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Celebrex may curb colon cancer, but with caveats
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(Reuters Health) - People who took a newer type of pain pill over a three-year period were less likely to develop polyps that could lead to colorectal cancer -- but at the expense of a higher risk of heart problems, new study findings report.
And when participants stopped taking the pain pill Celebrex (celecoxib) out of concerns over side effects, they eventually developed more polyps than people who had remained on an inactive, or placebo, drug throughout the study.
So should people concerned about their risk of colorectal cancer consider Celebrex?
"The findings in this study don't necessarily make that decision any easier," said Dr. Andrew Chan of Massachusetts General Hospital and Harvard Medical School, who did not participate in the research.
The study, published in the American Journal of Gastroenterology, received financial support from Pfizer, which sells Celebrex.
This is not the first study to suggest Celebrex and similar drugs -- known as COX-2 inhibitors - may reduce the risk of developing colon cancer, he said, but people need to balance that potential benefit with the higher risk of cardiovascular complications.
As a result, he said he suspects most people would choose to rely on regular colonoscopies to catch the disease in its early stages, rather than take a potentially risky drug for years.
But to people who have no underlying cardiovascular problems and a particularly high risk of colon cancer - they were diagnosed with it before perhaps, or have a strong family history - regular screening may not be enough, Chan noted.
"So for those patients, they might consider taking a drug like this," he said.
Colorectal cancer is the third most common cancer in men and women, and strikes 1.2 million people each year.
Other research has provided signs that COX-2 inhibitors, which block the COX-2 enzyme that causes inflammation, could also prevent colorectal cancer, as well as lung cancer in heavy smokers.
However, most COX-2 inhibitors ran into safety issues a few years after their approval, and now only Celebrex remains on the U.S. market. At a cost of several dollars per day, depending on dosage, it is much more expensive than older pain relievers such as ibuprofen.
During the study, Dr. Nadir Arber of Tel Aviv University and his colleagues reviewed data collected from 1,561 people with a history of colorectal cancer. More than half had received Celebrex for approximately 3 years, before concerns over the increased risk of cardiovascular problems caused researchers to discontinue the study.
The scientists then followed the people willing to continue the research for another 2 years, noting who developed new polyps, including advanced polyps with features that suggest they're more likely to become cancerous. Approximately half of the people who started the study agreed to continue.
Not surprisingly, Celebrex users were more likely to develop cardiovascular problems, including a 66 percent higher risk of serious cardiac disorders. But over the total 5-year period, people who took Celebrex were also less likely to develop new and advanced polyps than people who took a placebo.
Specifically, new polyps were found in 58 percent of people on placebo, and only 51 percent on Celebrex.
However, during the 5th year of the study alone, after the trial had been over for 2 years, 27 percent of Celebrex users developed new polyps, versus only 16 percent of people who had been on placebo - translating to a 66 percent higher risk among those who previously took Celebrex. Those who had been on Celebrex were also more likely to develop advanced polyps during that final year.
This rebound in risk actually makes biological sense, Chan told Reuters Health. If COX-2 inhibitors protect against colon cancer by blocking an enzyme pathway, when that blockage is released, the disease could occur "potentially at higher levels than had you never been on the drug in the first place," he said.
Still, the results are "very promising," Arber told Reuters Health by e-mail, adding he is now working to identify people who could benefit from the drug without experiencing the side effects.
Only half of the people who originally agreed to participate in the study remained after 5 years, and it's unclear how this might affect the results, noted Chan, whose own research suggests aspirin could prevent deaths from colorectal cancer.
However, for a study that lasts this long, "those are acceptable numbers," noted Arber.
If patients asked him whether they should take celecoxib to prevent colorectal cancer, Arber would tell them "no," he added. "They should speak with their doctor."
