Advances in Colorectal Cancer
New drugs show promise, but more research needs to be done.
Reviewed By Michael Smith
Colorectal cancer is the third most common cancer in the U.S. and the second most common cancer killer. But in the last few years, researchers have made new discoveries that may dramatically improve the prognosis for people living with the disease.
"This is a very exciting moment in the treatment of colorectal cancer," says Meg Mooney, MD, a senior investigator at the Clinical Investigational Branch at the National Cancer Institute. "For a long time, we just weren't able to do much in terms of making a real difference in a patient's care. But now we have new medications that really show improvement in the survival of people with the disease."
Admittedly, there's no miracle cure out there yet and a great deal of research still needs to be done. But these new discoveries are a cause for real hope.
For decades, Mooney says, the main drug treatment for colorectal cancer was limited to two drugs, Adrucil and Wellcovorin. But beginning in 2000, things began to change.
In that year, the FDA approved the chemotherapy drug Camptosar for first-line use in people with metastatic colorectal cancer -- cancer that has spread outside the colon and into other parts of the body. Studies show that people using a combination of Camptosar with other drugs lived longer than those using traditional chemotherapy.
Then more recently, a study by the National Cancer Institute showed that another chemotherapy drug, Eloxatin, was more effective than Camptosar when both were combined with the traditional chemotherapy drugs.
"After relying on the same two drugs for years, all of the sudden we have two more drugs that can help people with metastatic colorectal cancer live longer," Mooney tells WebMD. "In the last four years, a lot has happened."
Two news colorectal cancer drugs -- Avastin and Erbitux -- were approved by the FDA in February.
Antiangiogenesis, at Last?
The promising trials of the drug Avastin have been one of the biggest stories in the treatment of colorectal cancer. A recently published study of people with metastatic colorectal cancer found that those who received Avastin in addition to standard chemotherapy lived about four months longer than people who just received standard chemotherapy. This might not seem like a big improvement, but the study involved people with advanced colorectal cancer who often don't respond very well to treatment.
Avastin is the first of a long-awaited and new kind of cancer treatment, so-called angiogenesis inhibitors, which starve tumors by blocking blood vessel formation in them.
For many cancer researchers, antiangiogenesis has been the Holy Grail of drug development. Cancer cells need blood flow to grow, and the formation of new blood vessels is called angiogenesis. For decades, researchers have been working on a way to prevent the formation of new blood vessels.
Avastin is a monoclonal antibody, which is a manufactured version of the natural antibodies that the body uses to defend itself against foreign substances. It's designed to block the effects of the vascular endothelial growth factor (VEGF), a substance in the blood that helps these tumors grow new blood vessels.
Because of its specific target, Avastin also has few side effects, especially when compared with the toxic effects of traditional chemotherapy.
Researchers still have a lot to learn about the drug. The recent trial of Avastin was only in people with advanced colorectal cancer that had spread elsewhere in the body. The next step is to use Avastin in people with earlier stages of the disease, where the chances of curing it should be higher. Researchers are conducting trials now, Mooney says.
While the success of an angiogenesis inhibitor is exciting, Avastin has not been successful in treating other kinds of cancer.
"We know from an unsuccessful breast cancer trial that Avastin is not a magic bullet," says Helen Chen, MD, senior investigator in the Investigational Drug Branch at the National Cancer Institute. "At this time, it's hard to predict which patients with which cancer will benefit most. It's important to wait for the clinical trials to come out before we use Avastin in practice."
Erbitux, a new drug recently approved by the FDA for metastatic colorectal cancer, has also made news. When used in combination with the chemotherapy drug Camptosar, a study showed that Erbitux shrank the tumors in 23% of the people who had metastatic colorectal cancer and had exhausted other chemotherapy treatment options; it also slowed the tumor's growth by about four months. On its own, Erbitux shrank tumors by 11% and delayed the growth of the tumor by one-and-a-half months.
Like Avastin, Erbitux is a monoclonal antibody. It also blocks the effects of a growth factor, although a different one called epidermal growth factor (EGF), which encourages the development of cancer cells. Unlike traditional chemotherapy, in which toxic drugs don't discriminate between the tumor and healthy cells, Erbitux and Avastin are targeted and cause fewer side effects.
It's important to understand that Erbitux did not lengthen the lives of the people in the study. So the results may seem like modest success at best, and you may wonder at the benefit of shrinking a tumor if it doesn't help someone live longer.
