Side Effects Revealed:
Women’s Experiences With Aromatase Inhibitors
A Report From Breast Cancer Action
JANUARY 2007
Side Effects Revealed:
Women’s Experiences With Aromatase Inhibitors
By Marilyn T. Zivian, Ph.D., and Brenda Salgado, M.S.
JANUARY 2007
A Report From
55 New Montgomery Street, Suite 323
San Francisco, CA 94105
Phone: (415) 243-9301
Toll-free: (877) 2STOPBC
www.bcaction.org
[email protected]
This report is dedicated to the hundreds of women who generously took the time to
respond to Breast Cancer Action’s Aromatase Inhibitor Side Effects Survey and to
everyone who seeks to make informed decisions about the care they receive.
Table of Contents
Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Acknowledgements
BCA Reviewers
Survey Design Assistance
Barbara Brenner
Executive Director
Diane Tompkins, The Curious Company
Rebecca Farmer
Communications Officer
Graphic Design
Katrina Kahl
Communications Associate
Lisa Wanzor
Associate Director
Yvonne Day, Y. Day Designs
Printing
Inkworks Press
Breast Cancer Action wishes to thank the many women who participated in the survey and the organizations and
individuals who assisted in its distribution. This publication and quotes from survey respondents are available online at
www.bcaction.org.
©2007 Breast Cancer Action
Breast Cancer Action
Executive Summary
Aromatase inhibitors (AIs) are hormonal therapies approved for use in postmenopausal women with breast cancer.
Three AIs have been approved by the U.S. Food and Drug Administration (FDA): anastrozole (Arimidex), exemestane
(Aromasin), and letrozole (Femara).
Because AIs are relatively new drugs, little information is available about their long-term side effects. Breast Cancer
Action (BCA) is conducting a survey on the side effects women are experiencing while taking these drugs. The goal of
this survey is to provide information about side effects to patients, doctors, the FDA, the National Cancer Institute, and
other cancer organizations.
About the Survey
The AI Side Effects Survey was developed in 2005, and includes questions about the respondent’s age, place of
residence, the AI prescribed, date started and date stopped (if applicable), purpose of prescription, whether the patient
was given information by her health care provider about side effects and recommended duration of use, menopausal
status at the time of prescription, and other treatments received for breast cancer.
The questions are followed by a list of 38 side effects that was generated from FDA product information documents
for the three AIs. Respondents rated the side effects for severity (none, mild, moderate, or severe). Finally, respondents
were asked to report any additional side effects.
The sample of respondents is self-selected and may not be representative of the population of women taking AIs.
Therefore, the results cannot be generalized to the larger population.
Summary of Findings
The first 612 completed surveys received were analyzed for this report. Major findings include:
1. Most respondents (96%) reported one or more side effects.
2. The side effects reported by over 50% of respondents were: hot flashes (65%), bone pain (64%), feeling tired
(59%), muscle pain (58%), and insomnia (51%).
3. Many women reported side effects in addition to those on our list, including joint-related side effects, vaginal
atrophy and dryness, a rise in cholesterol levels, and general pain.
4. Over 50% of respondents stated that their menopause was not naturally occurring. For these women, menopause
was either pharmaceutically or surgically induced.
5. Ten women (1.6%) reported that they discontinued using an AI because of subsequent menstruation or vaginal
bleeding.
6. About 30% of the respondents discontinued the use of an AI—84% because of side effects they were experiencing,
and close to half of them (47%) specifically because of joint-related side effects.
7. Over one-third (37%) of respondents reported receiving no information from their doctors about short-term
side effects; nearly two-thirds (63%) reported receiving no information from their doctors about long-term side
effects.
1
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
2
Conclusions
While the population of survey respondents is not necessarily representative of all women taking AIs, the initial results
of our survey show that most women in our sample experienced one or more side effects. Many patients reported not
receiving information from their doctors about the side effects of AIs. However, these are relatively new drugs and
clinical trials rarely report on long-term side effects. Thus little information is available to doctors and patients about
the long-term side effects of AIs.
