|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3991-3996 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3745 Influence of Hormone Replacement Therapy on Tamoxifen-Induced Vasomotor Symptoms
From Cancer Research UK, Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, London; and the Department of Surgical Oncology, Newcastle Mater Hospital, University of Newcastle, Newcastle, United Kingdom Address reprint requests to Jack Cuzick, PhD, Cancer Research UK, Department for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom; e-mail: jack.cuzick{at}cancer.org.uk
PURPOSE: Tamoxifen is an effective drug, but its role in prevention is limited by its adverse effect profile. Non–life-threatening adverse effects, such as vasomotor symptoms, have an important influence in its use for prevention. Vasomotor symptoms were evaluated according to follow-up time, severity, and use of hormone replacement therapy (HRT) in a retrospective analysis. PATIENTS AND METHODS: In the International Breast Cancer Intervention Study-I study, 7,154 women at increased risk of breast cancer were randomly assigned to either tamoxifen 20 mg/d or placebo for 5 years. Women gave detailed information on any vasomotor symptoms at each 6-month follow-up visit. RESULTS: Hot flushes were reported more often in the tamoxifen group than in the placebo group (70.6% v 57.1%, respectively; odds ratio, 1.80; 95% CI, 1.63 to 1.99). Severe hot flushes were more strongly related to tamoxifen. In the tamoxifen arm, more women taking HRT at entry experienced hot flushes in the first 6 months than those who did not take HRT (60.8% v 49.2%, respectively; P = .09). In contrast, women on placebo taking HRT at entry experienced fewer hot flushes than women who stopped HRT (22.9% v 34.3%, respectively; P = .03). Furthermore, for women who first began HRT in the first 6 months of the trial compared with women who did not begin HRT, HRT seemed to be much more effective in controlling hot flushes in months 6 to 12 in the placebo arm (47.9% v 20.4%, respectively) than in the tamoxifen arm (51.4% v 39.0%, respectively). CONCLUSION: HRT use at entry or during the trial was not effective in alleviating hot flushes for women in the tamoxifen arm. Our retrospective study suggests that estrogen-based HRT has limited effectiveness among women receiving tamoxifen.
Tamoxifen is effective for both preventing1,2 and treating3 breast cancer. An overview of four randomized prevention trials on tamoxifen4 showed a 38% reduction in breast cancer incidence. However, tamoxifen's role in prevention is limited because of its adverse effect profile. Endometrial cancer and thrombotic events are most concern, but non–life-threatening adverse effects, such as vasomotor symptoms, also limit its use for prevention. Vasomotor symptoms, especially hot flushes, are a common problem for women taking tamoxifen. It is well known that hot flushes are more common in postmenopausal women with low estrogen concentrations.5 Women who are overweight, women who do little exercise, and smokers all have an increased risk of hot flushes.6 The presence, severity, and duration of hot flushes are extremely variable in menopausal women.7 Little is known about specific factors that can identify women at high risk of hot flushes. Possible predictors include smoking, maternal history of hot flushes, early age of natural menopause, surgical menopause, physical inactivity, anxiety, alcohol use, greater parity, and lower socioeconomic status.6,8 In addition, it is not known whether any of these factors are predictive of hot flushes that are associated with tamoxifen treatment. Estrogen-based hormone replacement therapy (HRT) is the most effective treatment for reducing vasomotor symptoms. Estrogen is either administered alone to a woman without a uterus or is administered in combination with progestin to a woman with a uterus. A quality-of-life study conducted by the Women's Health Initiative9 confirmed that estrogen and progestin improved vasomotor symptoms and even resulted in a small benefit in terms of sleep disturbance. However, it is not known whether HRT will work in the presence of tamoxifen. The International Breast Cancer Intervention Study (IBIS) -I is a randomized, double-blind, placebo-controlled, 5-year study of the effects of tamoxifen in women at high risk of developing breast cancer.2 Women were permitted to use HRT during the trial at the discretion of their doctor, although it was recommended to limit the duration to that required to control severe menopausal symptoms. During the IBIS-I study, approximately 70% of women in the tamoxifen arm reported hot flushes compared with 53% of the women in the placebo arm (odds ratio [OR], 1.80; 95% CI, 1.63 to 1.99). Here, we retrospectively investigate the extent to which HRT reduced vasomotor symptoms in women at high risk of breast cancer taking tamoxifen over a period of 5 years in the IBIS-I trial compared with women taking a tamoxifen placebo.
