Results of Raloxifene RUTH and STAR Trials

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Clinical trial results indicate that raloxifene has no effect on the risk of coronary heart disease and is equivalent to tamoxifen in reducing the risk of invasive breast cancer.

Sources: RUTH Trial, http://newsroom.lilly.com; STAR Trial; www.cancer.gov/newscenter.

The Eli Lilly Company and the National Cancer Institute released preliminary results from two large clinical trials involving raloxifene. The Raloxifene Use for the Heart (RUTH) study included more than 10,000 women from 26 countries, either at high risk for myocardial infarction or with known coronary heart disease. The participants were randomized to placebo or raloxifene, 60 mg daily, and followed for up to 7 years. There was no effect of raloxifene treatment on coronary heart disease events; however, there was a small increase in stroke mortality. Invasive breast cancer was a secondary end point, and there were fewer cases in the treated group compared to placebo. The women taking raloxifene had an increase in venous thromboembolic events. The numbers for breast cancer and venous thrombosis were not provided in the preliminary report.

The Study of Tamoxifen and Raloxifene (STAR) enrolled 19,747 women at increased risk of breast cancer who were randomized to treatment with either raloxifene, 60 mg daily, or tamoxifen, 20 mg daily, in more than 500 centers in the United States, Canada, and Puerto Rico. The reported results after an average treatment period of almost 4 years are listed in the Table on page 10.

The numbers of invasive breast cancers were identical in the 2 groups of women. It was estimated that these results were equivalent

to about a 50% reduction (based on the previous results in the tamoxifen prevention trial),1,2 but without a placebo arm, an accurate assessment was impossible. Raloxifene appears to achieve the same reduction as tamoxifen in invasive breast cancers with a lesser increase in venous thrombosis, and perhaps no increase in cataracts and uterine cancer. Fractures, as well as strokes and heart attacks, were equally prevalent in the two groups. "Quality of life" was said to be the same for both drugs.

Commentary

The results of the RUTH trial are not surprising. The known favorable impact of raloxifene on the cholesterol-lipid profile was not robust enough to prevent coronary events. Tom Clarkson has been teaching for many years that based on his monkey model, prevention of coronary events requires a direct impact on coronary vascular endothelium, an effect that is greater than and independent of lipid effects. In a 2-year randomized trial in monkeys reported 8 years ago, raloxifene exerted no protection against coronary artery atherosclerosis despite changes in circulating lipids similar to those achieved in women.3

The day after the release of the preliminary data, an article highlighting the STAR results appeared on the first page of my morning paper. The newspaper article and the release from the National Cancer Institute emphasized the "superiority" of raloxifene over tamoxifen, pointing out a lesser rate of uterine cancers, cataracts, and venous thromboembolic events with raloxifene. A National Cancer Institute spokesperson said that the ability to strengthen bones is an added bonus. One of the study investigators said that raloxifene will be the new yardstick for measuring other cancer-fighting drugs.

But wait a minute, there are some problems:

  1. Tamoxifen has been demonstrated to reduce the incidence of both lobular carcinoma-in-situ and ductal carcinoma-in-situ.1,2 In the 7-year follow-up report of the tamoxifen for prevention study, the risk for breast cancer was 0.57 (CI = 0.46-0.79), a 43% reduction, not the 50% cited in the results above, and the risk for in-situ disease was 0.63 (CI = 0.45-0.89), a 37% reduction.1 Not only did raloxifene not yield a reduction, the number of in-situ cancers with raloxifene was greater. What does this mean? If raloxifene is truly preventing breast cancer, this should produce a reduction in in-situ disease; the greater increase with raloxifene is inexplicable and disturbing.
  2. The fracture rates in the hip, wrist, and spine in the STAR trial were similar in the two groups. In the 7-year follow-up report of the US breast cancer prevention trial with tamoxifen, osteoporotic fractures were reduced by 32%; compared with placebo, there were 11 fewer hip fractures, 13 fewer spinal fractures, and 9 fewer fractures of the radius.1 However, even after 8 years of follow-up, no effect of raloxifene has been evident on non-vertebral fractures.4 A similar fracture rate in the STAR trial with the 2 treatments must reflect the incidence of spinal fractures. Neither tamoxifen nor raloxifene can achieve the efficacy in preventing all fractures well-proven with both hormone therapy and bisphosphonate treatment. Raloxifene's lack of effect on the risk of hip fractures makes it less advantageous than even tamoxifen for bone protection.
  3. The rate of strokes was equivalent in the 2 treatment arms; the rate of stroke was increased by 42% in the tamoxifen prevention trial (coming close, but not achieving statistical significance.1 A small increase in stroke mortality was reported in the RUTH trial. This is a serious risk for both drugs.

And there is a new player in this field, the class of drugs known as aromatase inhibitors. Aromatase inhibitors nearly completely inhibit total body production of estrogen in postmenopausal women. In clinical trials, aromatase inhibitors have been more effective and safer than tamoxifen for the treatment of estrogen-sensitive breast cancers in postmenopausal women, either for early disease or for metastatic breast cancer. The American Society of Clinical Oncology5 and the National Comprehensive Cancer Network (www.nccn.org), based on the results of clinical trials, now make the following recommendations:

  • Postmenopausal women with hormone-positive breast cancers should be treated with an aromatase inhibitor.
  • Treatment options include 5 years of aromatase inhibitor treatment alone or sequential therapy with 2-3 years of tamoxifen followed by aromatase inhibitor treatment for 2-5 years.
  • The optimal timing and duration of treatment have not been established.
  • Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen.
  • Aromatase inhibitor treatment has been associated with better response rates compared with tamoxifen in postmenopausal women with tumors overexpressing HER-2. This evidence is not strong, but should be considered.
  • Women finishing 5 years of treatment with tamoxifen should consider treatment with an aromatase inhibitor (for a minimum of 2.5 years).
  • There is insufficient evidence available to support the use of tamoxifen after treatment with an aromatase inhibitor.

The major problem with aromatase inhibitors has been an increase in fractures due to the profoundly low estrogen levels (nearly a 99% decrease) and the subsequent loss of bone, a risk that can probably be prevented with bisphosphonate treatment. Besides hot flushing, other side effects are arthritic complaints, reduced sexual function, and myalgia.6 Compared with tamoxifen, there is less, if any, endometrial stimulation, less venous thromboembolism, and slightly less hot flushing.

On-going trials are comparing one aromatase inhibitor with another (with and without an inhibitor of the cyclooxygenase system), 5 years of tamoxifen alone to 5 years of aromatase inhibitors, and sequential regimens comparing tamoxifen followed by an aromatase inhibitor and vice-versa. Large trials are also assessing the value of combining aromatase inhibitor treatment with ovarian suppression in premenopausal women with breast cancer. And appropriately, trials are testing the efficacy for prevention of breast cancer.

Given the greater efficacy and safety associated with aromatase inhibitors, one can safely predict that this class of drugs will perform better in the prevention trials as well. The problem of increased fractures can be prevented with adequate calcium and vitamin D supplementation and treatment with a bisphosphonate, once a month, once every 6 months, or even only once a year.7 It's too soon to jump on the raloxifene bandwagon.

References

  1. Fisher B, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 2005;97:1652-1662.
  2. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.
  3. Clarkson TB, et al. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab. 1998;83:721-726.
  4. Siris ES, et al. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to evista (CORE) Study. J Bone Miner Res. 2005;20:1514-1524.
  5. Winer EP, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005;23:619-629.
  6. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.
  7. Aapro M. Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: The Z-ZO-E-ZO-FAST program. Breast. 2006;15(1 Suppl):30-40.