AACR Prevention Conference: Research Roundup

NATIONAL HARBOR, MD—Long-term use of vitamins C and E in men did not lower the risk of prostate cancer or total cancer among vitamin E users or total cancer among vitamin C users, according to new preliminary data from a large study presented here at the American Association for Cancer Research's Seventh Annual International Conference on Frontiers in Cancer Prevention Research. Neither, though, did the vitamins cause any harm. The study results were a disappointment, since the rationale for the trial was that basic science and observational studies have supported a role for antioxidants in preventing cancer, especially prostate cancer. The results presented come from the Physicians' Health Study II, a large-scale, randomized clinical trial including 14,641 physicians who were at least 50 years old when they enrolled in the trial. Participants were followed for up to 10 years. In this trial, participants took either 400 international units (IU) of vitamin E every other day or a placebo, or 500 milligrams of vitamin C a day or a placebo. Study coauthor Howard D. Sesso, ScD, MPH, Assistant Professor of Medicine at Brigham and Women's Hospital, said the preliminary results of this study should help to clarify public health recommendations on taking vitamins E and C to prevent cancer. But, he noted, the results are not the last word: “The final component of the Physicians' Health Study II, testing daily multivitamin supplementation, remains ongoing.” NSAIDs Reduce PSA On a more hopeful note, taking aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) does appear to reduce levels of prostate-specific antigen (PSA), especially in men with prostate cancer, according to data from a study of 1,277 men over age 40 scheduled for a diagnostic prostate biopsy and enrolled in the Nashville Men's Health Study. The effect of aspirin on PSA was strongest in men who were later found to have prostate cancer. Interestingly, the men who took aspirin and those who did not had the same prostate volume, so it appears that aspirin works by a different mechanism than volume shrinkage, said lead investigator Jay H. Fowke, PhD, Assistant Professor of Medicine at Vanderbilt University. Dr. Fowke pointed out that while a reduction in PSA could have a beneficial effect on the development of prostate cancer, it is important to note that use of aspirin and other NSAIDs could lower PSA below the levels that raise clinical suspicion—and thus could be potentially harmful to the patient because such use could delay diagnosis. “Implications for prostate cancer screening recommendations and for clinical decision-making will require further investigation,” he and his coauthors concluded, noting that basing treatment on an artificially suppressed PSA score would be “problematic.” At the very least, the study suggests that men over age 40 should report their use of aspirin and other NSAIDs to their physicians, as was done in this study. DFMO Difluoromethylornithine (DFMO), a chemopreventive agent that inhibits the polyamine synthesis involved in regulation of cellular growth and differentiation, may help to prevent multi-stage progression in the proliferative disorder Barrett's esophagus, according to a pilot study from lead investigator Frank A. Sinicrope, MD, Professor of Medicine and Oncology at the Mayo Clinic. He said that because of the nature of cellular proliferation in Barrett's esophagus, patients with this condition are ideal candidates for a strategy to help prevent cellular progression to cancer. Dr. Sinicrope and his collaborators enrolled 10 patients with Barrett's esophagus and low-grade dysplasia; after six months of DFMO treatment, he said, one patient showed regression of dysplasia; eight had stable disease; and one showed progression of dysplasia, as shown on esophageal biopsies. Of the patients in the stable group, at six months two who started with extensive low-grade abnormal cells had only limited or focal dysplasia, as confirmed on biopsies—benefits which persisted at 12 months. “Overall, DFMO was well tolerated,” noted Dr. Sinicrope. One patient experienced subclinical, unilateral ototoxicity. In this pilot study, DFMO lowered the level of the polyamine putrescine, a target of the drug and a possible cancer risk marker. DFMO also reduced expression of the Kruppel-like factor 5 (KLF5) gene, a marker of abnormal esophageal cellular proliferation. Encouraged, Dr. Sinicrope said he and his collaborators plan a placebo-controlled chemoprevention trial of DFMO in patients with Barrett's esophagus. OT Editorial Board member Frank L. Meyskens, Jr., MD, the Daniel Aldrich, Jr. Endowed Chair and Professor of Medicine and Biological Chemistry at the University of California, Irvine, served as the senior member of a team that showed that DFMO reduced