New Insights about Cancer Causes, Prevention

From the American Association for Cancer Research

COX-2 Inhibition, Vitamin D, and Antihistamines

WASHINGTON, DC?Two studies highlighted at the American Association for Cancer Research (AACR) annual meeting reported new findings with significant clinical implications for cancer prevention in different patient populations, while another study demonstrated a potential link between antihistamines and the development of brain tumors. ? ?

Celebrex for Colon Cancer Prevention

New data have confirmed earlier findings that the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex), the only COX-2 inhibitor still on the market, currently approved for the treatment of rheumatoid arthritis, can also help prevent colon cancer in high-risk individuals.

However, persistent safety concerns associated with the COX-2 inhibitor class, notably the cardiovascular (CV) damage attributed to long-term, high-dose use, prevent recommending celecoxib for individuals at average risk.

Two major clinical trials concluded that overexpression of the COX-2 enzyme contributes to the spread of the colorectal polyps (adenomas) that can lead to cancer. One of every 5 adenomas develops into cancer if not removed.

The 2 randomized, double-blind trials showed that sustained higher doses of celecoxib for nearly 3 years reduced precancerous polyp formation, with the greatest benefit derived by those at highest risk of polyp recurrence.

"COX-2 inhibitors may reduce the occurrence of precursor colorectal adenomas in patients with a family history of the disease," investigator with the first trial, Monica M. Bertagnolli, MD, of Harvard University, Boston, pointed out. "The agents may prevent sporadic colorectal tumors as well."

N Engl J Med

The first trial, the Adenoma Prevention with Celecoxib (APC) study, published last year (. 2005; 352:1071-1080), enrolled 2035 patients at high risk of colon cancer. Patients were randomized to 3 groups: placebo (n = 679), 200 mg celecoxib (n = 685), and 400 mg celecoxib (n = 671); all doses were given twice daily. Some 30% of participants continued to use cardioprotective low-dose aspirin. Colonoscopy was performed in 90% of patients at 1 year and in 76% of patients at 3 years.

The 61% incidence of precancerous polyps in those receiving placebo was reduced by 33% to 45% (depending on the dose) in patients receiving celecoxib who were at high risk of colon cancer. At 33 months, however, the 2- to 3-fold increase in serious CV events, ranging from stroke to death, in patients taking celecoxib prompted early discontinuation of the trial.

Dr Bertagnolli summed up her findings: "Patients at high risk for colorectal cancer receiving celecoxib developed significantly fewer premalignant tumors?.The drug also was effective in preventing sporadic colorectal adenomas."

She continued, "But since the celecoxib regimen used in the APC trial was associated with an increased risk of cardiovascular events, we cannot currently recommend celecoxib for routine chemoprevention of sporadic colorectal adenomas."

The second study, called Prevention of Colorectal Sporadic Adenomatous Polyps with Celecoxib (PreSAP), enrolled 1561 patients at 107 sites in 32 countries. After removing all polyps, the investigators tested the effectiveness of celecoxib, 400 mg/day, for preventing the development of new polyps. ?

"Our results showed that celecoxib holds great promise for preventing cancer," said Nadir Arber, MD, MSc, head, Integrated Cancer Prevention Center, Tel Aviv. "The incidence of adenomas by year 3 was 40.3% in the placebo group, but significantly less in the celecoxib group. And the prevalence of adverse events was similar in both groups"--"74% versus 76.8%," respectively. (The exact percentage for the incidence of adenoma with celecoxib was still being analyzed at the time of the presentation.)

As may be expected of a COX-2 inhibitor, patients taking celecoxib had a higher risk of CV events compared with placebo (7.5% vs 4.6%, respectively), he pointed out. "Nevertheless, for patients at high risk of developing colorectal cancer, clinicians should consider celecoxib, while weighing the risk of potential CV events," Dr Arber concluded.

Vitamin D at Young Age Fights Breast Cancer Risk

A new population-based case-control study of women suggests that vitamin D may play a significant role in reducing breast cancer risk.

After interviewing 576 patients with breast cancer from health care institutions and 1135 patients without cancer who were randomly selected by telephone number, investigators found significant reductions in breast cancer risk in those who had either worked outdoors, taken part in outdoor activities, or consumed cod liver oil or high quantities of milk when they were young.

"Working an outdoor job between ages 10 and 19 resulted in an estimated 40% reduced risk of breast cancer, while frequent outdoor activities between ages 10 and 29 lowered breast cancer risk by an estimated 35%," said lead investigator Julie Knight, PhD, of the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Canada. "We believe this is evidence of a reduction of breast cancer risk associated with early exposure to the sun."

Taking vitamin D?rich cod liver oil between the ages of 10 and 19 years reduced the risk of breast cancer by 25%, and consuming at least 9 glasses of milk every week between the ages of 10 and 29 years reduced the risk by 35%.

"What you are exposed to during breast development may be very important in determining future breast cancer risk," said Dr Knight.

Antihistamines Linked to Gliomas

A report much discussed at the meeting show that individuals who use antihistamines regularly for ?6 months have a 3-fold greater risk of developing mid-grade brain tumors and a 2-fold greater risk of developing low-grade tumors.

"We're not implying that using antihistamines directly causes brain tumors but that the drugs may be part of a mix of factors that can lead to those tumors," said Michael Scheurer, PhD, fellow in cancer prevention, M.D. Anderson Cancer Center, Houston. "We believe an anti-inflammatory response is involved."

Using combined data from recent glioma studies conducted in California, the investigators compared antihistamine and anti-inflammatory drug use in 830 patients with brain tumors and in 831 controls matched for age, gender, and race. A total of 339 tumors were high-grade glioblastomas, 117 were mid-grade astrocytomas, and 154 were low-grade tumors.

Dr Scheurer referred to the finding that long-term antihistamine use was associated with brain tumor development as "a first," explaining that "no one has yet looked at the potential effects of antihistamines on brain tumors."