Journal of the National Cancer Institute Advance Access originally published online on May 27, 2008
JNCI Journal of the National Cancer Institute 2008 100(11):764-766; doi:10.1093/jnci/djn187
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© Oxford University Press 2008.
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Drugs To Prevent Colon Cancer Show Promise, But Hurdles Remain for Chemoprevention
A low-dose combination of sulindac and difluoromethylornithine (DFMO) reduced the risk of recurrent colorectal adenomas by 70% and high-risk adenomas by 92% compared with placebo in a randomized controlled trial, researchers reported in April at the annual meeting of the American Association for Cancer Research (AACR). Also, 5-year follow-up data from the Adenoma Prevention with Celecoxib (APC) trial showed that individuals who took celecoxib during the trial continued to be at lower risk of developing adenomas 2 years after they stopped taking the drug, compared with participants who took a placebo.
These results could fundamentally change chemoprevention, experts agree. The magnitude of the benefit in the sulindac–DFMO trial was larger than expected for any type of chemoprevention. (As designed, the trial would have been deemed a success if the combination had reduced the risk by 50%.) And the trial is the first to show that a combination of chemoprevention drugs is effective and safe. The APC data show that the use of nonsteroidal anti-inflammatory drugs, specifically a cyclooxygenase-2 (COX-2) inhibitor, reduces the development of adenomas instead of just masking the presence of lesions.
"The field of [nonsteroidal anti-inflammatory drugs] and COX-2 inhibitors—and in some people's minds, the entire concept of chemoprevention—was in ashes when the COX-2 selective inhibitor [toxicity] reports came out in 2005," said Scott Lippman, M.D., professor and chair of thoracic and head and neck medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston. Those reports, showing that celecoxib and rofecoxib (Vioxx) increased the risk of cardiovascular disease and death, garnered so much attention that when researchers reported the initial efficacy data from the APC trial in 2006, few noticed. "I think what we are seeing now in these two very important trials is that the phoenix is rising," Lippman said.
Chemoprevention With Sulindac and DFMO
To test the efficacy of the sulindac–DFMO combination, Frank Meyskens Jr., M.D., director of the Chao Family Comprehensive Cancer Center at the University of California, Irvine, and colleagues enrolled 375 volunteers in a randomized double-blind, placebo-controlled, phase III trial. All participants had had at least one polyp removed within the past 5 years. Patients in the active drug arm received 500 mg of DFMO and 150 mg of sulindac, which is half the dose typically used for arthritis treatment.
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After the first planned interim analysis, the data safety monitoring board recommended that the trial be unblinded because it had already met its predetermined endpoint and extended follow-up was unlikely to alter the results. With 267 patients eligible for evaluation, 17 (12.3%) in the active drug arm had developed at least one adenoma compared with 53 (41.1%) in the placebo arm—a 70% reduction in risk. The incidence of advanced adenomas was also substantially reduced in the combination arm, with one (0.7%) patient affected compared with 11 (8.5%) in the placebo arm, a relative risk reduction of 92%. Also, there was a 95% relative risk reduction in the incidence of multiple adenomas from 17 (13.2%) patients in the placebo arm to one (0.7%) in the DFMO–sulindac arm.
"This reduction is the largest reduction seen in any clinical trial to date," Meyskens said. "One could really not ask for a better clinical outcome. We feel that this landmark study now opens the door to further clinical development of the concept of combination chemoprevention."
Lippman, who was not involved in the trial, described the results more simply: "These are absolutely stunning findings," he said. He cautioned, however, that though the trial was not powered to detect a difference in cardiovascular side effects, there was a "worrisome trend" toward more toxicity that should be carefully evaluated in subsequent trials. Among those taking the drugs, 28 (14.7%) had cardiovascular side effects, compared with 22 (12.0%) in the control arm.
The researchers also detected a slight decrease in hearing among patients taking the combination versus those in the placebo group, but the difference was not noticeable to the individuals themselves. In fact, Meyskens likened the loss in sensitivity to the decibel measurement of two fingers’ being rubbed together. The researchers will continue to monitor this potential problem, however, because previous tests of DFMO at higher doses caused noticeable, though reversible, hearing loss.
Meyskens is discussing with the National Cancer Institute and the Southwest Oncology Group a larger, definitive trial, which will probably test the combination in 1,000 patients who have been treated for nonmetastatic colorectal cancer and are at high risk of relapse. The NCI is ready to fund the clinical aspects of the trial, Meyskens said, but the researchers are still looking for commercial support for the drug itself.
Five-Year APC Results
More than 2,000 patients participated in the APC trial and were randomly assigned to take 200 mg of celecoxib twice daily, 400 mg twice daily, or placebo for 3 years. The trial was stopped early when an interim analysis showed that patients taking celecoxib had an increased risk of cardiovascular problems.
At the time of discontinuation, participants had taken celecoxib or placebo for about 3 years. The initial efficacy analysis, reported in 2006, showed that patients on celecoxib had a statistically significant reduction in adenoma incidence, with a 29% reduction in the 200-mg arm and a 38% reduction in the 400-mg arm, relative to placebo. There was also a statistically significantly lower risk of advanced adenomas—55% lower in the 200-mg group and 64% lower in the 400-mg group.
Participants on celecoxib continued to experience a benefit at 5 years, though the magnitude has diminished, according to results presented at the AACR meeting by Monica Bertagnolli, M.D., associate professor of surgery at Harvard Medical School in Boston. The risk reduction for the cumulative incidence of any adenoma was 14% in the low-dose arm and 12% in the high-dose arm. For advanced adenomas, the risk was 41% lower in the low-dose arm and 26% lower in the high-dose arm.
