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Estrogen Replacement Therapy in Women with Breast Cancer: A Survey of Patient Attitudes
Estrogen Replacement Therapy in Women with Breast Cancer: A Survey of Patient Attitudes RENA VASSILOPOULOU-SELLlN, MD,
CYNTHIA ZOLINSKI,
ABSTRACT: Estrogen replacement therapy (ERT) is suggested for women with symptomatic estrogen deficiency, but patients with breast cancer are advised against ERT because of concerns that ERT may precipitate cancer recurrence. The attitudes of women with breast cancer regarding ERT is critical in the design of appropriate strategies for the management of their menopause. A randomly selected group of 224 women with breast cancer responded to an anonymous survey that addressed the presence of menopause, antecedent therapies, symptoms related to estrogen deficiency, concerns about osteoporosis or heart disease, attitude about ERT, and perception about ERT-related cancer risk. Among women who completed the survey, 77% were postmenopausal and 81% had had multimodality therapy. Of menopausal women, 27% believed they needed some treatment for menopause and 8% had taken ERT since cancer diagnosis. Most women were afraid that ERT may precipitate cancer recurrence (78%) but they also were concerned about the menopauserelated risk of osteoporosis (70%) and heart disease (72%). Overall, 44% of menopausal women were willing to consider ERT under medical supervision. Those treated with surgery alone were From the Section of Endocrinology, Department of Medical Specialties, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. We wish to thank all the women who took the time to share their attitudes about ERT by completing the survey. We are grateful to the nursing staffs of the outpatient Medical, Surgical, and Radiotherapy Breast clinics for encouraging their patients to participate in the survey. We are indebted to the following physicians who allowed us to present this survey to their patients: G. N. Hortobagyi, D. J. Booser, A. U. Buzdar, F. A. Holmes, V. M. Hug, R. L. Theriault, and R. S. Walters (Section of Breast Medical Oncology); M. D. McNeese and E. A. Strom (Division of Radiotherapy); F. C. Ames, M. 1. Ross, and E. S. Singletary (Division of Surgery). We also thank Mrs. Teo Spear for preparation of the manuscript. The findings of the survey were presented at the American Federation for Clinical Research, Southern Section meeting, January 1992. They appear in abstract form in Clinical Research 39:810A, 1991. Correspondence: Dr. Rena Vassilopoulou-Sellin, Section of Endocrinology, Box 15, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
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distinct in that 71% would consider ERT (p < 0.04). Premenopausal women were more concerned about osteoporosis (82% vs. 66% for postmenopausal), heart disease (92% vs. 73%), and the possibility that ERT may precipitate cancer recurrence (98% vs. 73%). Yet, at the same time, they were more willing to consider ERT under medical supervision (59% vs. 40% for menopausal). The present study underscores that women with breast cancer are very aware and concerned about the adverse health consequences of estrogen deficiency and would consider ERT under medical supervision. Treatment background, menopausal status, and symptomology affect patient attitudes toward ERT. It will be important to evaluate the role of ERT in the management of menopause in carefully selected women under rigorous medical supervision. KEY INDEXING TERMS: Breast cancer; Menopause; Estrogen replacement; Osteoporosis; Heart disease; Patient attitudes. [Am J Med Sci 1992; 304(3):145-149.]
W
ith the onset of estrogen deficiency, women may develop severe vasomotor instability, with debilitating hot flashes, genitourinary and sexual dysfunction, and even depression. These quality-of-life issues are compounded by serious increased morbidity and mortality from cardiovascular disease and osteoporosis among postmenopausal women. Estrogen replacement therapy (ERT) alleviates these adverse health consequences of menopause and is recommended to women with symptomatic 'estrogen deficiency in the general population. 1- 3 Women who have had breast cancer also develop estrogen deficiency, as a result of natural menopause or, prematurely, as a consequence of antineoplastic therapy. Although menopause in this group carries health risks similar to those in the general population, women with breast cancer are generally advised against receiving ERT because of concerns that it may adversely affect the course of their disease.
