Aspirin Use After Diagnosis Improves Survival in Older Adults With Colon Cancer

A Retrospective Cohort Study

Marlies S. Reimers, MD; Esther Bastiaannet, MSc; Myrthe P. P. van Herk-Sukel, PhD; Valery E. P. Lemmens, PhD; Colette B. M. van den Broek, MD; Cornelis J. H. van de Velde, MD, PhD; Anton J. M. de Craen, PhD; Gerrit Jan Liefers, MD, PhD

Disclosures

J Am Geriatr Soc. 2012;60(12):2232-2236. 

In This Article

Discussion

The current study found an independent strong association between longer survival and aspirin use after colon cancer diagnosis in older adults. This effect persisted after adjusting for several confounders and was present in most strata of colon cancer.

Since 1968, it has been suggested that aspirin may be a preventive agent against colorectal cancer.[16] Only recently has aspirin been mentioned as a possible adjuvant agent for colorectal cancer.[11] The current study indicates that aspirin could be an effective adjuvant agent in the treatment of colorectal cancer, especially in older, chemo-naive individuals with colon cancer, because aspirin use was associated with clinically and statistically significantly longer overall survival. To the knowledge of the authors, this is the first report that focuses on older adults with colon cancer specifically.

These results are consistent with results from a previous cohort study of 1,279 participants diagnosed with Stage I to III colorectal cancer that found longer overall survival in regular aspirin users than in nonusers (hazard ratio (HR) = 0.79, 95% CI = 0.65–0.97).[11] In the current study, aspirin users had a RR of 0.51 (95% CI = 0.38–0.70, P < .001) for overall survival. A major strength of this investigation is the use of a time-dependent covariate in the survival analyses and the large number of participants enrolled in the PHARMO database, which provided the unique opportunity to assess older adults with colon cancer specifically. By using two validated databases, the possibility of recall bias, which would be more likely with the use of questionnaires to assess aspirin use, was avoided.

These results underscore the findings of cardiovascular prevention trials, in which long-term aspirin use was associated with fewer deaths from cancer. HRs in these studies ranged from 0.63 to 0.85, which correspond with the findings of the current study in favor of aspirin use to reduce cancer death. Benefit increased with treatment duration and was consistent across the various populations included in these studies.[9,10] Nevertheless, aspirin was assessed as adjuvant treatment, starting after diagnosis of colon cancer, whereas these studies investigated aspirin use in the preventive setting, including aspirin use before diagnosis. The results of the current study suggest that aspirin use after cancer diagnosis is associated with a survival advantage over use before diagnosis. Also, the undertreatment of these elderly adults with adjuvant chemotherapy might explain the slightly greater survival advantage for older aspirin users in this cohort; younger individuals receive chemotherapy more often, with good results. Therefore, the absolute effect of aspirin could be higher in older adults with colon cancer who, without chemotherapy, have a higher a priori chance of developing metastases. This is also reflected in the larger effect of aspirin on survival in older adults with colon cancer without chemotherapy (HR = 0.71) and the previously published data in which a greater survival gain of aspirin use after diagnosis was found in older adults with colon cancer than in younger individuals.[2] Furthermore, expression of COX-2 may increase with age, which could be the reason for the larger effect of aspirin on survival in older adults with colon cancer.[17]

In recent studies in which prediagnosis NSAID use and survival after colorectal cancer diagnosis was evaluated, a greater reduction in colorectal cancer mortality risk after diagnosis with aspirin use was found than with overall NSAID use.[1,18,19] These results, along with the results of the current study, suggest that aspirin and not overall NSAID use, which was mostly used in all previous studies,[12,18] may be important in lengthening survival in individuals with colon cancer.

Most studies evaluated the use of aspirin or other NSAIDs before diagnosis. The current study established longer survival in aspirin users when aspirin use was started after cancer diagnosis and surgery. Also, because of the large number of participants in the total cohort (4,481 individuals with colorectal cancer), it was possible to perform an analysis on older chemo-naive individuals with colon cancer. Although these results are only hypothesis generating, they suggest that aspirin use as an adjuvant therapy for colon cancer treatment is a clinically relevant option, especially in older adults.

This study has limitations inherent to observational studies. First, aspirin use was not randomized, so it is possible that participants took aspirin for cancer-prevention purposes, although in the Netherlands, low-dose aspirin (80 mg) is prescribed exclusively for cardiovascular risk management and cannot be purchased over the counter. Second, the data were limited to prescribed drugs; it was not possible to obtain information regarding use of aspirin or other NSAIDs at home. Third, the smaller number of cardiac events could also explain the better prognosis, although a meta-analysis of aspirin use in the primary and secondary prevention of vascular disease showed a survival gain of approximately 5% for aspirin users.[20] This minimal gain in survival cannot explain the larger survival gain associated with aspirin use in the current study. Finally, there were differences in baseline characteristics of participants included in the investigation. Aspirin users underwent surgery more frequently than nonusers, had lower-stage disease, and were slightly younger, although the effect of aspirin persisted even after adjustment for these confounders and after stratification (Figure 2). More importantly, this longer survival in aspirin users in the current study and other observational studies was consistent with the findings of randomized trials.[21] Nevertheless, residual confounding may be present. This could only be resolved in a randomized clinical trial, one of which has already been started in Asia (ASCOLT NCT 00565708) and two of which are in preparation in Europe.[22]

Figure 2.

Adjusted rate ratio of overall survival (OS) with 95% confidence interval (CI) for aspirin use in older adults with colon cancer stratified according to sex, stage, age, adjuvant chemotherapy, comorbidity, incidence year, surgery, and grade. CVD = cardiovascular disease; DM = diabetes mellitus.

The exact mechanism by which aspirin exerts its activity is not completely understood. It is likely that the anti-inflammatory and chemopreventive effects of aspirin are mediated through direct inhibition of COX-1 and COX-2.[13,23,24] Approximately 70% of colorectal tumors express COX-2.[12] COX-2 plays an important role in colorectal carcinogenesis, invasion, angiogenesis, and metastasis. Several studies have shown that selective COX-2 inhibitors can reverse this COX-2 effect.[13] One study found a much lower risk of colorectal cancer–specific and overall mortality with tumors that overexpress COX-2.[11] High COX-2 expression was found to be associated with tumor metastases, and multiple studies have demonstrated COX-2 overexpression as a negative prognostic factor in colorectal cancer.[25,26,27] Also, studies have linked the COX enzyme-mediated mechanisms to the ability of tumors to initiate vascularization[28] and angiogenesis,[29] probably through the production of prostaglandin by COX-2.[30] This prostaglandin pathway may also be responsible for the regulation of apoptosis,[31] and evading apoptosis is one of the hallmarks of cancer.[32] By using aspirin, a COX-2 inhibitor, the effects of COX-2 on tumor progression can ultimately be altered in a positive way.

This is the first study focusing specifically on older adults with colon cancer. Elderly adults are a frequently overlooked, understudied, and often undertreated group of individuals. These findings may have important clinical implications in older adults with colorectal cancer. Demonstration of a significant therapeutic effect of a well-tolerated, inexpensive drug would be a major clinical advancement. In this study, aspirin emerges as an effective adjuvant agent, increasing overall survival in older adults with colon cancer, although a randomized trial in this age group is necessary to confirm the therapeutic role of aspirin and is currently being developed in the Netherlands.

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