WASHINGTON—Enrollment for the Study of Tamoxifen(Drug information on tamoxifen) and Raloxifene(Drug information on raloxifene) (STAR), the largest cancer prevention trial yet undertaken, began May 25, and randomization of participants to the trial’s two arms is expected to start in July. The double-blind study of 22,000 woman at increased risk of breast cancer will compare the two drugs’ effectiveness in preventing the disease as well as their side-effects profiles.
“Basically, the principal question that is being asked is whether raloxifene is superior to tamoxifen in reducing the incidence of breast cancer and whether it can do so with fewer adverse effects,’’ said Norman Wolmark, MD, chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP).
NSABP will conduct STAR for the National Cancer Institute at more than 400 centers in the United States, Canada, and Puerto Rico. Women in the tamoxifen arm will receive 20 mg/day and the raloxifene group will get 60 mg/day for 5 years. Each woman will get two pills to take daily, one her active drug and the second a placebo that looks like the other drug used in the trial.
Both tamoxifen (Nolvadex) and raloxifene (Evista) are selective estrogen-receptor modulators (SERMs). Tamoxifen has been used for more than 2 decades to treat breast cancer patients. Last year, results from the 13,000-woman Breast Cancer Prevention Trial (BCPT) showed that high-risk women taking tamoxifen for 5 years had a 49% lower incidence of the disease than women taking placebo.
Last October, the Food and Drug Administration approved the use of tamoxifen to reduce breast cancer incidence in high-risk women. However, tamoxifen users in the BCPT had significantly higher incidences of endometrial cancer, pulmonary embolism, deep vein thrombosis, and stroke.
The FDA approved raloxifene in December 1997 for the prevention of osteoporosis in postmenopausal women. Clinical trials have indicated that the drug may also reduce the risk of developing breast cancer and may not increase endometrial cancer risk. The incidences of deep vein thrombosis and pulmonary embolism, however, are similar to those with tamoxifen. These findings provide the rationale for STAR.
Enrollment criteria for STAR require a woman to be at least 35 years old, postmenopausal, and have at least a cumulative 1.66% increased risk of developing breast cancer over the next 5 years.
Premenopausal women are excluded because raloxifene “has yet to be adequately tested for long-term safety in premenopausal women,” according to NCI, which noted that it has recently begun a separate study evaluating the drug’s safety in that population.
Each potential STAR enrollee will complete a risk assessment form so that the NSABP can determine her risk profile. The woman can then use this information to help her decide whether to participate in STAR.
The computer calculation of risk uses a model developed at NCI that evaluates a number of factors. These include age; number of first-degree relatives diagnosed with breast cancer; whether a woman has had any children and her age at first delivery; the number of breast biopsies she has had, especially those with atypical hyperplasia; and her age at menarche. Women diagnosed with lobular carcinoma in situ are eligible for the study based solely on that diagnosis.
Women with a history of thrombosis, stroke, certain arrhythmias, uncontrolled hypertension, or diabetes are excluded from STAR. Women taking hormone replacement therapy or who have taken tamoxifen or raloxifene for no more than 3 months are eligible for the study 3 months after they stop their medication.
Follow-up Protocol
After randomization, “the follow-up is fairly straightforward,” said D. Lawrence Wickerham, MD, NSABP associate chairman. “They will have a breast exam twice a year, a mammogram and gynecological examination once a year, and screening blood work yearly.”
Initially, NCI planned to enroll 8,000 women in the first year of STAR, 5,000 in the second year, and 3,000 each in the following 3 years. Now, the Institute hopes all 22,000 participants can be enrolled within 36 months.
“When the results will be ready will be dependent on accrual rates, but certainly within the next 10 years we would expect to have those results, and if we can enter those 22,000 women rapidly, the results will be apparent more rapidly,” Dr. Wickerham said.
The NCI expects to spend between $75 and $100 million on the study over the next 10 years, Leslie Ford, MD, associate director for clinical research at the Division of Cancer Prevention, said at a press conference. That briefing coincided with local press conferences held in many cities where researchers are recruiting STAR participants. In addition, Eli Lilly and Co. has given NSABP a $36 million grant to defray recruitment costs and to help local researchers carry out the trial.