Patients Women aged 35 to 70 years who had at least a two-fold relative risk of developing breast cancer were eligible to join the trial. Women were randomly allocated to either 5 years of tamoxifen (20 mg/d) or matching placebo and were followed up every 6 months during the 5 years of treatment. All the adverse effects were subjectively rated by an observer and not by the participants. Use of HRT was permitted during the trial, but women had to experience menopausal symptoms. Women were defined as postmenopausal if they had experienced 12 consecutive months of amenorrhea. Furthermore, women aged 50 years or older were also categorized as postmenopausal if they had a hysterectomy alone or in combination with an oophorectomy. Women were defined as premenopausal if they still were menstruating or if they had a hysterectomy without oophorectomy and were aged 50 years or younger. Additional details of patients are available elsewhere.2 All patients (3,575 on placebo and 3,579 on tamoxifen) have been included in this analysis. Hot flushes, menstrual irregularities, and sweats were previously reported for a median follow-up time of 50 months.2 However, no details of timing, severity, or interaction with HRT were reported. We also extended the median follow-up time to 84 months, at which time 95.4% of patients had completed active treatment. Specific questions about hot flushes were asked at each 6-month follow-up visit but not at baseline, at which time only details of any menopausal symptoms were requested. Hot flushes were defined as mild, moderate, or severe. Information about use of HRT was collected both at baseline and at each follow-up visit. HRT groups were initially categorized as never users (never used HRT before trial), baseline users, and ex-users (used HRT at one point before the trial). Women were defined as baseline users if they had used HRT at any time 6 months before random assignment. Women were considered ex-users if they previously used HRT but stopped 6 months before random assignment. Details of HRT use during the trial were collected at each follow-up visit. Women were considered continuing users of HRT during a follow-up period if they took HRT for at least 1 month between follow-up visits.
Statistical Analysis P values for trend for ordered categoric variables were derived from the likelihood statistic based on the regression model. All other analyses were mainly based on comparisons of proportions. All P values are two sided, and all CIs are at the 95% level. All calculations were performed using STATA version 8.2 (STATA Corp, College Station, TX).
In the IBIS-I trial, 7,154 women were randomly assigned to either tamoxifen (n = 3,579) or placebo (n = 3,575). Of these women, 3,244 (45.3%) were premenopausal and 3,855 (53.9%) were postmenopausal. Of postmenopausal women, 40.1% were baseline users of HRT at entry, 22.6% were ex-users, and 37% had never taken HRT before joining the study (Table 1). Of the baseline users, 6.7% stopped at trial entry, and this was similar in both arms (59 women, 6.5%, on tamoxifen v 65 women, 6.8%, on placebo). At baseline, the rates of spontaneous reports of hot flushes, night sweats, and menstrual irregularities were similar in both treatment arms (Table 1). Detailed information about baseline characteristics has been published elsewhere.2
After a median of 84 months of follow-up, women in the tamoxifen group reported more hot flushes than women in the placebo group (2,527 women, 70.6%, on tamoxifen v 2,040 women, 57.1%, on placebo; OR, 1.83; 95% CI, 1.64 to 2.04). Overall, 4.1 hot flushes per tamoxifen patient were experienced over the active treatment period compared with 3.4 hot flushes per placebo patient. The majority of reports in both treatment arms were of mild or moderate severity. The rate of severe hot flushes was much smaller but somewhat more related to tamoxifen usage (OR, 1.97; 95% CI, 1.66 to 2.33; Table 2). Night sweats and menstrual irregularities were also significantly increased in the tamoxifen group (Table 2).