Aromatase inhibitors are indicated for use only in postmenopausal women with breast cancer. Based on responses, it is
apparent that some women who are not postmenopausal are being prescribed AIs—either because they were thought
to be postmenopausal but later resumed menstruating, or because they were premenopausal and had their ovarian
function supressed.1
The survey results clearly suggest that patients need better information about the side effects of AIs and whether the
use of AIs is actually appropriate for them.
Recommendations
1. Conduct additional research on short-term and long-term side effects of AIs.
2. Provide the results of this research to doctors and patients.
3. Use caution when prescribing AIs to perimenopausal women, as well as to premenopausal women who have been
rendered menopausal by chemotherapy or ovarian function suppression.
1 Three Phase III trials (SOFT IBCSG-24-02; TEXT IBCSG-25-02; PERCHE IBCSG-26-02) are currently looking at the use of
exemestane in premenopausal women whose ovarian function has been suppressed either surgically, pharmaceutically, or through
radiation of the ovaries. These trials were started in 2003, and results will not be available for several years. Until these trials are
completed, no data exist to support the use of AIs in women whose menopause is artificially induced.
Breast Cancer Action
INTRODUCTION
ntil recently, tamoxifen has been one of the primary drugs used in the treatment of breast cancer. When
it was approved for use, little was known about its long-term side effects. After being contacted by
women reporting side effects they were experiencing, BCA published a series of articles on tamoxifen
in its newsletter. As a result, BCA became an informal repository for women’s reports of side effects. Eventually breast
cancer patients’ informal reports to doctors and others prompted side effects research that confirmed their anecdotal
experiences.
U
Now, more than ten years later, AIs are quickly replacing tamoxifen as the drug of choice for treating hormoneresponsive breast cancer in postmenopausal women. As with tamoxifen a decade ago, little is known about the longterm side effects of these drugs. This time, BCA decided to systematically collect data on the side effects women have
been experiencing. BCA’s goals in providing this information are to enable patients to make better decisions, doctors to
make more informed recommendations, and the FDA to monitor AI side effects.
About Aromatase Inhibitors
Aromatase inhibitors are a type of hormone therapy for postmenopausal women with breast cancer. AIs prevent the
aromatase enzyme from converting the hormone androgen into estrogen. Produced by the adrenal gland and found
throughout the body, androgen is the principal source of estrogen for postmenopausal women. AIs have only been
approved for use by postmenopausal women. They are ineffective in premenopausal women whose ovaries are still
producing estrogen (which is not affected by the aromatase enzyme). None of these drugs has been approved by the
FDA for use by healthy women at high risk of developing breast cancer.
Three AIs are currently approved by the FDA for the treatment of breast cancer in postmenopausal women: anastrozole
(Arimidex), exemestane (Aromasin), and letrozole (Femara). Anastrozole and letrozole are both nonsteroidal
aromatase inhibitors. They are described as reversible because they bind reversibly to the aromatase enzyme.
Exemestane is a steroidal inhibitor that forms an irreversible bond with the aromatase enzyme, permanently stopping
the activity of the enzyme.
These drugs were first approved for treatment of advanced breast cancer in postmenopausal women on the following
dates: anastrozole in December 1995, letrozole in July 1997, and exemestane in October 1999. The FDA Indication and
Usage for the three AIs is as follows: 1
Anastrozole (Arimidex)
• Arimidex is indicated for adjuvant treatment of postmenopausal women with hormone-receptor-positive early
breast cancer.
• Arimidex is indicated for the first-line treatment of postmenopausal women with hormone-receptor-positive or
hormone-receptor-unknown locally advanced or metastatic breast cancer.
• Arimidex is indicated for the treatment of advanced breast cancer in postmenopausal women with disease
progression following tamoxifen therapy.
1 The indication and usage information for anastrozole, exemestane, and letrozole on pages 3 and 4 were taken from the FDA
web site, www.fda.gov, in October 2006.