prostatic volume as well as PSA levels in men at familial risk of prostate cancer. Dr. Meyskens, also Director of the Chao Family Comprehensive Cancer Center and Associate Vice Chancellor of Health Sciences, recently published this work in the AACR journal Cancer Epidemiology, Biomarkers and Prevention. At the AACR meeting he received an award for excellence in cancer prevention research (see page 31). Vitamin D New data presented at the meeting support the increasing body of evidence that vitamin D can help to prevent cancer. While research studies are still under way, “evidence suggests that raising vitamin D levels could prevent 50,000 cases per year of breast cancer in the United States and Canada,” said Cedric F. Garland, DrPH, Professor of Family and Preventive Medicine at the University of California San Diego (UDSD) and a member of the Moores UCSD Cancer Center. “The higher a woman's serum vitamin D level, the lower her risk of breast cancer,” he said. “No known compound offers greater ability to prevent and arrest invasive cancers than vitamin D.” In a presentation on dose-response relationships and vitamin D in the prevention of cancer, Dr. Garland and his coauthors estimated that high levels of vitamin D could eliminate 50% to 75% of cancer overall within five to 10 years. They further stated that vitamin D insufficiency is a controllable cause of cancers of the breast, colon, and kidney, and that such insufficiency is also associated with a higher incidence of cancers of the ovary and endometrium. Dr. Garland and his collaborators said that meta-analyses and systematic reviews of all studies of vitamin D levels in the blood relating to cancer incidence have shown that the dose-response relationship for cancer prevention is linear, beginning at about 20 ng/ml. The current recommended amount of vitamin D per day is 400 IU, which many experts consider too low. Dr. Garland said that since this vitamin is fat soluble, intakes should not exceed 2000 IU per day, the safe upper limit established by the Institute of Medicine. Calcium Calcium plays a role in the prevention of colorectal cancer, but only in the presence of a low calcium/magnesium ratio, according to a presentation from Qi Dai, MD, PhD, Assistant Professor of Medicine at Vanderbilt University. A high magnesium intake has been linked with a low risk of colorectal cancer, but Americans have amounts of magnesium intake similar to those of East Asians—and East Asia has a much lower colorectal cancer incidence than the United States. To test the hypothesis that the ratio of calcium to magnesium may be important in helping to prevent colorectal cancer, Dr. Dai and his colleagues enrolled 930 subjects who had had colorectal adenomas in the double-blind, placebo-controlled, randomized, four-year Calcium Polyp Prevention Study. The primary end point was recurrence of adenomas. “Calcium supplementation [1,000 milligrams a day] reduced the risk of adenoma recurrence only if the dietary ratio of calcium to magnesium intake was low before treatment and remained low during the treatment period,” Dr. Dai and his collaborators stated. Among those with a baseline calcium/magnesium ratio below the median, the risk of colorectal cancer adenoma recurrence was reduced by 32%. ‘Annual Report to Nation on the Status of Cancer’: For First Time, Decreased Incidence & Death Rates for All Cancers Combined for Both Men and Women The AACR cancer prevention conference was held just days before release of the annual report to the nation on cancer incidence and death rates issued by US cancer organizations (published in the December 3rd issue of the Journal of the National Cancer Institute). That report contained good news: For the first time since the annual report was issued in 1998, both incidence and death rates for all cancers combined are decreasing for both men and women. The declines are primarily due to a drop in some of the most common cancers, including those of the lung, prostate, breast, colon, and rectum. But the report also reveals wide geographical variations in US smoking patterns, indicating that the battle against cigarettes is far from over. At the AACR meeting, a study from Roswell Park Cancer Institute showed that patients who reported smoking more than 50-pack-years were seven times more likely to have their normal lung tissue progress to precancerous lesions compared with those who had never smoked, and that even low-grade precancerous lesions have the potential to progress to lung cancer. And since smoking is the most common preventable cause of cancer, Centers for Disease Control and Prevention Director Julie Gerberding, MD, said in a statement that the geographical variations highlight the need for a national recommitment to tobacco control programs.

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