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Estrogen Replacement, Breast Cancer
The possibility that ERT may precipitate breast cancer has long been a subject of intense investigation. For the general population, most studies have concluded that such risk is nonexistent or minimal. 4-9 However, despite the realization that ERT may have a place in the health maintenance of women with breast cancer,lO,11 studies have not included this group. Furthermore, very little is known about the attitudes of women in the general population toward ERT.12,13 No data cover the views of women with breast cancer about this vexing issue. Clearly, understanding how estrogen-deficient women perceive the issue ofERT is critical to the design of therapeutic strategies by the medical community. In the present study, we asked women with breast cancer attending outpatient clinics at The University of Texas M. D. Anderson Cancer Center to describe their concerns about estrogen deficiency and their attitudes about ERT through an anonymous survey. Methods
Over a 5 week period, 224 one page questionnaires, each accompanied by an explanatory cover letter, were given to a randomly selected population of female adult patients up to 65 years old with a history of breast cancer. The survey, available in Spanish and English, was distributed to registered patients who were seen for a follow-up or treatment visit at the outpatient Medical Oncology, Surgery, or Radiotherapy Breast clinics. The study was approved by the institutional committee for the protection of human subjects. Patients were informed that the survey was completely anonymous, and they were given the option to address related issues in person or through correspondence. Incomplete surveys (fewer than two-thirds of the questions answered or menopausal status not indicated) were excluded from analysis. Thus, the data from 206 surveys are presented. Because not all patients answered all questions, the number of responders is less than 206 in some cases. The survey consisted of nine questions (five multiple choice and four yes/no) that addressed the presence of menopause, types of antecedent cancer therapies, sense of well-being in general, symptoms related to estrogen deficiency, concerns about osteoporosis and heart disease, patient assessment of the need for and attitude toward ERT, and patient perception of ERT-related cancer risk. The data were analyzed to identify factors that influence patient attitudes about ERT. Statistical analyses were done with chi-squared and Fisher exact tests (EpiStat software; Epistat Services, Richardson, Texas).
23% still had regular menses (Table 1). Although 36 of 194 responders had received only one type of cancer treatment, 81% had received multimodality therapy, consistent with current views on the management of breast cancer. Almost half of menopausal women (44%) did not identify any symptoms specifically related to menopause. Although only 27% thought they needed some treatment for menopause at the time, a small number of women (12/157) had already taken ERT since being diagnosed with breast cancer. The fear that taking estrogen might precipitate a recurrence of breast cancer was very prominent (78%), although 44% of responders were willing to consider ERT under medical supervision. The interest in ERT was not determined by the severity of menopausal symptoms: 59% of premenopausal women also expressed interest in the eventual availability of ERT. The willingness to consider ERT despite concerns about cancer risk reflects the coexisting concerns most women have about menopause-related osteoporosis (70%) and heart disease (72%). Impact of Prior Therapy on Patient Attitudes Toward ERT. The extent and character of antineoplastic therapy
may affect patient perception about the severity of the medical condition and the relative risks of morbidity from estrogen deficiency versus cancer. Therefore, we analyzed patient attitudes about ERT according to the type of treatment or treatments for breast cancer (Table 2). In this analysis, we considered the response of the 159 most immediately interested (menopausal) women. Of these, eight did not specify their prior cancer Table 1. Summary of Patient Survey and Responses 1. Have your periods stopped? Yes 159/206* (77%)t No 47/206 (23%) 2. Describe medical condition and treatment Cancer 193/204 (95%) Surgery only 15/194 (8%) Benign 11/204 (5%) Medicalonly 21/194 (11%) Combinations 158/194 (81%) 3. Worried about osteoporosis Very 44/199 (22%) Some 95/199 (48%) Not 60/199 (30%) 4. Worried about heart disease Very 57/204 (28%) Some 100/204 (49%) Not 47/204 (23%) 5. Since menopause, felt "just not yourself' All the time 12/148 (8%) Some of the time 71/148 (48%) None of time 65/148 (44%) 6. Need treatment for menopause now Yes 41/153 (27%) No 112/153 (73%) 7. Worried that estrogen may precipitate cancer recurrence Very 79/192 (41%) Some 71/192 (37%) Not 42/192 (22%) 8. Ever took estrogen since diagnosis Yes 12/157 (8%) No 145/157 (92%) 9. Consider ERT under supervision Yes 77/174 (44%) No 97/174 (56%)
Results Patient Profile and Responses. Among women who
* Number responses/number patients who answered that question. t Percent of total.
completed the survey, 95% identified their medical condition as cancer; 77% were postmenopausal, while
Summary of survey as it was presented to patients and answers to survey questions.
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Table 2. Impact of Prior Therapy on Patient Attitudes aboutERT
Therapy Surgery Medical Radiation Surgery and medical Surgery and radiotherapy Medical and radiation Surgery, medical, and radiation
Would Consider ERT
No Interest
10/14* (71%)t 5/14 (36%) none 17/46 (37%):j: 2/4 1/2
4/14 (29%) 9/14 (64%) none 29/46 (63%):j: 2/4 1/2
16/47 (34%):j:
31/47 (66%):j:
* Number responders/number answering that question. t Percent of patients. :j: p < 0.05 vs. surgery alone. Medical = chemotherapy or tamoxifen.
