for the existing and investigational drugs. 8−11 In such instances, antiviral (Gemcitabine, Nelfinavir), 12,13 anticonvulsant (Valproic acid), 14 antifungal (Itraconazole), 15 osteoporosis (Raloxifene), 16 and other noncancer drugs like Thalidomide, 17,18 Aspirin, 19,20 Celecoxib, 21 Metformin, 22 Digoxin, 23 Nitroxoline, 24 etc. have been successfully repurposed with proven mechanism of action 2,25−28 in the treatment of cancer. Despite varied advantages of drug repurposing, clinical translations of repurposed drug have been limited by sufficient target tissue concentrations, 29 efficacy in phase II and phase III clinical trials, 30 and undefined regulatory guidelines. ...
p21-Activated kinase 1 (PAK1) is positioned at the nexus of several oncogenic signaling pathways. Currently, there are no approved inhibitors for disabling the transfer of phosphate in the active site directly, as they are limited by lower affinity, and poor kinase selectivity. In this work, a repurposing study utilizing FDA-approved drugs from the DrugBank database was pursued with an initial selection of 27 molecules out of ∼2162 drug molecules, based on their docking energies and molecular interaction patterns. From the molecules that were considered for WaterMap analysis, seven molecules, namely, Mitoxantrone, Labetalol, Acalabrutinib, Sacubitril, Flubendazole, Trazodone, and Niraparib, ascertained the ability to overlap with high-energy hydration sites. Considering many other displaced unfavorable water molecules, only Acalabrutinib, Flubendazole, and Trazodone molecules highlighted their prominence in terms of binding affinity gains through ΔΔG that ranges between 6.44 and 2.59 kcal/mol. Even if Mitoxantrone exhibited the highest docking score and greater interaction strength, it did not comply with the WaterMap and molecular dynamics simulation results. Moreover, detailed MD simulation trajectory analyses suggested that the drug molecules Flubendazole, Niraparib, and Acalabrutinib were highly stable, observed from their RMSD values and consistent interaction pattern with Glu315, Glu345, Leu347, and Asp407 including the hydrophobic interactions maintained in the three replicates. However, the drug molecule Trazodone displayed a loss of crucial interaction with Leu347, which was essential to inhibit the kinase activity of PAK1. The molecular orbital and electrostatic potential analyses elucidated the reactivity and strong complementarity potentials of the drug molecules in the binding pocket of PAK1. Therefore, the CADD-based reposition efforts, reported in this work, helped in the successful identification of new PAK1 inhibitors that requires further investigation by in vitro analysis.
... It was shown that the combination of Aspirin and TMZ can have a significant improvement in our desired outcome to increase the efficacy of GBM treatment efficacy. Several observational and biological studies have shown the anti-cancer effects of Aspirin for different cancers including glioblastoma [23][24][25]. It is shown that Aspirin can induce cell cycle arrest [26] which is consistent with our findings here. ...
Background
Glioblastoma Multiforme, an aggressive primary brain tumor, has a poor prognosis and no effective standard of care treatments. Most patients undergoing radiotherapy, along with Temozolomide chemotherapy, develop resistance to the drug, and recurrence of the tumor is a common issue after the treatment. We propose to model the pathways active in Glioblastoma using Boolean network techniques. The network captures the genetic interactions and possible mutations that are involved in the development of the brain tumor. The model is used to predict the theoretical efficacies of drugs for the treatment of cancer.
Results
We use the Boolean network to rank the critical intervention points in the pathway to predict an effective therapeutic strategy for Glioblastoma. Drug repurposing helps to identify non-cancer drugs that could be effective in cancer treatment. We predict the effectiveness of drug combinations of anti-cancer and non-cancer drugs for Glioblastoma.
Conclusions
Given the genetic profile of a GBM tumor, the Boolean model can predict the most effective targets for treatment. We also identified two-drug combinations that could be more effective in killing GBM cells than conventional chemotherapeutic agents. The non-cancer drug Aspirin could potentially increase the cytotoxicity of TMZ in GBM patients.
... Therefore, here is an attempt made to demonstrate how a researcher adopts a regulatory pathway for adding new indications to existing labels like Aspirin (Fig. 3). Notably, understanding of in vitro and in vivo experimentations, and prospective clinical trials have strongly instituted that Aspirin, an non-steroidal anti-inflammatory drug (NSAID) family drug, has anti-cancerous properties [5][6][7][8]. On a mechanistic note, the anti-cancerous activity of Aspirin starts with cyclooxygenase (COX) enzymes inhibition [9]. ...
Drug Repurposing (DR) is an alternative to the traditional drug discovery process. It is cost and time effective, with high returns and low risk process that can tackle the increasing need for interventions for varied diseases and new outbreaks. Repurposing of old drugs for other diseases has gained a wider attention, as there have been several old drugs approved by FDA for new diseases. In the global emergency of COVID19 pandemic, this is one of the strategies implemented in repurposing of old anti-infective, anti-rheumatic and anti-thrombotic drugs. The goal of the current review is to elaborate the process of DR, its advantages, repurposed drugs for a plethora of disorders, and the evolution of related academic publications. Further, detailed are the computational approaches: literature mining and semantic inference, network-based drug repositioning, signature matching, retrospective clinical analysis, molecular docking and experimental phenotypic screening. We discuss the legal and economical potential barriers in DR, existent collaborative models and recommendations for overcoming these hurdles and leveraging the complete potential of DR in finding new indications.
