Tamoxifen adverse effects

Options for adjuvant hormonal therapy in postmenopausal women include aromatase inhibitors (e.g. anastrozole, letrozole, or exemestane) either in place of or after tamoxifen. Adverse effects with aromatase inhibitors include hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea. 

As a result of these findings, a scheduled standard pelvic exploration is now an obligatory procedure in clinical trials with new SERMs. It is important to note that this adverse effect has not been associated with tamoxifen or toremifene therapy (Maenpaa et al. 1997 Fisher et al. 1998), and in the case of raloxifene, a post hoc metaanalysis of 6926 nonhysterectomized postmenopausal women participating in clinical trials for 3 years or more showed a significant 50% reduction in the incidence of surgery for repairing pelvic floor relaxation, reported as an adverse event, compared with placebo (Goldstein et al. 2001). 

In 122 postmenopausal patients with metastatic breast cancer who were randomized to exemestane 25 mg/day (n = 62) or tamoxifen 20 mg/day (n = 60), neither exemestane nor tamoxifen had adverse effects at 8, 24 or 48 weeks on concentrations of total cholesterol, HDL cholesterol, apolipoproteins A1 or B, or lipoprotein a (15). Exemestane lowered triglyceride concentrations while tamoxifen increased them. 

Idoxifene is another of the newer selective estrogen receptor modulators (SERMs), and preclinical data show that it has greater antiestrogenic activity than tamoxifen but lower estrogenic activity. It is not yet clear whether this affects its degree of usefulness or safety when it is used, for example, in cases of metastatic breast cancer. In comparisons of the two drugs in such patients the desired effects were similar and the incidence of adverse effects was essentially the same (14). 

In a randomized phase II trial in 47 such women in whom tamoxifen 20 mg/day had ceased to be effective, idoxifene showed only very slight evidence of activity possible drug-related adverse effects were similar in frequency to those with tamoxifen (hot flushes/flashes 13% versus 15%, mild nausea 20% versus 15%) (15). Endocrine and lipid analysis in both groups showed similar changes. 

Tamoxifen is commonly used in the treatment of breast carcinoma (1) the overall rates published for adverse effects vary very greatly, between 1 and 60% (2,3). It has also been used as a form of HRT to reduce bone loss and the incidence of fractures in high-risk cases (4). A combination of tamoxifen with ovarian suppression is as effective as the use of cytostatic drugs, and has been claimed to be better tolerated (5-7). 

The use of tamoxifen to prevent breast cancer has been reviewed (8). The merits of using tamoxifen to prevent mammary carcinoma in women who have never had the disease but are believed to be at high risk have been disputed (9), but it is clear that it would involve very long treatment and that one s view of the adverse effects might need to be revised for this class of users. The available data after 5,10, and 15 years of follow up confirmed an increase in the incidence of endometrial cancer and of thromboembolic complications and suggested ocular toxicity, but these effects were not common and should be more than balanced by the reduced risk of coronary heart disease and osteoporosis (8). 

One of the many controversies surrounding the use of tamoxifen in elderly women is whether after lumpectomy it should be accompanied by radiotherapy to potentiate the desired effect. It has been suggested that there is not a great deal of merit in adding radiotherapy to tamoxifen, since radiotherapy plus tamoxifen reduces local recurrence of breast cancer in elderly women compared with tamoxifen alone, but survival rates are not improved and benefits are offset by an increase in adverse effects (18). 

Tamoxifen versus aromatase inhibitors While tamoxifen is still widely regarded as the standard adjuvant endocrine treatment for postmenopausal women with localized breast cancer, provided it is hormone receptor positive, there are problems with recurrence and adverse effects. Reservations have recently been expressed about the future place of tamoxifen, and the case has been made that it is time to move from tamoxifen to the oral aromatase inhibitors (19). 

There may well be a role for combined therapy with both tamoxifen and an aromatase inhibitor if an optimal benefit to harm balance is to be attained, as suggested by a study of a combination of tamoxifen and exemestane for 8 weeks in 33 postmenopausal women with breast cancer (22). There was a striking absence of endocrine adverse effects. 

When tamoxifen is used in men (28), common adverse effects have included weight gain (25%), mood alterations (21%), hot flushes (21%), reduced libido (29%), and deep vein thrombosis (4%). The hot flushes respond well to oral clonidine 0.1 mg/day (29). 

Tamoxifen has several adverse effects on the skin, including edema, flushing, rashes, hyperhidrosis, urticaria, alopecia, and hypertrichosis. Radiation recall dermatitis, a severe painful inflammatory skin reaction in sites that have previously been exposed to ionized radiation, can occur in patients taking tamoxifen (59). In one case the tamoxifen was withdrawn and the skin healed spontaneously in 7 weeks (60). Toremifene, a tamoxifen analogue, was well tolerated during 18 months of continuous treatment no signs of radiation recall developed. 

De Muylder X, Neven P. Tamoxifen and potential adverse effects. Cancer J 1993 6 111. 

Despite the still uncertain adverse effects profile of tibolone, it continues to be used in relieving the hot flushes caused by anti-estrogen therapy, and does so in doses that cause no additional problems. In a further double-blind, placebo-controlled study of oral tibolone 2.5 mg/day in 70 postmenopausal women taking tamoxifen after breast cancer surgery tibolone reduced the severity of hot flushes and perhaps also their incidence (3). 

Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7-14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities. 

In fact, the most widely recognized adverse effects of tamoxifen are those related to the stimulatory effects on the endometrium. These effects include proliferation of the endometrium (Dijkhuizen et al., 1996 Hann et al., 1997 Lahti et al., 1993), formation of endometrial polyps (Cohen et al., 1997 Hann et al., 1997 Kedar et al., 1994a Lahti et al., 1993), hyperplasia (Cohen, 1997 Lahti et al, 1993), and cancer (Fisher et al, 1994 Rutqvist et al., 1995 Stearns and Gelmann, 1998 Wilking et al, 1997). Other reproductive side effects of tamoxifen are worsening of endometriosis (Buckley, 1990 Hajjar et al, 1993 Ismail and Maulik, 1997), adenomyosis (Cohen etal, 1997), and proliferation of benign uterine tumors (Cohen, 1997 Kang et al, 1996). 

In addition to its limited duration of beneficial effects in breast cancer, a serious problem associated with tamoxifen is its stimulatory effect on the endometrium, leading to endometrial hyperplasia and even cancer (Fisher etal., 1996 Kedar etal., 1994 Robinson etal., 1995). We thus have the example of a compound for which the benefits exerted on breast cancer and bone are accompanied by adverse effects in another tissue. In fact, as mentioned above, even the beneficial effects observed in breast cancer deserve some important comments because of the limit of 5 years of treatment, which raises practical questions about the use of this compound for prevention of breast cancer (Fisher et al., 1996) while, in fact, long-term use is required. Analogues of tamoxifen have... 

Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications. 

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