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Am J Gastroenterol advance online publication 19 April 2011; doi: 10.1038/ajg.2011.116 - pdf attached
Download the PDF here
Five-Year Analysis of the Prevention of Colorectal Sporadic Adenomatous Polyps Trial
Nadir Arber MD1, Julius Spicak MD2, Istvan Racz MD3, Miroslav Zavoral MD4, Aurora Breazna PhD5, Paola Gerletti BScD5, Maria J Lechuga MD5, Neal Collins MD5, Rebecca B Rosenstein PhD5, Craig J Eagle MD5 and Bernard Levin MD6 for the PreSAP Trial Investigators7
1. 1The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
2. 2Institute for Clinical and Experimental Medicine, Prague, Czech Republic
3. 3Petz Aladar County Hospital, Gyor, Hungary
4. 4Charles University in Prague, First Faculty of Medicine, Medical Department of the First Faculty and Central Military Hospital, Prague, Czech Republic
5. 5Pfizer, New York, New York, USA
6. 6The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (retired)
7. 7Investigators in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial are listed in Arber et al. (9)
ABSTRACT
OBJECTIVES:
Subjects in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial (PRESAP/NCT00141193/www.clinicaltrials.gov) were studied to determine efficacy and safety at a year 5 assessment.
METHODS:
In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colorectal adenomas removed within 3 months of the study's initiation were assessed after ~3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratified by cardioprotective aspirin use and randomized to receive orally 400 mg celecoxib (933 subjects) or placebo (628 subjects) once daily. Efficacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment.
RESULTS:
At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically significantly lower in the celecoxib group (51.4%) than in the placebo group (57.5%; P<0.001). Similarly, the cumulative rate of new advanced adenomas was significantly lower in the celecoxib group (10.0%) than in the placebo group (13.8%; P=0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0%) was 1.66 times more likely to have new adenomas than the placebo group (16.3%; P<0.0001). Similarly, the percentage of patients with new advanced adenomas was significantly higher in the celecoxib group (5.0%) than in the placebo group (3.8%) (P=0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95% confidence interval (CI) 1.01-2.73), selected renal/hypertension events (RR 1.35; 95% CI 1.09-1.68), and general vascular (RR 1.34; 95% CI 1.08-1.68) and cardiac disorders (RR 1.59; 95% CI 1.12-2.26) were higher in those taking celecoxib than in those on placebo.
CONCLUSIONS:
The year 5 cumulative measures of the incidence of new and advanced adenomas were significantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were significantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxygenase-2 inhibition. Consistent with what has been previously reported, increased risk of renal/hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection.
INTRODUCTION
Chemoprevention of sporadic colorectal adenomatous polyps is a promising approach to controlling colorectal cancer and its attendant morbidity and mortality. Worldwide, the highest rates of colorectal cancer occur in Australia and its neighbor New Zealand, western Europe, southern Europe, and North America, reflecting the fact that developed countries are home to almost 60% of all diagnosed cases (1). Approximately 1.2 million cases of colorectal cancer occur annually, and the disease ranks as the third most common cancer in women (after cancers of the breast and cervix uteri) and the third most common in men (after cancers of the lung and prostate) (1). Poor adherence to screening guidelines and lack of endoscopic capacity, even in industrialized countries, jeopardizes early detection of adenomas as well as cancer (2).
When cyclooxygenase-2 (COX-2) was found to be a determinative factor in adenoma formation in murine studies (3) and to be overexpressed in human adenomas and colorectal cancer (4,5), interest rose in using COX-2 inhibitors as chemopreventives. Three large trials were subsequently launched: the Adenoma Prevention with Celecoxib (APC) trial (6,7), the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial (8), and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial (9). All three demonstrated the utility of COX-2 inhibitors in preventing adenomatous polyps, but drug administration in all three was discontinued because of concerns over cardiovascular toxicity. Only in the PreSAP trial, a study of celecoxib (Celebrex; Pfizer, New York, NY) (10) 400 mg once daily, was the risk of cardiovascular events relative to those with placebo found not to be statistically significant at 3 years, although the number of events was small and the confidence interval was wide (relative risk (RR) 1.3; 95% confidence interval (CI) 0.6-2.6) (11).
Although not a selective nonsteroidal anti-inflammatory drug like celecoxib and other COX-2 inhibitors, aspirin is a well-recognized cardioprotective agent. Its emergence as a chemopreventive agent against colorectal cancer and its precursors through experimental (12,13,14) and observational studies (15), including cardiovascular disease studies (16,17), has been the subject of intensive scrutiny in the last decade (18,19,20,21,22,23,24,25). These factors warranted attention to the use of cardioprotective aspirin in the design and analysis of the three large celecoxib trials.
