New thinking on 'precancers' shows promise
From the February ACP-ASIM Observer, copyright © 2003 by the American College of Physicians-American Society of Internal Medicine.
By Deborah Gesensway
As cancer researchers place a new emphasis on preventing—not just treating—the dreaded disease, some say oncology is on the verge of a revolution that is already reshaping the way physicians attack certain types of "precancers."
While researchers once viewed cancer's development as a "black box" process, they now talk about a continuum from dysplasia and precancerous neoplasia to invasive and metastatic cancer. Armed with data from a limited number of studies, researchers now predict they will be able to stop or slow cancer much earlier.
As science provides more evidence to back up this view, doctors may not have to wait until patients have end-stage cancer to treat them. They will instead be able to stop or turn back the clock on the disease before it is able to progress to its natural—and potentially deadly—end.
While the predictions sound futuristic, progress in cancer research is already bearing fruit for clinicians. In addition to improved surgical techniques to remove precancerous lesions, the FDA has already approved several drugs to treat precancerous lesions that researchers say may progress to cancer. Many more drugs are in the pipeline.
New breakthroughs are 'moving our approach to cancer treatment earlier, far in advance of symptoms.'—Ernest T. Hawk, ACP-ASIM Member
"All this is moving our approach to cancer treatment earlier, far in advance of symptoms," explained Ernest T. Hawk, ACP-ASIM Member, chief of gastrointestinal cancer prevention at the National Cancer Institute (NCI). The real payoff will come, he claimed, when physicians can focus less on treating late-stage cancers with tens or even hundreds of molecular aberrations, a strategy he said often proves futile. Instead, they will be able to turn their attention to early disease.
The emerging view of how cancer develops and grows, a process known as carcinogenesis, comes on the heels of progress in several areas over the last decade.
In general, researchers have melded knowledge from the burgeoning field of cell biology with dramatic improvements in screening technology, which allow them to observe pre-invasive stages of cancer. At the same time, improved epidemiological data have helped cancer researchers better identify which patients, with which cancer precursors, are most likely to develop cancer.
Some of the most promising advances in chemopreventive agent development have come to light in preventing colorectal cancer. In late 1999, the FDA approved celecoxib (Celebrex), a COX-2 nonsteroidal anti-inflammatory drug (NSAID), for an entirely new use.
While the drug was already being marketed to arthritis patients, the FDA approved it to treat a rare genetic disorder called familial adenomatous polyposis (FAP). Studies showed that celecoxib could reduce the number of polyps in FAP patients, many of whom will later develop hundreds of colorectal polyps and face a much higher risk of developing colon cancer at a young age.
FDA approval was an important step, experts say, because research had proven only that FAP patients who took the NSAID could reduce the number of polyps, or precancers, in their bodies. The study did not show that those same patients reduced their risk of developing colon cancer, in part because the research did not continue long enough to collect that data.
Many researchers, however, hope that reducing the number of polyps will also reduce the risk of developing colon cancer. As a result, they say the FDA's approval adds to their small arsenal of chemopreventive agents.
The FDA's decision harkens back to a day nearly two decades ago, when the agency approved statins to lower cholesterol. Scott M. Lippman, FACP, professor of cancer medicine and prevention and chairman of the department of clinical cancer prevention at the University of Texas M.D. Anderson Cancer Center in Houston, said that at the time, there were no randomized controlled trial data showing that lowering serum lipids reduced cardiovascular disease, although "epidemiolgical studies showed a strong association between cholesterol levels and heart disease."
Conducting clinical studies to prove that statins reduce deaths from heart disease would have required lengthy, difficult research. The FDA, however, decided to approve statins without those kind of data, accepting the argument that lowering cholesterol was a good way to reduce heart disease, although that claim was unproven at the time. "Now we know many years later that these lipid-lowering drugs reduce major cardiovascular disease events," Dr. Lippman said.