3
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
4
Exemestane (Aromasin)
• Aromasin is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor-positive early
breast cancer who have received two to three years of tamoxifen and are switched to Aromasin for completion of a
total of five consecutive years of adjuvant hormonal therapy.
• Aromasin is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has
progressed following tamoxifen therapy.
Letrozole (Femara)
• Femara is indicated for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early
breast cancer.
• Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women who
have received five years of adjuvant tamoxifen therapy.
• Femara is indicated for first-line treatment of postmenopausal women with hormone-receptor-positive or
hormone-receptor-unknown locally advanced or metastatic breast cancer.
• Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease
progression following anti-estrogen therapy.
Methods
reast Cancer Action’s AI Side Effects Survey was developed from April to July 2005. The Tamoxifen Side
Effects Survey conducted by Breast Cancer Action Nova Scotia1 in 1999 served as an initial model for
the survey in the present study. The AI Side Effects Survey included demographic questions about the
respondents’ age and place of residence. These were followed by questions concerning the drugs themselves: specific
AI prescribed, date started, date stopped (if applicable), purpose of prescription, and whether or not the health care
provider gave information on short- and long-term side effects and expected duration of use.
B
Respondents were also asked about menopausal status at time of prescription, prior use of tamoxifen, and treatments
they had previously received for breast cancer (lumpectomy, mastectomy, chemotherapy, radiation, and/or hormonal
therapy). The survey included a list of 38 side effects that respondents rated according to severity (none, mild,
moderate, or severe). The list was generated from the adverse effects noted in FDA product information documents
for the three AIs. This information was accessed on the FDA web site in April 2005, when the survey was developed.
Finally, respondents were asked if they had experienced any additional side effects. Respondents’ confidentiality was
maintained by separating e-mail addresses from survey data when received.
The AI Side Effects Survey was posted on the BCA web site (www.bcaction.org/AISurvey) on August 17, 2005. The
survey was announced via e-mail, the print BCA newsletter, and a press release. Other breast cancer and women’s
health organizations (e.g., Living Beyond Breast Cancer, National Women’s Health Network, and the Women’s Cancer
Resource Center) announced the AI Side Effects Survey through newsletters, e-mails, and web links. Several clinics
requested and received print copies of the AI Side Effects Survey for their clients.
The cutoff date for receipt of surveys for initial analysis was July 5, 2006. By that date 612 completed surveys had been
1
Breast Cancer Action Nova Scotia is allied but not affiliated with Breast Cancer Action.
Breast Cancer Action
5
received. BCA has continued to receive additional survey responses, and those received after July 5, 2006, will be
included in a follow-up report.
Completed online surveys were received by BCA in e-mail form. Completed print surveys mailed to BCA were entered
by hand into the data set. All data were imported into an Excel spreadsheet, which was then imported into SPSS
(Version 14.0 for Windows) for data analysis.
The sample of respondents is self-selected and may not be representative of the population of women taking AIs. For
example, it may overrepresent women experiencing side effects. In addition, because the survey was conducted online,
it may underrepresent women with limited computer literacy and accessibility. The survey is currently limited to
English speakers. For all of these reasons, the results cannot be generalized to the larger population.
RESULTS
Respondents
Respondents came from 42 U.S.
states, nine Canadian provinces, five
European countries, Australia, and
the Middle East. Two respondents did
not provide a location.
The U.S. Census Data (2000) and the
American Cancer Society’s Cancer
Facts and Figures 2005 were used to
determine whether the U.S. survey
respondents were representative of
the distribution of breast cancer cases
across the United States. A Pearson
Product Moment Correlation (r)
comparing the number of survey
respondents from each state to the
expected number of women with
breast cancer in each state showed
that the two distributions were
similar (r = 0.917, p< .000 twotailed).
Table 1 displays the number of women in
each age group who were taking one of the
three aromatase inhibitors: anastrozole,
letrozole, or exemestane. A chi square
analysis, Χ2 = 7.134; d.f. = 8; 0.75>p>0.50,
indicated that the distribution of women in
each age group taking one of the aromatase
inhibitors was not statistically significant.