... Powered evidences have been raised in past decades showing that regular low dose aspirin use may reduce the morbidity and mortality of cancers (11)(12)(13)(14)(15)(16)(17), mainly including gastrointestinal cancer, breast cancer, prostate cancer. There are growing evidence in recent years suggesting that aspirin could reduce the mortality in patients with esophageal cancer, especially after diagnosed or treated by standard therapy like esophagectomy (11,18,19). ...
Improved survival in esophageal cancer patients with regular aspirin use have been reported. However, with conflicting experimental results existed, an explicit definition on the role of aspirin as an adjuvant chemotherapy of esophageal cancer remains unestablished. We have summarized the current epidemiologic trials evidence over antitumor effect of aspirin in esophageal cancer in the past decades, and most of the clinical data supports that long-term regular aspirin use could reduce the mortality and improve the survival in patients with esophageal cancer. Although most of the clinical trials of aspirin on esophageal cancer are designed focusing on the prediagnosed chemo-preventive role, other than the post-diagnosed therapeutic role, it has been suggested by some studies that aspirin use as an adjuvant treatment after the standard surgery in esophageal cancer may benefit more. In the meanwhile, post diagnosed aspirin use may lead to lower risk of hemorrhage and other side effects of NSAIDs. Potential involved molecular pathways in the antitumor activities of aspirin are under studied worldwide for years and the possible mechanisms so far are reviewed in this article as cyclooxygenase (COX)-dependent pathways and COX-independent pathways, involving anti-inflammatory activity, apoptosis, platelet deactivation, PIK3CA mutation specificity and heparanase-related microenvironment changes of tumor cells. NOSH-aspirin has been developed as a succedaneum of aspirin with a wider application ranges by reducing the risk of hemorrhage in aspirin users. Further clinical and basic studies are suggested focusing on whether regular aspirin use as an adjuvant treatment prolongs survival and prevents recurrence in patients with esophageal cancer.
... Patients who had completed two years on aspirin had a relative reduction (RR) in incident bowel cancer (RR 0.37; 0.18, 0.78) and other cancers. As well as these studies, which do not give final answers, from the general population and genetically predisposed individuals, there is also evidence aspirin might be used as an adjunct treatment of cancer [9]. This suggests aspirin might be exerting effects on a wide range of cancer pathways and at a variety of stages in the carcinogenic pathway. ...
The clinical use of aspirin, first synthesized over 100 years ago, entered a new phase in 1974 with the reporting of the first randomised trial showing a reduction in vascular disease deaths from low-doses. More recent evidence suggests that the medicine is effective against cancer, which makes aspirin of very considerable potential importance to public health improvement and potentially also to clinical practice. It appears that prophylactic aspirin is being increasingly used throughout the community. There is need therefore for the risks and benefits of low-dose aspirin, and its' role within healthcare and within public health, to be widely discussed not least as media reports are bringing this issue into the public domain. It also follows that policy decisions need to be taken as to whether or not its use should be actively promoted. In particular, it is important that Doctors and healthcare practitioners are well informed of the risks and benefits so that they can impart this knowledge during consultations. Furthermore, it is important that low-dose aspirin is not perceived as a substitute for a healthy lifestyle, but that it is recommended and uptake monitored alongside other protective behaviours to improve on health gain, such as smoking cessation, moderate alcohol intake, exercise and diet.
... Non-steroidal anti-inflammatory drugs, including aspirin, have been available for many years and are widely used throughout the world (8). Aspirin as a treatment for cancer is currently of interest (9,10). Randomised trials assessing the effect of aspirin on the cardiovascular system and disease have also collected data on cancer incidence. ...
Melatonin is an endogenous hormone primirarily known for its action on the circadian rhythms. But preclinical studies are reporting both its radioprotective and radiosensitising properties, possibly mediated through an interaction between melatonin and the regulation of estrogens. Melatonin pre-treatment prior to ionising radiation was associated with a decrease in cell proliferation and an increase in p53 mRNA expression, leading to an increase in the radiosensitivity of breast cancer cells. At the same time, a decrease in radiation- induced side effects was described in breast cancer patients and in rodent models. This review examines the potential for melatonin to improve the therapeutic outcomes of breast radiation therapy, specifically estrogen receptor positive patients. Evidence suggest that melatonin may offers a novel, non-toxic and cheap adjuvant therapy to improve the existing treatment modalities. But further research is required in the clinical setting before a clear understanding of its therapeutic benefits is determined.
