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© 2003 American Society for Clinical Oncology Side Effects of Adjuvant Endocrine Treatment in Premenopausal Breast Cancer Patients: A Prospective Randomized Study
From the Unit of Psychosocial Oncology and Rehabilitation, Department of Oncology, Karolinska Hospital; Department of Oncology, Huddinge University Hospital, Stockholm; and Institution of Public Health and Caring Sciences, Bioethics, Uppsala University, Uppsala, Sweden. Address reprint requests to Marianne Nystedt, MSc, RN, Unit of Psychosocial Oncology and Rehabilitation, Karolinska Hospital, S-171 76, Stockholm, Sweden; email: marianne.nystedt{at}home.se.
Purpose: To compare the effect of adjuvant endocrine therapies with and without chemotherapy on physical symptoms, anxiety, and depressive symptoms in premenopausal women with breast cancer in a randomized clinical trial (the Zoladex in Premenopausal Patients trial). Patients and Methods: The patients were randomly assigned to goserelin, goserelin plus tamoxifen, tamoxifen alone, or no endocrine therapy. The duration of the endocrine treatment was 2 years. The groups were observed for 3 years after primary treatment (ie, during 2 years of active treatment as well as 1 year after cessation of the adjuvant endocrine therapy). All patients with node-positive disease received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), which was given concurrently with the endocrine treatment. Results: Patients treated with CMF typically reported higher levels of physical symptoms than did patients who did not receive CMF. It was only among patients who did not receive chemotherapy that the endocrine treatment had differential effects. Goserelin was most burdensome and resulted in similar symptom levels as those of CMF, whereas the side effects of tamoxifen alone were milder. After cessation of the endocrine treatment, the side effects diminished in patients who had not received CMF, whereas patients treated with CMF reported ongoing problems at the 3-year follow-up. In contrast, anxiety and depressive symptoms were not significantly affected by endocrine treatment or chemotherapy during the 3 years of assessment. Conclusion: Goserelin and tamoxifen resulted in menopausal symptoms, but these symptoms were reversible. However, women treated with CMF experienced physical symptoms throughout the whole study period.
TAMOXIFEN IMPROVES both recurrence-free survival and overall survival in early-stage breast cancer.1 Thus, tamoxifen is now the hormonal treatment of choice among both premenopausal and postmenopausal patients with estrogen receptor–positive disease. The endocrine effects of tamoxifen vary depending on age, menopausal status, and duration of treatment. In postmenopausal women, tamoxifen has weak estrogenic effects. In contrast, in premenopausal patients, the antagonistic estrogenic properties predominate.2,3 Commonly reported side effects associated with tamoxifen are vasomotor and gynecologic symptoms.4–6 Ovarian ablation by irradiation or surgery produces a significant improvement of both recurrence-free survival and overall survival in patients younger than 50 years of age.7 During the 1990s, luteinizing hormone-releasing hormone (LHRH) analogues were tested in adjuvant settings. The hormonal effects of ovarian ablation achieved by such drugs are similar to those of surgery or irradiation.8 Goserelin suppresses ovarian function, which results in a decrease of estradiol levels to postmenopausal levels.9 The assumed reversibility of menopausal symptoms that are caused by LHRH analog treatment is an advantage compared with surgical or radiologic ovarian ablation. In a study comparing goserelin with and without tamoxifen, hot flushes, vaginal discharge, and vaginal soreness reached similar levels, regardless of treatment.10 Polychemotherapy significantly prolongs relapse-free and overall survival in early-stage breast cancer, especially in women younger than 50 years of age.11 However, chemotherapy, particularly with alkylating agents, has a severe ovarian impact, which results in the disruption of hormone production and decreased circulating levels of estrogen.12 Vasomotor symptoms, weight gain, vaginal dryness, and atrophy are some of the side effects frequently associated with chemotherapy.12–15 In normal menopause, hot flushes are a frequent vasomotor symptom experienced by 70% to 90% of perimenopausal women; vaginal dryness or decreased vaginal lubrication is experienced by 40% to 60% of perimenopausal women.12,16 In a prospective study of perimenopausal women only, vasomotor symptoms were significantly related to menopausal status.17 Several studies have addressed the issue of the effect of a breast cancer diagnosis and different treatments on mental well-being.18–21 Dow et al18 found that psychologic distress from cancer diagnosis and treatment and fear of recurrent disease were problematic. Likewise, fatigue and sleep disturbances were persistent after treatment ended. The prevalence of anxiety and depressive symptoms was not increased in breast cancer patients attending a mammographic clinic when compared with women without breast cancer at the same clinic.21 In an earlier report that was based on the first year of follow-up of premenopausal patients, we found that adjuvant goserelin was associated with higher levels of physical symptoms compared with tamoxifen and an endocrinologically untreated control group.22 The aim of the present study was to compare, over a 3-year period (ie, during 2 years of active treatment as well as 1 year after cessation of endocrine therapy), the effect of adjuvant endocrine therapies on physical symptoms, anxiety, and depressive symptoms in premenopausal breast cancer patients with and without chemotherapy.
