NEWS

Trials Examine Intraepithelial Neoplasia as a Marker for Cancer

Tom Reynolds

For cancer chemoprevention, the definitive question—whether an agent reduces the risk of invasive cancer—typically takes many years, thousands of phase III trial participants, and millions of dollars to answer.

In search of quicker, preliminary answers, clinical prevention researchers are increasingly focusing their efforts on intraepithelial neoplasia (IEN), a group of cellular and genetic abnormalities that have been shown to be associated with invasive cancer at nearly every solid tumor site.

The initial report of the American Association for Cancer Research IEN Task Force, published in the February 2002 Clinical Cancer Research, offers, for each major cancer site, evidence of the links between IEN and invasive cancer and suggestions for the design of prevention trials.

The task force described several circumstances where effective chemoprevention agents could be beneficial, such as the prevention or treatment of IEN in patients with hereditary conditions such as familial adenomatous polyposis (FAP), which is a precursor to colon cancer. Prevention drugs also could offer more acceptable alternatives to surgical treatments that cause dysfunction (such as esophagectomy for dysplastic Barrett’s esophagus) or are not widely used despite likely effectiveness (such as colon polypectomy, which is estimated to be chosen by fewer than one in six patients who could benefit). Finally, the task force noted, chemoprevention might improve outcomes after cancer treatment by halting the recurrence of IEN.

Phase II prevention trials using various forms of IEN as eligibility criteria and/or endpoints are under way for most common cancers. They will be instrumental in guiding plans for large-scale trials of promising agents and in many cases will help advance knowledge about the relationships of biochemical and genetic markers to IEN and cancer.

"These phase II trials are extremely important," said Peter Greenwald, M.D., director of the National Cancer Institute’s Division of Cancer Prevention. "We can’t jump into many STAR-sized trials [22,000 women in NCI’s Study of Tamoxifen and Raloxifene]. Phase II trials tell us when we have a biological effect and provide key information for deciding when to move forward into definitive phase III trials."



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Dr. Peter Greenwald

 
All these trials enlist participants who have an elevated risk of cancer compared with the general population—either existing IEN or hereditary risk factors—and are testing agents that are approved for other indications or have shown strong suggestions of efficacy in epidemiologic, preclinical, and phase I studies.

Each cancer type demands its own chemoprevention strategy, Greenwald said, but related approaches may be effective across multiple sites. One commonality is the arachidonic acid pathway, a major mechanism producing pain and inflammation. Among agents that act on this pathway, the COX-2 inhibitor celecoxib (Celebrex, Pharmacia Corp., Peapack, N.J.) is one of the few cancer preventives thus far to gain Food and Drug Administration approval for reduction of polyps in patients with FAP (see News, Feb. 16, 2000, p. 297). Phase II trials of celecoxib to prevent several other cancers are ongoing (see News, Feb. 20, 2002, p. 248).

Targeting the other branch of the arachidonic acid pathway are lipoxygenase and leukotriene inhibitors, drugs primarily used to treat asthma. One such drug, zileuton (Zyflo, Abbott Laboratories, Abbott Park, Ill.), is under evaluation in a phase II lung cancer prevention trial in smokers and ex-smokers with bronchial dysplasia, led by Omer Kucuk, M.D., of Wayne State University in Detroit. Patients receive zileuton or placebo for 6 months, then cross over to the opposite group.

Results of another bronchial dysplasia trial, led by Stephen Lam, M.D., at the University of British Columbia, Vancouver, Canada, were published in the July 3, 2002 issue of the Journal. Lam and colleagues gave the organosulfur compound anethole dithiolethione (ADT) to 112 current and former smokers with dysplasia. (ADT is related to Oltipraz, an agent tested for lung cancer chemoprevention but found to have high levels of toxicity.) On follow-up bronchoscopy, they found that the progression rate of existing premalignant lesions and the appearance of new lesions were lower in the group given ADT compared with a placebo group.

For breast cancer, Carol Fabian, M.D., of the University of Kansas Medical Center, Kansas City, is leading a phase II trial testing the third-generation selective estrogen-receptor modifier arzoxifene (also known as LY 353381 hydrochloride) in women who have breast hyperplasia and a high risk for breast cancer. Prospective participants undergo a fine-needle aspiration (FNA) procedure that is designed to enhance hyperplasia detection through random tissue sampling. Women qualify if they have evidence of hyperplasia with atypia or without atypia but with a BRCA1 or BRCA2 gene mutation, a 10-year Gail model risk of at least 4%, or a personal history or strong family history of breast cancer.

Arzoxifene is a product of Eli Lilly and Co., Indianapolis, Ind., which manufactures the second-generation SERM raloxifene. Studies in rats showed arzoxifene has several potential advantages over other SERMs, Fabian said: greater bioavailability and higher anti-estrogenic potency in the breast than raloxifene, and reduced estrogenicity in the uterus compared with either tamoxifen or raloxifene.

