COLUMBUS, OhioChemopre-vention trials in recent years have led
to new chemoprevention agents and also unexpected negative findings,
Winfred F. Malone, PhD, MPH, said at the 4th Annual Congress of the
Society for Nutritional Oncology Adjuvant Therapy (NOAT). He
described a number of published and ongoing clinical trials.
Dr. Malone is section chief of the Chemoprevention Branch of the
NCIs Division of Cancer Prevention & Control. The
Chemoprevention Branch is currently sponsoring more than 70 clinical
trials, with more than 700 compounds under investigation.
The chemoprevention of breast cancer has seen spectacular
breakthroughs and progress culminating in the approval of tamoxifen
[Nolvadex] last October as an agent to reduce the incidence of breast
cancer in high-risk women, he said.
Other chemoprevention trials have achieved notoriety for both
positive and negative findings, Dr. Malone said. The ATBC
(alpha-tocopherol, beta-carotene) Cancer Prevention Study, for
instance, found a 41% drop in prostate cancer mortality in men taking
alpha-tocopherol (vitamin E). But it also showed an unanticipated
increase in lung cancer among male smokers who took a beta carotene supplement.
Many promising chemopreventive agents for prostate cancer are
also under investigation, Dr. Malone said. Agents in phase II
trials include selenium, vitamin E, vitamin D analogs, sulindac,
finasteride (Proscar) analogs, flutamide (Eulexin), bicalutamide
(Casodex), and toremifene (Fareston).
Investigators have hypothesized that selenium supplementation may
reduce the incidence of nonmelanoma skin cancer. A randomized,
double-blind che-moprevention trial of 1,312 patients with a history
of basal cell or squamous cell carcinoma of the skin found that the
incidence of these skin cancers was unaffected by selenium. However
total cancer incidence was lower in the selenium group. The selenium
group also had fewer prostate, colorectal, and lung cancers (Clark LC
et al: JAMA 276:1957-1963, 1996).
Cyclooxygenase (COX) inhibitors are receiving a great deal of
attention for their possible role in colorectal cancer
chemoprevention. Investigators are looking at nonsteroidal
anti-inflammatory drugs (NSAIDs), including aspirin and sulindac, and
the selective COX2 inhibitor celecoxib (Celebrex, recently approved
for use in arthritis).
The COX1 and COX2 enzymes are involved in the production of
prostaglandins, which are necessary for inflammation and may play a
role in cancer development. COX inhibitors are thus believed to
interfere with cancer development through the modulation of
COX inhibitors, however, have gastrointestinal side effects that
limit their routine use. Scientists hope to reduce these side effects
by developing drugs such as celecoxib that target only COX2. The COX1
enzyme is found throughout the body, whereas COX2 is generally not
expressed in normal tissues.
A large, phase III trial investigating the prevention of polyps with
aspirin and folic acid is currently being conducted by John Baron,
MD, PhD, of Dartmouth Medical School. The trial has enrolled about
1,000 patients. The daily aspirin dose is 80 mg or 325 mg. The
endpoint for the study is the appearance of an adenomatous polyp
between randomization and year 3 of the study.
An earlier trial failed to establish an association between aspirin
and a reduction in colorectal cancer during 5 years of randomized
treatment (Gann PH et al: J Natl Cancer Inst 85:1220-1224, 1993).
A randomized, double-blind trial of 22 patients with familial
adenomatous polyposis (FAP) found a regression of polyps in patients
treated with sulindac (Giardiello FM et al: N Engl J Med
An ongoing phase II multidose safety and efficacy study of celecoxib
is being conducted at M.D. Anderson and St. Marks, London,
England. The study has enrolled more than 75 patients with FAP.
One significant outcome of the study has been a 40% change in
number of adenomas relative to the baseline, Dr. Malone said.
Despite the interest in COX inhibitors for colorectal cancer
prevention, he said, much remains to be learned about its use,
including appropriate dosage, length of treatment, and target populations.
Calcium and Colorectal Adenomas
Calcium is another agent being examined for its role in the
prevention of colorectal adenomas. The results of a randomized trial
of more than 800 patients found that calcium supplementation reduced
the risk of at least one recurrent adenoma by 17%. This was a
modest but important result, Dr. Malone noted (Baron JA et al: Gastroenterology
Breast Cancer Prevention
Several agents are under investigation for the chemoprevention of
breast cancer. Although the effectiveness of tamoxifen has been
demonstrated, it has significant side effects, including an increase
in endometrial cancer. In January, the National Cancer
Institute was scheduled to begin funding a trial of raloxifene
[Evista] vs tamoxifen with 22,000 patients, Dr. Malone said.
Raloxifene, although similar to tamoxifen, selectively avoids
estrogenic stimulation of the uterine endometrium. The results of the
Multiple Outcomes of Raloxifene Evaluation (MORE) trial showed that
it reduced the incidence of breast cancer without affecting the
endometrium. The National Surgical Adjuvant Breast and Bowel Project
(NSABP), the same group that conducted the tamoxifen trial, will
conduct the Study of Tamoxifen and Raloxifene (STAR).
The chemoprevention of contralateral breast cancer with the agent
fenretinide (4-HPR) is the subject of an ongoing study. As of 1998,
1,670 patients had completed the study, and 203 patients were still
enrolled. The patients in the study are women with previously
resected stage I or II breast cancer with limited lymph node
Interim analyses in 1995-1997 showed no significant differences in
contralateral disease, overall neoplastic events, or survival in the
study population overall. However, fenretinide was found to reduce
contralateral breast cancers in the premenopausal group. A phase II
study is examining the effects of low-dose tamoxifen given in
combination with fenretinide.