In the year 5 PreSAP study extension reported here, concluded 2 years after the last dose of study medication, our a priori objective was to evaluate the year 5 colonoscopy findings in all subjects who completed the year 3 colonoscopy and to evaluate the off-treatment safety in all subjects enrolled in the 3-year blinded core phase of the study and any extension. That is, at the year 5 analysis, using methods similar to those used in the year 3 analysis, we wanted to determine if the celecoxib group had fewer new adenomas and fewer new advanced adenomas than the placebo group, to characterize the adenomas removed at the year 5 colonoscopy, and to determine the risk of serious adverse events (SAEs).
DISCUSSION
This randomized, double-blind, placebo-controlled study of 400 mg of celecoxib (once daily) studied subjects after ~3 years on and 2 years off treatment. The cumulative rates of new adenomas and the rates of advanced adenomas for those in the celecoxib group were significantly lower than those in the placebo group, a residual effect from the strongly significant lowering of risk during the study's first 3 years. In contrast, the interval rates of new adenomas and new advanced adenomas after 2 years off treatment were found to be significantly higher in the celecoxib group than in the placebo group, an effect that may be because of loss of inhibition by celecoxib. As mentioned above, new adenomas refers to the first on-study adenomas detected in these subjects, all of whom had undergone colonoscopy and polypectomy within 3 months of study initiation.
Adenoma characteristics studied included the mean number of newly detected adenomas, the mean size of the largest adenoma detected, and the overall adenoma burden, but analysis indicated significant differences between groups only in the number of newly detected adenomas. These were, however, significant for both cumulative and interval measures, although in opposite directions. Although the study was not designed specifically to measure post-treatment recurrence, the higher values in the trial's celecoxib group for year 5 may indicate findings similar to the discovery by Baron et al. (34) of a higher risk of small adenomas in the year following therapy cessation in subjects who were treated with rofecoxib, an effect characterized as protective against larger adenomas. Although this explanation is not our own, it seems possible that a truncated "natural" process might resume in an "unnatural" or overcompensatory manner. Investigators reason that when an intervention is associated with greater numbers of small adenomas or with lower rates of development of advanced adenomas rather than other lesions, the mechanism at work may be a constraint on the adenoma-to-carcinoma progression responsible for advancing small adenomas to villous or larger adenomas (18,34,35). In our study, however, at year 5 we found measures of all three adenoma characteristics (the number of new adenomas, the diameter of the largest adenoma, and the sum of all diameters of all adenomas excised from the patient) to be higher in the off-treatment celecoxib group than in the off-treatment placebo group. Although it is true that there were no statistically significant differences found between the celecoxib and placebo groups in largest adenoma size or adenoma burden, whether measured cumulatively or at intervals, there were dramatic differences between the two groups on the breadth of the range of values: in the celecoxib group in the post-treatment period, as many as 16 new adenomas were detected at colonoscopy (placebo, 5 was maximum); adenomas were as large in diameter as 30 mm (placebo, 3.7 mm), and adenoma burden was as high as 30.3 mm (placebo, 4.5 mm). This was not true in the subgroup taking aspirin, a nonsteroidal anti-inflammatory drug that has not been associated with unusual post-treatment recurrence (23). Although having more new adenomas in the celecoxib group than in the placebo group may be attributable to the cessation of the COX-2 inhibition, determining the cause will require further study.
More than three-quarters of those participating in the extension study (76.9%) experienced AEs of any type, and 22.5% experienced AEs that were classified as serious. Patients enrolled in the trial were vulnerable: more than a fourth of the patients enrolled in this trial were ³65 years of age, and at baseline 472 (50.6%) of the celecoxib group and 297 (47.3%) of the placebo group had a significant medical history or a current abnormality related to cardiovascular disease. Over the full study duration, including ~2 years off treatment, celecoxib, compared with placebo, was associated with an increased risk of serious and general cardiac disorders, serious selected renal/hypertensive events, and general vascular disorders, providing additional evidence of an association between COX-2 inhibition and such AEs. The seriousness of this risk is a critical consideration in determining the appropriate use of celecoxib to prevent colorectal adenomas.
Colorectal cancer was detected in nine cases: five were diagnosed at the year 1 colonoscopy, two at year 3, and two at year 5. Of these, eight were in the celecoxib group (0.9%), and one was in the placebo group (0.2%). The five cases diagnosed at year 1 are thought to represent either incomplete excision or disease undetected at baseline colonoscopy. If either was the explanation, these cases were well established before patients received the first dose of celecoxib and did not represent a target for chemoprevention but for treatment. Medical history was not favorable: all cases were in patients who had previously had polyps removed and 3 were in patients who had a parent with colorectal cancer.
