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Managing Patients on Endocrine Therapy: Focus on Quality-of-Life Issues

Authors' Affiliations: ¹ McMaster University, Hamilton, Ontario, Canada and ² Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada

Requests for reprints: Kathleen I. Pritchard, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Phone: 416-480-4616; Fax: 416-480-6002; E-mail: kathy.pritchard{at}sw.ca.

	Abstract

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Purpose: To review the health-related quality of life (QOL) of women treated with adjuvant hormonal therapy.

Experimental Design: To review the limited QOL data from randomized trials of tamoxifen versus placebo and ovarian ablation versus none. To discuss QOL results from randomized trials of aromatase inhibitors compared with tamoxifen or placebo for adjuvant therapy of postmenopausal women with estrogen receptor–positive and/or progesterone receptor–positive breast cancer.

Results: QOL is generally good in up to 3 years of follow-up with either tamoxifen or aromatase inhibitors. Vasomotor and sexual complaints remain problematic, however, in only a small proportion of women. There are fewer data regarding the QOL effects of ovarian ablation, which may nonetheless be more substantial.

Conclusion: Tamoxifen and aromatase inhibitors cause specific vasomotor or gynecologic symptoms, which may affect sexual function. However, clinical benefits of these agents are generally achieved without major detrimental effect on overall QOL.

The effect of adjuvant hormonal therapy on QOL is an important consideration in treatment decision making. Standard hormonal therapies now include not only adjuvant tamoxifen and ovarian suppression but the relatively new third-generation aromatase inhibitors. Hormonal therapies are often given for a long duration. Five years of such therapy is now standard, and 10 years is increasingly being used. The duration of adjuvant endocrine therapies may be extended even longer in the future. These therapies are accompanied by a number of toxicities related to estrogen withdrawal or antagonism, including vasomotor symptoms, vaginal dryness, urogenital and sexual dysfunction, and in some instances, muscle or joint pain (4). Hormonal therapies are also at least anecdotally associated with other symptoms, including weight gain, hair loss, fatigue, and depression. Until recently, there have been limited QOL information from randomized trials of endocrine therapy, but now, such data are being collected and reported more frequently.

	Tamoxifen

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The effects of tamoxifen on QOL are best obtained from two randomized trials (Table 1). The Wisconsin Tamoxifen Trial included 140 postmenopausal women with lymph node–negative breast cancer who were randomly assigned to receive tamoxifen or placebo (5). Investigators collected data on symptoms and overall QOL over 24 months. Women receiving tamoxifen were found to have increased hot flashes (67% versus 45% at 6 months, P < 0.01). Gynecologic symptoms, such as bleeding, irritation, and vaginal discharge, were also more common (30% versus 15% at 6 months; P < 0.05) in those receiving tamoxifen. No differences were reported with respect to nausea, fatigue, joint pain, depression, irritability, gastrointestinal distress, or overall QOL.

	Ovarian Suppression

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There has been less evaluation of QOL in premenopausal women undergoing ovarian suppression. In a substudy of the Zoladex in Premenopausal Patients trial, 149 women with node-negative breast cancer who did not receive adjuvant chemotherapy were randomized to no endocrine treatment (n = 37), goserelin (n = 38), goserelin plus tamoxifen (n = 39), or tamoxifen alone (n = 35; ref. 8). QOL was assessed with the Hospital Anxiety and Depression Scale and a symptom checklist at baseline, 3.5 months, and 12 months after randomization. Anxiety and depression were not significantly different in any of the arms. There were more intense and earlier vasomotor symptoms (e.g., flushing and palpitations) and vaginal dryness in women treated with goserelin compared with those treated with tamoxifen. More vaginal discharge and irregular bleeding were reported by women treated with tamoxifen, however.

	Aromatase Inhibitors

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Aromatase inhibitors in postmenopausal women are now proving very successful in increasing distant and overall disease-free survival and in preventing contralateral breast cancer compared with tamoxifen when given immediately after surgery, after 2 to 3 years of tamoxifen, and particularly extended adjuvant therapy after 5 years of tamoxifen, a setting in which there was no previous consensus on any useful endocrine therapy. Aromatase inhibition results in a marked decrease in estrogen synthesis, leading to minimal levels of circulating estrogen. Treatment with aromatase inhibitors seems to be associated with a number of adverse effects that are similar but perhaps less intense than those experienced by premenopausal women treated with ovarian suppression. Hot flashes, arthritis, arthralgia, muscle pain, and an increase in osteoporosis and in the rate of bone fracture have been reported (9–11). To date, there have been quite a number of randomized trials of these agents in the adjuvant setting (12). Fortunately, four of the largest trials examining these agents have included extensive QOL studies (see Table 2).