TABLE 1. Number of Respondents
By Age and Aromatase Inhibitor Prescribed
AROMATASE INHIBITOR
Anastrozole
nonsteroidal
Letrozole
nonsteroidal
Exemestane
steroidal
Total
20–39a
8
3
2
13
40–49
72
25
20
117
50–59
173
104
55
332
60–69
74
38
21
133
70+
9
3
5
17
Total
336
173
103
612
Age Group
b
a Includes one respondent 20–29 years old. All others were 30–39 years old
b Includes two respondents 80+ years old. All others were 70–79 years old.
FIGURE 1.
Percentage of Respondents
by Aromatase Inhibitor
Letrozole
28%
Exemestane
Anastrozole
17%
55%
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
6
The majority of respondents (95%) were between 40 and 69 years of age.
Almost all the respondents (96%) were postmenopausal at the time the AI was prescribed to them. However, less
than half of the respondents entered menopause naturally (46%). The remaining women reported their menopause
was artificially induced, either surgically through hysterectomy or oopherectomy (18%), or through the use of
pharmaceuticals (36%). Twenty-two women reported that they were not postmenopausal at the time the AI was
prescribed; seven women did not respond to this question.
Ten respondents (1.6%) reported discontinuing use of an AI because they were not truly menopausal and began
menstruating and/or they experienced vaginal bleeding.
Side Effects
The vast majority of respondents (96%) reported experiencing one or more of the 38 side effects. Table 2 lists the
number of respondents who reported one or more side effects, broken out by age and by AI. There was no significant
difference by age group or by aromatase inhibitor in the number of women who experienced one or more side effects,
Χ2 = 6.07; d.f. = 8; .75>p>.50, n.s.
TABLE 2. Number of Respondents
Who Reported One or More Side Effects
AROMATASE INHIBITOR
Age
Group
Anastrozole
nonsteroidal
Letrozole
nonsteroidal
Exemestane
steroidal
Total
20–39
6
3
2
11
40–49
70
25
20
115
50–59
169
99
55
323
60–69
71
34
20
125
70+
9
3
5
17
Total
325
164
102
591
Only 3.4% of the respondents (21 women) reported experiencing none of the 38 listed side effects. Eleven of these
women were taking anastrozole, nine were taking letrozole, and one was taking exemestane.
Breast Cancer Action
7
Figure 2 displays the percentage of respondents reporting each of the 38 side effects across the three AIs.
FIGURE 2.
Percent of Respondents Reporting Each Side Effect
Hot flashes
Bone pain
Feeling tired
Muscle pain
Insomnia
Mental fuzziness
Weight gain
Increased sweating
Anxiety
Hair thinning
Depression
Legs/arms swelling
Constipation
Dizziness
Osteoporosis
Headache
Shortness of breath
High blood pressure
Cough
Flu-like symptoms
Nausea
Stomach pain
Sinusitis
Diarrhea
Loss of appetite
Anemia
Bronchitis
Rash
Urinary tract infection
Leukopenia
Vaginal bleeding
Bone fracture
Hypercalcemia
Pleural efflusion
Vomiting
Thromboembolism
Heart attack
Stroke
64.9%
64.1%
59.2%
58.2%
51%
47.9%
44.9%
38.0%
32.5%
31.7%
29.4%
27%
20.4%
20.3%
19%
19%
17.2%
14.7%
13.9%
13.4%
13.1%
12.7%
12.6%
8.8%
8.7%
7.8%
6.9%
6.4%
5.9%
4.4%
3.3%
3.1%
2.8%
1.6%
1.4%
.5%
.3%
.1%
Respondents were asked to rate each of the 38 side effects according to the following severity ratings: none, mild,
moderate, or severe. For analysis purposes, the responses were ranked as 0, 1, 2, or 3, respectively. Table 3 lists average
severity ratings for all 38 side effects for each age group.
