Home: Educational Supplement: Appendix

Impact of Tamoxifen Adjuvant Therapy on Symptoms,
Functioning, and Quality of Life

Patricia A. Ganz, M.D.

Tamoxifen has been an integral part of systemic adjuvant therapy for breast cancer patients since the early 1980s, initially being administered primarily to postmenopausal, node-positive patients, and then subsequently to both premenopausal and postmenopausal patients with hormone-receptor-positive, node-negative tumors (Fisher, Costantino, Redmond, et al., 1989). More recently, tamoxifen has been demonstrated to benefit both women with noninvasive breast cancer and women at high risk for breast cancer (Gail, Costantino, Bryant, et al., 1999). Although the toxicities of tamoxifen are mild compared to combination chemotherapeutic regimens, concerns about the side effects of tamoxifen have become more prominent with the increasing use of this agent in women with very early stage disease (or high risk only), where the absolute gains in quantity of life are modest (Fisher, Costantino, Wickerham, et al., 1998). If symptoms are nearly universal with a treatment and its absolute benefits are small, one can begin to question the personal costs of such therapy. This is the current dilemma of women with very early stage breast cancer who must decide whether or not to take tamoxifen.

Everyday Symptoms and Quality of Life Concerns Associated With Tamoxifen

Many women who have received treatment for breast cancer (surgery, radiation therapy, and adjuvant chemotherapy or hormonal therapy) have anecdotally reported a range of symptoms that have been attributed to tamoxifen, including vasomotor symptoms (hot flashes, sweats), weight gain, depression, hair loss, joint pains, fatigue, vaginal dryness, and diminished sexual functioning (Ganz, Rowland, Desmond, et al., 1998). Many of these symptoms could be due to the concurrent effects of premature menopause induced by chemotherapy or the withdrawal of hormone replacement therapy, along with the psychosocial impact of a cancer diagnosis. Although clinicians tend to remember patients for whom the use of tamoxifen seemed to be associated with severe symptoms that had a major impact on quality of life, there are large numbers of other women who have tolerated tamoxifen adjuvant therapy well and experienced no change in quality of life. Therefore, placebo-controlled trials offer the strongest form of evidence for determining whether increased symptoms are attributable to tamoxifen therapy.

The toxicity of adjuvant tamoxifen therapy has been evaluated in two randomized, placebo-controlled trials. In the Wisconsin Tamoxifen Trial (Love, Cameron, Connell, et al., 1991), 140 postmenopausal, node-negative patients were randomly assigned to tamoxifen or a placebo. Using an interviewer-administered questionnaire, patients were asked to evaluate a range of symptoms, overall toxicity, anxiety, and quality of life. Followup occurred over a 24- month period. Key findings included an increase in hot flashes reported by women on tamoxifen (67.2 percent versus 45.4 percent for placebo at 6 months, p<0.01), with severe hot flashes in 20.3 percent versus 7.6 percent for placebo at 6 months, p<0.04. Gynecological symptoms (vaginal discharge, irritation or bleeding) were more frequent in tamoxifen users (29.7 percent versus 15.1 percent for placebo at 6 months, p<0.05), but these were predominantly mild in severity. There were no differences between the two groups in the symptoms of racing heart, bone pain, joint pain, gastrointestinal distress, nausea, vomiting, sweaty hands, difficulty sleeping, irritability, depression, or fatigue. Finally, there was no adverse effect on quality of life as measured by nonstandardized questionnaires.

The NSABP B-14 trial of tamoxifen in node-negative, estrogen receptor-positive (ER+) pre- and postmenopausal women (Fisher, Costantino, Redmond, et al., 1994) was a much larger double-blind, placebo-controlled trial, with more than 1,400 women in each study group. However, the study obtained no self-reported data on symptoms or quality of life. Nevertheless, detailed toxicity evaluation of this trial demonstrated a pattern of symptoms similar to that found in the Wisconsin trial. Over the course of 5 years of therapy, 64.1 percent of the patients treated with tamoxifen reported hot flashes, compared to 47.7 percent of placebo patients. Vaginal discharge was noted in 29.7 percent of tamoxifen-treated patients, compared to 15.2 percent of placebo patients. There were no significant differences in reports of weight gain, weight loss, fluid retention, nausea and vomiting, or diarrhea. Protocol therapy was discontinued in an equal number of patients in both groups, but in the tamoxifen group there were more withdrawals (about 50 percent) that were attributed to treatment toxicity.