treatment and 24 did not answer the question on ERT (the analysis thus reflects the views of 127 responders). Patients were not asked to identify the estrogenreceptor status of their tumors. However, we reasoned that women treated with tamoxifen might tend to represent those with receptor-positive disease and thus might have a heightened fear of ERT. However, a subgroup analysis using the Fisher exact test showed no significant differences between menopausal patients receiving chemotherapy and those receiving tamoxifen (p > 0.05). Therefore, we consolidated the two groups into a "medical therapy" group. Overall, 40% of menopausal women were willing to consider ERT under medical supervision. The patients whose cancer was treated with surgery alone are distinct and represent the one group in which most women would consider ERT (71%). In contrast, only 37% of the women who received both surgery and medical therapy were interested in ERT. There were no significant differences in attitudes among women who received any of the other combinations of treatments (p > 0.5); approximately a third of those were willing to take ERT. A significant difference in attitude was evident for the surgery-only patients versus those receiving all other treatments (p < 0.04). This difference may reflect the impact of relatively limited disease on patient outlook or the impact of the attitudes of the medical oncology community. Of the menopausal women, 12 of 157 (8%) stated they had taken ERT since the diagnosis of breast cancer. Despite the attitude patterns of the group as a whole, prior therapy did not predict ERT use among these patients. Prior therapy had included chemotherapy, surgery, chemotherapy/surgery, chemotherapy/ radiotherapy, chemotherapy/surgery/radiotherapy, chemotherapy/surgery/tamoxifen and radiotherapy,
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
and surgery/tamoxifen/radiotherapy. Two patients had received chemotherapy/surgery/tamoxifen. Impact of Menopause on Patient Concerns About Health Issues Related to Estrogen Deficiency. Subgroup
analyses were performed for premenopausal and menopausal patients to assess whether menopause specifically affects patient attitudes (Table 3). Most premenopausal women (82%) were at least somewhat concerned about osteoporosis compared to 66% of menopausal women. Almost all premenopausal women (92%) were at least somewhat concerned about the increased risk of heart disease compared to 73 % of menopausal women. The differences in patient concerns between the two groups were significant for osteoporosis (p < 0.02) and heart disease (p < 0.001). In addition, the fear that ERT could precipitate breast cancer was more prominent among premenopausal women (98%) 'than menopausal women (73%), although all patients clearly were very concerned about this issue. Thus, younger women appear to have more concerns about the long-term health impact of estrogen deficiency. Subgroup analysis indicated that 56% (83/148) of the women "have not felt like themselves" since menopause, at least some of the time. Although only 27% (41/153) thought they needed treatment for menopause at this time, 63% (26/41) of these women would consider beginning ERT under medical supervision at some time in the future. Discussion
The present study underscores that women with breast cancer are very aware and concerned about the adverse health consequences of estrogen deficiency. Although afraid that ERT may precipitate cancer recurrence, they are interested in exploring the use of ERT under medical supervision. Despite the prevailing opinion that ERT should be avoided in this setting, a
Table 3. Impact of Menopause on Patient Concerns
Concern Osteoporosis Cardiovascular Fear of recurrence Consider ERT
Degree of concern Very Some Not Very Some Not Very Some Not
Menopausal 34/154* 68/154 52/154 42/157 72/157 43/157 64/149 44/149 41/149 54/135
(22%)t (44%) (34%) (27%) (46%) (27%):j: (43%) (30%) (27%):j: (40%)
Premenopausal 10/45 (22%) 27/45 (60%) 8/45 (18%) 15/47 (32%) 28/47 (60%) 4/47 (9%):j: 15/43 (35%) 27/43 (63%) 2/43 (2%):j: 23/39 (59%)
* Number responders/number answering question. t Percent of patients. :j: p < 0.05 for menopausal vs. premenopausal.
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small number of cancer patients opt for ERT outside the setting of oncologic supervision, presumably because of debilitating menopausal symptoms. The survey results suggest that treatment background, menopausal status, and symptomatology affect patient attitudes toward ERT. The observation that women treated with surgery alone are significantly more willing than those receiving multimodality therapy to consider ERT can be interpreted two ways. First, it is possible that an increasing number of medical treatments preselect patients with more advanced or aggressive cancer. Such women may be more concerned with immediate health priorities, less willing to take perceived risks that may affect their disease, and thus less willing to consider ERT. Alternatively, women who have been treated only with surgery may not be under the supervision of a medical oncologist and, therefore, may be less influenced by the prevailing opinion that ERT is hazardous and should be avoided. The present anonymous survey does not allow us to distinguish between these two possibilities because we did not interview the participants. The finding that 8% of menopausal women take ERT outside the cancer center setting underscores the sensitivity of this issue and the importance of confidentiality in surveys of patient attitudes on this topic. Results of this study confirm that health concerns about the postmenopausal risks of osteoporosis and heart disease are widely shared by women with breast cancer, especially premenopausal women. Older women might have been expected to be most concerned because they represent the group that has immediate symptoms and estrogen deficiency-related morbidity. Instead, we found