Non-steroidal anti-inflammatory drugs (NSAIDs) are an important part of the pharmaceutical treatment of pain and inflammation and have shown promise in providing a protective effect from cancer. However, there are dose-dependent safety concerns related to cardiovascular impact, bleeding risks and gastrointestinal distress related to the use of NSAIDs.
"The medical community has traditionally been skeptical about the use of NSAIDs," according to Byron L. Cryer, MD, associate professor of internal medicine at the University of Texas Southwestern Medical Center. "These new findings suggest the need to further investigate the potential effects of additional low-dose and combinational applications for NSAID medications, which seem to be proving effective in preventing disease."
Chemopreventive Effectiveness of Celecoxib Two Years After Cessation of Treatment
Unless detected early, the mortality rate for colon cancer is high. With colon cancer screening rates only at about 30 percent in the U.S., additional options to prevent colon cancer are eagerly sought. In this three-year, randomized, placebo-controlled, double-blind study, investigators sought to determine if the use of a chemopreventive drug could reduce adenoma (benign tumor) burden.
The study followed 1,561 adenoma-prone patients in 32 countries to determine if patients treated with a single 400-mg daily dose of celecoxib (twice the approved osteoarthritis dose) had lower rates of benign polyps than those treated with a placebo. Celecoxib has previously demonstrated efficacy in preventing adenomatous polyp recurrence, however, questions have been raised about the cardiac profile of celecoxib and other common prescription arthritis pain relievers.
For those randomized to celecoxib, 400 mg daily, relative risk (RR) of new adenomatous polyp was 0.64 (95 percent confidence interval [CI], 0.56–0.75); p < 0.001) and that for advanced adenomatous polyp was 0.49 (95 percent CI, 0.33–0.73; p < 0.001) through year three compared with placebo.
Additionally, no statistically significant difference was found in the rate of side effects between the two groups at year three. When concerns over cardiovascular risk prompted cessation of drug administration based on results from another adenoma prevention study, 1,043 subjects were given the option to continue safety assessments for at least two years after treatment ended and undergo a final colonoscopy at year five.
Overall, the cumulative five-year rate of detecting any adenomatous polyp and that of detecting advanced adenomatous polyp were lower in the celecoxib 400 mg daily group (RR, 0.75; 95 percent CI, 0.65–0.86; p < 0.0001), and that for advanced adenomatous polyp detection was 10 percent in the celecoxib group and 13.8 percent in the placebo group (RR, 0.64; 95 percent CI, 0.457–0.887; p = 0.0072). However, the proportion of subjects with new adenomatous polyp, at year five only, was higher in the celecoxib group.
Over the five years of the study, including approximately three years on treatment and two years off treatment, cardiac disorders occurred in 10.4 percent of patients randomized to celecoxib 400 mg and in 6.5 percent of those randomized to placebo. In the two years off treatment very few serious cardiac disorders occurred (1 percent placebo, 1.4 percent celecoxib). Subjects who received celecoxib 400 mg experienced a slightly higher rate of adverse (77.9 percent vs. 75.4 percent for placebo) and serious adverse events (23.9 percent vs. 20.6 for placebo) over the five-year study period.
These data, together with additional new placebo-controlled analyses of celecoxib cardiovascular safety, suggest that chemoprevention with celecoxib may be safe and effective for some high risk colorectal adenoma patients with low cardiovascular risk.
"We know the drug is effective to reduce the incidence and recurrence of adenoma," said Nadir Arber, MD, head of the Integrated Cancer Prevention Center at Tel Aviv Medical Center, Tel Aviv University, Israel. "However, advances are needed to either use the drug in lower doses or develop combination therapy that can produce the same effect without the adverse side effects."
A Meta-Analysis of Rectal NSAIDs in the Prevention of Post-ERCP Pancreatitis
Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure by which a physician can enter through the mouth to perform interventions on the bile ducts and pancreas. This common procedure, however, may injure or cause inflammation to the pancreas causing pancreatitis, in which the patient may suffer from abdominal pain, nausea, vomiting, further hospitalization and, in extreme cases, death.