A three-way multivariate analysis [MANOVA, Repeated Measures: Age (5) x AI (3) x Side Effect (38)] showed that the
women’s severity ratings were significantly different between the side effects (F = 33.702, d.f. = 37, p = .000).
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
8
TABLE 3. Average Severity Ratings of Side Effects, Overall and by Age Group
Overall
20-39
40-49
50-59
60-69
70+
Significant
Difference by
Age Group
Hot flashes
1.23
1.54
1.21
1.35a
.94b
.94
p = .003
Bone pain
1.31
.85
1.30
1.47a
1.06b
.65
p = .000
Feeling tired
1.08
.54
.97
1.19
.98
.94
Muscle pain
1.18
.69
1.19
1.27
1.06
.65
Insomnia
.94
.85
.93
1.02
.81
.47
Mental fuzziness
.80
.54
.88
.87
.65
.29
Weight gain
.80
.69
.91
.84
.66
.65
Increased sweating
.69
.92
.65
.74
.62
.41
Anxiety
.53
.54
.49
.58
.47
.47
Hair thinning
.51
.15
.38
.55
.57
.35
Depression
.48
.38
.54
.49
.41
.29
Legs/arms swelling
.40
.62
.40
.42
.34
.29
Constipation
.34
.00
.36
.34
.36
.12
Dizziness
.28
.23
.32
.29
.25
.06
Osteoporosis
.28
.15
.21
.32
.29
.18
Headache
.30
.38
.35
.33
.19
.24
Shortness of breath
.26
.00
.25
.27
.38
.24
High blood pressure
.23
.00
.15
.21
.35
.24
Cough
.19
.15
.12
.22
.20
.06
Flu-like symptoms
.22
.00
.24
.26
.15
.00
Nausea
.18
.23
.15
.19
.17
.24
Stomach pain
.18
.08
.14
.22
.19
.18
Sinusitis
.21
.23
.08
.22
.31
.12
Diarrhea
.12
.15
.12
.13
.12
.06
Loss of appetite
.13
.00
.14
.12
.14
.29
Anemia
.10
.08
.12
.09
.12
.18
Bronchitis
.09
.00
.03
.10
.15
.12
Rash
.09
.15
.09
.10
.05
.12
Urinary tract infection
.09
.08
.03
.08
.16
.12
Leukopenia
.06
.23
.05
.05
.07
.06
Vaginal bleeding
.04
.00
.09
.04
.02
.06
Bone fracture
.06
.00
.07
.05
.06
.18
Hypercalcemia
.05
.00
.03
.05
.08
.00
Pleural efflusion
.02
.00
.02
.03
.02
.06
Vomiting
.02
.00
.02
.03
.01
.00
Thromboembolism
.00
a
.00
a
.00
a
.01
a
.00
.18b
Heart attack
.01
.00
.00
.00
.02
.00
Stroke
.00
.00
.00
.00
.01
.00
Side Effect
p = .000
Breast Cancer Action
There was also a significant interaction
effect for Side Effect x Age (F = 1.592,
d.f. = 148, p = .000), showing that, for
some side effects, there were significant
differences in the severity ratings
between age groups.
9
FIGURE 3.
Severity by Age for Hot Flashes, Bone Pain, and Thromboembolism
2.0
HOT FLASHES
BONE PAIN
THROMBOEMBOLISM
SEVERITY RATING
One-way ANOVAs were performed
1.5
for each individual side effect to
determine where significant differences
existed between the age groups. When
conducting a large number of ANOVAs
(38 in this case), it is possible that some
1.0
significant differences may emerge due
to chance. Thus, a significance level of p
≤ .01 was used. Three side effects were
found to have significant differences
0.5
between age groups: hot flashes, bone
pain, and thromboembolism. The
p values for these three side effects
are noted in the far right column in
Table 3, with significant differences
0.0
20–39
between particular age groups noted by
superscripts a and b. The presence of
superscripts a and b denotes that there is
a significant difference between those particular age groups.