When the researchers looked at one time point, the 5-year colonoscopy, which was performed approximately 1.5–2 years after drug discontinuation, "there was an equal incidence of discovery of new lesions between the treated and the placebo groups," Bertagnolli said. This finding appeared to be generally true for both any adenoma and advanced adenomas. The higher-dose group did have a statistically significantly higher incidence rate of advanced lesions, though the absolute numbers were small.
"It somewhat allays our concerns that what chemopreventive drugs are doing is suppressing disease from discovery, which then rebounds significantly when you remove the drug," she said. "We did not see that."
Pointing to the continued reduction in the incidence of high-risk adenomas, Ray DuBois, M.D., Ph.D., provost and executive vice president for academic affairs at M. D. Anderson and current president of AACR, said, "That is a lot more lasting effect than anyone anticipated."
Celecoxib Safety
The 5-year analysis also provided a second look at the effect of celecoxib on heart disease. There were 172 cardiovascular or thrombotic events in the 2,035 patients in the study, affecting 3.8% of patients in the placebo group, 6.0% in the low-dose arm, and 7.5% in the high-dose arm. However, when the patients were stratified based on their cardiovascular risk factors before enrollment, including smoking, hypertension, diabetes, cerebrovascular disease, and atherosclerosis, the cardiovascular risk due to the drug appeared to be confined to those with baseline risks. In patients who had no cardiovascular risk factors at baseline, 0.9% in the placebo arm developed cardiovascular problems during the trial, compared with 3.9% in the low-dose group and 1.9% in the high-dose group. By contrast, patients with one or more cardiovascular risk factors had a dose-dependent increase in cardiovascular complications. Among the participants with one risk factor, 2.2% in the placebo group had cardiovascular toxicity, as did 3.7% in the 200-mg arm and 4.9% in the 400-mg arm. For the trial participants with two or more risk factors, who made up about half of the study population, the rates were even higher, with 5.9%, 8.2%, and 11.2% affected in the placebo, low-dose, and high-dose arms, respectively.
"The balance of risk and benefit is particularly important in prevention where we are dealing with healthy individuals, or at least asymptomatic individuals at early stages of disease process," said Ernie Hawk, M.D., vice president and head of the division of cancer prevention and population sciences at M. D. Anderson, who helped lead the APC trial while at the NCI.
Hawk and colleagues have examined the cardiovascular risks associated with celecoxib in 7,950 patients enrolled in six randomized placebo-controlled trials, each of which treated patients for at least 3 years. Patients treated with 200 mg of celecoxib once daily had no statistically significant increase in cardiovascular risk, whereas those on a 200-mg twice-daily regimen had a 1.8-fold increase in risk compared with placebo and those on the highest dose of 400 mg twice daily had a 3.1-fold increase. As with the participants in the APC trial, patients who were at highest risk of problems were those who had cardiovascular risk factors before entering the trial.
"It appears from this pooled analysis of data across six trials that in low-risk cardiovascular individuals the dose of celecoxib is not as big an issue," Hawk said at the AACR meeting during a forum on the future of chemoprevention. "Clearly with the lowest dose given once a day, there do not appear to be the same sorts of risks that we are all very worried about with the use of this agent." The finding, he noted, needs to be reproduced in prospectively designed randomized trials, which are ongoing.
"The field got a black eye 2 years ago," DuBois said. "But it doesn’t look like it was as bad as everyone was saying back then." With careful patient selection and the right dose, it may be possible to use celecoxib safely, he said.
Overcoming Hurdles for Prevention
But even if effective, safe regimens can be identified, barriers still exist for the implementation of chemoprevention, said Ellen V. Sigal, Ph.D., chairperson and founder of Friends of Cancer Research, a nonprofit advocacy group based in Washington, D.C. One of the key challenges is the validation of biomarkers that can be used to identify high-risk patients who will benefit from chemoprevention, as well as biomarkers that can be used for ongoing assessment during therapy. In that area, colorectal cancer prevention is ahead of many malignancies because clinicians and researchers can use polyp formation as a marker, and the U.S. Food and Drug Administration has accepted a reduction in polyps as an adequate endpoint in at least some high-risk patient groups.
But in talking to executives in large pharmaceutical and biotechnology companies, she found that many of them were hesitant to enter the field of chemoprevention because there is no straightforward regulatory path to approval for these agents. Because relatively healthy individuals will be taking these agents, regulators and consumers have a high bar for safety. Compounding that issue is the fact that there are few ways to monitor the effectiveness of chemoprevention. And even if a drug were to gain approval, the prolonged duration of clinical prevention trials means that little patent time would remain, and thus it would be difficult to make a profit on the effort. "Under the current system, many companies believe that recouping the investment made would be really impossible," she said.
The results from the DFMO–sulindac trial are remarkable, Sigal acknowledged. "The problem is you can’t take one study in isolation. Until we start to get some confidence, better data, and some more science—and perhaps less hysteria in the media—it is going to be a very difficult environment to develop these drugs."
DuBois agrees and said that he has been in discussion with the director of the NCI about how to address some of the issues. The NCI, he said, plans to hold a meeting in the fall with leading scientists in different areas to work out a plan for the future of chemoprevention research. In the meantime, DuBois thinks that the new data are cause for optimism in chemoprevention research. "I think there is a proof of concept now that it can work in certain populations. It does cause side effects, but if you stratify correctly you can avoid those serious side effects."
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