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

info@bcaction.org

Th is report is dedicated to the hundreds of women who generously took the time to respond to Breast Cancer Action’s Aromatase Inhibitor Side Eff ects 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

Breast Cancer Action wishes to thank the many women who participated in the survey and the organizations and individuals who assisted in its distribution. Th is publication and quotes from survey respondents are available online at www.bcaction.org.

©2007 Breast Cancer Action

BCA ReviewersBarbara BrennerExecutive Director

Rebecca FarmerCommunications Offi cer

Katrina KahlCommunications Associate

Lisa WanzorAssociate Director

Survey Design AssistanceDiane Tompkins, Th e Curious Company

Graphic DesignYvonne Day, Y. Day Designs

PrintingInkworks Press

Breast Cancer Action 1

Executive Summary

Aromatase inhibitors (AIs) are hormonal therapies approved for use in postmenopausal women with breast cancer. Th ree 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 eff ects. Breast Cancer Action (BCA) is conducting a survey on the side eff ects women are experiencing while taking these drugs. Th e goal of this survey is to provide information about side eff ects to patients, doctors, the FDA, the National Cancer Institute, and other cancer organizations.

About the Survey

Th e AI Side Eff ects 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 eff ects and recommended duration of use, menopausal status at the time of prescription, and other treatments received for breast cancer.

Th e questions are followed by a list of 38 side eff ects that was generated from FDA product information documents for the three AIs. Respondents rated the side eff ects for severity (none, mild, moderate, or severe). Finally, respondents were asked to report any additional side eff ects.

Th e sample of respondents is self-selected and may not be representative of the population of women taking AIs. Th erefore, the results cannot be generalized to the larger population.

Summary of Findings

Th e fi rst 612 completed surveys received were analyzed for this report. Major fi ndings include:

Most respondents (96%) reported one or more side eff ects.

Th e side eff ects reported by over 50% of respondents were: hot fl ashes (65%), bone pain (64%), feeling tired (59%), muscle pain (58%), and insomnia (51%).

Many women reported side eff ects in addition to those on our list, including joint-related side eff ects, vaginal atrophy and dryness, a rise in cholesterol levels, and general pain.

Over 50% of respondents stated that their menopause was not naturally occurring. For these women, menopause was either pharmaceutically or surgically induced.

Ten women (1.6%) reported that they discontinued using an AI because of subsequent menstruation or vaginal bleeding.

About 30% of the respondents discontinued the use of an AI—84% because of side eff ects they were experiencing, and close to half of them (47%) specifi cally because of joint-related side eff ects.

Over one-third (37%) of respondents reported receiving no information from their doctors about short-term side eff ects; nearly two-thirds (63%) reported receiving no information from their doctors about long-term side eff ects.

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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 eff ects. Many patients reported not receiving information from their doctors about the side eff ects of AIs. However, these are relatively new drugs and clinical trials rarely report on long-term side eff ects. Th us little information is available to doctors and patients about the long-term side eff ects 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

Th e survey results clearly suggest that patients need better information about the side eff ects of AIs and whether the use of AIs is actually appropriate for them.

Recommendations

Conduct additional research on short-term and long-term side eff ects of AIs.

Provide the results of this research to doctors and patients.

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 Th ree 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. Th ese 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 artifi cially induced.

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Breast Cancer Action 3

INTRODUCTION

Until 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 eff ects. Aft er being contacted by women reporting side eff ects 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 eff ects. Eventually breast cancer patients’ informal reports to doctors and others prompted side eff ects research that confi rmed their anecdotal experiences.

Now, more than ten years later, AIs are quickly replacing tamoxifen as the drug of choice for treating hormone-responsive breast cancer in postmenopausal women. As with tamoxifen a decade ago, little is known about the long-term side eff ects of these drugs. Th is time, BCA decided to systematically collect data on the side eff ects 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 eff ects.

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. Th ey are ineff ective in premenopausal women whose ovaries are still producing estrogen (which is not aff ected 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.

Th ree 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. Th ey 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.

Th ese drugs were fi rst 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. Th e 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 fi rst-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 Th e 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.

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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 fi ve 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 fi ve years of adjuvant tamoxifen therapy.

Femara is indicated for fi rst-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

Breast Cancer Action’s AI Side Eff ects Survey was developed from April to July 2005. Th e Tamoxifen Side Eff ects Survey conducted by Breast Cancer Action Nova Scotia1 in 1999 served as an initial model for the survey in the present study. Th e AI Side Eff ects Survey included demographic questions about the

respondents’ age and place of residence. Th ese were followed by questions concerning the drugs themselves: specifi c 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 eff ects and expected duration of use.

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). Th e survey included a list of 38 side eff ects that respondents rated according to severity (none, mild, moderate, or severe). Th e list was generated from the adverse eff ects noted in FDA product information documents for the three AIs. Th is 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 eff ects. Respondents’ confi dentiality was maintained by separating e-mail addresses from survey data when received.