40–49
50–59
60–69
70+
AGE
The severity ratings for hot flashes are higher for the younger age groups. However, the only significant difference
found was between the severity ratings of the 50- to 59-year-olds and 60- to 69-year-olds. Though the severity rating
for the youngest age group is the highest, it is important to note that the sample size for the youngest age group was
small, making significant differences less likely.
The severity ratings for bone pain are highest for the 50- to 59-year-old group. The difference between the severity
ratings of the 50-to 59-year-olds and 60- to 69-year-olds was significant.
The severity ratings for thromboembolism are significantly higher for the 70-plus-year-old group than for any other
group. However, as Figure 3 demonstrates, the severity rating for this side effect is very low in all age groups.
Table 4 displays side effects reported by respondents that were not specified in the survey. Only those side effects that
were reported by at least 1% of respondents are included in the table. The most commonly reported additional side
effects were joint-related (e.g., joint pain, arthritis, stiffness). The next most commonly reported side effects were
vaginal atrophy/dryness, a rise in cholesterol levels, and general pain. Multiple respondents also reported neurological,
bone-related, and muscular side effects, as well as feeling very aged.
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
10
TABLE 4. Number of Respondents (Percent in Parentheses)
Reporting Side Effects Not Specified in the Survey
AROMATASE INHIBITOR
Side Effect
Anastrozole
nonsteroidal
(n = 336)
Letrozole
nonsteroidal
(n = 173)
Exemestane
steroidal
(n = 103)
Number (%)
Joint pain/arthritis/stiffness
43 (13)
21 (12)
20 (20)
Vaginal atrophy/dryness
11 (3)
9 (5)
2 (2)
Rise in cholesterol level
15 (4)
4 (2)
2 (2)
Pain in hands/feet/back/in general
10 (3)
7 (4)
1 (1)
Skin dryness/itchiness/dry scalp
7 (2)
7 (4)
1 (1)
Numb/tingling/hands/fingers/legs
6 (2)
4 (2)
3 (3)
Osteopenia
5 (1)
7 (4)
–
Trigger thumbs/fingers/toes
7 (2)
2 (1)
2 (2)
Loss of libido
6 (2)
4 (2)
1 (1)
Muscle weakness/loss of strength
6 (2)
4 (2)
1 (1)
Feeling aged
5 (1)
3 (2)
1 (1)
Memory problems
6 (2)
3 (2)
–
Swelling hands/feet/fingers/joints
5 (1)
1 (.6)
2 (2)
Carpal tunnel syndrome
3 (.8)
2 (1)
2 (2)
Neuropathy
2 (.6)
1 (.6)
4 (4)
Tendonitis
4 (1)
2 (1)
–
If respondents listed more than one side effect, they were counted for each side effect listed. Statistical analyses were
therefore not performed for data presented in Table 4.
The following side effects were also reported but experienced by fewer that 1% of respondents: racing heart/
arrhythmia/palpitations, dry eyes, slower healing of soft tissue injury, dry mouth, reduced range of motion, chemical
taste in mouth, nosebleeds/blisters/cold sores, vaginal discharge, loss of coordination, leg cramps, blood in urine, nails
brittle/thin/fungus, poorer vision, emotionally labile, diabetes, bruise easily, night sweats, tremors, irritable bowel
syndrome, Graves’ disease, floater in eye, lymphedema, Raynaud’s disease, chest pain, bladder inflammation, restless
leg syndrome, increased facial hair, emotionless, loss of taste/smell, elevated liver function, and poorer balance.
Breast Cancer Action
11
AI Usage
No significant differences were found in the average length of time respondents had been taking an aromatase
inhibitor. On average the women had been taking an AI for approximately 23 months (anastrozole 22.88 months,
exemestane 20.64 months, letrozole 23.60 months). There was also no significant difference between age groups in how
long they had been taking an aromatase inhibitor.
Of the 612 respondents, 30% discontinued the use of an AI. Between the three AIs, there was no significant difference
in the number of respondents who discontinued use, X2 = 12.80, d.f. = 8, .25>p>.10, n.s. (27%, 36%, and 31%
discontinued using anastrozole, exemestane, and letrozole, respectively).
