- Email: [email protected]
Biography of Emmy Noether
Effect of Endocrine Treatment on Sexuality in Premenopausal Breast Cancer Patients: A Prospective Randomized Study By Gunilla Berglund, Marianne Nystedt, Christina Bolund, Per-Olow Sjo ¨ de´n, and Lars-Erik Rutquist Purpose: To study the sexual effects of the 2-year adjuvant goserelin (Zoladex [Zeneca AB, So ¨derta ¨ lje, Sweden]) alone, tamoxifen alone, and Zoladex and tamoxifen in combination (ZT) versus no adjuvant endocrine therapy among premenopausal breast cancer patients with or without chemotherapy in a controlled clinical trial (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients). Patients and Methods: This prospective study examined several aspects of sexuality through the use of self-administered questionnaires, which were completed by patients at seven points of assessment for 3 years after randomization. Results: Patients treated with chemotherapy had a higher level of sexual dysfunction than did patients who received no systemic treatment. The addition of endocrine treatment did not alter this result. In contrast, among patients who did not receive chemotherapy,
Zoladex and ZT produced a significantly higher level of dysfunction from 1 to 2 years after inclusion, as compared with those who received no endocrine treatment. Tamoxifen alone did not produce side effects. After termination of endocrine treatment, sexual dysfunction began to diminish. Those with chemotherapy had high and frequently increasing levels of dysfunction even after 2 to 3 years of independent of endocrine treatment. Zoladex had a negative effect on sexual fear, which was reduced by the addition of tamoxifen. Conclusion: Zoladex increased sexual dysfunction during treatment among patients without chemotherapy, but the disturbances of sexual functioning were reversible. The use of adjuvant chemotherapy was associated with continued sexual problems, even at 3 years after randomization. J Clin Oncol 19:2788-2796. © 2001 by American Society of Clinical Oncology.
ETERMINANTS OF sexual problems among healthy women seem to be multifactorial,1 and the relationship between the hormonal changes associated with menopause and sexuality is unclear.2 Chemotherapy (Ch) has been found to lower sexual activity during and after cancer treatment.3 Prior use of Ch has also been shown to be a predictor of poor sexual functioning at all ages4 and especially among young women who were made menopausal prematurely as a result of Ch.5 On the other hand, adjuvant tamoxifen does not seem to affect sexuality negatively in women older than 50 years,6 and women who received tamoxifen did not differ in this respect from those who had no systemic therapy.7 However, in a randomized study, the effect of adjuvant treatment with a luteinizing hormone-releasing hormone agonist, goserelin (Zoladex [Zeneca AB, So¨derta¨lje, Sweden]), administered to obtain a
chemical castration, was investigated with and without additional tamoxifen.8 The proportion of patients experiencing an adverse effect on sexual activity during treatment was 15% in the Zoladex group and 10% in the combined (ZT) group.8 To summarize, Ch has a negative effect on breast cancer patients’ sexuality both during and for some time after treatment, especially among premenopausal women.5 Tamoxifen does not seem to affect sexuality negatively among postmenopausal women,6 whereas there is little data available concerning younger women. The aims of the present study were to compare overall sexual functioning of groups of premenopausal breast cancer patients with and without Ch in a controlled clinical trial comparing treatment with Zoladex alone, tamoxifen alone, and the ZT combination versus endocrinologically untreated controls. The groups were monitored for 3 years after primary treatment, ie, 1 year after termination of the adjuvant endocrine treatment.
D
From the Departments of Oncology, Karolinska Hospital and Huddinge University Hospital, Stockholm; and Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. Supported by the Stockholm Cancer Society, Stockholm, Sweden. Submitted October 28, 1999; accepted March 1, 2001. Address reprint requests to Gunilla Berglund, PhD, Department of Public Health and Caring Sciences, Uppsala University, Uppsala Science Park, S-75183 Uppsala, Sweden; email: [email protected] or [email protected]. © 2001 by American Society of Clinical Oncology. 0732-183X/01/1911-2788
2788
PATIENTS AND METHODS
Patients The present study is part of a randomized clinical trial9 evaluating the effects of adjuvant endocrine treatment in premenopausal women with breast cancer (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients)(Fig 1). The inclusion criteria for the trial were (1) histologically verified invasive breast cancer, (2) premenopausal menstrual status (last menstruation ⬍ 6 months ago), (3)
Journal of Clinical Oncology, Vol 19, No 11 (June 1), 2001: pp 2788-2796
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2789
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY
axillary lymph nodes were also offered radiation therapy to the breast chest wall and the regional lymph nodes (50 Gy/5 weeks). Between 1990 and 1994, patients in the Stockholm area who agreed to participate in the randomized clinical trial (Fig 1) were asked to participate also in the present study. A total of 293 (72%) potentially eligible trial patients (149 with no Ch [NCh] and 144 with Ch) agreed to participate in the present study. Noninclusion was due to administrative failure (n ⫽ 40), language difficulties (n ⫽ 20), declined participation (n ⫽ 21), and concurrent disease (n ⫽ 7). There were no statistically significant differences between participants and nonparticipants concerning allocated endocrine therapy, type of surgery, or age (data not shown). Demographic and medical characteristics of the 293 included patients are listed in Table 1. Only the proportion of unmarried patients differed significantly (Table 1) between the ZT and the Zoladex groups (P ⬍ .05).