The number of newly reported hot flushes during treatment was only elevated for patients on tamoxifen at the 6-month visit, compared with patients on placebo (48.6% v 25.4%, respectively; OR, 2.77; 95% CI, 2.50 to 3.06), and was similar to placebo thereafter (Fig 1), indicating a rapid onset in affected women. Continuing hot flushes on tamoxifen remained elevated for the entire treatment period, but there was slow decline towards placebo level, and reports were at a similar level by the 5-year visit. Overall, slightly more women on tamoxifen dropped out compared with women on placebo (Fig 2). However, it can be seen from Figure 2 that the higher dropout rates occurred only in the first 18 months and were similar to placebo levels thereafter.
Risk Factors For premenopausal women in the placebo group, the risk of developing hot flushes at any time increased with age up to age 54 years (P < .001). However, for postmenopausal women, the highest rates were seen in women aged 45 to 54 years, with lower rates in younger and older women (Table 3). Additionally, for postmenopausal women, hot flushes were also lower if menopause had occurred several years previously. A clear trend of risk with increasing BMI was seen in both the placebo and tamoxifen arms (both P = .001). The risk was higher for ex-users of HRT at entry (OR, 1.69; 95% CI, 1.18 to 2.24) and for ex-smokers at entry (OR, 1.51; 95% CI, 1.11 to 2.05) but not for baseline users at entry.
For women in the tamoxifen group, the risk of developing hot flushes was significantly higher for baseline users of HRT (OR, 2.27; 95% CI, 1.61 to 3.21) and for ex-users (OR, 2.00; 95% CI, 1.40 to 2.87, Table 3) compared with never users at entry. Again, postmenopausal women had a lower risk of developing hot flushes as the time since menopause increased (OR, 0.53; 95% CI, 0.37 to 0.77; P < .001). As for premenopausal women on placebo, a trend in developing hot flushes was seen with increasing age up to age 59 years (P < .001). For postmenopausal women, the highest rates were seen in women aged 45 to 59 years (Table 3).
Interaction With HRT
Overall, 71% of women in the tamoxifen group reported hot flushes at some time during the 5-year treatment period. Severe hot flushes were more related to tamoxifen use than mild and moderate hot flushes. The rates of hot flushes and other symptoms were lower in our study than in the Breast Cancer Prevention Trial (BCPT) P1 study.10 This is likely because of the allowance of HRT use in IBIS-I but not in BCPT-P1. Additionally, symptoms were based on self-reported questionnaires in the BCPT study, whereas our data were based on clinician-reported information. A beneficial effect of taking HRT on vasomotor symptoms, particularly hot flushes, was observed in women in the placebo group who were taking HRT at entry and continued to do so during the trial. For women who developed hot flushes in the first 6 months and who were not taking HRT at entry, HRT only showed efficacy in the placebo group. Neither of these effects was seen in the tamoxifen arm. In addition, the differential effect of HRT on hot flushes between treatment arms reinforces the lack of beneficial effect of HRT in tamoxifen users. However, it must be remembered that this analysis was retrospective, and the influence of HRT on tamoxifen-induced adverse effects was not a primary end point of the study. An ideal study would have integrated the value of HRT on a placebo-controlled basis. Women taking HRT at entry had higher rates of hot flushes in the first 6 months compared with nonusers. In keep with previous reports,11 women taking HRT are likely to experience more hot flushes, regardless of whether they are taking tamoxifen. Although women taking HRT are a self-selected group, the differential effectiveness between women on tamoxifen and placebo indicates a lack of effect in the former group. In the placebo group, ex-users of HRT experienced a rebound effect for hot