that premenopausal cancer patients were more worried than older patients about the eventual risk of osteoporosis and heart disease. Furthermore, they also were more concerned about the ERT-related risk of cancer recurrence and were more willing to consider ERT at some future time. This apparent contradiction may reflect that these younger women have a longer term outlook of risk versus benefit issues, or it may reflect that they wish to be more active participants in health care decisions. Osteoporosis and heart disease are major health problems in postmenopausal women. The risk of cardiovascular mortality increases I8-fold after menopause and is directly related to estrogen deficiency.14 Cardiovascular disease remains the leading cause of death among women in the United States, with approximately 350,000 deaths per year, compared to approximately 40,000 deaths per year from breast cancer. 15 Estrogen supplementation improves patients' lipid profiles and reduces the risk of coronary vascular disease. 16,17 Estrogen deficiency-related osteoporosis, the most common metabolic bone disease of women,18,19 is associated with an overall mortality in excess of 148
50,000 deaths per year. 20,21 ERT can reduce or prevent the loss of bone and the development of osteoporosis,2,22 thus reducing osteoporosis-associated morbidity and mortality. Although ERT is used to alleviate menopausal complications in the general population, the fear of reactivating the cancer has precluded the use of ERT in women with breast cancer. The association between estrogen administration and the development of mammary tumors was made primarily based on in vitro and animal studies. 23-25 The link between estrogen and the initiation of breast cancer in humans is inferred from epidemiologic studies that show protective effects of early first pregnancy, early menopause, late menarche, and early oophorectomy.26 Abnormal metabolism, rather than the availability of estradiol, has been implicated by some investigators.27 No reported studies show that ERT adversely affects the natural history of breast cancer. However, estrogen deficiency is accompanied by significant longterm morbidity and mortality, and women with breast cancer are very concerned about it. We believe that it will be important to evaluate the role of ERT in the management of menopause in carefully selected women with breast cancer, under rigorous medical supervision. References 1. Estrogen replacement in the menopause. Council on Scientific Affairs. JAMA 249:359-361, 1983. 2. Consensus Conference: Osteoporosis. JAMA 252:799-802, 1984. 3. Lufkin EG, Carpenter PC, Ory SJ, Malkasian GD, Edmonson JH: A. Estrogen replacement therapy: Current recommendations. Mayo Clin Proc 63:453-460,1988. 4. Steinberg KK, Thacker SB, Smith J, et al: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265:1985-1990, 1991. 5. Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 315:405-410, 1986. 6. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C: The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 321:293-297, 1989. 7. Stadel BV, Schlesselman JJ, Murray PA: Oral contraceptives and breast cancer (letter). Lancet 1257-1258, 1989. 8. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE: Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 264: 2648-2653, 1990. 9. Dupont WD, Page DL: Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 151:67-72, 1991. 10. Stoll BA, Parbhoo S: Treatment of menopausal symptoms in breast cancer patients (letter). Lancet 1:1278-1279, 1988. 11. Wile AG, DiSaia P: Hormones and breast cancer. Am J Surg 157:438-442, 1989. 12. Kadri AZ: Hormone replacement therapy-a survey of premenopausal women in a community setting. Br J Gen Pract 41: 109-112, 1991. 13. Schmitt N, Gogate J, Rothert M, et a1. Capturing and clustering women's judgment policies: The case of hormonal therapy for menopause. Journal of Gerontology: Psychological Sciences 46: 92-101, 1991.
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14. Gordon T, Kannel WB, Hjortland MC, McNamara PM: Menopause and coronary heart disease. Ann Intern Med 85:157-161, 1978. 15. Bush TL, Barrett-Connor E: Estrogen use in cardiovascular disease. Epidemiol Rev 7:80-89, 1985. 16. Stampfer MJ: Postmenopausal estrogen use in heart disease. N Engl J Med 316:164-165, 1987. 17. Richelson LS, Wahner HW, Melton LJ III, Riggs BL: Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 316:1273-1275, 1984. 18. Lindsay R, MacLean A, Kruszewski A, Hart DM, Clark AC, Garwood J: Bone response to termination of estrogen treatment. Lancet 1325-1327, 1978. 19. Riggs BL, Melton LJ III: Osteoporosis, the state-of-the-art 1987. A review. Semin Nucl Med 17:283-292, 1987. 20. A Special Conference: Osteoporosis-National Conference on Women's Health Series. Bethesda, MD, October 30,1987. 21. Barrett-Connor E: Postmenopausal estrogen, cancer and other considerations. Womens Health 11:179-195, 1986.
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22. Ettinger B, Genant HK, Cann CE: Postmenopausal bone loss is prevented by treatment with low dosage estrogen with calcium. Ann Intern Med 106:40-45, 1987. 23. Welsh CW: Host factors effecting the growth in carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Breton Huggins. Cancer Res 45:3415-3443, 1985. 24. Aitken SC, Lippman ME: Effect of estrogen and anti-estrogens on growth-regulatory enzymes in human breast cancer cells in tissue culture. Cancer Res 45:1611-1620, 1985. 25. Lippman ME, Dickson RB, Bates S, et al: Autocrine and paracrine growth regulation of human breast cancer. Breast Cancer Res Treat 7:59-70,1986. 26. Fishmon J: Endocrine participation in the etiology of breast cancer, in Harris J, Hellman S, Henderson IC, Kinne D, (eds): Breast Diseases. New York, J. B. Lippincott Co., 1987, pp 104-106. 27. Longcope C: Relationship of estrogen to breast cancer, of diet to breast cancer, and of diet to estradiol metabolism. J Natl Cancer Inst 82:896-897,1990.