Several studies have investigated ways to prevent pancreatitis following ERCP, predominantly through the use of medications given to the patient at the time of the procedure. This meta-analysis examined the potential protective effect of NSAIDs in the prevention of pancreatitis following ERCP.
Researchers aggregated the data from four clinical trials, with a total of 912 patients examined. They then combined the results statistically. The investigators found that overall, there was indeed a protective effect found through NSAID use at the time ERCP is performed. Patients who received NSAIDs during the procedure were 64 percent less likely to develop pancreatitis and 90 percent less likely to develop moderate to severe pancreatitis.
"The ERCP community has been skeptical about adopting the use of NSAIDs during ERCP because of prior lack of efficacy of other agents and concerns that the drug may cause bleeding," said B. Joseph Elmunzer, MD, division of gastroenterology, University of Michigan Medical Center. "However, our study suggests that if a single dose of NSAID is given at the time of ERCP, there is a protective effect and it doesn’t appear to increase the risk of bleeding."
The study found that 15 patients needed to be treated with NSAIDs to prevent one case of pancreatitis. It should be noted that of the four trials aggregated for this study, two enrolled only high-risk patients and two enrolled a more general population of patients. Additionally, the studies looked at the effects of two different NSAIDs — diclofenac and indomethacin.
Combinational Chemoprevention Using Low Dose Aspirin and Urso in Barrett’s Mucosa
A combination of Urso and aspirin is successful in preventing the development of esophageal adenocarcinoma in rodents, resulting in a cancer risk reduction of 58 percent, compared to other approaches. Esophageal cancer related to heartburn is one of the most rapidly increasing cancers in Western countries and leads to 10,000 deaths in the US each year. Urso modifies bile salt composition and possesses chemoprevention potential in vivo.
Researchers are trying to find the explanation for the rapid rise in this type of esophageal cancer. It is speculated that the aging population, rise in obesity and inadequately treated heartburn may contribute to the development of this cancer. Esophageal cancer is closely linked to heartburn, in which acid and bile from the stomach and intestines regurgitate into the food pipe and damage its lining. Unfortunately, this cancer is deadly and only 10 to 15 percent of patients diagnosed with this cancer survive for five years. Treatment options are limited. Surgery entails removing the food pipe, which is a major undertaking and compromises the patient’s quality of life.
When healthy patients are treated with Urso, especially patients with liver disease, it greatly reduces the concentration of toxic, carcinogenic bile. Also, researchers found that patients who take drugs to decrease injury or inflammation like aspirin are less likely to be diagnosed with this cancer.
Navtej S. Buttar, MD, assistant professor of medicine in the department of gastroenterology at the Mayo Clinic, Minnesota, explored whether a combined approach of Urso and aspirin would be beneficial. "We wanted to approach both the cause and the consequence at the same time," he said.
This combined approach could be more effective and perhaps safe, too. "There are different pathways through which cancer can escape, so you need to block more than one road leading to that progression," Buttar said. "If you can block the effect of cancer-promoting bile by using Urso, you could see a better effect than just using aspirin alone." Conversely, using only Urso may not be that promising because while it lowers bad bile salts, it also raises an enzyme — COX2 — which may cause inflammation.
For this study, investigators gave rodents heartburn, which ultimately led to cancer. They treated the rodents with a combination of low doses of Urso and aspirin. The result was a reduction in cancer risk of nearly 60 percent. Investigators researched the cancer cells of Barrett’s esophagus and exposed them to the dual combination as well and found it be highly effective in decreasing the number of any surviving cancer cells.
Dr. Buttar said the combination also caused the immortal cells to age and die off. "If we can use pathways to cause aging in cancer cells and make them quiet, they’re probably not going to grow into big tumors," he said.