Switching to aromatase inhibitors after about 2 years of tamoxifen. To date, only one trial has reported on QOL assessment for aromatase inhibitors following 2 years of tamoxifen. The Intergroup Exemestane Study (IES) randomized postmenopausal women with early breast cancer who remained disease free after 2 to 3 years of tamoxifen to receive exemestane or further tamoxifen to complete a total of 5 years of adjuvant therapy (10). Of 4,742 women randomized, 582 participated in the QOL substudy over 24 months (13). QOL was assessed with the Functional Assessment of Cancer Therapy-Breast questionnaire and an endocrine subscale at months 3, 6, 12, 18, and 24 months. There were no differences in QOL between the two treatment groups. Endocrine symptoms, in particular vasomotor symptoms, improved over time. No differences were noted between the groups for any endocrine symptoms aside from vaginal discharge, which decreased in patients treated with exemestane.

Aromatase inhibitors versus tamoxifen as initial adjuvant therapy. This context for the use of aromatase inhibitors has been the most widely studied with respect to QOL. In the Arimidex, Tamoxifen, Alone, or in Combination trial, Fallowfield et al. studied QOL over a period of 24 months in postmenopausal women with early breast cancer following primary treatment (14). In this substudy, 1,021 of the 9,366 patients randomized were evaluated: 335 patients received anastrozole, 347 tamoxifen, and 339 the combination. The Functional Assessment of Cancer Therapy-Breast and endocrine subscale were used in this study. Compliance with the QOL assessment was 85%. Overall QOL improved over time, and there was no significant difference between groups. Fallowfield et al. did, however, observe a decrease in QOL related to endocrine symptoms from baseline to 3 months for all treatments. For specific endocrine symptoms, the differences between the groups were small. There were more patients reporting cold sweats (8% versus 11%, P < 0.05), vaginal discharge (1% versus 5%, P < 0.05), and irritation (3% versus 5%, P < 0.05) in the tamoxifen-alone arm, and more patients reporting vaginal dryness (16% versus 8%, P < 0.05), pain on intercourse (18% versus 8%, P < 0.05), and loss of sexual interest (16% versus 9%, P < 0.05) in the anastrozole-alone arm. These results were recently updated to 5 years of follow-up (15). Overall, QOL continued to improve slightly over time with no differences seen between groups. Following the initial worsening at 3 months, the endocrine subscale scores stabilized. No differences were observed between groups in the endocrine subscale, but differences in specific endocrine symptoms seen previously remained.

In another upfront adjuvant therapy trial, symptoms were recorded for the first 12 months in 997 postmenopausal women randomized to tamoxifen or exemestane following primary surgical treatment or adjuvant chemotherapy (16). Exemestane was associated with a decrease in the proportion of patients reporting vaginal discharge and an increase in the proportion reporting vaginal dryness and bone or muscle aches.

Comparison of the QOL studies of aromatase inhibitors is problematic because of the differences related to the timing of adjuvant therapy, the aromatase inhibitors evaluated, the comparison arm of the studies, and the instruments used to assess QOL. The QOL instruments used in these studies have been widely validated. The Functional Assessment of Cancer Therapy-Breast instrument used in two of the trials was developed for breast cancer patients. The SF-36 used in MA.17 (and in National Surgical Adjuvant Breast and Bowel Project P1) also has been widely used in breast cancer patients and shown to be sensitive to important differences in quality of life (3, 17). Despite the variability in trial design and instruments used to assess QOL, the results of all four studies were very similar. Third generation inhibitors seem to have specific effects on vasomotor and gynecologic symptoms and sexual function, but no major adverse affect on overall quality of life has been observed. Mindful of the limitations to the cross-study comparisons, there does not seem to be any differences in studies reporting the use of aromatase inhibitors after tamoxifen versus up front initial therapy or in the different aromatase inhibitors used. However, it should be noted that follow-up is still relatively short for most trials reporting QOL, and evaluation of long-term effects of treatment is needed. Newer third-generation trials comparing different aromatase inhibitors will provide important information regarding comparative QOL.