But Mooney points out that this wasn't the trial's purpose.
"The results may seem disappointing, but the study wasn't designed to see if [Erbitux] helps people live longer," she says. Instead, the purpose was to see if the drug worked well enough to merit further trials, which it did.
According to Mooney and Chen, further trials are now under way testing the full potential benefits of the drug. As with the current Avastin trials, the next step is to try Erbitux in people with less advanced colorectal cancer and in combination with other medications.
Focusing on Inflammation
In one recent study published in The Journal of the American Medical Association, researchers found that higher levels of a marker for inflammation -- C-reactive protein, or CRP -- in the blood were associated with an increased risk of colon cancer. After studying the records of 22,000 people, researchers found that people with high levels of CRP were 2.5 times more likely to eventually develop colon cancer than those with low levels.
"We've seen that inflammation is an underlying component of a lot of diseases, including cancer," says Mooney. "The next step is to see whether we can manipulate that mechanism and alter the course of the disease."
Many researchers have looked at using drugs that reduce inflammation, in the hopes that they might cut the risk of colorectal cancer. And there is evidence that using a class of such drugs, nonsteroidal anti-inflammatory drugs, or NSAIDs, does just that. This class of drugs includes that humble and trusted resident of everyone's medicine tablet, aspirin.
"We know that people who use NSAIDs reduce their risk of developing colon cancer," says Polly Newcomb, PhD, Head of the Cancer Prevention Program at the Fred Hutchinson Cancer Research Center. "It's very exciting."
However, she points out that researchers don't yet know what dosage should be used. Also, some doctors are concerned that the risks of using NSAIDs, such as increased danger of bleeding and ulcers, may outweigh the benefits.
Newcomb and Mooney say that the next step is to try using NSAIDs in people who already have colorectal cancer to see if they help lengthen life or shrink tumors. Several studies are being conducted now.
Screening and Prevention
The connection between colorectal cancer and inflammation has potential implications in how the disease can be prevented as well. If further studies establish the relationship between high levels of CRP and colorectal cancer, it's possible that researchers could develop a blood test that would identify people at high risk of the disease. Other new screening tests are also in development.
While researchers are devising new ways of identifying people at risk of colorectal cancer, Newcomb points out that the screening tests we have now work pretty well.
"About 60%-80% of all cases of colorectal cancer can be prevented by endoscopies," she tells WebMD.
The endoscopy -- a procedure in which a doctor examines the colon with a device inserted into the rectum -- does not have a good reputation, Newcomb admits. "People worry it's unpleasant, and it's not as easy as a blood test," she says, "but it works pretty well."
The reason endoscopies -- either sigmoidoscopy or colonoscopy -- are so successful at preventing colorectal cancer is that they can detect abnormalities, such as polyps, that may be precursors to developing cancer. While other cancer screening tests, such as a mammography for breast cancer, only find cancer that's already in the body, endoscopies can catch abnormalities before they turn cancerous.
While people may avoid getting an endoscopy, Newcomb points out that the benefits are long lasting - five to 10 years or more -- because the test is so accurate.
Newcomb also says that researchers continue to look at the effects of diet and exercise on colorectal cancer risk. A number of studies have found that regular exercise does cut the risk; other studies have suggested that a diet low in meats and high in vegetables may do the same.
While all of these new medications and developments are cause for enthusiasm, it's important to realize that there's a lot we don't know. Research breakthroughs may not translate into something that tangibly benefits the average patient until years later, if at all.
For instance, the FDA has only approved Erbitux for people with metastatic colorectal cancer, which is the most advanced and hardest to cure. Only further study will tell how much impact it and other new drugs will have on earlier stages of the disease. For now, Mooney and Chen stress that these medications should not be used in stages of colorectal cancer for which they haven't been approved.
Much of the work for researchers now is to sort out how to best use these new medications. While they may not grab headlines, some of the most important advances may come in the details: tinkering with different dosages, treatment regimens, and combinations of drugs.
But while it's important to guard against over-optimism, there is still a great deal to be encouraged about.
"Within the last few years, there's been tremendous progress," says Mooney. "While none of these treatments are the penicillin for colorectal cancer, they're still important steps forward."
And with time and research, all of these smaller steps may yet add up to something big.
Published Feb. 25, 2004.
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