flushes. Current users of HRT in the placebo group developed fewer hot flushes than ex-users (Table 3) and, therefore, benefited from continuous use of HRT. A similar effect was seen in a study conducted by Ockene et al,12 in which more than half of the women with vasomotor symptoms also reported these symptoms after discontinuing use of HRT. However, no difference between the development of hot flushes between ex-users and current users was seen in women receiving tamoxifen. These results support our view that HRT is not effective in the presence of tamoxifen. A possible mechanism for the lack of effectiveness of HRT is based on the saturation of the estrogen receptor with tamoxifen. Tamoxifen binds to the estrogen receptor and blocks the effects of estrogen on the breast. Dowsett and Haynes13 summarized published data on steady-state serum concentrations of tamoxifen and its major metabolites. Overall, the data indicated an activity ratio of 1,558:1 of tamoxifen and its metabolites to estradiol at the estrogen receptor. This corresponds to an almost total saturation of the estrogen receptor in the breast by tamoxifen in postmenopausal women (99.94% occupancy) and suggests that modulation of estrogen levels will have little impact in the presence of tamoxifen. This prediction was confirmed in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study,14 which compared tamoxifen against anastrozole alone or the combination of anastrozole plus tamoxifen. Results from the ATAC trial showed that the combination treatment was equivalent to tamoxifen and significantly worse than anastrozole alone. In particular, this study showed that lowering estrogen levels with the aromatase inhibitor anastrozole in the presence of tamoxifen produced no additional effect on breast cancer recurrence or adverse effects. Our observations suggest that similar effects occur on estrogen receptors in the CNS. Phytoestrogens are nonsteroidal compounds derived from plants, which have weak estrogenic properties. Quella et al15 evaluated the effect of soy phytoestrogen in breast cancer survivors who were also taking tamoxifen or raloxifene in a double-blind cross-over study. No effect on hot flushes was seen. Two other studies, one comparing the antidepressant fluoxetine with placebo16 and the other comparing megestrol acetate with placebo,17 both showed an improvement and control in hot flushes. In several studies,18-22 antidepressants have produced a reduction in hot flushes compared with placebo, primarily in women with a history of breast cancer. In a meta-analysis conducted by Nelson et al,23 nonhormonal therapies for menopausal hot flushes showed evidence for efficacy in controlling hot flushes in symptomatic women. However, several studies24-26 suggest that interactions between tamoxifen metabolism and coadministered antidepressants may be associated with altered tamoxifen activity. Nevertheless, these trials suggest that approaches for the management of tamoxifen-induced hot flushes that are not solely mediated via the estrogen receptor might be more effective.
The authors indicated no potential conflicts of interest.
We thank all the women in the International Breast Cancer Intervention Study (IBIS) -I study for their dedicated participation. We also acknowledge the effort of the IBIS-I investigators (see online Acknowledgment). Members of the International Breast Cancer Intervention Study-I steering group were as follows: E. Anderson, M. Baum, K. Buser, S. Cawthorn, J. Cuzick (Chairman), M. Dowsett, H. Earl, D. Eccles, L. Fallowfield, I. Fentiman, J. Forbes, W.D. George, F. Gilbert, H. Hamed, J. Hearn, C. Holcombe, K. Holli, A. Howell, S. Huson, M. Lansdown, K. Law, M. Lee, T.W.J. Lennard, J. Mackay, F. Macneil, R.E. Mansel, P. McAleese, K. McMichael, C. Normand, W. Odling-Smee, T. Oivanen, O. Pagani, T. Powles, R. Sainsbury, P. Sauven, R.D. Stewart, A. Stotter, A. Thompson, J. Toy, A. Wilkinson, and J. Williamson.