Procedure Fig 1. Study design: All patients treated with breast conservation were offered radiotherapy to the breast parenchyma (50 Gy/5 weeks). Abbreviations: pT, pathologic tumor; pN, pathologic node; CMF, cyclophosphamide, methotrexate, and fluorouracil.
primary surgery consisting of a modified radical mastectomy or a sector resection plus axillary dissection, (4) histopathologic tumor size ⱖ 10 mm with or without node-positive axillary nodes, and (5) no clinical evidence of distant metastases. Exclusion criteria were (1) inoperable breast cancer, (2) prior radiotherapy, and (3) prior Ch and/or current hormonal therapy. Patients were thus eligible irrespective of their hormone receptor status. The trial design was prospective, including four randomization groups: (1) Zoladex, (2) ZT, (3) tamoxifen, and (4) control. The duration of endocrine treatment was 2 years. All patients with node-positive disease were offered six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil–type Ch. Patients with four or more positive
Table 1.
In conjunction with providing information about the clinical trial, a research nurse informed the patients about the present study. The voluntary nature of the study was emphasized and confidentiality was guaranteed. The Karolinska Institute Regional Ethics Committee approved the randomized clinical trial as well as the present study. There were seven points of assessment (the numbers and percentages of NCh and Ch patients, respectively, are listed): (1) baseline, occurring after surgery but before randomization and before decisions about adjuvant systemic treatment (n ⫽ 149 [100%]/142 [99%]), (2) 3 to 4 months after randomization (n ⫽ 143 [95%]/139 [97%]), (3) 12 months after randomization (n ⫽ 136 [91%]/128 [89%]), (4) 18 months after randomization (n ⫽ 132 [89%]/118 [82%]), (5) 24 months after randomization (n ⫽ 125 [84%]/115 [80%]), (6) 30 months after randomization (n ⫽ 120 [81%]/106 [74%]), and (7) 36 months after randomization (n ⫽ 129 [87%]/115 [80%]). Patient attrition during the 3 years was due to medical reasons (mainly disease recurrence varying between zero and 9% at different points of assessment), administrative failures (⬍ 1% to 4%), declined
Demographic and Medical Characteristics of the Study Sample Randomization Group
ZT Characteristic
No.
No. Age, years Stages pT ⬎ 10 (pN0) pN 1-3 pN 4 ⫹ Additional treatment Chemotherapy Chemo- and radiotherapy No additional treatment Surgery Radical mastectomy Partial mastectomy Civil status Married/cohabitant Single
Z %
80
27
No.
74
45.3
T %
25
No.
67
45.7
C %
23
No.
%
73
44.9
25 45.1
39 28 13
49 35 16
38 25 11
51 34 15
35 21 11
52 31 16
38 24 11
52 33 15
20 21 20
25 26 25
17 18 20
23 24 27
16 16 15
24 24 22
13 21 17
18 29 23
48 32
60 40
41 33
55 45
36 31
54 46
39 34
53 47
68 12
85 15
48 25
65 34
49 17
73 25
51 22
70 30
Abbreviations: Z, Zoladex; T, tamoxifen; C, control; pT, pathologic tumor; pN, pathologic node.
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2790
BERGLUND ET AL Table 2.
Patient Attrition at Seven Points of Assessment
Administrative Failure (n)
Change of Residence (cum n)
Declined Participation (n)
Medical Reasons (n)
Deceased (cum n)
No.
%
2 5 8 9 13 9 2
0 1 1 (2) 1 (3) 1 (4) 0 (4) 0 (4)
0 3 7 10 7 11 5
0 2 11 17 21 26 16
0 0 1 3 (4) 5 (9) 8 (17) 5 (22)
2 11 29 43 53 67 49
0.6 4 10 15 18 23 17
1
15
0-9
Baseline 3-4 months 12 months 18 months 24 months 30 months 36 months %
1-4
Total
8
Abbreviation: cum, cumulative.