... However, the economic impact of a small number of still clinically relevant drugs ending patent protection is relatively modest compared with far higher numbers and costs of the new drug arrivals. Alternatively there is interest in re-purposing drugs currently licensed for non-oncological indications [11], although challenges in assimilating previous data and generating the required evidence in a cancer setting remain [12]. ...
... Aspirin has exhibited anti-cancer activity in a variety of cancers through both COX-dependent and independent pathways, exhibiting good activity against breast, brain, gastrointestinal, esophageal, pancreatic, prostate, lung and colorectal cancers [69][70][71]. In various cancer types like colorectal, esophageal cancer, aspirin is now in Phase III clinical trials. ...
Increased investments and development of new technologies in drug discovery have barely improved the outcome of medicinal entities in the drug discovery market from a long time. Minimal success rates of drug approvals, poor safety profiles, and long development processes are some of many hurdles encountered in the drug discovery field. Therefore, drug repurposing can provide an alternative approach to meet the demands of the new, potent and safe anticancer agents in terms of both economic cost and time efficiency. The common molecular pathways of different diseases and secondary indications of most of the approved drugs, and advances in genomics, informatics and biology, as well as the availability of approved or safe drug libraries can certainly provide an improved and efficient way of screening safer drugs for new indications. Promising results of drug repurposing in different therapeutic areas have encouraged the scientific community to discover new drugs for different diseases using this methodology. Herein, we provide a general overview of structurally and functionally diverse approved drugs that have been repurposed as anti-cancer drugs.
... Although evidence for the promising anticancer activity of aspirin has been reported [68], the underlying mechanisms are still unclear even though AMPK activation, and NF-kB and mTOR inhibition have been confirmed in pancreatic and colorectal cancer cells [69,70]. Migration and invasion of malignant mesothelioma cells are inhibited by aspirin via a high-mobility group box 1 (HMGB1)-mediated mechanism; HMGB1 is an inflammatory molecule involved in the initiation and progression of this tumor type [71]. ...
Drug repositioning is gaining increasing attention in drug discovery because it represents a smart way to exploit new molecular targets of a known drug or target promiscuity among diverse diseases, for medical uses different from the one originally considered. In this review, we focus on known non-oncological drugs with new therapeutic applications in oncology, explaining the rationale behind this approach and providing practical evidence. Moving from incompleteness of the knowledge of drug-target interactions, particularly for older molecules, we highlight opportunities for repurposing compounds as cancer therapeutics, underling the biologically and clinically relevant affinities for new targets. Ideal candidates for repositioning can contribute to the therapeutically unmet need for more-efficient anticancer agents, including drugs that selectively target cancer stem cells.
... Aspirin is also missing from our list despite significant levels of interest in the anti-cancer properties that it may possess. While there is some evidence that aspirin may have some influence on cancer treatment post-diagnosis [45,46], the bulk of attention has been on the prophylactic use of aspirin, including for those at high risk due to Lynch Syndrome [47], or from previous incidence of colorectal cancer (CRC) [48]. And, as with metformin, there is also a wide range of pre-clinical and clinical activity around aspirin and cancer such that there is little that a project such as ours could do to add to the debate, in contrast to the situation with lesser investigated drugs such as mebendazole, nitroglycerin, or cimetidine. ...
The Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well-characterised non-cancer drugs for new uses in oncology. The rationale for this project is presented, examining current issues in oncological drug development, challenges for health systems, and existing and future patient needs. In addition to discussing the advantages of repurposing, the paper also outlines some of the characteristics used in the selection of drug candidates by this project. Challenges in moving candidate drugs into clinical trial and subsequent practice are also discussed.
... Because aspirin use was associated with decreased risk of death from breast cancer, this suggests that aspirin has a direct interaction with the disease, with PTGS-2 inhibition a potential molecular mechanism for aspirin to halt the growth of a tumour and prevent metastasis. It would be very interesting if the survival benefit gained is due to something as nonspecific as PTGS-2 inhibition, thus supporting the current prospective trials of aspirin in breast and other cancer types (Phillips et al, 2013). ...
Background:
Aspirin use has been associated with a reduced cancer incidence and fewer deaths from cancer. This study examined whether women with breast cancer prescribed aspirin postdiagnosis had improved survival.
Methods:
An observational, population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death records in Tayside, Scotland. All community prescriptions for aspirin in women with breast cancer were extracted and use postdiagnosis for each individual examined using Cox's proportional hazard models. The main outcome measures were all-cause mortality and breast cancer-specific mortality.
Results:
Four thousand six hundred and twenty-seven patients diagnosed with breast cancer between 1 January 1998 and 31 December 2008 were followed up until 28 February 2010. Median age at diagnosis was 62 (IQR 52–74). One thousand eight hundred and two (39%) deaths were recorded, with 815 (18%) attributed to breast cancer. One thousand and thirty-five (22%) patients were prescribed aspirin postdiagnosis. Such aspirin use was associated with lower risk of all-cause mortality (HR=0.53, 95% CI=0.45–0.63, P<0.001) and breast cancer-specific mortality (HR=0.42, 95% CI=0.31–0.55, P<0.001) after adjusting for age, socioeconomic status, TNM stage, tumour grade, oestrogen receptor status, surgery, radiotherapy, chemotherapy, adjuvant endocrine therapy and aspirin use prediagnosis.