Th e AI Side Eff ects Survey was posted on the BCA web site (www.bcaction.org/AISurvey) on August 17, 2005. Th e 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 Eff ects Survey through newsletters, e-mails, and web links. Several clinics requested and received print copies of the AI Side Eff ects Survey for their clients.

Th e 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 affi liated with Breast Cancer Action.

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Breast Cancer Action 5

received. BCA has continued to receive additional survey responses, and those received aft er 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.

Th e 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 eff ects. In addition, because the survey was conducted online, it may underrepresent women with limited computer literacy and accessibility. Th e 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, fi ve European countries, Australia, and the Middle East. Two respondents did not provide a location.

Th e 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 two-tailed).

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 signifi cant.

Letrozole

28%Anastrozole

55%Exemestane

17%

TABLE 1. Number of Respondents By Age and Aromatase Inhibitor Prescribed

AROMATASE INHIBITOR

Age GroupAnastrozolenonsteroidal

Letrozolenonsteroidal

Exemestanesteroidal

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+b 9 3 5 17

Total 336 173 103 612

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

Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors 6

Th e 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%). Th e remaining women reported their menopause was artifi cially 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

Th e vast majority of respondents (96%) reported experiencing one or more of the 38 side eff ects. Table 2 lists the number of respondents who reported one or more side eff ects, broken out by age and by AI. Th ere was no signifi cant diff erence by age group or by aromatase inhibitor in the number of women who experienced one or more side eff ects, 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

Anastrozolenonsteroidal

Letrozolenonsteroidal

Exemestanesteroidal

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 eff ects. 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 eff ects across the three AIs.

Respondents were asked to rate each of the 38 side eff ects 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 eff ects for each age group.

A three-way multivariate analysis [MANOVA, Repeated Measures: Age (5) x AI (3) x Side Eff ect (38)] showed that the women’s severity ratings were signifi cantly diff erent between the side eff ects (F = 33.702, d.f. = 37, p = .000).

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%

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%

27%

20.4%20.3%

32.5%38.0%

31.7%29.4%

FIGURE 2.Percent of Respondents Reporting Each Side Effect

Side Effects Revealed: Women’s Experiences With Aromatase Inhibitors 8

TABLE 3. Average Severity Ratings of Side Effects, Overall and by Age Group

Side Effect Overall 20-39 40-49 50-59 60-69 70+ Signifi cant

Difference by Age Group

Hot fl ashes 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 effl usion .02 .00 .02 .03 .02 .06

Vomiting .02 .00 .02 .03 .01 .00

Thromboembolism .00 .00a .00a .01a .00a .18b p = .000

Heart attack .01 .00 .00 .00 .02 .00

Stroke .00 .00 .00 .00 .01 .00

Breast Cancer Action 9

0.0

0.5

1.0

1.5

2.0

70+ 60–6950–5940–4920–39

SE

VE

RIT

Y R

ATIN

G

AGE

HOT FLASHES

BONE PAIN

THROMBOEMBOLISM

FIGURE 3. Severity by Age for Hot Flashes, Bone Pain, and Thromboembolism

Th ere was also a signifi cant interaction eff ect for Side Eff ect x Age (F = 1.592, d.f. = 148, p = .000), showing that, for some side eff ects, there were signifi cant diff erences in the severity ratings between age groups.

One-way ANOVAs were performed for each individual side eff ect to determine where signifi cant diff erences existed between the age groups. When conducting a large number of ANOVAs (38 in this case), it is possible that some signifi cant diff erences may emerge due to chance. Th us, a signifi cance level of p ≤ .01 was used. Th ree side eff ects were found to have signifi cant diff erences between age groups: hot fl ashes, bone pain, and thromboembolism. Th e p values for these three side eff ects are noted in the far right column in Table 3, with signifi cant diff erences between particular age groups noted by superscripts a and b. Th e presence of superscripts a and b denotes that there is a signifi cant diff erence between those particular age groups.

Th e severity ratings for hot fl ashes are higher for the younger age groups. However, the only signifi cant diff erence found was between the severity ratings of the 50- to 59-year-olds and 60- to 69-year-olds. Th ough 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 signifi cant diff erences less likely.

Th e severity ratings for bone pain are highest for the 50- to 59-year-old group. Th e diff erence between the severity ratings of the 50-to 59-year-olds and 60- to 69-year-olds was signifi cant.

Th e severity ratings for thromboembolism are signifi cantly higher for the 70-plus-year-old group than for any other group. However, as Figure 3 demonstrates, the severity rating for this side eff ect is very low in all age groups.