149
CYNTHIA ZOLINSKI,
ABSTRACT: Estrogen replacement therapy (ERT) is suggested for women with symptomatic estrogen deficiency, but patients with breast cancer are advised against ERT because of concerns that ERT may precipitate cancer recurrence. The attitudes of women with breast cancer regarding ERT is critical in the design of appropriate strategies for the management of their menopause. A randomly selected group of 224 women with breast cancer responded to an anonymous survey that addressed the presence of menopause, antecedent therapies, symptoms related to estrogen deficiency, concerns about osteoporosis or heart disease, attitude about ERT, and perception about ERT-related cancer risk. Among women who completed the survey, 77% were postmenopausal and 81% had had multimodality therapy. Of menopausal women, 27% believed they needed some treatment for menopause and 8% had taken ERT since cancer diagnosis. Most women were afraid that ERT may precipitate cancer recurrence (78%) but they also were concerned about the menopauserelated risk of osteoporosis (70%) and heart disease (72%). Overall, 44% of menopausal women were willing to consider ERT under medical supervision. Those treated with surgery alone were From the Section of Endocrinology, Department of Medical Specialties, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. We wish to thank all the women who took the time to share their attitudes about ERT by completing the survey. We are grateful to the nursing staffs of the outpatient Medical, Surgical, and Radiotherapy Breast clinics for encouraging their patients to participate in the survey. We are indebted to the following physicians who allowed us to present this survey to their patients: G. N. Hortobagyi, D. J. Booser, A. U. Buzdar, F. A. Holmes, V. M. Hug, R. L. Theriault, and R. S. Walters (Section of Breast Medical Oncology); M. D. McNeese and E. A. Strom (Division of Radiotherapy); F. C. Ames, M. 1. Ross, and E. S. Singletary (Division of Surgery). We also thank Mrs. Teo Spear for preparation of the manuscript. The findings of the survey were presented at the American Federation for Clinical Research, Southern Section meeting, January 1992. They appear in abstract form in Clinical Research 39:810A, 1991. Correspondence: Dr. Rena Vassilopoulou-Sellin, Section of Endocrinology, Box 15, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
BS
distinct in that 71% would consider ERT (p < 0.04). Premenopausal women were more concerned about osteoporosis (82% vs. 66% for postmenopausal), heart disease (92% vs. 73%), and the possibility that ERT may precipitate cancer recurrence (98% vs. 73%). Yet, at the same time, they were more willing to consider ERT under medical supervision (59% vs. 40% for menopausal). The present study underscores that women with breast cancer are very aware and concerned about the adverse health consequences of estrogen deficiency and would consider ERT under medical supervision. Treatment background, menopausal status, and symptomology affect patient attitudes toward ERT. It will be important to evaluate the role of ERT in the management of menopause in carefully selected women under rigorous medical supervision. KEY INDEXING TERMS: Breast cancer; Menopause; Estrogen replacement; Osteoporosis; Heart disease; Patient attitudes. [Am J Med Sci 1992; 304(3):145-149.]
W
ith the onset of estrogen deficiency, women may develop severe vasomotor instability, with debilitating hot flashes, genitourinary and sexual dysfunction, and even depression. These quality-of-life issues are compounded by serious increased morbidity and mortality from cardiovascular disease and osteoporosis among postmenopausal women. Estrogen replacement therapy (ERT) alleviates these adverse health consequences of menopause and is recommended to women with symptomatic 'estrogen deficiency in the general population. 1- 3 Women who have had breast cancer also develop estrogen deficiency, as a result of natural menopause or, prematurely, as a consequence of antineoplastic therapy. Although menopause in this group carries health risks similar to those in the general population, women with breast cancer are generally advised against receiving ERT because of concerns that it may adversely affect the course of their disease.
145
Estrogen Replacement, Breast Cancer
The possibility that ERT may precipitate breast cancer has long been a subject of intense investigation. For the general population, most studies have concluded that such risk is nonexistent or minimal. 4-9 However, despite the realization that ERT may have a place in the health maintenance of women with breast cancer,lO,11 studies have not included this group. Furthermore, very little is known about the attitudes of women in the general population toward ERT.12,13 No data cover the views of women with breast cancer about this vexing issue. Clearly, understanding how estrogen-deficient women perceive the issue ofERT is critical to the design of therapeutic strategies by the medical community. In the present study, we asked women with breast cancer attending outpatient clinics at The University of Texas M. D. Anderson Cancer Center to describe their concerns about estrogen deficiency and their attitudes about ERT through an anonymous survey. Methods
Over a 5 week period, 224 one page questionnaires, each accompanied by an explanatory cover letter, were given to a randomly selected population of female adult patients up to 65 years old with a history of breast cancer. The survey, available in Spanish and English, was distributed to registered patients who were seen for a follow-up or treatment visit at the outpatient Medical Oncology, Surgery, or Radiotherapy Breast clinics. The study was approved by the institutional committee for the protection of human subjects. Patients were informed that the survey was completely anonymous, and they were given the option to address related issues in person or through correspondence. Incomplete surveys (fewer than two-thirds of the questions answered or menopausal status not indicated) were excluded from analysis. Thus, the data from 206 surveys are presented. Because not all patients answered all questions, the number of responders is less than 206 in some cases. The survey consisted of nine questions (five multiple choice and four yes/no) that addressed the presence of menopause, types of antecedent cancer therapies, sense of well-being in general, symptoms related to estrogen deficiency, concerns about osteoporosis and heart disease, patient assessment of the need for and attitude toward ERT, and patient perception of ERT-related cancer risk. The data were analyzed to identify factors that influence patient attitudes about ERT. Statistical analyses were done with chi-squared and Fisher exact tests (EpiStat software; Epistat Services, Richardson, Texas).