Conclusions:
Aspirin use postdiagnosis of breast cancer may reduce both all-cause and breast cancer-specific mortality. Further investigation seeking a causal relationship and which subgroups of patients benefit most await ongoing randomised controlled trials.
... 105 These results have prompted "Add-Aspirin," a large-scale, randomized and doubleblind clinical trial in patients with early-stage common solid tumors, the planning of which is well underway. 106 Despite aspirin having significant anti-platelet effects, its ability to reduce P-selectin expression on platelets is inconclusive, with the results of studies ranging from aspirin reducing, having no effect, or increasing P-selectin expression on platelets. 107 Moreover, an in vitro study of platelets exposed to aspirin demonstrated a dose-dependent reduction in the expression of P-selectin and GpIIb/ IIIa on the platelet surface. ...
Background:
Despite a wealth of preclinical and observational data, prospective data regarding the use of metformin in lung cancer is extremely limited.
Methods:
We pooled individualized data from two prospective trials evaluating metformin plus platinum-based chemotherapy, with or without bevacizumab, in non-diabetic patients with untreated advanced NSCLC. In addition to reporting on clinical efficacy and safety endpoints, we also explored metformin's activity in key molecular cohorts.
Results:
33 patients were included in the pooled analysis, of whom 70% were current or previous smokers. 82% had standard tissue molecular testing results available. KRAS, EGFR, and LKB1 mutation prevalence was 48%, 26%, and 8.3%, respectively. Composite median PFS was 6 months for all patients (95% CI: [1.36, 7.96]), 7.2 months for KRAS mutants (95% CI: [1.18, 9.21]), and 6.6 months for EGFR mutants (95% CI: [1.18, 15.29]). Composite median OS was 14.8 months for all patients (95% CI: [8.25, 19.99]), 17.5 months for KRAS mutants (95% CI: [8.86, 26.96]), and 13.3 months for EGFR mutants (95% CI: [2.60, 25.86]). Lymphopenia was the most common grade 3 AE (12%), followed by leukopenia, nausea, vomiting, and hypertension (9% each). There were 2 grade 4 AEs, neutropenia (21%) and sepsis (3%), and 1 grade 5 AE (colonic perforation) attributed to bevacizumab.
Conclusion:
Our results confirm the previously shown efficacy and tolerability of metformin in combination with chemotherapy and highlight encouraging activity in key molecular cohorts. Future efforts should build on this work by prospectively studying metformin in these molecular subgroups.
According to the pharmacophore combination principle, a set of new 3′,4′,5′-trimethoxy flavonoid salicylate derivatives was designed, synthesized and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment of compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while had no effect the cell cycle of HCT-116 cells. What’s more, WB analysis suggested that HIF-1α, tubulin, HK-2 and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v which was illuminated by analyzing the crystal structure of compound 10v in complex with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
Introduction: Evidence from pre-clinical studies and observational data suggest that metformin and aspirin are good candidates for adjuvant therapies, though definitive phase III trials have not been completed. Prior to the initiation of this work, the Add-Aspirin trial had been conceived and funded with several potential challenges related to the implementation and design identified. Evidence to support the evaluation of metformin in a phase III adjuvant basket trial had not been systematically evaluated. Methods: I examined the implementation and conduct of the Add-Aspirin trial during its first year at individual UK research centres. Baseline clinical characteristics, and the feasibility and effect of the run-in period, in the first 500 participants was also examined. Additionally, I conducted a systematic review and meta-analysis to investigate the effect of metformin use on survival outcomes for individual tumour types in the adjuvant setting. Results: Centres recognised the efficiencies offered from a basket trial design particularly in terms of gaining approvals, staffing and data entry, though some unanticipated set-up and recruitment challenges have been identified. The baseline clinical characteristics were largely as expected. Overall, 88% of participants were randomised. The run-in period was effective in identifying, and preventing randomisation of participants who had less than 80% adherence (5.0%), and participants who developed significant aspirin related toxicities (1.2%). Other nonrandomisations were mostly due to minor toxicity and/or personal choice. A systematic review and meta-analysis found that metformin use was associated with significant benefits in recurrence-free survival, overall survival and cancer-specific survival in early-stage colorectal and prostate cancer. Conclusion: Opening a large multi-tumour type basket trial with an active run-in period was found to be feasible, but minor conduct modifications have been recommended and protocol amendments implemented. Metformin could be a useful adjuvant agent, and randomised control trials in colorectal and prostate cancer are advocated.
Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.
Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial – a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible – limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research.