Respondents who discontinued use of an AI were asked why they chose to do so. Table 5 lists the reasons women reported
for stopping the use of the AI. Only the reasons given by more than 1% of respondents are included in the table.
TABLE 5. Reasons Stated for Discontinuing Use of AI (More Than 1% of Respondents)
AROMATASE INHIBITOR
Reasons
Anastrozole
nonsteroidal
(n = 336)
Letrozole
nonsteroidal
(n = 173)
Exemestane
steroidal
(n = 103)
Number (%)
Joint pain/inflammation/stiffness
41 (12.7)
18 (10.4)
13 (12.6)
Pain/bone pain/muscle pain
18 (5.4)
21 (12.1)
7 (6.8)
Disabling/debilitating/intolerable side effects
20 (6.0)
7 (4.1)
5 (4.7)
Fatigue/exhaustion
6 (1.8)
10 (5.8)
4 (3.8)
Vaginal bleeding/not truly menopausal
7 (2.1)
2 (1.2)
1 (1.0)
Swelling/bloated
6 (1.8)
3 (1.7)
1 (1.0)
Depression/mood changes
4 (1.2)
4 (2.3)
–
Disease progression
5 (1.5)
1 (0.6)
1 (1.0)
Headaches
3 (0.8)
1 (0.6)
2 (1.9)
Gastrointestinal problems/nausea
3 (0.8)
3 (1.7)
–
Hair loss
3 (0.8)
1 (0.6)
2 (1.9)
Memory/concentration loss
1 (0.3)
3 (1.7)
2 (1.9)
The following other reasons given for discontinuing use were reported by fewer than 1% of respondents: severe bone
density loss, vaginal dryness/pain/withering, weight gain, no further benefit, extremely high cholesterol, insomnia,
dizziness, nervousness/anxiety, atrial fibrillation, completed five years or prescribed period, surgery, chemotherapy, hot
flashes, rash/hives, hormone-receptor-negative, high blood calcium exacerbated, bone fractures, rising liver function,
radiation, dry skin, shortness of breath, neuropathy, nose blisters, heart attack, trigger thumbs, flu-like symptoms, and
high blood pressure.
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
12
Table 6 shows the number of years doctors recommended their patients remain on the aromatase inhibitors. This data
analysis does not distinguish between women taking AIs for advanced breast cancer and women taking them in the
adjuvant setting for early breast cancer. The number of years doctors recommended respondents stay on letrozole was
significantly longer than the time recommended for anastrozole (p = .002) or exemestane (p = .000).
TABLE 6. Number of Years Doctors Recommended
That Respondents Should Take the AI
AROMATASE INHIBITOR
Anastrozole
nonsteroidal
(n = 245)
Letrozole
nonsteroidal
(n = 86)
Exemestane
steroidal
(n = 65)
Mean
20–39 (n = 8)
4.2
15.0
5.0
5.7
40–49 (n = 71)
5.0
5.6
4.4
5.0
50–59 (n = 217)
5.2
5.5
4.3
5.2
60–69 (n = 90)
5.4
5.9
4.3
5.3
70+ (n = 10)
5.0
5.0
2.7
4.3
Mean
5.2
5.7
4.3
5.2
Age Group
Total n = 396 Grand mean = 5.2
A significant interaction effect between the number of years recommended by a doctor, respondent age, and aromatase
inhibitor was found. For our respondents, the number of years that doctors suggested they stay on exemestane
decreases with increasing age, but this is not true for the other two aromatase inhibitors. For anastrozole and letrozole,
the recommended time either increases or is similar across the age groups. However, interaction effects for this data
should be treated with caution because of the small sample size for the 20- to 39-year-old and 70-plus-year-old age
groups.
A significantly smaller percentage of respondents (37%) reported receiving information about long-term side effects
than the percentage of respondents (63%) who reported receiving information about short-term side effects (Χ2 =
39.82, d.f. = 8; p < .001).