23% still had regular menses (Table 1). Although 36 of 194 responders had received only one type of cancer treatment, 81% had received multimodality therapy, consistent with current views on the management of breast cancer. Almost half of menopausal women (44%) did not identify any symptoms specifically related to menopause. Although only 27% thought they needed some treatment for menopause at the time, a small number of women (12/157) had already taken ERT since being diagnosed with breast cancer. The fear that taking estrogen might precipitate a recurrence of breast cancer was very prominent (78%), although 44% of responders were willing to consider ERT under medical supervision. The interest in ERT was not determined by the severity of menopausal symptoms: 59% of premenopausal women also expressed interest in the eventual availability of ERT. The willingness to consider ERT despite concerns about cancer risk reflects the coexisting concerns most women have about menopause-related osteoporosis (70%) and heart disease (72%). Impact of Prior Therapy on Patient Attitudes Toward ERT. The extent and character of antineoplastic therapy
may affect patient perception about the severity of the medical condition and the relative risks of morbidity from estrogen deficiency versus cancer. Therefore, we analyzed patient attitudes about ERT according to the type of treatment or treatments for breast cancer (Table 2). In this analysis, we considered the response of the 159 most immediately interested (menopausal) women. Of these, eight did not specify their prior cancer Table 1. Summary of Patient Survey and Responses 1. Have your periods stopped? Yes 159/206* (77%)t No 47/206 (23%) 2. Describe medical condition and treatment Cancer 193/204 (95%) Surgery only 15/194 (8%) Benign 11/204 (5%) Medicalonly 21/194 (11%) Combinations 158/194 (81%) 3. Worried about osteoporosis Very 44/199 (22%) Some 95/199 (48%) Not 60/199 (30%) 4. Worried about heart disease Very 57/204 (28%) Some 100/204 (49%) Not 47/204 (23%) 5. Since menopause, felt "just not yourself' All the time 12/148 (8%) Some of the time 71/148 (48%) None of time 65/148 (44%) 6. Need treatment for menopause now Yes 41/153 (27%) No 112/153 (73%) 7. Worried that estrogen may precipitate cancer recurrence Very 79/192 (41%) Some 71/192 (37%) Not 42/192 (22%) 8. Ever took estrogen since diagnosis Yes 12/157 (8%) No 145/157 (92%) 9. Consider ERT under supervision Yes 77/174 (44%) No 97/174 (56%)
Results Patient Profile and Responses. Among women who
* Number responses/number patients who answered that question. t Percent of total.
completed the survey, 95% identified their medical condition as cancer; 77% were postmenopausal, while
Summary of survey as it was presented to patients and answers to survey questions.
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Table 2. Impact of Prior Therapy on Patient Attitudes aboutERT
Therapy Surgery Medical Radiation Surgery and medical Surgery and radiotherapy Medical and radiation Surgery, medical, and radiation
Would Consider ERT
No Interest
10/14* (71%)t 5/14 (36%) none 17/46 (37%):j: 2/4 1/2
4/14 (29%) 9/14 (64%) none 29/46 (63%):j: 2/4 1/2
16/47 (34%):j:
31/47 (66%):j:
* Number responders/number answering that question. t Percent of patients. :j: p < 0.05 vs. surgery alone. Medical = chemotherapy or tamoxifen.