The acronym S.A.M. (statins, aspirin, metformin) is a simplistic clinician and patient method of remembering the three most important off-label “natural” products that should be primarily discussed with individuals concerned about breast cancer. And simultaneously it sends a message to patients to always consider the largest source of morbidity and mortality in the world and the need to improve overall health while still allowing the maximum potential benefit against more disease-specific issues. S.A.M. are all low-cost, generic, derived from “natural” sources and have more positive data in the area of breast cancer prevention and reducing the risk of recurrence compared to any dietary supplement I have researched over the past 30 years. S.A.M. is also a unisex name that can be applied to women or men because similar potential benefits in patients concerned about prostate cancer mirror those of breast cancer in regard to off-label or integrative medicine utilization (both diseases are hormonally manipulated as one of their primary forms of treatment). Interestingly, there are now multiple dietary supplements that appear to mimic S.A.M. that could potentially serve as current and future options for those intolerant to S.A.M. and/or those in need of even more treatment options.
Aims:
Regular aspirin use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer. Preclinical data show that aspirin down-regulates PI3 kinase (PI3K) signalling activity through cyclo-oxygenase-2 (COX-2) inhibition, leading to the hypothesis that the effect of aspirin might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. The aim of this study was to assess the relationship between PIK3CA status and the efficacy of regular use of aspirin after diagnosis on overall survival in colorectal cancer patients.
Materials and methods:
We identified studies that compared post-diagnosis aspirin efficacy in colorectal cancer patients identified by PIK3CA status. Hazard ratios for overall survival were meta-analysed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was carried out by weighted linear meta-regression. All statistical tests were two-sided.
Results:
The overall effect of aspirin was not significant (summary risk estimate = 0.82; 95% confidence interval 0.63-1.08, P = 0.16; I(2) = 57%). In PIK3CA mutant disease (n = 588), aspirin use reduced total mortality by 29% (summary risk estimate = 0.71; 95% confidence interval 0.51-0.99, P = 0.04; I(2) = 0%), whereas in PIK3CA wild-type disease (n = 4001), aspirin use did not reduce overall mortality (summary risk estimate = 0.93; 95% confidence interval 0.61-1.40; P = 0.7; I(2) = 80%) (P interaction = 0.39). There was a beneficial trend for aspirin on cancer-specific survival in PI3KCA mutated subjects (summary risk estimate = 0.37, 95% confidence interval 0.11-1.32, P = 0.1), albeit with high heterogeneity (Q chi-squared = 3.41, P = 0.07, I(2) = 70.7%).
Conclusion:
These findings suggest that the benefit of post-diagnosis aspirin treatment on overall mortality in colorectal cancer may be more marked in PIK3CA mutated tumours, although the low number of studies prevents definitive conclusions. Trials addressing this issue are warranted to assess the efficacy of aspirin in the adjuvant setting.
Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper.
Purpose:
In a recent analysis of a large clinical database, postdiagnosis aspirin use was associated with 57% lower prostate cancer-specific mortality (PCSM) among men diagnosed with nonmetastatic prostate cancer. However, information on this association remains limited. We assessed the association between daily aspirin use and PCSM in a large prospective cohort.
Patients and methods:
This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study-II Nutrition Cohort in 1992 or 1993 and June 2009. Aspirin use was reported at enrollment, in 1997, and every 2 years thereafter. During follow-up through 2010, there were 441 prostate cancer deaths among 8,427 prostate cancer cases with information on prediagnosis aspirin use and 301 prostate cancer deaths among 7,118 prostate cancer cases with information on postdiagnosis aspirin use.
Results:
Compared with no aspirin use, neither prediagnosis nor postdiagnosis daily aspirin use were statistically significantly associated with PCSM (prediagnosis use, multivariable-adjusted hazard ratio (HR) = 0.92, 95% CI 0.72 to 1.17, postdiagnosis use, HR = 0.98; 95% CI, 0.74 to 1.29). However, among men diagnosed with high-risk cancers (≥ T3 and/or Gleason score ≥ 8), postdiagnosis daily aspirin use was associated with lower PCSM (HR = 0.60; 95% CI, 0.37 to 0.97), with no clear difference by dose (low-dose, typically 81 mg per day, HR = 0.50; 95% CI, 0.27 to 0.92, higher dose, HR = 0.73; 95% CI, 0.40 to 1.34).
Conclusion:
A randomized trial of aspirin among men diagnosed with nonmetastatic prostate cancer was recently funded. Our results suggest any additional randomized trials addressing this question should prioritize enrolling men with high-risk cancers and need not use high doses.
Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. Methods We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. Results In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0.79, 95% CI 0.68-0.92, p=0.003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0.66, 0.50-0.87; gastrointestinal cancers, 0.46, 0.27-0.77; both p=0.003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0.80, 0.72-0.88, p<0.0001; gastrointestinal cancers, 0.65, 0.54-0.78, p= 7.5 years: all solid cancers, 0.69, 0.54-0.88, p=0.003; gastrointestinal cancers, 0.41, 0.26-0.66, p=0.0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0.66, 0.56-0.77, p<0.0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age the absolute reduction in 20-year risk of cancer death reaching 7.08% (2.42-11.74) at age 65 years and older. Interpretation Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.
Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.
We obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1.
Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction).
Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.).
The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.
Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.
In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001).
Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.
Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.
Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. However, the influence of aspirin on survival after diagnosis of colorectal cancer is unknown.