Cancer researchers like Dr. Lippman compare eliminating polyps to prevent colorectal cancer to reducing cholesterol levels in order to prevent heart disease. "We have a lot of data consistent with the theory that reductions in polyps mean reductions in colon cancer incidence and mortality rate, which is an ideal measure of an agent's success" he said. "To require randomized controlled trials to show a reduction in cancer mortality if you treat precancer, however, would be prohibitively large, long and expensive."
Since the success of the FAP work, colon cancer researchers have begun studying other anti-inflammatory drugs, including aspirin, celecoxib and rofecoxib. The goal of the studies, which are underway, is to examine whether they can reduce polyps in a lower risk population—those with prior colorectal polyps. Experts hope that if the drugs can in fact reduce polyps, the FDA will approve them to treat precancers—even if their effect on cancer incidence or mortality remains unproven.
Researchers acknowledge that such a move will require FDA officials—and eventually the public—to change the way they think about cancer. Physicians and patients alike will need to accept the idea that precancer, which rarely manifests any clinical symptoms, is a disease that needs to be treated, just as high cholesterol is now considered worth treating.
The new thinking about cancer and precancers is also leading to a new emphasis on breast cancer prevention. In 1998, the FDA approved tamoxifen citrate (Novaldex) for use in women at high risk for breast cancer. The decision was significant because the FDA approved the drug to reduce the risk of cancer, not just to treat it.
Research had shown that the breast precancer known as ductal carcinoma in situ (DCIS) responded to the same treatment as breast cancer per se. Surgery, radiation and drugs like tamoxifen all produced similar effects on both DCIS and full-fledged breast cancer.
When women with DCIS lesions were treated with tamoxifen, their chances of developing breast cancer dropped nearly 50%, according to David S. Alberts, MD, professor of medicine, pharmacology and public health and director of cancer prevention and control at the University of Arizona.
Perhaps even more interestingly, Dr. Alberts said, research on tamoxifen has helped researchers establish links between cancer and neoplasia. Women in the large NCI-sponsored breast cancer prevention trial who had atypical hyperplasia—a very early, less progressed phase of what is now considered the carcinogenesis pathway—also responded to tamoxifen. As a result, Dr. Alberts said, "We need to think about treating neoplasia."
Tamoxifen taught cancer researchers an important lesson, Dr. Lippman said. It showed that that one drug "is active early in every stage of breast carcinogenesis, from metastatic breast cancer down to prevention in high-risk women with or without clinically evident premalignant lesions."
When you combine this clinical observation, Dr. Lippman said, with cell biologists' findings that premalignant lesions exhibit certain features—such as clonal expansion and spread—that everyone assumed were unique to cancer cells, it becomes difficult to argue that precancer is radically different from cancer. In his mind, at least, both conditions deserve full treatment.
Drugs in the pipeline
Cancer researchers, led in large part by the American Association for Cancer Research, loudly make a similar argument these days. They want to convince drug makers, the government and academia to invest in developing chemopreventive drugs that the FDA can approve to treat precancers.
Besides approving celecoxib for FAP patients and tamoxifen citrate for DCIS, the FDA has given the nod to only four other agents to combat precancers: topical 5-FU and topical diclofenac for actinic keratosis (a skin precancer), and intravesical BCG and valrubicin for superficial bladder cancer (a bladder precancer).
Several more chemopreventive agents are in the research and approval pipeline, however. These include COX-2 inhibitors and aspirin for colon, esophageal and other GI track cancers, as well as for skin cancers; raloxifene for breast precancer; retinoids for skin, head and neck precancers; and several agents for treating bladder intraepithelial neoplasia.
Researchers are also looking at the synergy that seems to result when they combine several drugs targeting different characteristics of carcinogenesis. Still others are working on tumor vaccines.
Some researchers predict that as drugs and other technologies are developed to treat precancers, medical practice will change significantly. "Ten to 20 years from now, oncologists' practices will focus on earlier progression of lesions," said Arizona's Dr. Alberts.