treatment and 24 did not answer the question on ERT (the analysis thus reflects the views of 127 responders). Patients were not asked to identify the estrogenreceptor status of their tumors. However, we reasoned that women treated with tamoxifen might tend to represent those with receptor-positive disease and thus might have a heightened fear of ERT. However, a subgroup analysis using the Fisher exact test showed no significant differences between menopausal patients receiving chemotherapy and those receiving tamoxifen (p > 0.05). Therefore, we consolidated the two groups into a "medical therapy" group. Overall, 40% of menopausal women were willing to consider ERT under medical supervision. The patients whose cancer was treated with surgery alone are distinct and represent the one group in which most women would consider ERT (71%). In contrast, only 37% of the women who received both surgery and medical therapy were interested in ERT. There were no significant differences in attitudes among women who received any of the other combinations of treatments (p > 0.5); approximately a third of those were willing to take ERT. A significant difference in attitude was evident for the surgery-only patients versus those receiving all other treatments (p < 0.04). This difference may reflect the impact of relatively limited disease on patient outlook or the impact of the attitudes of the medical oncology community. Of the menopausal women, 12 of 157 (8%) stated they had taken ERT since the diagnosis of breast cancer. Despite the attitude patterns of the group as a whole, prior therapy did not predict ERT use among these patients. Prior therapy had included chemotherapy, surgery, chemotherapy/surgery, chemotherapy/ radiotherapy, chemotherapy/surgery/radiotherapy, chemotherapy/surgery/tamoxifen and radiotherapy,
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
and surgery/tamoxifen/radiotherapy. Two patients had received chemotherapy/surgery/tamoxifen. Impact of Menopause on Patient Concerns About Health Issues Related to Estrogen Deficiency. Subgroup
analyses were performed for premenopausal and menopausal patients to assess whether menopause specifically affects patient attitudes (Table 3). Most premenopausal women (82%) were at least somewhat concerned about osteoporosis compared to 66% of menopausal women. Almost all premenopausal women (92%) were at least somewhat concerned about the increased risk of heart disease compared to 73 % of menopausal women. The differences in patient concerns between the two groups were significant for osteoporosis (p < 0.02) and heart disease (p < 0.001). In addition, the fear that ERT could precipitate breast cancer was more prominent among premenopausal women (98%) 'than menopausal women (73%), although all patients clearly were very concerned about this issue. Thus, younger women appear to have more concerns about the long-term health impact of estrogen deficiency. Subgroup analysis indicated that 56% (83/148) of the women "have not felt like themselves" since menopause, at least some of the time. Although only 27% (41/153) thought they needed treatment for menopause at this time, 63% (26/41) of these women would consider beginning ERT under medical supervision at some time in the future. Discussion
The present study underscores that women with breast cancer are very aware and concerned about the adverse health consequences of estrogen deficiency. Although afraid that ERT may precipitate cancer recurrence, they are interested in exploring the use of ERT under medical supervision. Despite the prevailing opinion that ERT should be avoided in this setting, a
Table 3. Impact of Menopause on Patient Concerns
Concern Osteoporosis Cardiovascular Fear of recurrence Consider ERT
Degree of concern Very Some Not Very Some Not Very Some Not
Menopausal 34/154* 68/154 52/154 42/157 72/157 43/157 64/149 44/149 41/149 54/135
(22%)t (44%) (34%) (27%) (46%) (27%):j: (43%) (30%) (27%):j: (40%)
Premenopausal 10/45 (22%) 27/45 (60%) 8/45 (18%) 15/47 (32%) 28/47 (60%) 4/47 (9%):j: 15/43 (35%) 27/43 (63%) 2/43 (2%):j: 23/39 (59%)
* Number responders/number answering question. t Percent of patients. :j: p < 0.05 for menopausal vs. premenopausal.
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Estrogen Replacement, Breast Cancer
small number of cancer patients opt for ERT outside the setting of oncologic supervision, presumably because of debilitating menopausal symptoms. The survey results suggest that treatment background, menopausal status, and symptomatology affect patient attitudes toward ERT. The observation that women treated with surgery alone are significantly more willing than those receiving multimodality therapy to consider ERT can be interpreted two ways. First, it is possible that an increasing number of medical treatments preselect patients with more advanced or aggressive cancer. Such women may be more concerned with immediate health priorities, less willing to take perceived risks that may affect their disease, and thus less willing to consider ERT. Alternatively, women who have been treated only with surgery may not be under the supervision of a medical oncologist and, therefore, may be less influenced by the prevailing opinion that ERT is hazardous and should be avoided. The present anonymous survey does not allow us to distinguish between these two possibilities because we did not interview the participants. The finding that 8% of menopausal women take ERT outside the cancer center setting underscores the sensitivity of this issue and the importance of confidentiality in surveys of patient attitudes on this topic. Results of this study confirm that health concerns about the postmenopausal risks of osteoporosis and heart disease are widely shared by women with breast cancer, especially premenopausal women. Older women might have been expected to be most concerned because they represent the group that has immediate symptoms and estrogen deficiency-related morbidity. Instead, we found that premenopausal cancer patients were more worried than older patients about the eventual risk of osteoporosis and heart disease. Furthermore, they also were more concerned about the ERT-related risk of cancer recurrence and were more willing to consider ERT at some future time. This apparent contradiction may reflect that these younger women have a longer term outlook of risk versus benefit issues, or it may reflect that they wish to be more active participants in health care decisions. Osteoporosis and heart disease are major health problems in postmenopausal women. The risk of cardiovascular mortality increases I8-fold after menopause and is directly related to estrogen deficiency.14 Cardiovascular disease remains the leading cause of death among women in the United States, with approximately 350,000 deaths per year, compared to approximately 40,000 deaths per year from breast cancer. 