To examine the association between aspirin use after colorectal cancer diagnosis on colorectal cancer-specific and overall survival.
Prospective cohort study of 1279 men and women diagnosed with stage I, II, or III colorectal cancer. Participants were enrolled in 2 nationwide health professional cohorts in 1980 and 1986 prior to diagnosis and followed up through June 1, 2008.
Colorectal cancer-specific and overall mortality.
After a median follow-up of 11.8 years, there were 193 total deaths (35%) and 81 colorectal cancer-specific deaths (15%) among 549 participants who regularly used aspirin after colorectal cancer diagnosis, compared with 287 total deaths (39%) and 141 colorectal cancer-specific deaths (19%) among 730 participants who did not use aspirin. Compared with nonusers, participants who regularly used aspirin after diagnosis experienced a multivariate hazard ratio (HR) for colorectal cancer-specific mortality of 0.71 (95% confidence interval [CI], 0.53-0.95) and for overall mortality of 0.79 (95% CI, 0.65-0.97). Among 719 participants who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate HR for colorectal cancer-specific mortality of 0.53 (95% CI, 0.33-0.86). Among 459 participants with colorectal cancers that were accessible for immunohistochemical assessment, the effect of aspirin differed significantly according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04). Regular aspirin use after diagnosis was associated with a lower risk of colorectal cancer-specific mortality among participants in whom primary tumors overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76), whereas aspirin use was not associated with lower risk among those with primary tumors with weak or absent expression (multivariate HR, 1.22; 95% CI, 0.36-4.18).
Regular aspirin use after the diagnosis of colorectal cancer is associated with lower risk of colorectal cancer-specific and overall mortality, especially among individuals with tumors that overexpress COX-2.
Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) to a greater degree than other non-gastrointestinal cancers, but the molecular basis for this difference is unknown. We previously reported that aspirin induces signal-specific I kappa B alpha degradation followed by NF kappa B nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. Here, we explored the hypothesis that cell-type specific effects on NF kappa B signalling are responsible for the observed differences in protection by aspirin against CRC compared to breast and gynaecological cancers. We also assessed whether COX-2 expression, mutation status of adenomatous polyposis coli (APC), beta-catenin, p53, or DNA mismatch repair (MMR) genes in CRC lines influenced aspirin-induced effects. We found that aspirin induced concentration-dependent I kappa B alpha degradation, NF kappa B nuclear translocation and apoptosis in all CRC lines studied. However, there was no such effect on the other cancer cell types, indicating a considerable degree of cell-type specificity. The lack of effect on NF kappa B signalling, paralleled by absence of an apoptotic response to aspirin in non-CRC lines, strongly suggests a molecular rationale for the particular protective effect of NSAIDs against CRC. Effects on NF kappa B and apoptosis were observed irrespective of COX-2 expression, or mutation status in APC, beta-catenin, p53 and DNA MMR genes, underscoring the generality of the aspirin effect on NF kappa B in CRC cells. These findings raise the possibility of cell-type specific targets for the development of novel chemopreventive agents.
Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. Methods Our analysis included all five large randomised trials of daily aspirin (>= 75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. Findings Of 17 285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6.5 years (SD 2.0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0.64, 95% CI 0.48-0.84, p=0.001; adenocarcinoma, HR 0.54, 95% CI 0.38-0.77, p=0.0007; other solid cancers, HR 0.82, 95% CI 0.53-1.28, p=0.39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0.52, 95% CI 0.35-0.75, p=0.0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0.69, 95% CI 0.50-0.95, p=0.02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0.45, 95% CI 0.28-0.72, p=0.0009), particularly in patients with colorectal cancer (HR 0.26, 95% CI 0.11-0.57, p=0.0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0.31, 95% CI 0.15-0.62, p=0.0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0.50, 95% CI 0.34-0.74, p=0.0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0.65, 95% CI 0.53-0.82, p=0.0002), but not the risk of other fatal cancers (HR 1.06, 95% CI 0.84-1.32, p=0.64; difference, p=0.003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. Interpretation That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis.
Objective:
Aspirin is associated with a reduced risk of developing colorectal cancer. This study examined whether patients with colorectal cancer prescribed aspirin had improved survival.
Design:
An observational population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death certificate records in Tayside, Scotland. All community prescribed aspirin pre- and post-diagnosis was extracted and periods of aspirin use post-diagnosis for each individual were analysed using Cox proportional hazard models. Main outcome measures were all-cause and colorectal mortality from death certificates.
Results:
Two thousand nine hundred ninety patients were identified with colorectal cancer between 1st January 1997 and 30th December 2006 and followed up until 28th February 2010. Median age at diagnosis was 73 (interquartile range [IQR] 65-80) with 52% male. One thousand nine hundred ninety-eight (67%) deaths were recorded with 1021 (34%) attributed to colorectal cancer. One thousand three hundred forty (45%) patients used aspirin at some stage of the study period. Aspirin use post-diagnosis was associated with lower risk of all cause mortality (hazard ratio [HR]=0.67, 95% confidence interval [CI]=0.57-0.79, p<0.001) and colorectal cancer specific mortality after allowing for age, Dukes' stage, gender, socio-economic status and aspirin use pre-diagnosis. Increasing age and stage at diagnosis were associated with increased risk, with more affluent patients at reduced risk.