Supported by Cancer Research UK, Oncosuisse Switzerland, and by National Health and Medical Research Council Grants No. 920876, 950319, 980381, 209811, and 401200 (J.F.). Presented at the British Breast Group Meeting, July 1, 2005, London, United Kingdom; and the 9th International Nottingham Breast Cancer Conference, September 13-16, 2005, Nottingham, United Kingdom. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 2. International Breast Cancer Intervention Study Investigators: First results from the International Breast Cancer Intervention Study (IBIS-I): A randomised prevention trial. Lancet 360: 817-824, 2002[CrossRef][Medline] 3. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365: 1687-1717, 2005[CrossRef][Medline] 4. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcome in breast-cancer prevention trials. Lancet 361: 296-300, 2003[CrossRef][Medline] 5. Erlik Y, Meldrum DR, Judd HL: Estrogen levels in postmenopausal women with hot flashes. Obstet Gynecol 59: 403-407, 1982 6. Gold EB, Sternfeld B, Kelsey JL, et al: Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol 152: 463-473, 2000 7. Stearns V, Ullmer L, Lopez JF, et al: Hot flushes. Lancet 360: 1851-1861, 2002[CrossRef][Medline] 8. Freeman EW, Sammel MD, Grisso JA, et al: Hot flashes in the late reproductive years: Risk factors for Africa American and Caucasian women. J Womens Health Gend Based Med 10: 67-76, 2001[CrossRef][Medline] 9. Hays J, Ockene JK, Brunner RL, et al: Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 348: 1839-1854, 2003 10. Day R, Ganz P, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P1-Study. J Clin Oncol 17: 2659-2669, 1999 11. Loprinzi CL, Zahasky KM, Sloan JA, et al: Tamoxifen-induced hot flushes. Clin Breast Cancer 1: 52-56, 2000[Medline] 12. Ockene JK, Barad DH, Cochrane BB, et al: Symptom experience after discontinuing use of estrogen plus progestin. JAMA 294: 183-193, 2005 13. Dowsett M, Haynes BP: Hormonal effects of aromatase inhibitors: Focus on premenopausal effects and interaction with tamoxifen. J Steroid Biochem Mol Biol 86: 255-263, 2003[CrossRef][Medline] 14. ATAC Trialists' Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359: 2131-2139, 2002[CrossRef][Medline] 15. Quella SK, Loprinzi CL, Barton DL, et al: Evaluation of soy phytoestrogens for the treatment of hot flushes in breast cancer survivors: A North Central Treatment Group Trial. J Clin Oncol 18: 1068-1074, 2000 16. Loprinzi CL, Sloan JA, Perez EA, et al: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20: 1578-1583, 2002 17. Quella SK, Loprinzi CL, Sloan JA, et al: Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 82: 1784-1788, 1998[CrossRef][Medline] 18. Loprinzi CL, Kugler JW, Sloan JA, et al: Venlafaxine in management of hot flushes in survivors of breast cancer: A randomized controlled trial. Lancet 356: 2059-2063, 2000[CrossRef][Medline] 19. Barton D, La VB, Loprinzi CL, et al: Venlafaxine for the control of hot flashes: Results of a longitudinal continuation study. Oncol Nurs Forum 29: 33-40, 2002[Medline] 20. Stearns V, Slack R, Greep N, et al: Paroxetine is an effective treatment for hot flashes: Results from a prospective randomized clinical trial. J Clin Oncol 23: 6919-6930, 2005 21. Kimmick GG, Lovato J, McQuellon R, et al: Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 12: 114-122, 2006[CrossRef][Medline] 22. Pandya KJ, Morrow GR, Roscoe JA, et al: Gabapentin for hot flashes in 420 women with breast cancer: A randomised double-blind placebo-controlled trial. Lancet 366: 818-824, 2005[CrossRef][Medline] 23. Nelson HD, Vesco KK, Haney E, et al: Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA 295: 2057-2071, 2006 24. Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95: 1758-1764, 2003 25. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97: 30-39, 2005 26. Goetz MP, Rae JM, Suman VJ, et al: Pharmocogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flushes. J Clin Oncol 23: 9312-9318, 2005 Submitted October 24, 2005; accepted June 15, 2006. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
