Thursday, April 17, 2008

UA 'home run' is hit vs. cancer of colon

[Source: Carla McClain, Arizona Daily Star] - Striking a major blow against a top killer — colon cancer — a new drug therapy cuts the threat of this disease by as much as 90 percent in high-risk patients, University of Arizona scientists announced Monday.

The new therapy — combining the drug DFMO and an anti-inflammatory known as sulindac — was tested in patients who had developed precancerous colon polyps, putting them at high risk for full-fledged colon cancer.

Overall, their likelihood of developing more dangerous polyps was cut by 70 percent after three years on the combination therapy.

But in the most threatened patients — those who had large or multiple polyps — the risk of recurrence was slashed by a stunning 95 percent. That is more than double the preventive effect of other known therapies against colon cancer, including aspirin.

"This has really hit a home run," said Dr. David S. Alberts, director of the Arizona Cancer Center, where about 50 of the 300 patients in the study were tested and where much of the basic research and patient analysis was conducted.

"It is by a long shot the most effective therapy we have found to prevent this cancer, with very little toxicity," Alberts said.

In a cautionary note, researchers warned that the DFMO-sulindac therapy faces at least two more years of clinical trials before it will be "ready for prime-time" use in the United States.

"Although the five clinical trials we have completed show this therapy to be no more toxic than plain aspirin, we are always concerned about that issue and want further testing before this goes to the general population," said Eugene Gerner, director of the UA Cancer Center's gastrointestinal cancer program.

Gerner is the study's co-investigator, teaming with Dr. Frank Meyskens, director of the Chao Family Cancer Center at the University of California at Irvine and a former University of Arizona cancer researcher.

Their results won high praise when presented Monday at the annual meeting of the American Association for Cancer Research in San Diego.

Calling the findings "spectacular," Michael Sporn, pharmacology and toxicology professor at Dartmouth Medical School, said they "represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths."

Colon cancer — the second-worst cancer killer in the United States — strikes nearly 150,000 Americans every year and kills about 60,000. Only lung cancer kills more.

In recent years, scientists have hurled a myriad of agents — drugs, vitamins and minerals — at high-risk patients, trying to stop colon polyps from recurring after being surgically removed.

But the results have been mixed and often conflicting. Among the most promising therapies, aspirin appears to cut polyp regrowth by slightly less than 30 percent. Celecoxib (brand name Celebrex) — an NSAID, or non-steroidal anti-inflammatory drug, similar to sulindac — has shown a 40 percent risk reduction, but it carries cardiovascular risks. The mineral calcium has at best reduced regrowth by about 20 percent.

The DFMO-sulindac combination more than doubled those rates in some cases and was especially powerful in preventing advanced polyps most likely to lead to cancer.

"That's the real breakthrough," Gerner said. "We have shown for the first time that a combination strategy can dramatically reduce this threat for the patients at highest risk.

"Further testing will tell us if this therapy might be useful for others at risk — those who have a family history of colon cancer, but have not yet developed polyps," Gerner added.

One of the key drugs in the new therapy — DFMO, or difluoromethylornithine — is a synthetic amino acid known to interfere with the carcinogenic process. But used alone, it proved toxic at doses needed for treating advanced cancer. By combining it with the NSAID sulindac, the research team was able to cut the DFMO to one-fiftieth of that dose, all but eliminating toxic effects.

"There is a great hope that we will be able to prevent colon cancer effectively using this method," Meyskens said. "We had not been able to do this before due to the high toxicity of available therapies."

The study involved about 300 patients who had at least one colon polyp within the previous five years. They were given either the daily combination DFMO (500 milligrams) and sulindac (150 mg), or a placebo.

After three years, the risk of a recurrent polyp dropped from 41.1 percent in the placebo group to 12.3 percent with treatment — a 70 percent reduction.

Even more striking, the risk in patients with advanced polyps dropped from 8.5 percent in the placebo group to 0.7 percent in the treatment group — a 92 percent reduction.

And for those in the most danger — patients with multiple previous polyps — the rate of re-growth plunged from 13.2 percent in the placebo group to 0.7 percent in the treatment group — a 95 percent reduction.

The results were so dramatic that the trial was stopped early and the results released.

Finally, an analysis of side effects and toxicity found no significant difference between the treatment and placebo groups.

The study was funded in part by the National Cancer Institute's Specialized Program of Research Excellence in GI Cancers.

The Arizona Cancer Center is one of only five institutions nationwide to receive a GI SPORE grant. Originally funded in 2002, it is the largest new grant awarded to the University of Arizona College of Medicine in the past 10 years. It was renewed in 2007 for another five years and funded at $12 million.

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