Cancer, treatment raloxifene

Phase trials and the FDA approval process often require seven to eight years. Raloxifene (2.28) (Figure 2.12) was initially approved to treat osteoporosis. After being on the market for several years, raloxifene was reported to be an effective treatment for certain forms of breast cancer. Estimate how much time would be required for clinical trials and approval of raloxifene as a breast cancer treatment. Justify your answer. 

STAR trial (Study of tamoxifen and raloxifene), which was completed in 2006, demonstrated additional utility of raloxifene in the prevention and treatment of breast cancer. In fact, the absence of associated uterotrophic effects with raloxifene suggests that it may be a safer agent than tamoxifen for use as a chemopreventative in high-risk postmenopausal women [3] therefore, raloxifene has very recently become a new option for breast cancer prevention now available for physicians and their patients. 

Raloxifene treatment of osteoporosis was associated with a 76% risk reduction for estrogen-receptor positive breast cancer. An additional study showed that this reduced risk continues for up to 8 years. Among women at high risk for breast cancer, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and had a lower risk of thromboembolic events. 

The second group of SERMs includes drugs such as raloxifene (previously named keoxifene), arzoxifene (Fig. 2.2), and LY-117018. Raloxifene was initially designed as a drug to treat breast cancer, but its clinical development was later focused on prevention and treatment of postmenopausal osteoporosis,... 

Fig. 10.8. Hazard ratio of presenting an endometrial cancer as the consequence of treatment with tamoxifen or raloxifene (MORE study). Reproduced with permission from Cuzick et al. (2003)...

From the first evaluations a positive effect of raloxifene tratment on the incidence of breast cancer was detected (Cummings et al. 1999). During the 4 years of treatment 79 breast cancer cases were detected and 77 of them were confirmed by the review board. In the placebo group 44 cases were identified, of which 39 were invasive, whereas in the raloxifene-treated group 33 cases were detected and 22 were invasive. The differences between both groups appeared progressively and tended to increase over time. This means a relative risk of 0.38 (IC 95% 0.24-0.58) or, in other words, a reduction in the incidence of breast cancer of 68%. 

During the 4 years of the trial 61 cases of breast cancer were reported and confirmed. Of these, 30 were in the placebo group (28 invasive) and 31 were in the raloxifene group (24 invasive). This means a 59% reduction in the incidence of invasive breast cancer in the raloxifene group as compared with women receiving placebo (2.1 vs. 5.2 cases per 1000 woman-years HR = 0.41, Cl = 0.24 to 0.71). Only nine intraductal, noninvasive breast cancers were detected, seven in the raloxifene group and two in the placebo group. The treatment with raloxifene reduced the overall incidence of breast cancer by 50%. The results... 

Fig. 10.10. Cumulative incidence of invasive breast cancers during 8 years of treatment either with raloxifene (dotted line) or placebo (solid line) Reproduced with permission from Martino et al. (2004)...

Delmas and coworkers (2005) have analyzed the impact of raloxifene treatment on breast cancer incidence over the 8 years of MORE plus CORE depending on the classification of the participants as osteopoenic or osteoporotic. For women assigned to placebo, more cases of invasive and ER(+) invasive breast cancers were reported in the osteopenic than in the osteoporotic group. 

Cummings SR, Duong T, Kenyon E et al. (2002a) Serum estradiol level and risk of breast cancer during treatment with raloxifene. J Am Med Assoc 287 216-220... 

Cauley JA, Norton L Lippman ME, Eckert S, Krueger KA, Purdie DW, et al. (2001) Continued breast cancer risk reduction in postmenopasusal women treated with raloxifene 4 year results from the MORE trial. Breast Cancer Res Treatment 65 125-134... 

First we shall describe the effects of tamoxifen, a first-generation SERM used as adjuvant treatment in women with breast cancer, on uterine leiomyomas and endometriosis. Considerable space will be devoted to raloxifene, a second-generation SERM administered for the prevention and treatment of postmenopausal women recently tested for the treatment of these two sex-hormone-related diseases. Unfortunately, at present no or very little data are available on the new third-generation SERMs such as lasofoxifene, idroxifene, droloxifene, ospemifene, azomifene, fulvestrant, and MDL 103.323. 

At present, the only SERMs routinely used in clinical practice are tamoxifen and raloxifene. Tamoxifen is used essentially as adjuvant treatment in women with breast cancer. Its use is related to estrogenic effects on the uterus. Specifically, tamoxifen can be associated with an increase not only in endometrial hyperplasia and cancer risk but also in uterine leiomyoma dimensions and in a risk of developing active endometriotic lesions. 

The most commonly observed side effect in patients taking raloxifene or tamoxifen was hot flashes (Agnusdei 1999 Muchmore 2000 Miller 2002). In the study by Mounts et al. (2002) in breast cancer patients < 56 years of age, the most frequent complaints during tamoxifen treatment were hot flashes (85%) and disturbed sleep (55%), whereas in the CORE study (Martino et al. 2004) hot flashes were observed in 12.5% of the raloxifene group vs. 6.9% in the placebo group. 

---