Table 4 displays side eff ects reported by respondents that were not specifi ed in the survey. Only those side eff ects that were reported by at least 1% of respondents are included in the table. Th e most commonly reported additional side eff ects were joint-related (e.g., joint pain, arthritis, stiff ness). Th e next most commonly reported side eff ects were vaginal atrophy/dryness, a rise in cholesterol levels, and general pain. Multiple respondents also reported neurological, bone-related, and muscular side eff ects, 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 Specifi ed in the Survey

AROMATASE INHIBITOR

Side EffectAnastrozolenonsteroidal(n = 336)

Letrozolenonsteroidal(n = 173)

Exemestanesteroidal

(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/fi ngers/legs 6 (2) 4 (2) 3 (3)

Osteopenia 5 (1) 7 (4) –

Trigger thumbs/fi ngers/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/fi ngers/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 eff ect, they were counted for each side eff ect listed. Statistical analyses were therefore not performed for data presented in Table 4.

Th e following side eff ects 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, fl oater in eye, lymphedema, Raynaud’s disease, chest pain, bladder infl ammation, restless leg syndrome, increased facial hair, emotionless, loss of taste/smell, elevated liver function, and poorer balance.

Breast Cancer Action 11

AI Usage

No signifi cant diff erences 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). Th ere was also no signifi cant diff erence 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 signifi cant diff erence 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

ReasonsAnastrozolenonsteroidal(n = 336)

Letrozolenonsteroidal(n = 173)

Exemestanesteroidal

(n = 103)

Number (%)

Joint pain/infl ammation/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)

Th e 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 benefi t, extremely high cholesterol, insomnia, dizziness, nervousness/anxiety, atrial fi brillation, completed fi ve years or prescribed period, surgery, chemotherapy, hot fl ashes, 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, fl u-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. Th is 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. Th e number of years doctors recommended respondents stay on letrozole was signifi cantly 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

Age GroupAnastrozolenonsteroidal(n = 245)

Letrozolenonsteroidal

(n = 86)

Exemestanesteroidal(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

Total n = 396 Grand mean = 5.2

A signifi cant interaction eff ect 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 eff ects 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 signifi cantly smaller percentage of respondents (37%) reported receiving information about long-term side eff ects than the percentage of respondents (63%) who reported receiving information about short-term side eff ects (Χ2 = 39.82, d.f. = 8; p < .001).

Breast Cancer Action 13

CONCLUSIONS

The initial results of this survey show that the vast majority (96%) of the respondents reported at least one side eff ect, and that many patients reported not receiving information from their doctors about the short-term and long-term side eff ects of these drugs. Th e sample of respondents is self-selected and may not

be representative of the population of women taking AIs. Th erefore, the results cannot be generalized to the larger population.

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 eff ects. Clinical trials of AIs, while providing short-term side eff ect information, rarely report on the long-term side eff ects. It is important that patients have information about both short-term and long-term side eff ects in order to make fully informed decisions about their treatment.

BCA is gravely concerned about the widespread occurrence of some side eff ects among respondents. Th e side eff ects reported by over 50% of respondents were: hot fl ashes (65%), bone pain (64%), feeling tired (59%), muscle pain (58%), and insomnia (51%). Th e average severity ratings for the side eff ects appear low, but it is important to note that the averages include women who did not experience that side eff ect at all (ranked as 0).

Only three side eff ects were found to have signifi cant diff erences between age groups: hot fl ashes, bone pain, and thromboembolism. However, some age groups had small sample sizes, making signifi cant diff erences between age groups less likely. Th e youngest age group rated severity of hot fl ashes higher than any other age group, but this group’s sample size is small. In other cases statistically signifi cant diff erences may be found between age groups but may not necessarily hold clinical signifi cance for patients. Th e oldest age group rated severity of thromboembolism signifi cantly higher than any other age group, but all age groups rated the severity of this side eff ect very low.

Many women reported side eff ects not included on our list, including joint-related side eff ects, vaginal atrophy and dryness, a rise in cholesterol levels, and general pain. Additionally, several respondents reported neurological, bone-related, and muscular side eff ects, 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 suff ering from adverse eff ects. 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 eff ects—joint-related side eff ects were the primary reason respondents (47%) chose to stop taking the AI.

Th e results also demonstrate that AIs are being prescribed for some women who are not postmenopausal or who have had menopause artifi cially induced. Aromatase inhibitors are only indicated for use in postmenopausal women with breast cancer. Survey responses indicate that there are two diff erent 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.

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 artifi cially induced in over 50% of these women.

Th ree 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. Th ese 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.

Th e results of the BCA Aromatase Inhibitor Side Eff ects Survey clearly indicate that patients deciding whether or not to take these drugs need to be fully informed about the side eff ects and whether the use of AIs is actually appropriate for them. It is imperative that additional research be conducted on the side eff ects of these drugs.

Recommendations

Conduct additional research on short-term and long-term side eff ects of AIs.

Provide the results of this research to doctors and patients.

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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