15 Estrogen supplementation improves patients' lipid profiles and reduces the risk of coronary vascular disease. 16,17 Estrogen deficiency-related osteoporosis, the most common metabolic bone disease of women,18,19 is associated with an overall mortality in excess of 148
50,000 deaths per year. 20,21 ERT can reduce or prevent the loss of bone and the development of osteoporosis,2,22 thus reducing osteoporosis-associated morbidity and mortality. Although ERT is used to alleviate menopausal complications in the general population, the fear of reactivating the cancer has precluded the use of ERT in women with breast cancer. The association between estrogen administration and the development of mammary tumors was made primarily based on in vitro and animal studies. 23-25 The link between estrogen and the initiation of breast cancer in humans is inferred from epidemiologic studies that show protective effects of early first pregnancy, early menopause, late menarche, and early oophorectomy.26 Abnormal metabolism, rather than the availability of estradiol, has been implicated by some investigators.27 No reported studies show that ERT adversely affects the natural history of breast cancer. However, estrogen deficiency is accompanied by significant longterm morbidity and mortality, and women with breast cancer are very concerned about it. We believe that it will be important to evaluate the role of ERT in the management of menopause in carefully selected women with breast cancer, under rigorous medical supervision. References 1. Estrogen replacement in the menopause. Council on Scientific Affairs. JAMA 249:359-361, 1983. 2. Consensus Conference: Osteoporosis. JAMA 252:799-802, 1984. 3. Lufkin EG, Carpenter PC, Ory SJ, Malkasian GD, Edmonson JH: A. Estrogen replacement therapy: Current recommendations. Mayo Clin Proc 63:453-460,1988. 4. Steinberg KK, Thacker SB, Smith J, et al: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265:1985-1990, 1991. 5. Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 315:405-410, 1986. 6. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C: The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 321:293-297, 1989. 7. Stadel BV, Schlesselman JJ, Murray PA: Oral contraceptives and breast cancer (letter). Lancet 1257-1258, 1989. 8. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE: Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 264: 2648-2653, 1990. 9. Dupont WD, Page DL: Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 151:67-72, 1991. 10. Stoll BA, Parbhoo S: Treatment of menopausal symptoms in breast cancer patients (letter). Lancet 1:1278-1279, 1988. 11. Wile AG, DiSaia P: Hormones and breast cancer. Am J Surg 157:438-442, 1989. 12. Kadri AZ: Hormone replacement therapy-a survey of premenopausal women in a community setting. Br J Gen Pract 41: 109-112, 1991. 13. Schmitt N, Gogate J, Rothert M, et a1. Capturing and clustering women's judgment policies: The case of hormonal therapy for menopause. Journal of Gerontology: Psychological Sciences 46: 92-101, 1991.
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14. Gordon T, Kannel WB, Hjortland MC, McNamara PM: Menopause and coronary heart disease. Ann Intern Med 85:157-161, 1978. 15. Bush TL, Barrett-Connor E: Estrogen use in cardiovascular disease. Epidemiol Rev 7:80-89, 1985. 16. Stampfer MJ: Postmenopausal estrogen use in heart disease. N Engl J Med 316:164-165, 1987. 17. Richelson LS, Wahner HW, Melton LJ III, Riggs BL: Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 316:1273-1275, 1984. 18. Lindsay R, MacLean A, Kruszewski A, Hart DM, Clark AC, Garwood J: Bone response to termination of estrogen treatment. Lancet 1325-1327, 1978. 19. Riggs BL, Melton LJ III: Osteoporosis, the state-of-the-art 1987. A review. Semin Nucl Med 17:283-292, 1987. 20. A Special Conference: Osteoporosis-National Conference on Women's Health Series. Bethesda, MD, October 30,1987. 21. Barrett-Connor E: Postmenopausal estrogen, cancer and other considerations. Womens Health 11:179-195, 1986.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
22. Ettinger B, Genant HK, Cann CE: Postmenopausal bone loss is prevented by treatment with low dosage estrogen with calcium. Ann Intern Med 106:40-45, 1987. 23. Welsh CW: Host factors effecting the growth in carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Breton Huggins. Cancer Res 45:3415-3443, 1985. 24. Aitken SC, Lippman ME: Effect of estrogen and anti-estrogens on growth-regulatory enzymes in human breast cancer cells in tissue culture. Cancer Res 45:1611-1620, 1985. 25. Lippman ME, Dickson RB, Bates S, et al: Autocrine and paracrine growth regulation of human breast cancer. Breast Cancer Res Treat 7:59-70,1986. 26. Fishmon J: Endocrine participation in the etiology of breast cancer, in Harris J, Hellman S, Henderson IC, Kinne D, (eds): Breast Diseases. New York, J. B. Lippincott Co., 1987, pp 104-106. 27. Longcope C: Relationship of estrogen to breast cancer, of diet to breast cancer, and of diet to estradiol metabolism. J Natl Cancer Inst 82:896-897,1990.
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