Breast Cancer Action
CONCLUSIONS
he initial results of this survey show that the vast majority (96%) of the respondents reported at least one
side effect, and that many patients reported not receiving information from their doctors about the shortterm and long-term side effects of these drugs. The sample of respondents is self-selected and may not
be representative of the population of women taking AIs. Therefore, the results cannot be generalized to the larger
population.
T
Because aromatase inhibitors are relatively new in the breast cancer treatment setting, little information is available
to doctors and patients about their long-term side effects. Clinical trials of AIs, while providing short-term side effect
information, rarely report on the long-term side effects. It is important that patients have information about both
short-term and long-term side effects in order to make fully informed decisions about their treatment.
BCA is gravely concerned about the widespread occurrence of some side effects among respondents. The side effects
reported by over 50% of respondents were: hot flashes (65%), bone pain (64%), feeling tired (59%), muscle pain (58%),
and insomnia (51%). The average severity ratings for the side effects appear low, but it is important to note that the
averages include women who did not experience that side effect at all (ranked as 0).
Only three side effects were found to have significant differences between age groups: hot flashes, bone pain, and
thromboembolism. However, some age groups had small sample sizes, making significant differences between age
groups less likely. The youngest age group rated severity of hot flashes higher than any other age group, but this group’s
sample size is small. In other cases statistically significant differences may be found between age groups but may not
necessarily hold clinical significance for patients. The oldest age group rated severity of thromboembolism significantly
higher than any other age group, but all age groups rated the severity of this side effect very low.
Many women reported side effects not included on our list, including joint-related side effects, vaginal atrophy and
dryness, a rise in cholesterol levels, and general pain. Additionally, several respondents reported neurological, bonerelated, and muscular side effects, as well as feeling very aged.
Although the 612 women who participated in this survey may not be representative of the general population of
women taking AIs, many women clearly are suffering from adverse effects. Some are so disabling that they have
decided to discontinue using an AI. Approximately 30% of women reported discontinuing use of an AI; 84% of them
discontinued use due to intolerable side effects—joint-related side effects were the primary reason respondents (47%)
chose to stop taking the AI.
The results also demonstrate that AIs are being prescribed for some women who are not postmenopausal or who have
had menopause artificially induced. Aromatase inhibitors are only indicated for use in postmenopausal women with
breast cancer. Survey responses indicate that there are two different scenarios in which some premenopausal women
were prescribed AIs, although the FDA has not approved any of the AIs for use in this setting.
In one scenario, doctors may assume their patients are postmenopausal because they are no longer menstruating, yet
the patients may still have premenopausal levels of estrogen and some residual ovarian function. Ten respondents
(1.6%) reported discontinuing use of an AI because they were not truly menopausal and began menstruating and/or
they experienced vaginal bleeding.
13
Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors
14
In the second scenario, some doctors knowingly prescribed AIs for women who were not naturally postmenopausal.
Although 96% of respondents were postmenopausal at the time their AI was prescribed, menopause was artificially
induced in over 50% of these women.
Three Phase III trials (SOFT IBCSG-24-02; TEXT IBCSG-25-02; PERCHE IBCSG-26-02) are currently looking
at the use of exemestane in premenopausal women whose ovarian function has been suppressed either surgically,
pharmaceutically, or through radiation of the ovaries. These trials were started in 2003, and results will not be available
for several years. Until these trials are completed, no data exist to suggest AIs are appropriate for use in premenopausal
women.
The results of the BCA Aromatase Inhibitor Side Effects Survey clearly indicate that patients deciding whether or not to
take these drugs need to be fully informed about the side effects and whether the use of AIs is actually appropriate for
them. It is imperative that additional research be conducted on the side effects of these drugs.
Recommendations
1. Conduct additional research on short-term and long-term side effects of AIs.
2. Provide the results of this research to doctors and patients.
3. Use caution when prescribing AIs to perimenopausal women, as well as to premenopausal women who have been
rendered menopausal by chemotherapy or ovarian function suppression.
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