Patients From 1990 to 1996, a prospective, multicenter, randomized adjuvant trial was conducted (Zoladex in Premenopausal Breast Cancer Patients [ZIPP] trial). The aim was to assess the value of different types of adjuvant endocrine therapy. The current report relates to patients included in the Stockholm Breast Cancer Study Group.23 After primary surgery, premenopausal women (last menstruation < 6 months from the start of the study) with invasive breast cancer were randomly assigned to one of the following treatment conditions: LHRH analog goserelin (G group), goserelin plus tamoxifen (GT group), tamoxifen alone (T group), or an endocrinologically untreated control group (C group). The duration of endocrine therapy was 2 years. Node-positive patients were treated with six cycles of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) given concurrently with the endocrine treatment. Randomization was carried out by telephone to a central office, where the patient identifiers were recorded before the allocated treatment was revealed to the responsible physician. Treatment allocation was based on balanced lists using the permuted block technique. The design of the clinical trial is summarized in Fig 1  .
Between October 1990 and June 1994, 408 patients were included in the randomized study; of these, 293 (72%) participated in the present study. Noninclusion was caused by administrative failure (n = 27), language difficulties (n = 20), declined participation (n = 21), and concurrent disease (n = 7); in addition, 40 patients were never contacted because they were treated at hospitals outside of Stockholm, Sweden. There were no statistically significant differences between participants and nonparticipants that related to allocated endocrine therapy, type of surgery, or age (data not shown). Clinical characteristics of the present study sample, listed in Table 1 , were recorded at inclusion.
Procedure Informed consent was obtained from the participants before they were randomized to treatment arms. In conjunction with the information about the clinical trial, a research nurse informed the women verbally and in writing about the present study. It was stressed that participation was strictly voluntary, and confidentiality was guaranteed. The study was approved by the Karolinska Institute Regional Ethics Committee (Stockholm, Sweden). The patients completed the questionnaires in connection with their regular medical check-ups at the outpatient clinics. There were seven points of assessment. These seven assessment points were given at baseline; that is, after surgery and before randomization (150 node-negative and 143 node-positive disease patients), and 3 to 4 months (143 node-negative and 139 node-positive disease patients), 12 months (136 node-negative and 128 node-positive disease patients), 18 months (132 node-negative and 118 node-positive disease patients), 24 months (125 node-negative and 115 node-positive disease patients), 30 months (120 node-negative and 106 node-positive disease patients), and 36 months (129 node-negative and 115 node-positive disease patients) after randomization. The patients treated with CMF completed the questionnaire for the assessment at 3 to 4 months before the fourth course of CMF. The patients with breast-conserving surgery completed the questionnaire at the regular check-up 4 weeks after cessation of radiotherapy.
