Efficacy and Safety of Celecoxib on the Incidence of Recurrent Colorectal Adenomas: A Systematic Review and Meta-analysis

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Cancer Management and Research
Cancer Management and Research

DISCUSSION

Previous meta-analyses suggested a substantial protective effect of non-aspirin NSAIDs on colorectal adenoma recurrence.8–12 Although the exact mechanism of action remains to be elucidated, both COX-dependent and COX-independent mechanisms have been shown to contribute to the antitumor effects. Despite such promising data, use of long-term NSAIDs for cancer prevention is not very well received due to their significant toxicity, especially CV toxicity.8,11 However, CV toxicity of NSAIDs is a complicated phenomenon, which is a result of a complex interplay mainly between baseline CV risk and the nature of each NSAID along with its dose. Celecoxib, a selective COX-2 inhibitor, is among a few NSAIDs that have been tested in a number of studies for CRC prevention. Although its efficacy in this indication looked initially promising, CV toxicity shown from cancer prevention trials thwarted the interest of the medical community.

Nevertheless, a previous review has suggested that moderate dose of celecoxib (≤400 mg/day) might not be associated with an increased CV risks.26 Recently, the PRECISION trial25 which was a large, randomized, CV safety trial comparing celecoxib at ≤400 mg/day with ibuprofen and naproxen suggested that celecoxib at this dose may not confer unacceptable CV risk along with other serious adverse events. As a result, a comprehensive evaluation to understand the totality of its risk–benefit in this important indication may be warranted. Our study was designed to shed some light into this important question. To the best of our knowledge, this study combined the entire body of relative and absolute efficacy and safety of celecoxib at different doses. We also tried to gage the magnitude of risk and benefit in patients with varying risk of adenomas to increase understanding of the risk–benefit equation, which may vary with different levels of risk. Thus, a clearer picture of an agent with multidimensional effects can be seen.

The results of our study showed that celecoxib demonstrated a dose-dependent effect in the reduction of adenoma recurrence and the risks of serious adverse events during a follow-up of up to 3 years. Our findings on celecoxib are consistent with those from previous meta-analyses8–10 regarding the benefits of non-aspirin NSAIDs for the prevention of recurrent adenomas. For risk–benefit balance, we found that benefit of celecoxib at 400 mg/day may outweigh the risks of adverse events in patients with high-risk adenomas. It is important to note that the absolute risk of serious CV events associated with NSAIDs was greatest among individuals with high CV risk at baseline.13,26,42 Our analysis demonstrated no significant risks of CV events in patients on celecoxib 400 mg/day for 1–3 years despite that 45% of the study population were at high CV risk. This finding is consistent with the previous meta-analysis of randomized trials which reported no significant increase in CV risk with celecoxib 400 mg/day.19,43 Data from other observational studies also support such findings.26 As a result, celecoxib 400 mg/day could potentially be considered as a viable chemopreventive agent in patients with high risk of adenomas but with low CV risk. In addition, subgroup analysis based on different dosing regimens suggested that celecoxib 400 mg once daily may have a much better safety profile on CV events compared with 200 mg twice daily. The finding that twice daily dosing may confer greater CV risk than once daily dosing of celecoxib in our study is consistent with previous meta-analysis along with other mechanistic studies.19Twice daily dosing of celecoxib has been shown to increase blood pressure more than that in once daily dosing.44 A previous pharmacodynamic study conducted in healthy volunteers suggested that prostacyclin levels can recover to normal levels 12 hours after a single daily dose of celecoxib.45 This raised a possibility of a more complete prostacyclin inhibition with twice daily than once daily dosing which ultimately leads to higher CV risk. Several other hypotheses have been proposed to explain differences in types and dosing of NSAIDs vs CV risk including different levels of inhibition of endothelial NO synthase46 and differential effects on the enhancement of methylarginines formation.47However, the exact mechanism of this difference remains unknown.