"A real problem right now is that physicians in this field call themselves either therapists or preventionists, and that has to stop," he continued. "From my point of view, it's a continuum. You can't separate the fields, because the approaches or interventions used to turn back the carcinogenesis pathway or to block it are the same concepts, and often the same drugs, used to treat advanced cancer."
In the traditional view of cancer care, oncologists treat advanced stages of the disease, while precancer treatment is the bailiwick of physicians in other specialties. Gastroenterologists look for colorectal polyps and Barrett's esophagus, urologists handle prostate and bladder precancers, and dermatologists care for skin precancers.
Cancer prevention, meanwhile, has been delegated to internists and family physicians, who preach about the evils of smoking and the benefits of good diet and exercise while urging patients to get mammograms, PSA tests and colonoscopies.
Traditional prevention strategies may take on an even greater role given the breakthroughs in understanding cancer development and progression.
Researchers emphasize that those traditional prevention strategies remain important and may take on an even greater role given the breakthroughs in understanding cancer development and progression.
"I have found that internists don't pay much attention to family history information," said Raymond N. DuBois, MD, professor of gastroenterology and cancer prevention at Vanderbilt University in Nashville, who is a lead investigator on a large study of celecoxib and colon cancer. Less than one-third of Americans over 50 get screened for colon cancer or precancer, he explained, "and the general internists and family physicians really have control over that."
In addition, he said, many internists already recommend aspirin for their heart patients and NSAIDs for patients with arthritis. "If a certain dose was shown to also have an effect on cancer," he added, "I think they would be very interested in that."
The NCI's Dr. Hawk would like to encourage internists to get more involved in enrolling their patients in cancer prevention clinical trials, many of which are listed on the NCI Web site.
Although precancer research may not change internists' practice tomorrow, "it very likely will change the standard of care for many people in the next five to 10 years," Dr. Lippman said. He believes research conducted over the last decade has led to and validated two major convergences of thought about medical practice.
First, the line between prevention and therapy is growing fuzzier, especially when clinicians focus on early cancer development. Second, many of the same agents—aspirin, for instance—seem to work for several diseases of aging, such as atherogenesis and carcinogenesis.
"These two convergences represent a sea change in the way we think about cancer medicine," he said.
Deborah Gesensway is a freelance writer in Glenside, Pa.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.
Cancer prevention experts say that several scientific discoveries and papers have helped move their field from theory to practice.
In the early 1990s, the National Polyp Study demonstrated that identifying adenomas and removing them reduced the incidence of colorectal cancer. Ernest T. Hawk, ACP-ASIM Member, chief of GI cancer prevention at the National Cancer Institute, said that work going on at about the same time shed light on the similarities between genetic signatures within precancers and later-stage cancers. This led to the realization that invasive cancer results when genetic defects accumulate over time.
Today, researchers assume that the vast majority of cancer starts with some sort of precancer—such as intraepithelial neoplasia (IEN) in the case of epithelial cancers—and that removing these early lesions reduces the risks of them developing into later-stage disease.
Findings from the National Surgical Adjuvant Breast and Bowel Project, which enrolled 13,000 women, represented another landmark in the field. That study demonstrated that a drug that prevented cancer-in this case, tamoxifen-also reduced precancerous lesions by stimulating neoplasia cells to undergo a process called programmed cell death. Data continue to accumulate showing a direct relationship between precancer and cancer.
At the same time, ongoing research has unraveled more of the mystery of what happens to cells and genes as they progress from normal states to cancer. Other research has shed light on the mechanisms by which specific treatments work, as well as the long-noted but misunderstood association between inflammation and cancer development.
For signs of where the field is going, Dr. Hawk suggested looking to the fledgling fields of genomics and proteomics, where researchers are now searching for proteins and other molecular signatures distinct to neoplasia that may show up in blood, stool or urine.
An article in the Feb. 16, 2002, Lancet described how women with ovarian cancer were identified through serum proteomics. Another group of researchers also reported in the October 2002 Journal of the National Cancer Institute that patterns of proteins found in patients' blood serum could help distinguish between prostate cancer and benign conditions.
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