further participation (15%), death (8%), or change of residence (1%) (Table 2). Patients completed the questionnaires in connection with their regular medical check-ups at outpatient clinics. At the first assessment, the research nurse was present in case the patient had questions regarding the questionnaire. Background data on stage of disease, type of surgery, additional treatment, marital status, and so on were collected at inclusion (Table 1). The Relationship and Sexuality Scale, a 19-item questionnaire developed for the assessment of patients’ relationships and sexuality, was used (Appendix 1). Patient perceptions were assessed concerning emotional closeness (or distance) in relationships, affection, sexual desire, arousal, orgasm, and frequency of sexual intercourse. Some aspects of the relationship and sexual activity were assessed for the period of the previous 2 weeks. Most response formats used ordinal category scales (0 to 3 or 0 to 4) (Appendix 1). Numbers indicate problem levels. A factorial analysis was performed on 13 items in this scale (varimax, oblique rotation, eigenvalues ⬎ 1). Six items were excluded because they did not concern sexuality or relationship (item 1), were completed only by a minority of patients (items 17 and 18), or because their scale was not ordinal (items 5, 14, and 19). Criteria for included items were at least one interitem correlation of ⱖ 0.40, and factor loading of ⱖ 0.40 (items 6, 7, and 15 omitted).10 Three factors explained 35%, 15%, and 12% of the variance, respectively. Interfactor correlations were 0.52 to 0.60. Factor 1 (alpha ⫽ 0.88) was sexual function (SFU) and included items 2, 3, 4, 11, and 12 (range, zero to 18). Factor 2 (alpha ⫽ 0.77) was sexual frequency (SFR) and included items 8, 13, and 16 (range, zero to 8). Factor 3 was sexual fear (SF) and included items 9 and 10 (range, zero to eight). Alpha could not be estimated for factor 3 because only two items were included. The interitem correlation was 0.34. Items 1, 5, 6, 7, 14, and 15 (single items), not included in any of the factors, were analyzed separately.
Statistical Methods 2 was performed to test the demographic comparability of groups (Table 1). Analyses of variance (repeated measures) were performed on a four-factor design involving (1) Ch versus NCh, (2) Zoladex versus no Zoladex (NZ), (3) tamoxifen versus no tamoxifen (NT), and (4) the points of assessment.11 Separate analyses were performed at 2 years (ie, at the end of endocrine treatment) including all previous assessments, and at 3 years including the baseline, 30-month, and 36-month assessments. These two points of analysis were chosen as a compro-
mise so as not to lose patients who dropped out after the 2-year completion of endocrine treatment and yet cover the treatment period as a whole. In case of significant interactions, between-group comparisons were performed using the Tukey honest significance difference test. T tests of independent samples were used for comparisons between the two means (Table 3). Missing values in the Relationship and Sexuality Scale were replaced by the individual scores recorded at the previous assessment,12 or as the mean of two adjacent scores. A two-sided P value of less than .05 was considered statistically significant. To test the reliability of the chosen substitution method, one variable (information at 2.5 years with 11 missing values) was chosen at random for comparison with an alternative method. Using the method described above, mean values for the control, tamoxifen, Zoladex, and ZT groups were 1.60, 1.67, 1.73, and 1.78, respectively. The substitution of missing values by group means yielded the values 1.61, 1.70, 1.75, and 1.80, respectively. The correlation between the resulting two distributions was 0.99. The number of substituted missing values varied between zero and 14 for different items and assessment points between them.
Table 3.
Factor Structure of the Relationship and Sexuality Scale Factor Loading, Oblique Rotation
Factor Item
Sexual function 2. Negatively affected 3. Disease–sexual arousal 4. Treatment–sexual arousal 11. Frequency of intercourse 12. Possibility to reach orgasm Sexual frequency 8. Hugs and kisses 13. Satisfied with frequency 15. Intercourse last 2 weeks Sexual fear 9. Afraid of intercourse 10. Partner afraid Variance explained, %
Factor 1
Factor 2
Factor 3
0.82 0.80 0.98 0.66 0.67
0.14 ⫺0.20 ⫺0.08 0.07 0.15
0.07 0.27 ⫺0.07 0.29 ⫺0.05
⫺0.07 0.32 0.08
0.69 0.80 0.62
0.28 ⫺0.15 0.21
0.22 0.22 35
⫺0.00 0.30 15
0.70 0.67 12
*Each factor includes underlined items below.
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2791
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY Table 4.