Table 2
Instrument When the present study was planned in 1989, some standardized instruments were available.24–27 All of these instruments were considered too general and did not include the anticipated physiologic effects of endocrine treatment. The instrument we eventually used was partly taken from a questionnaire developed for breast cancer studies at our center,28 and the Physical Symptoms and Problem List was complemented with questions that addressed the possible effects of endocrine therapy in premenopausal women. To ensure face validity, these lists of symptoms were developed in collaboration with experienced oncologists. The new questionnaire was tested in a pilot study on patients and on healthcare professionals as controls. Content validity was assessed through interviews with physicians and nurses working in a breast cancer care unit. In the present study, the following sections of the questionnaire were analyzed: First, the sociodemographic background section included questions related to age, living arrangements, and work status. Second, the Physical Symptoms and Problem Scale22 consisted of 24 items used to assess side effects of endocrine treatment. The 24 items were selected from a 42-symptom checklist with the criteria that at least 20% of the sample reported problems. The third assessment period (after 1 year of endocrine treatment) was chosen for analysis. There were five response categories that ranged in score from 0 (not at all) to 4 (very much). The patients were asked to rate their perception of symptoms and problems during the last week. Nystedt et al22 derived seven factors by principal component analysis. Because of their supposed sensitivity to endocrine treatment and chemotherapy, the following factors were analyzed: vasomotor symptoms (alpha = 0.90; hot flushes, feeling warm, sweating); changes in body image (alpha = 0.62; increased weight and changes in body image); memory and concentration problems (alpha = 0.80; poor memory, concentration problems, irritability); sleep disturbances (alpha = 0.92; difficulty in sleeping, difficulty in falling asleep, waking up several times with difficulties falling asleep again, waking up earlier than desired); and fatigue (alpha = 0.69; tiredness, decreased physical fitness, headache). Vaginal dryness and vaginal discharge were analyzed as single items. Finally, the Hospital Anxiety and Depression (HAD) scale29 consists of 14 items divided into two subscales termed anxiety and depression (score range, 0 to 21). The HAD scale has been found to be easy to administer, well accepted by the patients, and sensitive to mood changes that may occur during the course of a disease.30
Statistical Methods To minimize loss of power, missing values were imputed at individual levels along the following lines. For the HAD scale, recommendations were applied; that is, missing data were imputed if a respondent answered at least half of the items in a subscale.33 The missing values were then replaced by the mean of the other scores in the subscales. For the Physical Symptoms and Problem Scale, missing data were replaced by the mean of the two adjacent scores.34 However, missing values at the 36-month assessment were replaced by the previous assessment score.
Missing Data The number of patients with missing data varied from one to 11 across assessment points (3 to 4 months, n = 2; 12 months, n = 6; 18 months, n = 11; 24 months, n = 11; 30 months, n = 11; and 36 months, n = 1). The intraindividual variability of scores for patients with missing data was low during the treatment period. The number of patients did not differ significantly in the groups (G, n = 6; GT, n = 3; T, n = 7; C, n = 5; and G + CMF, n = 4; GT + CMF, n = 7; T + CMF, n = 5; and C + CMF, n = 5).
Sick Leave
Vasomotor Symptoms
At 0 to 24 months of follow-up, there was a significant three-way chemotherapy x endocrine treatment x time interaction effect [F(12,916) = 1.98; P = .05]. This second-order interaction indicates that chemotherapy had a negative effect on the T and C groups but not on the G and GT groups during endocrine treatment. This pattern was confirmed by post hoc analyses. Likewise, endocrine treatment had no effect on CMF-treated patients but had a differential effect on patients not treated with CMF. That is, the C group maintained a significantly lower symptom level during the treatment period than did the endocrine treatment groups G, GT, and T. In addition, the G and GT groups also reported significantly higher problem levels than did the T group [endocrine treatment x time interaction, F(12,916) = 5.04; P < .0001]. This pattern was not found at baseline when all groups were similar, but it was confirmed during treatment by post hoc analysis at most points of assessment. In the analysis based on 0, 30, and 36 months’ assessments, all groups that were administered CMF maintained a high symptom level compared with baseline; in contrast, groups not treated with CMF experienced decreased problems after conclusion of endocrine treatment [chemotherapy x time interaction, F(2,446) = 30.95; P < .0001].