In a recent cross-sectional study of symptoms and quality of life in breast cancer survivors (an average 3 years after diagnosis), Ganz, Roland, Meyerowitz, et al. (1998) used state of the art self-reported measures to evaluate patients according to type of adjuvant therapy. Hot flashes and night sweats were reported significantly more often in survivors taking tamoxifen than in survivors who had not received any adjuvant therapy. The rates were comparable to those in the placebo-controlled trials described above. Vaginal discharge also increased at rates similar to those in the placebo-controlled trials. Other symptoms (vaginal dryness, weight gain, difficulty concentrating, forgetfulness) were not significantly affected by tamoxifen therapy. Importantly, no significant differences in quality of life or depressed mood could be attributed to the use of adjuvant tamoxifen therapy, in spite of significant increases in vasomotor and vaginal symptoms. Most recently, the Breast Cancer Prevention Trial (BCPT), a randomized, double-blind, placebo-controlled study of more than 13,000 healthy high-risk women, found no detrimental effects on mood and on quality of life from tamoxifen therapy, even though vasomotor symptoms and vaginal discharge were significantly increased by the treatment (Day, Ganz, Costantino, et al., 1999).

Impact of Tamoxifen on Sexual Functioning

Research in both healthy women and women with breast cancer demonstrates an age-related decline in sexual functioning. In the BCPT, rates of sexual activity with a partner did not differ by tamoxifen or placebo status, although a subtle decline in sexual activity was noted for both groups across the first 3 years of the trial. In addition, very subtle changes in becoming sexually aroused and difficulty having orgasm were noted in the women treated with tamoxifen. In the recent cross-sectional studies of breast cancer survivors, no significant differences in sexual health and functioning were found between the survivors and healthy postmenopausal women. A detailed study of the predictors of sexual health after breast cancer (Ganz, Desmond, Belin, et al., 1999) found that chemotherapy, and not tamoxifen, was the most significant treatment-related variable predicting sexual dysfunction, and was associated with a greater risk of vaginal dryness, a symptom not usually related to tamoxifen therapy.

Serious Risks of Tamoxifen Therapy

Women with small tumors in the breast who must decide whether or not to take adjuvant tamoxifen must weigh the other potential consequences of this therapy, such as endometrial cancer, cataracts, blood clots, and strokes. These are rare, however. Although the relative reduction in risk of breast cancer recurrence is uniform across all stages of disease, the absolute benefit decreases in patients with earlier stage disease and very small invasive cancers. The risks of tamoxifen must be balanced against the potential gains in terms of prevention of local and systemic breast cancer recurrence, improved overall survival, and reduction in the risk of contralateral breast cancer. These risks are strongly associated with advancing age, other health conditions, and the presence or absence of a uterus. Data from the BCPT on the relative risk and absolute frequency of these adverse events are useful in discussions with women concerned about the risks of tamoxifen therapy.

Conclusion

The major symptoms attributable to tamoxifen therapy are hot flashes, sweats, and vaginal discharge. Other common symptoms associated with aging and the menopause, such as joint pains, changes in mood, weight gain, and difficulty concentrating, cannot be directly ascribed to tamoxifen therapy, and are more likely the result of the estrogen deficiency associated with menopause. There is no evidence that breast cancer survivors who take tamoxifen have a poorer quality of life or increased risk of depression. Sexual functioning after breast cancer is most often affected by the presence of vaginal dryness, which is not a specific side effect of tamoxifen but is probably the result of age-related estrogen deficiency and possibly an effect of chemotherapy. Although life-threatening risks caused by tamoxifen therapy, including endometrial cancer, blood clots, and strokes are rare, they cannot be ruled out. Women with breast cancer must therefore evaluate carefully all of the risks and benefits of tamoxifen adjuvant therapy before embarking on such treatment.

References

Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-69. Abstract.

Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479-84. Abstract.

Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-37. Abstract.

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, 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;90:1371-88. Abstract.

Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, Vogel V. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829-46. Abstract.

Ganz PA, Day R, Ware JE Jr, Redmond C, Fisher B. Base-line quality-of-life assessment in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 1995;87:1372-82. Abstract.

Ganz PA, Desmond KA, Belin TR, Meyerowitz BE, Rowland JH. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol 1999;17:2371-80. Abstract.

Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life after breast cancer: understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501-14. Abstract.

Ganz PA, Rowland JH, Meyerowitz BE, Desmond KA. Impact of different adjuvant therapy strategies on quality of life in breast cancer survivors. Recent Results Cancer Res 1998;152:396- 411. Abstract.

Love RR, Cameron L, Connell BL, Leventhal H. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 1991;151:1842-7. Abstract.