Sexual Activity Among Women at Baseline and 2 Years Later
2 Year Assessment
Activity Inactivity
Baseline Activity
Baseline No Activity
n ⫽ 145 67% n ⫽ 22 10%
n ⫽ 21 10% n ⫽ 29 13%
RESULTS
Sexual Activity At baseline, 77% of the patients considered themselves to be sexually active. Approximately 67% of the total patient group reported some degree of sexual activity (Appendix 1, item 5) at baseline and 2 years later, whereas 13% reported no activity. An additional 10% of patients were active at baseline and inactive 2 years later, whereas the reverse was true for another 10% (Table 4). Effects of Ch, Zoladex, Tamoxifen, and Assessment on SFU, SFR, and SF Ch/NCh, Zoladex/NZ, tamoxifen/NT, and assessments are listed for SFU in Table 5, for SFR in Table 6, and for SF in Table 7. Separate analyses were performed for sexually active patients and for all patients, including the sexually inactive. The latter group could not be analyzed separately due to its small size. Response patterns were similar in both analyses but somewhat more distinct when based only on the sexually active. Thus results are listed for this group only. Table 5.
For SFU during the first 2 years, there were significant main negative effects of Ch (Table 5) (F ⫽ 7.36 [1,168], P ⬍ .01), Zoladex (F ⫽ 4.73 [1,168], P ⬍ .05), and assessment (F ⫽ 3.60 [3,594], P ⬍ .05). In addition, the two-way interaction for Zoladex ⫻ assessment was significant (F ⫽ 2.69 [3,507], P ⬍ .05), ie, the negative effect of Zoladex increased with time, whereas the NZ groups (control and tamoxifen) were maintained at the same level. Likewise, the Ch ⫻ Zoladex interaction (F ⫽ 8.24 [1.168], P ⬍ .01) indicates that Zoladex had a negative effect on NCh patients and no effect on patients administered Ch. The three-way interactions among Ch ⫻ Zoladex ⫻ tamoxifen (F ⫽ 6.70 [1,168], P ⬍ .01) indicate that the effect of Zoladex was negative only among NCh patients and likewise when tamoxifen was added, whereas tamoxifen alone had no such negative effect. On the contrary, among patients administered Ch there was no additional effect from the use of Zoladex, ZT, or tamoxifen. The Ch ⫻ Zoladex ⫻ assessment interaction (F ⫽ 2.90 [3,507], P ⬍ .05) indicates that Zoladex had a negative effect only on NCh patients, that the effect increased by assessment, and that there was no negative effect on patients administered Ch. Finally, Zoladex ⫻ tamoxifen ⫻ assessment (F ⫽ 3.69 [3,507], P ⬍ .05) showed that tamoxifen had a negative effect only when added to Zoladex and not alone and that the effect worsened each assessment, whereas the control and tamoxifen did not deteriorate over assessments. Post hoc tests (honest significance difference) were computed between groups with and without Ch (eg, Zoladex with and without Ch), whereas
Mean Values for Sexual Function Among Sexually Active Patients With or Without Chemotherapy, Zoladex, and Tamoxifen at 7 Points of Assessment
Without chemotherapy Control T Z ZT With chemotherapy Control T Z ZT
CTX
Z
T
No.
Baseline/ Covariate
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0* 0 0 0
0* 0 1 1
0* 1 0 1
16-18 19-20 19-22 29-31
8.00 7.40 7.18 8.39
7.39 8.08 8.27 8.69
6.92 7.98 9.91 9.76
6.72 7.75 10.20 9.87
6.94 8.48 10.80 9.79
7.13 8.05 9.55 9.41
7.25 7.84 9.11 9.24
1 1 1 1
0 0 1 1
0 1 0 1
16-20 17-18 16-17 26-31
8.10 7.89 9.53 8.52
10.58 8.97 9.94 10.26
10.90 9.11 9.76 11.03
10.48 9.81 10.03 10.47
9.88 10.42 10.53 10.76
10.34 10.53 10.66 10.65
11.19 10.35 10.75 11.38
Abbreviations: CTX, chemotherapy; Z, Zoladex; T, tamoxifen. *Zero (0) indicates “with” the specified treatment, and one (1) indicates “without” the specified treatment. NOTE. Underlined mean values: Z (0 1 0) versus controls (0 0 0) and ZT (0 1 1) versus controls (0 0 0) at the same point of assessment are significantly different (Tukey’s HSD). Bold numbers indicate significant differences between controls with (1 0 0) and without (0 0 0) chemotherapy, and so on. Two years: main negative effects of chemotherapy (F ⫽ 7.36 [1,168], P ⬍ .01), Zoladex (F ⫽ 4.73 [1,168], P ⬍ .05) and assessments (F ⫽ 3.60 [3,594], P ⬍ .05). Two-way interactions: Zol ⫻ assessment, (F ⫽ 2.69 [3,507], P ⬍ .05); chemotherapy ⫻ Zol, (F ⫽ 8.24 [1,168], P ⬍ .01). Three-way interactions: chemotherapy ⫻ Zol ⫻ Tam, (F ⫽ 6.7 [1,168], P ⬍ .01); chemotherapy ⫻ Zol ⫻ assessment, (F ⫽ 2.90 [3,507], P ⬍ .05); and Zol ⫻ Tam ⫻ assessment, (F ⫽ 3.69 [3,507], P ⬍ .05). Baseline, 30, and 36 months: main negative effect of chemotherapy (F ⫽ 12.33 [1,149], P ⬍ .001).