Vaginal Dryness
At 0 to 24 months, the patients administered CMF reported experiencing more problems with vaginal dryness than patients not treated with CMF [F(1,233) = 5.98; P = .05]. The main effect of time was significant. Patients reported more problems after the start of treatments [F(4,932) = 27.95; P < .0001]. The main effect of endocrine treatments [F(3,233) = 4.91; P = .01] and the endocrine treatments’ differential effects on the time course of patients’ vaginal dryness were significant [F(12,932) = 2.93; P = .001]. The G group reported more problems with vaginal dryness over time compared with each of the three other groups. Furthermore, the GT and T groups reported increased vaginal dryness compared with the C group at several points of assessment. At 0, 30, and 36 months, there was a continued negative main effect of chemotherapy, time, and the interaction of chemotherapy and time [F(2,454) = 5.95; P = .01]. The C, T, and GT groups treated with CMF reported more severe problems with vaginal dryness than the corresponding groups not treated with CMF. There were no significant differences between the groups not treated with CMF at 36 months. The side effects caused by endocrine therapy were found to decrease as a function of time.
Vaginal Discharge
At 0 to 24 months, post hoc tests indicated that the T groups who received or did not receive CMF experienced significantly more vaginal discharge than the other groups. However, the problems were moderate. At the peak of symptoms (score range, 0 to 4), mean values were as follows for the groups: C, 0.22; G, 0.27; GT, 0.24; and T, 0.66 [main effect of endocrine treatment, F(3,236) = 6.13; P = .001]. Vaginal discharge was reported to increase during treatment in comparison with baseline and remained more or less constant across time [main effect of time, F(4,944) = 13.52; P = .001]. For the 0- and 30-month and the 36-month analysis, as in the 0- to 24-month analysis, the main effects of endocrine treatment [F(3,227) = 3.05; P = .05] and time [F(2,454) = 11.65; P = .001] were significant. Confirmed by post hoc analysis, the T group reported more problems than the other groups. The problems increased from baseline to 30 months and, thereafter, decreased. In conclusion, tamoxifen resulted in vaginal discharge, but the problems were moderate and diminished during the third year.
Changes in Body Image
At 0 to 24 months, patients that were administered CMF reported significantly more problems associated with changes in body image than patients not treated with CMF. The effect of time was also significant. Patients reported more problems during the treatment period relative to baseline. Two-way interactions between CMF and time [F(4,924) = 7.63; P = .0001] and between endocrine treatment and time were significant [F(12,924) = 3.67; P = .0001]. A three-way interaction of CMF x endocrine treatment x time was also significant [F(12,924) = 2.26; P = .01]. The three-way interaction reveals that during treatment, but not before, patients not treated with CMF in the G (at 12, 18, and 24 months) and the GT groups (at 18 and 24 months) reported significantly more problems than patients in the C group regarding changes in body image. However, there was no significant difference between T and C groups. The analyses at 0, 30, and 36 months revealed continued significant negative effects of chemotherapy and a significant two-way interaction of CMF x time [F(2,446) = 7.2; P = .001]. The negative effects of CMF were still reported at the 30-month assessment, but at 36 months there were no significant differences between the treatment groups who received and who did not receive CMF.
Memory and Concentration Problems
Sleep Disturbances Mean values and SDs are listed in Table 8 .
At 0 to 24 months, sleep disturbances were similar in the GT and G groups independent of CMF, whereas the T group not treated with CMF had less severe problems during treatment in comparison with the corresponding group treated with CMF (mean score, 0.80 to 1.75 at 24 months) [CMF x endocrine treatment interaction, F(3,228) = 2.65; P = .05]. No significant difference was observed between the C groups. At 0, 30, and 36 months, the two-way interaction between CMF and time was significant [F(2,446) = 3.48; P = .05]. Compared with baseline, there were negative effects of CMF at the 30-month assessment; however, at the 36-month assessment, the symptom levels were maintained or even decreased for most patients.