For high-dose celecoxib (800 mg/day), despite yielding slightly higher efficacy (18 more cases of advanced adenoma prevented compared with 400 mg/day), the overall risk was most likely unacceptable. With 108 advanced adenomas prevented, the trade-off was 82 excess CV events per 1,000 patients treated with 800 mg/day of celecoxib. This finding is very much consistent with previous meta-analysis, RCTs, and observational studies which indicated a high risk of CV events with a high dose of celecoxib. As a result, celecoxib at 800 mg/day is clearly not a viable option for this indication. Of interest is the fact that no trial has ever been conducted to evaluate celecoxib at a dose of 100–200 mg/day as a chemopreventive agent. Although the efficacy of this low dose is uncertain, adverse effects of celecoxib at ≤200 mg/day would most likely be less than 400 mg/day. This may allow celecoxib to be more acceptable for long-term use if it can be demonstrated to show some efficacy for this indication at this low level of dosing.

The preventive effect of celecoxib, as shown in our analysis, waned after ≥2 years of treatment cessation. The lack of a sustained clinical effect may reflect a rebound of COX-2 expression, or cessation of an alternative mechanism independent of COX-2 inhibition, as described previously.30,48This is consistent with an increased risk of adenomas after 2 years of celecoxib discontinuation in the PreSAP trial,30 which is similar to the APPROVe study with rofecoxib.32 These data suggested that celecoxib may need to be employed on a long-term basis. Since both efficacy and adverse events can be cumulative, future study of celecoxib may need to be long term to fully elucidate the true balance on risk and benefit of this agent.

Our study has several important limitations. First, the limited number of trials along with their short duration, some of which were terminated early, may not provide sufficient data to genuinely represent the long-term risk and benefit of celecoxib. Second, by using a pooled estimate of population data from the National Cancer Institute pooling project, our analysis may be limited by the nature of the source data that were derived mainly from a Caucasian population and a specific geographical area. Since significant differences exist among various subtypes of CRC across the world, the applicability of such data to other parts of the world may be limited. This is also the case for pooled estimate on CV events where different rates of CV events are seen among different racial groups and geographical areas. Third, we did not analyze the impact of aspirin use on the risk–benefit of celecoxib. This was due to the fact that we were unable to obtain patient-level data of these included trials. Aspirin could potentially alter the risk–benefit balance of celecoxib if used concomitantly. This is due to the fact that aspirin has a modest protective effect on CRC and CV events, yet possesses gastrointestinal toxicity along with major bleedings.10,49,50 As a result, readers should be aware of this limitation. Lastly, based on these limitations, our data are useful only for hypothesis generation and cannot be considered definitive. Future research on celecoxib as a chemopreventive agent may potentially be considered but must be employed at a dose of ≤400 mg either once or twice daily.

CONCLUSION

In this comprehensive evaluation with risk–benefit integrated analysis, celecoxib at the dose of ≤400 mg/day could potentially be considered as a viable chemopreventive option, especially with a 400 mg once daily regimen. This may be particularly attractive in patients with high risk of adenomas but with low CV risk. Example of this patient group is a patient who has a history of high-risk adenomas and also has <5% of a 10-year risk of developing atherosclerotic CV disease. Celecoxib at a higher dose should be discouraged due to the unacceptable high level of risk compared with small benefit gained by increasing the dose beyond 400 mg/day. However, more long-term trials on celecoxib at a dose of ≤400 mg either once or twice daily are warranted to fully elucidate the true balance on risk and benefit of this agent.

Transparency declaration

The corresponding authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.

Data sharing statement

Technical appendix and dataset are available from the corresponding author.

Acknowledgments

The authors wish to thank Professor Brian L Furman, Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, UK, for his valuable comments and support which helped to improve the manuscript, and Mr Razman Shah Mohd Razali, reference librarian, International Medical University, for providing the full-text articles whenever needed.

Disclosure

The authors report no conflicts of interest in this work.


Sajesh K Veettil,1 Surakit Nathisuwan,2 Siew Mooi Ching,3–5 Peerawat Jinatongthai,6,7 Kean Ghee Lim,Siang Tong Kew,9 Nathorn Chaiyakunapruk7,10–12
1Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; 2Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 3Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 4Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia; 5Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Selangor, Malaysia; 6Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand; 7School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia; 8Department of Surgery, Clinical School, International Medical University, Seremban, Malaysia; 9Department of Internal Medicine, School of Medicine, International Medical University, Kuala Lumpur, Malaysia; 10Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand; 11School of Pharmacy, University of Wisconsin, Madison, WI, USA; 12Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, Malaysia  

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Source: Cancer Management and Research.
Originally published January 9, 2019

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