	Suggestions for Management of Endocrine Symptoms

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QOL issues may have important implications particularly for specific women. Thus, it is important that clinicians following these women take a careful history with regard to treatment adverse effects and discuss directed symptom management with them. Some specific, if imperfect, pharmacologic treatments are available for the relief of vasomotor symptoms, including selective serotonin reuptake inhibitors, such as venlafaxine and the antihypertensive agent clonidine. Therapy for vaginal dryness and dyspareunia is problematic. Water-soluble lubricants, such as KY Jelly, can be useful, but remedies that involve local estrogen are often more effective. These can include E-String, which releases estrogen in a slow and regular fashion, or the sparing use of vaginal estrogen cream two to thrice weekly. These therapies for dyspareunia were allowed in studies, such as MA.17, and did not interfere with the observed efficacy. Whether anti-breast cancer efficacy could be superior without the use of these local estrogens is not clear. The use of local estrogens may be more problematic in patients receiving aromatase inhibitors as therapy, because the presumed mechanism of action of an aromatase inhibitor is to reduce systemic estrogen to extremely low levels, whereas tamoxifen is believed to acting by competing with estrogen in interacting with hormone receptors on tumor cells. Directed symptom-specific therapy programs, such as that described by Ganz et al., have proved even more effective in reducing a variety of symptoms (18). There are well-established treatments for osteoporosis and reduction of cardiovascular risk that apply to these as to other postmenopausal women. Exercise and weight loss may also help in general QOL as well as improving cardiovascular and bone health.

In the future, postmenopausal women with estrogen and/or progesterone receptor positive disease (perhaps as many as 70% of all postmenopausal women with breast cancer) may be receiving extended treatment with adjuvant endocrine therapy. It will be very important for clinicians to monitor these patients for compliance with that therapy and for minimization of any associated short-term and long-term toxicities and QOL changes. Future research in this area as well as careful clinical management will remain important.

	Open Discussion

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Dr. Carlos Arteaga: Many of these women are well below retirement age. Has anybody developed some index of work productivity outside the house? This goes to the issue of years lost to the disease.

Dr. Pritchard: When we first did the MA.5 trial with CEF and CMF, one of the data managers pointed out to me that more women on one arm than the other were having to take time off from work. There was at that time no questions in any of these quality-of-life scores that captured that. You are asking an important question, and there are items in some of the current quality-of-life instruments that address working and work productivity in a better way than they used to.

Dr. Steven Come: What is your practice in terms of the use of vaginal estrogen in patients with sexual complaints? Do you have theoretical concerns about doing that in women on AIs?

Dr. Pritchard: I ask patients about their general functioning and symptoms, including sexual functioning. Some of these women have such terrible symptoms that they really have to use something. In my practice, I recommend Estring and some vaginal creams. I prefer Estring, because I think it is absorbed more minimally and more consistently, but the data are actually very poor. In MA.17, we allowed the use of either Estring or local vaginal estrogen, and the trial worked in spite of that.

Dr. Come: Is there any overall epidemiologic issue with the fact that the proportion of patients in these quality-of-life studies is so small, compared with the overall study?

Dr. Pritchard: In MA.17 there was quite a large number. In the NCIC we have had a long history of doing quality-of-life studies, so our centers just do it. They don't even complain anymore. These studies have shown us some specific areas that we should be discussing with our patients more. It may be that 90% of them don't have these problems, but 5% may be having a big problem and we don't always hear about it. In terms of symptoms and what therapy you choose, I get some patients who are really frightened of the AIs because they have had bad arthritis. It may not be logical; they may not be the one who is going to get the musculoskeletal effects, but they are just too scared to be on a drug that might make their functioning worse. So those are the kinds of issues where I am picking and choosing between the drugs.

Dr. James Ingle: There is a lot of evidence now about the tolerability of the AIs in this population. I think the age/menopausal interaction that Tim Whelan identified is really interesting [J Clin Oncol, in press]. It goes along with what you would expect. You take a younger woman and radically change her estrogen levels and you are going to have more symptoms. You take a 70-year-old woman who has slowly drifted down in estrogen levels, and it is not that big a deal.

Dr. Arteaga: The effects may be tolerable, but I am also getting the message from the cardiac and sexual data that God made estrogens for a number of good reasons. There is the concept being explored by Southwest Oncology Group of combining an AI with fulvestrant. There are a lot of oncogenic inputs and in many tumors the ER may still be working as a transcriptional unit in the absence of any hormones, so it makes sense to test that. However, that combination is going to produce a profound hypoestrogenic state. Are these data telling us that that experiment should be done in a very well-defined population? There may be some population in which that strategy, AI plus a ER down-regulator, may be justified, because there is a molecular rationale to do it. At what point do you cross that boundary of potential benefit versus toxicity, because the combination will be pretty toxic?

Dr. Pritchard: I think we need to be studying these people, but we don't even know that it is going to produce worse cardiac toxicity. The issue of estrogen's effects on the heart is a bit up for grabs right now. You see a whiff of a difference in cardiac disease in several of these studies. But in MA.17 there was no difference, and there are several randomized trials of tamoxifen versus no treatment that actually show cardiac protection. Most of what we may be seeing in these studies may be tamoxifen's cardioprotective effects versus AI. That could still be a reason to lean toward tamoxifen, but we need a lot more data on the cardiac issue. If it is a big difference, and if it really holds up, that could be a real problem because cardiac events are the competing cause of mortality and disease in this patient age group.

Dr. Ingle: Putting things in perspective, I think that this minor signal of the cardiac data is something that people are going to have to pay attention to. In the IES study, 0.5% more patients on exemestane had a myocardial infarction compared with the tamoxifen treatment group [Coombes RC, et al., presented at the 2004 San Antonio Breast Cancer Symposium]. However, in talking to women, you learn that they don't want their cancer to come back. If they have had breast conservation therapy, they don't want a local recurrence, because then they lose their breasts. They want to keep their breasts. So the major driver is preventing breast cancer.

Dr. Pritchard: It worries me more that 5 or 10 years from now we may see a lot of women with undertreated osteopenia and osteoporosis, because it is a condition that is undertreated in the population anyway.

	Footnotes

 
Grant support: Canadian Breast Cancer Research Alliance and the National Cancer Institute of Canada.

Presented at the Fifth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, June 13-14, 2005.

Received 10/ 5/05; revised 11/ 8/05; accepted 11/15/05.

	References

Top Abstract Tamoxifen Ovarian Suppression Aromatase Inhibitors Suggestions for Management of... Open Discussion References

 

1. Guyatt GH, Jaeschke R. Measurements in clinical trials: choosing the appropriate approach. Quality of life assessment in clinical trials. In: Spilker B, editor. Quality of life assessments in clinical trials. New York: Raven Press; 1990. p. 37–46.
2. Goodwin PJ, Black JT, Bordeleau L, Ganz PA. Health-related quality-of-life measurement in randomized clinical trials in breast cancer: taking stock. J Natl Cancer Inst 2003;95:263–81.[Abstract/Free Full Text]
3. Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE, Belin TR. Quality of life in long-term disease free survivors of breast cancer: a follow-up study. J Natl Cancer Inst 2002;94:39–47.[Abstract/Free Full Text]
4. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:6931–40.[Abstract/Free Full Text]
5. Love RR, Cameron L, Connell B. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 1991;151:1842–7.[Abstract]
6. 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 1998;90:1371–88.[Abstract/Free Full Text]
7. Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659–69.[Abstract/Free Full Text]
8. Nystedt M, Berglund G, Bolund C. Randomized trial of adjuvant tamoxifen and/or goserelin in premenopausal breast cancer. Acta Oncol 2000;39:959–68.[CrossRef][Medline]
9. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.[Abstract/Free Full Text]
10. Coombes RC, Hall E, Gibson L, et al. A randomized trial of exemestane after two to 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–91.[Abstract/Free Full Text]
11. The ATAC Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003;98:1802–10.[CrossRef][Medline]
12. Ingle JN. Adjuvant endocrine therapy for postmenopausal women with early breast cancer. Clin Cancer Res 2006;12:1031–6s.
13. Fallowfield LJ, Price MH, Hall E, Coombes RC, Bliss JM. Intergroup Exemestane Study: results of the quality of life sub-protocol [abstract 4]. Br Cancer Res Treat 2004;88:S9.[CrossRef]
14. Fallowfield L, Cella D, Cuzick J. Quality of life of postmenopausal women in the Arimidex, tamoxifen, alone or in combination (ATAC) adjuvant breast cancer trial. J Clin Oncol 2004;22:4261–71.[Abstract/Free Full Text]
15. Cella D, Fallowfield L, on behalf of the ATAC Trialists Group. Five year quality of life follow-up of adjuvant endocrine therapy for postmenopausal women in the Arimidex (A), tamoxifen (T), alone or in combination (ATAC) Trial [abstract 577]. J Clin Oncol 2005;23:16S.
16. Asmar L, Cantrell J, Vukelja S. A planned comparison of menopausal symptoms during the first year in 1,000 patients receiving either exemestane or tamoxifen in a double-blind adjuvant hormonal study [abstract 516]. J Clin Oncol 2004;22:14S.
17. Ganz PA, Moinpour CM, Pauler DK, et al. Health status and quality of life in patients with early-stage Hodgkins's disease treated on Southwest Oncology Group Study 9133. J Clin Oncol 2003;21:3512–9.[Abstract/Free Full Text]
18. Ganz PA, Greendale GA, Peterson LM, Zibecchi L, Kahn B, Belin TR. Managing menopausal symptoms in breast cancer survivors: results of a randomized controlled trial. J Natl Cancer Inst 2000;92:1054–64.[Abstract/Free Full Text]

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