Fatigue
Anxiety and Depressive Symptoms (score range, 0 to 21) At 0 to 24 months, neither endocrine treatment nor CMF had a significant effect on patients’ perceived anxiety and depressive symptoms. The effect of time was significant in patients with anxiety problems [F(4,748) = 9.77; P < .0001] but not in patients with problems associated with depression. The highest mean value of anxiety (6.94) was at baseline (ie, after breast cancer surgery), and the lowest mean value was at 24 months (4.02). Mean values for depressive symptoms were 3.47 and 2.93 at baseline and 24 months, respectively. No interaction effects were observed. At 0, 30, and 36 months, for both anxiety and depressive symptoms, the main effect of time was significant [F(2,402) = 18.6; P < .0001 and F(2,384) = 3.50; P = .05, respectively[. The symptom level was lower at 30 and 36 months compared with the baseline value. No other main and interaction effects were noted.
The randomized trial, which formed the basis for the current trial, was closed for patient entry in 1996. An analysis of treatment efficacy at a median follow-up of approximately 5 years has been presented elsewhere.35 There was a statistically significant benefit regarding event-free survival for patients allocated to goserelin. Other recent trials have indicated that adjuvant goserelin further improves treatment outcome when added to adjuvant cytotoxic chemotherapy,36 or they have shown that results achieved with a combination of goserelin and tamoxifen are comparable with those achieved with adjuvant chemotherapy in patients with estrogen receptor–positive disease.37 Policy decisions about how the clinical trial results should be translated into clinical practice should also take into account observations regarding psychologic and physical side effects, such as those reported here. Participants in the present study were breast cancer patients with node-negative and node-positive disease. Node-positive patients were treated with a 6-month CMF course after surgery. The main result of this study is that endocrine therapy had differential effects only in patients not treated with CMF. Chemical castration with goserelin was associated with the highest level of menopausal symptoms; the effect of tamoxifen was found to be slower and milder. Vasomotor symptoms and vaginal dryness were the most troublesome side effects, which were caused by decreased estrogen levels. The endocrinologically untreated group scored low. Chemotherapy compared with no chemotherapy resulted in pronounced side effects independent of endocrine treatment. Overall, in patients who did not receive cytotoxic chemotherapy, the negative effects of endocrine treatment were limited to the active treatment period; during follow-up, the effects of endocrine treatment decreased systematically. In contrast, side effects continuously were observed after the end of endocrine treatment in patients treated with CMF, probably because of castration by chemotherapy.12 In our study, the goserelin treatment abruptly sent the women into menopause. The goserelin-treated patients (G and GT groups) reported a higher degree of vasomotor symptoms compared with the tamoxifen-treated patients (T group) or controls (C group). Similarly, the T group experienced significantly more vasomotor symptoms than the C group. This finding is consistent with other studies.3,10 Chemotherapy and its side effects have been investigated in numerous studies and vasomotor symptoms are well documented.13–15 However, to our knowledge, no other study has demonstrated the pattern of endocrine treatment with and without CMF (eg, the T group and the C group not treated with CMF reported significantly less severe vasomotor symptoms than the corresponding groups treated with CMF). Furthermore, patients in the goserelin groups (G and GT groups) treated with CMF reported the same level of symptoms as patients in the goserelin groups not treated with CMF. Vaginal epithelium is sensitive to declining levels of estrogen, and vaginal dryness is an early symptom associated with decreasing levels of estrogen.12 Goserelin suppresses ovarian function, whereby the estrogen levels decrease rapidly, within 3 weeks from start of treatment.38 In our study, goserelin resulted in marked vaginal dryness in the patients not treated with CMF compared with the three other treatment groups at 3 to 4 months. The symptoms were delayed when tamoxifen was given alone or added to goserelin, indicating that the side effects from goserelin were mitigated by the addition of tamoxifen. In postmenopausal women, tamoxifen has been shown to exhibit partial estrogen-agonist properties in, for instance, bone and endometrium. It is possible that such partial agonist properties help to explain that symptoms associated with goserelin were mitigated by the addition of tamoxifen. In agreement with other studies,12,13 women in this study who received CMF and endocrine therapy had significantly more problems with vaginal dryness compared with women who received no adjuvant therapy. CMF resulted in ongoing symptoms for at least 2 to 2.5 years after termination of CMF. Vaginal discharge, as an effect of tamoxifen, has been reported in other studies.3,4 In this study, it was demonstrated that goserelin, in addition to