Conclusions:
Our study suggests that aspirin use post-diagnosis of colorectal cancer may reduce both all cause and colorectal cancer specific mortality. However further work is required to ensure this is a causal relationship and to identify whether it is best used in specific groups of patients.
Unlabelled:
Tumor cells transit from the primary tumor via the blood circulation to form metastases in distant organs. During this process, tumor cells encounter a number of environmental challenges and stimuli that profoundly impact their metastatic potential. Here, we review the cooperative and dynamic host-tumor cell interactions that support and promote the hematogenous dissemination of cancer cells to sites of distant metastasis. In particular, we discuss what is known about the cross-talk occurring among tumor cells, platelets, leukocytes, and endothelial cells and how these cell-cell interactions are organized both temporally and spatially at sites of extravasation and in the early metastatic niche.
Significance:
Metastasis is a function not only of tumor cells but also involves cooperative interactions of those cells with normal cells of the body, in particular platelets and leukocytes. These other cell types alter the behavior of the tumor cells themselves and of endothelial cells lining the vasculature and assist in tumor cell arrest and extravasation at sites of metastasis and subsequently in the establishment of tumor cells in the early metastatic niche. A better understanding of the important role that these contact and paracrine interactions play during metastasis will offer new opportunities for therapeutic intervention.
Purpose:
Experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, but clinical data have been limited. We investigated whether use of ACs was associated with the risk of death from prostate cancer.
Patients and methods:
This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of prostate cancer-specific mortality (PCSM) was compared between the AC and non-AC groups.
Results:
After a median follow-up of 70 months, risk of PCSM was significantly lower in the AC group compared with the non-AC group (3% v 8% at 10 years; P < .01). The risks of disease recurrence and bone metastasis were also significantly lower. In a subgroup analysis by clinical risk category, the reduction in PCSM was most prominent in patients with high-risk disease (4% v 19% at 10 years; P < .01). The benefit from AC was present across treatment modalities (RT or RP). Analysis by type of AC medication suggested that the PCSM reduction was primarily associated with aspirin. Multivariable analysis indicated that aspirin use was independently associated with a lower risk of PCSM (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02).
Conclusion:
AC therapy, particularly aspirin, was associated with a reduced risk of PCSM in men treated with RT or RP for prostate cancer. The association was most prominent in patients with high-risk disease.
Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett's oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose.
Aspirin has been associated to a reduced risk of colorectal and possibly of a few other common cancers.
To provide an up-to-date quantification of this association, we conducted a meta-analysis of all observational studies on aspirin and 12 selected cancer sites published up to September 2011.
Regular aspirin is associated with a statistically significant reduced risk of colorectal cancer [summary relative risk (RR) from random effects models = 0.73, 95% confidence interval (CI) 0.67-0.79], and of other digestive tract cancers (RR = 0.61, 95% CI = 0.50-0.76, for squamous cell esophageal cancer; RR = 0.64, 95% CI = 0.52-0.78, for esophageal and gastric cardia adenocarcinoma; and RR = 0.67, 95% CI = 0.54-0.83, for gastric cancer), with somewhat stronger reductions in risk in case-control than in cohort studies. Modest inverse associations were also observed for breast (RR = 0.90, 95% CI = 0.85-0.95) and prostate cancer (RR = 0.90, 95% CI = 0.85-0.96), while lung cancer was significantly reduced in case-control studies (0.73, 95% CI = 0.55-0.98) but not in cohort ones (RR = 0.98, 95% CI = 0.92-1.05). No meaningful overall associations were observed for cancers of the pancreas, endometrium, ovary, bladder, and kidney.
Observational studies indicate a beneficial role of aspirin on colorectal and other digestive tract cancers; modest risk reductions were also observed for breast and prostate cancer. Results are, however, heterogeneous across studies and dose-risk and duration-risk relationships are still unclear.
Clinical guidelines for prophylactic aspirin use currently only consider the cardiovascular benefits of aspirin, weighed against the potential harm from aspirin-induced bleeding. Daily aspirin use has been convincingly shown to reduce the risk of colorectal cancer and recurrence of adenomatous polyps, but in average-risk populations, these benefits alone do not outweigh harms from aspirin-induced bleeding. Recently published secondary analyses of cardiovascular trials provide the first randomized evidence that daily aspirin use may also reduce the incidence of all cancers combined, even at low doses (75-100 mg daily). This Review considers the general mechanism of action that defines aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) as a class, the specific advantages of aspirin over other NSAIDs for prophylactic use, the current evidence concerning the main health outcomes affected by aspirin use, and the hypothesis that inhibition of platelet activation may mediate both the cardioprotective and cancer-preventive effects of low-dose aspirin. It also considers how even a 10% reduction in overall cancer incidence beginning during the first 10 years of treatment could tip the balance of benefits and risks favourably in average-risk populations.
Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control.
Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics.
Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses.
That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis.
None.
Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention.
We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status.
Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009).
Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer.
None.
Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo.
In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990.
861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups.
600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment.
European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.
Photodynamic therapy (PDT) effectiveness can be improved by employing combined modality approaches involving pharmaceuticals targeting the tumor microenvironment and/or tumor cell death pathways. In one approach, combining PDT with celecoxib improves long-term tumoricidal activity without increasing normal tissue photosensitization. However, side effects arising from the use of coxib based cyclooxygenase-2 (COX-2) inhibitors, including cardiovascular injury, decreases the clinical applications of this class of compounds. A growing number of studies demonstrate that the tumoricidal actions of coxibs such as celecoxib involve non-COX-2 mediated mechanisms. The celecoxib analog, 2,5-dimethyl celecoxib (DMC), lacks COX-2 inhibitory activity but exhibits cytotoxic properties comparable to the COX-2 inhibitor celecoxib. We compared the effectiveness of DMC and celecoxib in modulating PDT response at both the in vitro and in vivo level using a C3H/BA murine mammary carcinoma model. Both DMC and celecoxib blocked PDT induced expression of the pro-survival protein survivin, enhanced the endoplasmic reticulum stress (ERS) response of PDT, and increased both apoptosis and cytotoxicity in BA cells exposed to combination protocols. DMC enhanced the in vivo tumoricidal responsiveness of PDT without altering PGE2 levels. Our data demonstrates that DMC improved PDT by increasing apoptosis and tumoricidal activity without modulating COX-2 catalytic activity. Our results also suggest that celecoxib mediated enhancement of PDT may involve both COX-2 dependent and independent mechanisms.
Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events.
We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries.
In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older.
Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.
None.
We examined the effect of aspirin on survival following resection for squamous cell carcinoma (SCC) of the esophagus or adenocarcinoma of the gastric cardia.
Patients who underwent esophagectomy for these cancers between May 2000 and December 2002 were allocated to one of three groups and given daily either a low dose of aspirin, placebo, or no tablets.
The 5-year survival for all patients on aspirin (445) was 51.2%, placebo (658) 41%, and no tablet (495) 42.3% (P = 0.04 for difference between treatments). The 5-year survival for all SCC patients on aspirin (267) was 49.8%, placebo (433) 42.2%, and no tablet (343) 41.2% (P = 0.26). There was a significant improvement in survival for patients with adenocarcinoma of the cardia on aspirin compared with the two control groups combined (P = 0.029). Survival for T2N0M0 SCC patients was significantly improved with aspirin (71) compared with placebo (167) or no tablet (134) (P = 0.0004). However, there was no significant difference between the survival curves for T2N0M0 adenocarcinoma patients on aspirin (21) and the two control groups combined (65) (P = 0.29).
The results of this preliminary study support further investigation of aspirin as adjuvant therapy to improve survival in subsets of postesophagectomy patients.
To assess the incidence of gastrointestinal haemorrhage associated with long term aspirin therapy and to determine the effect of dose reduction and formulation on the incidence of such haemorrhage.
Meta-analysis of 24 randomised controlled trials (almost 66 000 participants). Intervention: Aspirin compared with placebo or no treatment, for a minimum of one year.
Incidence of gastrointestinal haemorrhage.
Gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68; 95% confidence interval 1.51 to 1.88); the number needed to harm was 106 (82 to 140) based on an average of 28 months' therapy. At doses below 163 mg/day, gastrointestinal haemorrhage occurred in 2.30% of patients taking aspirin compared with 1.45% taking placebo (1.59; 1.40 to 1.81). Meta-regression showed no relation between gastrointestinal haemorrhage and dose. For modified release formulations of aspirin the odds ratio was 1.93 (1.15 to 3.23).
Long term therapy with aspirin is associated with a significant increase in the incidence of gastrointestinal haemorrhage. No evidence exists that reducing the dose or using modified release formulations would reduce the incidence of gastrointestinal haemorrhage.
Preclinical and clinical studies have clearly shown a benefit of nonsteroidal anti-inflammatory drug (NSAID) use in reducing cancer risk. However, the adverse gastrointestinal and cardiovascular side effects associated with NSAIDs and COX-2 selective inhibitors (coxibs) have provoked more scrutiny of the precise role of specific downstream mediators in the prostaglandin (PG) signaling cascade. NSAIDs and coxibs inhibit PG biosynthesis. One of the PGs produced at high levels in the tumor microenvironment is PGE(2), which is thought to play a major role in cancer progression. Thus, a better understanding of PGE(2) signaling could enable identification of novel and safer therapeutic targets downstream of the cyclooxygenase enzymes. We review the emerging molecular mechanisms by which COX-2-derived PGE(2) is involved in cancer progression and delineate potential opportunities for development of novel pharmacologic approaches utilizing this pathway.
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.
- Rothwell P.
- Fowkes F.
- Zanchetti A.
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.