"The trial’s primary endpoint is to determine at 6 months if the cytology improved in the treatment group or placebo group," she said. "We’re also looking at risk biomarkers including breast density and IGF-1." All 200 women on the trial, including those initially in the placebo group, received arzoxifene after 6 months.

Other studies enrolling participants with hereditary risk include trials to prevent endometrial and prostate cancers. At the University of Texas M. D. Anderson Cancer Center, Houston, a trial led by Karen Lu, M.D., is comparing the efficacy of medroxyprogesterone versus contraceptive pills containing ethinyl estradiol and norgestrel in preventing endometrial carcinogenesis in women with inherited mutations in one of six genes associated with hereditary nonpolyposis colon cancer.

At the University of California, Irvine, researchers are enrolling men with a strong family history of prostate cancer, based on number of affected relatives and their age of disease onset, to test the preventive potential of DFMO (difluoromethylornithine). DFMO—which is enjoying a resurgence of interest in chemoprevention research after being discarded as a potential cancer treatment, according to UC-Irvine investigator Anne Simoneau, M.D.—inhibits an enzyme in the pathway that produces the nucleic-acid-unwinding polyamines: putrescine, spermidine, and spermine. Polyamines, while ubiquitous, are most highly concentrated in the semen-producing prostate gland, and in vitro and animal studies suggest that DFMO has activity against prostate and other cancers. Results of a preliminary trial appeared in the January 3, 2001 issue of the Journal.

As endpoints, the DFMO trial will examine polyamine levels along with other biomarkers associated with polyamines, such as matrilysin and alpha integrin, and general markers of cell proliferation and apoptosis, Simoneau said.

Also in prostate cancer, two trials are evaluating the preventive potential of selenium, following a 1996 skin cancer trial suggesting the element may have greater effectiveness against other cancers, particularly in prostate cancer (see News, Jan. 15, 2003, p. 98). Although the phase III SELECT trial of vitamin E and selenium (see News, Aug. 1, 2001, p. 1132) is open to men with no evidence of disease, a phase II intergroup trial will target men 40 or older with high-grade prostatic intraepithelial neoplasia (PIN). Because they are enrolling men at high risk, the investigators can use a cancer incidence endpoint and a total of 450 men and still expect to complete the trial in a relatively short time, said James Marshall, Ph.D., of the Roswell Park Cancer Institute in Buffalo, N.Y., who chairs the trial for the Southwest Oncology Group. High-grade PIN with no evidence of cancer is a fairly uncommon finding, Marshall said. To enter this selenium trial, men must have either two sextant (six-core) biopsies or one 10-core biopsy to rule out invasive cancer.

"It is critical that we find out what to do with men who have this apparently high-risk lesion," Marshall said. "If, in fact, this is prostate cancer looking for a place to happen, we need to identify drugs that protect against it. At present the alternatives for men with PIN, other than additional biopsies, are quite limited."

In cervical cancer, a trial led by Bobbie Gostout, M.D., of the Mayo Clinic in Rochester, Minn., is testing the topical immune-response modifier imiquimod in women undergoing surgery for recurrent or high-grade cervical intraepithelial neoplasia. Imiquimod cream was approved by the FDA in 2002 to treat genital warts, which are caused by human papillomavirus. The drug works by activating T cells to respond to HPV antigens.

"Our idea was to increase the chances that a woman’s immune system responds effectively to the virus, and clears the virus, so she is not at risk for cervical cancer," Gostout said. Data are not yet available for the primary endpoint, recurrent dysplasia, but early laboratory results are encouraging.

"Interferon-gamma levels increased 107 times over baseline in imiquimod-treated women, and TNF-alpha increased about 116 times," she said.

NCI’s Greenwald, although enthusiastic about the potential of IEN trials as crucial stepping-stones, cautions that definitive evidence will have to come, site-by-site, from large-scale, long-term trials with cancer endpoints. As a near-obligate precursor of invasive cancer, IEN presents an attractive target. But conversely, relatively few IEN cases develop into cancer. Thus, chemoprevention researchers must sort out which "precancerous" lesions truly present a threat.

"We have to know more about the molecular patterns and which subsets are going to go on to invasive cancer," Greenwald said. "And that’s going to take a combination of good lab work tied to the clinical work in pathology, and integrating that with prospective epidemiology and clinical trials that have incidence or mortality endpoints."

"The biomedical research community has got burned a few times recently," he added, in cases such as hormone replacement therapy and AIDS drugs, where preliminary findings and early over-enthusiasm proved unfounded. "Particularly in this early stage of clinical prevention research, we want to make sure that we’re not taking shortcuts that are misleading, and that we really prove the point."


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Selected Phase II Chemoprevention Trials for Intraepithelial Neoplasia

 


             
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