tamoxifen, diminished such side effects. Changes in body image consisted of items related to increased weight and changes in how patients perceived their body image. Many women wrote comments in the questionnaire that they perceived themselves as "getting older and heavier" after initiation of CMF and/or goserelin. Weight gain has been reported in several studies as a common problem in women after chemotherapy.14,15 In our study, the patients treated with CMF reported significantly more changes in body image than the patients not treated with CMF. In the latter (no CMF), the patient groups treated with goserelin reported significantly more changes in body image compared with the endocrinologically untreated group. In patients not treated with CMF, the problems diminished when endocrine treatment was concluded. However, the tamoxifen group did not report increased problems with changes in body image or weight gain. With regard to weight gain, this finding is in accord with Day et al4 and Kumar et al39 who observed no relation between tamoxifen and weight gain, but it is not in accordance with, for example, Hoskin et al40 who observed weight gain among premenopausal women receiving tamoxifen. The baseline questionnaire was completed a few weeks after breast cancer diagnosis and surgery. Problems associated with the surgery may contribute to sleep disturbances. In our study, we did not ask about the reasons for the sleep disturbances. However, it is reasonable to assume that vasomotor symptoms, including sweating, could be one reason to account for sleep disturbances after the start of treatment.17 During the 3 years of assessment, fatigue (tiredness, decreased physical fitness, and irritability) was the most frequent problem mentioned by approximately 56% of the whole sample; this result was in accordance with observations by McPhail.16 Surgery and radiotherapy may influence the negative effects of the cancer disease. However, neither CMF nor endocrine treatment was found to have any effect on fatigue, memory, and concentration problems. One possible reason is that all subjects were breast cancer patients with approximately the same side effects from diagnosis and surgery. Even if the side effects from chemotherapy and endocrine therapy can be problematic, the menopausal symptoms did not lead to significantly increased anxiety and depressive symptoms. What is the clinical importance of this study? Juniper et al41 have proposed that a significant difference of 0.5 within groups across time can be interpreted as clinically significant. If this rule is applied, most of the observed significant mean differences, especially for vasomotor symptoms, were greater than 0.5. However, Juniper et al41 developed this criterion on a questionnaire in which the items were scored on a seven-point scale. If one considers that the present scale was a five-point scale and that pair-wise comparisons of means were between groups instead of within groups, a difference of 0.5 implies a conservative interpretation of the clinical significance in this material. Therefore, a reasonable conclusion is that most of the significant mean differences among the randomized groups are clinically meaningful. Some of the problems investigated in this study were found not to differ among the treatment groups or the mean levels of perceived problems are low. This type of finding, in our opinion, is not trivial and is particularly important for the clinician who wants to enlighten patients about the consequences of their treatments. Therefore, detailed knowledge of even minor or nonexistent differences in the side effects of alternative treatments should be given as a basis for the patient’s choice. Effects of endocrine treatment on sexuality in our patients were analyzed previously.42 In that study, goserelin increased sexual dysfunction in patients who did not receive CMF, but this effect proved reversible. In contrast, in patients who received CMF, sexual dysfunction continued into the third year after randomization. Thus, the pattern in that study was the same as in this report. At the time of the initiation of the trial, 2 years of adjuvant tamoxifen was a standard duration at most centers in Europe. However, 5 years of tamoxifen therapy has now become the accepted standard worldwide. This change may impact the duration of symptoms among patients receiving tamoxifen, particularly because the recommended duration of goserelin treatment ranges between 2 and 5 years. This might change the relative impact of the two treatments on physical symptoms in those not receiving chemotherapy, so the current result should be evaluated against this background. In conclusion, menopausal symptoms seemed to be a significant concern of premenopausal women receiving goserelin, tamoxifen, and/or CMF. In patients who did not receive CMF, the endocrine treatment had clear differential effects; for example, goserelin resulted in the same symptom level as did CMF, whereas the side effects of tamoxifen alone were milder with the exception of vaginal discharge. After termination of endocrine treatment, the side effects diminished in patients who did not receive CMF. However, patients treated with a 6-month CMF course after surgery reported ongoing problems during the third year.