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2792
BERGLUND ET AL Table 6.
Without chemotherapy Control Tamox Zoladex ZolTam With chemotherapy Control Tamox Zoladex ZolTam
Mean Values for Sexual Frequency Among Sexually Active Patients
CTX
Z
T
No.
Baseline
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0 0 0 0
0 0 1 1
0 1 0 1
15-18 17-21 20-22 28-31
5.06 4.71 4.41 4.87
4.72 4.88 5.59 4.84
5.44 4.76 6.16 5.02
5.03 3.97 6.36 5.32
4.64 4.92 6.77 5.02
5.53 4.50 6.40 5.46
5.80 4.94 5.80 5.36
1 1 1 1
0 0 1 1
0 1 0 1
15-20 17-18 16-17 26-31
5.40 5.39 5.24 5.39
5.90 5.50 5.82 5.35
5.95 5.14 5.82 6.32
6.13 5.83 5.65 5.48
6.18 6.50 6.09 5.68
6.10 6.59 6.06 6.08
6.00 7.00 6.00 6.69
NOTE. No significant main effects or interactions.
randomization groups were compared for groups with and without Ch separately (Table 5). In the analysis based on the baseline, 30-month, and 36-month assessments, there was a significant main negative effect of Ch only (F ⫽ 12.33 [1,149], P ⬍ .001). SFU problems among patients administered Ch did not decrease over the 3 years of assessment despite the fact that both Ch and endocrine treatment had been stopped. Thus, when added to Ch, endocrine treatment did not make sexual side effects worse. The negative effect of Ch or of the disease itself did not diminish with time or at the termination of Ch or endocrine treatment. To summarize, during endocrine treatment (at 12, 18, and 24 months) there were significant differences between the Zoladex and ZT groups and control group among those who did not receive Ch. However, patients administered the ZT combination did not differ significantly from the Zoladex group. Thus Zoladex had a negative effect on SFU during treatment that was not reduced by the addition of tamoxifen. However, all
Table 7.
Without chemotherapy Control Tamox Zoladex ZolTam With chemotherapy Control Tamox Zoladex ZolTam
endocrine treatment effects were reversible on cessation of treatment. Among patients administered Ch, endocrine treatment did not change dysfunction levels significantly. The control group with Ch had significantly major negative effects on SFU as compared with the NCh control group throughout the 3 years. At 36 months, all the NCh groups reported fewer negative effects than all the Ch groups. For SFR, there was no significant main effect or interaction, but there was a tendency for a Ch ⫻ Zoladex ⫻ assessment interaction (F ⫽ 2.52 [3,510], P ⬍ .06) in the 2-year analysis. Due to the absence of a significant difference, group means were not analyzed in a post hoc test. For SF, there was a main negative effect of Zoladex during endocrine treatment (baseline to 24 months) (F ⫽ 6.04 [1,181], P ⬍ .05) and afterward (baseline to 30 months and 36 months) (F ⫽ 4.44 [1,166], P ⬍ .05). There was a significant two-way interaction during the first 2 years for Zoladex ⫻ tamoxifen (F ⫽ 6.65 [1,181], P ⬍ .05), ie,
Mean Values for Sexual Fear Among Sexually Active Patients
CTX
Z
T
No.
Baseline Covariate
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0 0 0 0
0 0 1 1
0 1 0 1
19-21 21-22 22-24 32-33
0.86 0.64 0.29 0.79
0.53 0.73 0.79 0.39
0.67 0.73 1.29 0.55
0.52 0.57 1.38 0.59
0.43 0.70 1.54 0.79
0.16 0.33 1.59 0.97
0.74 0.60 1.20 0.73
1 1 1 1
0 0 1 1
0 1 0 1
16-21 17-18 17-18 30-34
0.52 0.78 0.94 0.79
1.05 0.94 1.29 1.12
0.67 0.69 1.41 1.18
0.67 1.00 1.59 1.00
0.57 0.83 1.32 1.07
0.75 1.12 1.36 1.32
1.00 1.41 1.33 1.42
NOTE. Underlined mean values among patients without chemotherapy: Z (0 1 0) versus controls (0 0 0), ZT (0 1 1), and T (0 0 1) at the same point of assessment are significantly different (Tukey’s HSD), likewise indicated with italics among patients with chemotherapy. Bold numbers indicate significant differences between groups with and without chemotherapy. Two-years: main negative effect of Zoladex, (F ⫽ 6.04 [1,181], P ⬍ .05). Two-way interaction: Zol ⫻ Tam, (F ⫽ 6.65 [1,181], P ⬍ .05). Baseline, 30-, and 36 months: main negative effect of Zoladex, (F ⫽ 4.44 [1,166], P ⫽ .05). Two-way interaction: Zol ⫻ Assess, (F ⫽ 8.30 [1,167], P ⬍ .005).
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2793
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY Table 8.
Sexually Active Patients Not Administered Chemotherapy Comparisons at the 24-Month Assessment Mean Values
Item
Z (n ⫽ 23-26)
Controls (n ⫽ 20-22)
P
Factor
Negatively affected Disease–sexual arousal Treatment–sexual arousal Frequency of intercourse Possibility to reach orgasm No. of hugs and kisses Satisfaction with intercourse Frequency (no.) of intercourse Fear of intercourse Partner’s fear
1.62 1.76 1.82 3.12 2.67 1.66 2.39 2.98 1.04 0.46
0.27 1.19 1.13 2.43 2.02 1.10 1.76 1.83 0.10 0.32
⬍ .001 ⬍ .05 ⬍ .0001 ⬍ .01 ⬍ .005 ⬍ .01 NS ⬍ .01 ⬍ .01 NS
Sexual func Sexual func Sexual func Sexual func Sexual func Frequency Frequency Frequency Fear Fear
Abbreviations: NS, not significant; func, function.
Zoladex alone was significantly more burdensome than in combination with tamoxifen among Ch and NCh patients, whereas the effects of tamoxifen alone were similar to the effects of the combination. During the follow-up period (baseline to 30 months and 36 months), the interaction was between Zoladex ⫻ assessment (F ⫽ 8.30 [1,167], P ⬍ .005), ie, negative effects increased with time for patients administered Zoladex, whereas it did not for the NZ groups (control and tamoxifen). Thus endocrine treatment for patients administered Ch had no negative impact on SFU and SFR but did have a negative impact on SF. In contrast, the negative impact of Zoladex as compared with control among NCh patients included both SFU and SF. Tamoxifen alone and in combination decreased SF among all patients independent of Ch/NCh. Comparisons of Zoladex and Control Groups on SFU, SFR, and SF at 24 Months
Vaginal Dryness
T tests were performed between the NCh Zoladex and control groups concerning the specific items included in SFU, SFR, and SF at the 24-month assessment, which was Table 9.
the assessment point of maximal differences (Table 8). The Zoladex group had a consistently higher dysfunction level concerning all SFU items than did the control group. These items included whether sexual life had been negatively affected after the onset of the cancer disease, the cancer disease affecting sexual arousal, cancer treatment affecting sexual arousal, the change of frequency of sexual intercourse, and the capacity to reach orgasm as compared with before the onset of breast cancer. Two of the SFR items differed in the same direction significantly between the Zoladex and the control groups, ie, frequency of intercourse and quantity of hugs and kisses during the last 2 weeks. Patients’ fear of intercourse was significantly higher in the Zoladex group than in the control group. This was not the case for the partners of these patients (Table 8).
Sexual activity was not related to vaginal dryness. Furthermore, among patients with moderate to severe problems, sexual activity was high (Table 9).
Vaginal Dryness and Its Relation to Sexual Activity and the Factors of Sexual Function, Sexual Frequency, and Sexual Fear at the Peak of Symptoms (24-month follow-up)
Control patients Tamoxifen patients Zoladex patients Zoldex ⫹ tamoxifen Sexually active Sexually inactive
Factor function Factor frequency Factor fear
Minor Problems With Vaginal Dryness (n ⫽ 221)
Major Problems With Vaginal Dryness (n ⫽ 32)
56 54 49 62 144 45
6 6 12 8 22 5
Mean
Mean
9.44 4.36 1.72
12.24 5.43 2.48
2
3.69 0.37
P
3,253
NS
1,216
NS
t
⫺3.74 ⫺2.35 ⫺2.28
P
201 206 204
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⬍ .0005 ⬍ .05 ⬍ .05
2794
BERGLUND ET AL
The majority (70%) of the women in the present study had lost their menses at the 2-year follow-up. Problems with SFU were significantly higher among these women (n ⫽ 132; mean, 10.17; SD, 4.03) as compared with women still menstruating (n ⫽ 31; mean, 8.37; SD, 3.30). The high number of patients with menses loss also among the tamoxifen and control groups suggests that many women were perimenopausal rather than purely premenopausal. Patient Information Analysis of variance (repeated measure) was used to analyze three-way interactions among Ch, Zoladex, tamoxifen, and assessment concerning patient satisfaction with information about possible effects of disease and treatment on sexuality. All patient groups rated their satisfaction with received information significantly higher with time, during the first 2 years (F ⫽ 79.64 [4,1044], P ⬍ .000) and from baseline to 30 months and 36 months (F ⫽ 123.30 [2,482], P ⬍ .000). There was a significant two-way interaction between Ch and assessment during the first 2 years (F ⫽ 4.16 [4,1044], P ⬍ .005) with groups in which patients were administered Ch generally more satisfied than NCh patients, whereas all groups improved significantly over time. At 24 months after inclusion, approximately 27% of patients stated that they had received insufficient information. DISCUSSION
The randomized trial that formed the basis for the current trial was closed for patient entry in 1996. All patients allocated to systemic treatment as part of the trial have thus had the opportunity to conclude their 2-year treatment schedule. A first analysis of treatment efficacy at a median follow-up of approximately 4 years was recently presented.13 There was a statistically significant benefit among patients allocated Zoladex in terms of event-free survival. Their relative hazards ratio (compared with patients not allocated Zoladex) was 0.77 (95% confidence interval, 0.66 to 0.90, P ⬍ .001), which corresponds to a relative reduction of events with 23% of patients. The benefit of Zoladex seemed to be somewhat less among those who received concurrent tamoxifen, but the difference compared with patients treated with Zoladex alone was not statistically significant. There was also a survival difference favoring the Zoladex-allocated patients (relative hazards ratio, 0.82; 95% confidence interval, 0.67 to 1.05), but this difference was not statistically significant (P ⫽ .12). Zoladex improves treatment outcome also when added to adjuvant cytotoxic Ch.14,15 The purpose of the Sex and Relationship Scale elaborated for the present study was to distinguish effects on sexuality of Zoladex, tamoxifen, and the combination of ZT among patients receiving Ch and NCh. Factor analysis was used for
data reduction and scale construction. Three factors explained 62% of the variance and the scale differentiated between adjuvant treatments with and without Ch. Administration of endocrine treatment to patients receiving Ch had no significant impact on SFU and SFR. Although problem levels decreased after the cessation of endocrine treatment among patients not receiving systemic treatment, patients administered Ch maintained a high level of dysfunction throughout the study period. Their dysfunction levels during the first 2 years were comparable to those of the Zoladex group among patients with no Ch. These negative effects of Ch are in line with findings of other researchers eg, Schover et al16 and Ganz et al.6,17 One possible explanation is that Ch disrupts hormone production by the ovaries. Circulating levels of estrogens decrease, accompanied by elevated levels of follicle-stimulating hormone and luteinizing hormone. Also levels of androgens, which are assumed to promote sexual desire, decrease. These effects of Ch may be so strong that the effects of other systemic treatments (eg, Zoladex) are masked by Ch. Neither the present study nor that by Ganz et al17 found any effect of tamoxifen when added to Ch (except SF). Thus the present findings mainly contradict Kaplan’s suggestion18 that the addition of Zoladex or tamoxifen to Ch exacerbates its sexual side effects. Some studies19,20 have demonstrated the role of androgens in the maintenance of sexual interest after surgical menopause. However, Cawood et al1 found no evidence that hormonal parameters at baseline predict measures of sexuality. The differences in sexual function obtained by endocrine treatment and Ch in the present randomized study could be assumed to have been occasioned by differences in estrogens and androgens caused by Ch and Zoladex. Zoladex and ZT had a significant negative effect on most parameters of sexuality among patients not receiving Ch. Women treated with Zoladex or ZT perceived their sexuality as negatively affected by cancer treatment and their disease. Frequency of sexual intercourse also diminished for this patient group. Difficulty in attaining orgasm developed in all three endocrinologically treated groups but was worse among Zoladex-treated patients. The medical castration produced by Zoladex causes an endocrinologic postmenopausal status and, biologically, it could be expected that the addition of tamoxifen would produce the same effect as among initially postmenopausal women, ie, sexuality would not be negatively affected.6 The findings of the present study suggest that tamoxifen does not significantly ameliorate the negative effect of Zoladex in this respect (except with respect to SF). Generally, tamoxifen alone did not differ significantly from Zoladex, ZT, or control. However, tamoxifen had a decreasing effect on SF and a positive effect on sexual intercourse in the entire patient group. Fornander et al21
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EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY
suggested that tamoxifen has weak estrogenic effects on the vaginal epithelium and increases the bioavailable fraction of androgens. This may explain the positive effect of tamoxifen alone and the ameliorating effect of its combination with Zoladex on SF and frequency of sexual intercourse. Patients administered Zoladex indicated more fear of sexual intercourse as compared with control patients and with those administered tamoxifen and the combination ZT. An interpretation of this fear among the Zoladex patients is that it is due to pain during sexual intercourse, ie, an effect of the castration causing poor lubrication and vaginal dryness.22 However, we found that 69% of the patients with pronounced problems of vaginal dryness were sexually active; ie, retaining sexual activity does not imply an absence of sexual problems. Thus other reinforcements maintain sexual activity despite this fear. This indicates the high degree of complexity of several problems. For node-negative patients, SFU dysfunctions diminished after the termination of Zoladex treatment, ie, at the 30month and 36-month assessments. At 3 years, problem
levels were similar to those before the start of Zoladex treatment with the exception of SF. It is probable that SF decreases more slowly than other sexual problems. In a quality-of-life study of survivors 8 years after breast cancer treatment, Dorval et al23 found that these women still reported lower satisfaction with their sexual life in general than women in the same age group who never had cancer. In the present study, the control groups controlled for endocrine treatment among patients with and without Ch. However, our design did not include a noncancer premenopausal group. Thus it is possible that negative effects of the cancer disease continue at an elevated level compared with what occurs in a noncancer control group. In conclusion, an increased use of Zoladex in the adjuvant setting seems reasonable due to its clinical benefit in terms of event-free survival and reversibility of sexual problems induced by Zoladex. Also, when added to Ch, Zoladex does not contribute to the deterioration in sexual functioning resulting from Ch. There is, however, a need for more research about how to ameliorate sexual problems during treatment.
APPENDIX Relationship and Sexuality Estimate the situation during the last two weeks. Answer all questions even if you have no permanent partner or if you have not initiated your sexual life yet after disease and treatment. Put a cross in the square which is the most appropriate in your case. 1. I think I have received sufficient information about how disease and treatment (including surgery) might affect my sexual life. _ don’t agree at all _ slightly agree _ agree a lot _ fully agree 2. My sexual life has been negatively affected after the initiation of the cancer disease. _ not at all _ slightly _ rather much _ much _ very much 3. The cancer disease has affected my sexual desire. _ increased _ no difference _ decreased _ all gone _ inadequate question 4. The cancer treatment has affected my sexual desire. _ increased _ no difference _ decreased _ all gone _ inadequate question 5. Sexual intercourse whenever I want is. . . . _ impossible, I don’t _ I don’t think of sex. I _ impossible, my partner _ sometimes possible. _ always possible. have any partner. don’t want to. is not able to or doesn’t want any sex. 6. My partner and I have got emotionally separated during the course of the disease. _ unchanged _ slightly _ rather much _ much _ very much 7. My partner and I have come closer during the course of the disease. _ unchanged _ slightly _ rather much _ much _ very much 8. I am satisfied with the frequency of hugs and kisses between us. _ not at all _ slightly _ rather much _ much _ very much 9. I am afraid of sexual intercourse. _ never _ rarely _ sometimes _ often _ always 10. I feel my partner is afraid of sexual intercourse. _ never _ rarely _ sometimes _ often _ always 11. The frequency of sexual intercourse has changed now as compared to before my breast cancer disease. _ increased a lot _ somewhat increased _ no change _ somewhat decreased _ inadequate question 12. My possibility to reach orgasm has changed now as compared to before my breast cancer disease. _ increased a lot _ somewhat increased _ no change _ somewhat decreased _ inadequate question
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_ inadequate question
_ inadequate question _ inadequate question _ inadequate question _ inadequate question _ inadequate question
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BERGLUND ET AL
APPENDIX (Cont’d) 13. I am satisfied with my present frequency of sexual intercourse. _ not at all _ slightly _ rather much _ much _ very much 14. I use oestrogen ointment or sticks. _ yes _ no 15. My female identity has been negatively affected after the initiation of the cancer disease. _ not at all _ slightly _ rather much _ much _ very much 16. During the last two weeks I have had sexual intercourse _ no time. _ once. _ twice. _ three times. _ at least four times. SKIP THE FOLLOWING QUESTIONS IF YOU HAVEN’T HAD SEXUAL INTERCOURSE DURING LAST TWO WEEKS. 17. I have had an orgasm during sexual intercourse _ each time. _ mostly. _ about half of the times. _ rarely. _ never. 18. The sexual life is very pleasant for me. _ not at all _ slightly _ rather much _ much _ very much 19. The one taking initiative in sexual activity is mostly. . . _ me. _ my partner. _ both. _ don’t know. _ inadequate question
_ inadequate question
_ inadequate question _ inadequate question
_ inadequate question
REFERENCES 1. Cawood E, Bancroft J: Steroid hormones, the menopause, sexuality and well-being of women. Psychol Med 26:925-936, 1996 2. Collins A, Landgren BM: Reproductive health, use of estrogen and experience of symptoms in premenopausal women: A populationbased study. Maturitas 20:101-111, 1995 3. Valle J, Clemons M, Hayes S, et al: Sexuality in women receiving chemotherapy for breast cancer. