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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 womens 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.
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