We thank the patients for providing important information about physiologic side effects during their breast cancer treatment. We also thank the nurses involved for their skillful help with the data collection.
Supported by the Cancer Society of Stockholm and the King Gustav V Jubilee Fund, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
1. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview over the randomised trials. Lancet 351:1451–1467, 1998[CrossRef][Medline] 2. Fornander T, Rutqvist LE, Wilking N, et al: Oestrogenic effects of adjuvant tamoxifen in postmenopausal breast cancer. Eur J Cancer 29A:497–500, 1993[CrossRef][Medline] 3. Wolf DM, Jordan VC: Gynecologic complications associated with long-term adjuvant tamoxifen therapy for breast cancer. Gynecol Oncol 45:118–128, 1992[CrossRef][Medline]
4. Day R, Ganz PA, Constantino 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 P-1 study. J Clin Oncol 17:2659–2669, 1999
5. Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifen for breast cancer: Twenty-eight years later. J Clin Oncol 13:513–529, 1995 6. Powles TJ, Jones AL, O’Brien MER, et al: The Royal Marsden Hospital pilot tamoxifen chemoprevention study. Breast Cancer Res Treat 31:73–82, 1994[CrossRef][Medline] 7. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: An overview over the randomized trials. Lancet 348:1189–1196, 1996[CrossRef][Medline]
8. Boccardo F, Rubagotti A, Perotta A, et al: Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: Results of a multicentric Italian study. Ann Oncol 5:337–442, 1994 9. Jonat W: Luteinising hormone-releasing hormone analogues: The rationale for adjuvant use in premenopausal women with early breast cancer. Br J Cancer 78:5–8, 1998 10. Jonat W, Kaufmann M, Blamey RW, et al: A randomised study to compare the effect of luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer 31A:137–142, 1995[CrossRef][Medline] 11. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930–942, 1998[CrossRef][Medline] 12. Knobf MT: Natural menopause and ovarian toxicity associated with breast cancer therapy. Oncol Nurs Forum 25:1519–1530, 1998[Medline] 13. Young-McCaughan S: Sexual functioning in women with breast cancer after treatment with adjuvant therapy. Cancer Nurs 19:308–319, 1996[CrossRef][Medline] 14. Fallowfield LJ, Leaity SK, Howell A, et al: Assessment of quality of life in women undergoing hormonal therapy for breast cancer: Validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat 55:189–199, 1999[Medline]
15. Goodwin PJ, Ennis M, Pritchard KI, et al: Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis. J Clin Oncol 17:120–129, 1999 16. McPhail G: Menopause as an issue for women with breast cancer. Cancer Nurs 22:164–171, 1999[CrossRef][Medline] 17. Collins A, Landgren B-M: Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: A population-based study. Maturitas 20:101–111, 1995 18. Dow KH, Ferell BR, Leigh S, et al: An evaluation of the quality of life among long-term survivors of breast cancer. Breast Cancer Res Treat 39:261–273, 1996[CrossRef][Medline] 19. Bleiker EM, Pouwer F, van der Ploeg HM, et al: Psychological distress two years after diagnosis of breast cancer: Frequency and prediction. Patient Educ Couns 40:209–217, 2000[CrossRef][Medline] 20. Ganz PA, Coscarelli A, Fred C, et al: Breast cancer survivors: Psychosocial concerns and quality of life. Breast Cancer Res Treat 38:183–199, 1996[CrossRef][Medline] 21. Ellman R, Thomas BA: Is psychological wellbeing impaired in long term survivors of breast cancer? J Med Screen 2:5–9, 1995[Medline] 22. Nystedt M, Berglund G, Bolund C, et al: Randomized trial of adjuvant tamoxifen and/or goserelin in premenopausal breast cancer: Self-rated physiological effects and symptoms. Acta Oncol 