Dosing and duration of therapy may be factors that could be manipulated to achieve benefit with less risk. Once-daily dosing with 400 mg has its merits. In comparison with the twice-daily dosing in the APC trial, once-daily dosing was associated in years 1, 3, and 5 with lower incidence of new adenomas and with lower cumulative measures for both new and advanced adenomas; furthermore, the adjudicated evaluation of cardiovascular events when treatment ended found rates in the celecoxib group in the PreSAP study not to be significantly different from those of the placebo group (6,7,9,11). Definitive efficacy and safety comparisons, of course, require randomized trials.
This study, one in the vanguard of placebo-controlled colorectal cancer chemoprevention trials with a COX-2 inhibitor, demonstrates in cumulative measures that the celecoxib group has lower rates of recurrent and advanced adenomatous polyps after 3 years on therapy and 2 years off therapy. Associated increased RRs in cardiac disorders, vascular disorders, and renal/hypertension events and the increases in adenoma measures after therapy discontinuation significantly limit the potential use of this compound to those at high risk for colorectal neoplasia and without significant risk for cardiovascular sequelae and affect therapy duration. In the APC follow-up study, Bertagnolli et al. (7) reported significant dose-dependent reductions in advanced adenomas and adverse renal, gastrointestinal, and cardiovascular effects of celecoxib at doses of 200 mg twice daily and 400 mg twice daily.
As observed by others and as indicated in our results, prevention of advanced adenomas appears to be a particularly appropriate target for celecoxib, as demonstrated by the ability of celecoxib to reduce the number of colorectal polyps in patients with familial adenomatous polyposis (36), its ability in this trial to reduce sporadic advanced adenoma rates by 50% in the first year of treatment (9), its ability to be effective over time against such adenomas, and its ability to control adenoma size and burden. However, the occurrence of larger adenomas after treatment cessation at year 5 draws attention to the need to consider AEs after drug withdrawal.
It should be pointed out that this study has intrinsic limitations in terms of known clinical outcomes. Such uncertainty is among the reasons that no calculation of the possible reduction in colorectal cancer-mediated morbidity and mortality is undertaken here. Another fundamental reason is that calculations of that sort were never conceived to be part of the PreSAP trial analysis. It must be remembered that adenoma formation is only a surrogate marker of colon cancer and that the vast majority of adenomas do not progress to cancer. On the other hand, cardiac and vascular disorders are associated with significant morbidity and mortality, with cardiovascular disease claiming more lives worldwide every year than any other cause (37).
Statistically significantly increased risk of cardiac disorders and renal/hypertension sequelae in this extension phase of the PreSAP trial make apparent just how personalized the practice of medicine may need to become if chemopreventives carrying associated risks are to be utilized. On a clinical level, currently, celecoxib serves what has been termed a "niche" population-those with familial adenomatous polyposis-and proposals have pondered mixing and matching clinical factors (age, cardiovascular risk and therapies, and gastrointestinal risk and therapies) for consideration (38). On a molecular level, in the Health Professionals Follow-up Study and the Nurses' Health Study, aspirin use failed to reduce the risk of colorectal cancers in those in whom COX-2 expression was low or absent but statistically significantly reduced risk in those in whom COX-2 expression was high (39). Highly individualized adenoma risk profiles were demonstrated in the Aspirin/Folate Polyp Prevention Study (40). In this randomized trial of aspirin treatment in a population with a history of colorectal adenoma occurrence, investigators found that two COX-2 single-nucleotide polymorphisms were associated with statistically significant increased risk for adenoma recurrence, and evidence suggested that in a specific genotype the protective effect of an 81-mg daily dose of aspirin was modified (41). A prespecified study conducted after the APC trial closed investigated whether there was an association between a higher risk of synchronous advanced or recurrent adenomas and the number or presence of nondysplastic aberrant crypt foci, but none was found (42); nonetheless, these types of trials are those that are expected eventually to identify reliable surrogate end point biomarkers. Such findings indicate that physicians will have to be adept in assessing risk-benefit ratios while designing new clinical trials and pursuing other tools, including enhanced patient characterization and molecular profiling of adenomas. Meanwhile, investigators may also need to revisit dosing schedules, study therapy duration, and create combinations of active agents (43) to serve those patients who have the least vulnerability to cardiovascular and renal/hypertensive risk and the most to gain from effective chemoprevention.
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