39:959–968, 2000[CrossRef][Medline] 23. Stockholm Breast Cancer Study Group: Stockholm adjuvant breast cancer trials 5–8. Stockholm, Sweden, Oncologic Centre, 1992 24. Berner M, Bobbit RA, Carter WB, et al: The Sickness Impact Profile: Development and final revision of a health status measure. Med Care 19:787–805, 1981[Medline] 25. Hunt SM, McKenna SP, McEwen J: The Nottingham Health Profile: Subjective health status and medical consultations. Soc Sci Med 15:221–229, 1981 26. Schipper H, Clinch J, McMurray A: Measuring the quality of life of cancer patients: The Functional Living Index-Cancer—Development and validation. J Clin Oncol 2:472–483, 1984[Abstract] 27. Heinrich RL, Schag CC, Ganz PA: Living with cancer: The Cancer Inventory of Problem Situations. J Clin Psychol 40:972–980, 1984[Medline] 28. Berglund G, Bolund C, Fornander T, et al: Late effects of adjuvant chemotherapy and postoperative radiotherapy on quality of life among breast cancer patients. Eur J Cancer 27:1075–1081, 1991[Medline] 29. Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370, 1983[Medline] 30. Herrmann C: International experiences with the Hospital Anxiety and Depression Scale: A review of validation data and clinical results. J Psychosom Res 42:17–41, 1996[Medline] 31. Howell DC: Statistical Methods of Psychology (ed 3). Belmont, CA, Duxbury Press, 1992 32. Polit D, Hungler B: Nursing Research: Principles and Methods. Philadelphia, PA, Lippincott, 1995, pp 416–419 33. Morris J, Coyle D: Quality of life questionnaires in cancer clinical trials: Imputing missing values. Psychooncology 3:215–222, 1994 34. Neymark N, Kiebert W, Torfs K, et al: Methodological and statistical issues of quality of life (QoL) and economic evaluation in cancer clinical trials: Report of a workshop. Eur J Cancer 34:1317–1333, 1998[CrossRef][Medline] 35. Rutqvist LE: Zoladex and tamoxifen as adjuvant therapy in premenopausal breast cancer: A randomised trial by the Cancer Research Campaign (C.R.C.) Breast Cancer Trials Group, the Stockholm Breast Cancer Study Group, The South-East Sweden Breast Cancer Group & the Gruppo Interdisciplinaire Valutazione Interventi in Oncologia (G.I.V.I.O.). Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 251) 36. Davidson N, O’Neill A, Vukov A, et al: Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: An Eastern Cooperative Oncology Group phase III intergroup trial (E5188, INT-0101). Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 249) 37. Jakesz R, Hausmaninger H, Samonigg H, et al: Comparison of adjuvant therapy with tamoxifen and goserelin vs. CMF in premenopausal stage I and II hormone-responsive breast cancer patients: Four-year results of Austrian Breast Cancer Study Group (ABCSG) Trial 5. Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 250) 38. Kaufman M, Minckwitz G: New hormones, in Bonnadonna G, Hortobagyi G, Gianni A (eds): Textbook of Breast Cancer. London, United Kingdom, Martin Dunetz Ltd, 1997, pp 297–304 39. Kumar NB, Allen K, Cantor A, et al: Weight gain associated with adjuvant tamoxifen therapy in stage I and II breast cancer: Fact or artifact? Breast Cancer Res Treat 44:135–143, 1997[CrossRef][Medline] 40. Hoskin PJ, Ashley S, Yarnold JR: Weight gain after primary surgery for breast cancer: Effect of tamoxifen. Breast Cancer Res Treat 22:129–132, 1992[CrossRef][Medline] 41. Juniper EF, Guyatt GH, Willan A, et al: Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 47:81–87, 1994[CrossRef][Medline]
42. Berglund G, Nystedt M, Bolund C, et al: Effect of endocrine treatment on sexuality in premenopausal breast cancer patients: A prospective randomized study. J Clin Oncol 19:2788–2796, 2001 Submitted April 2, 2002; accepted January 29, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test.
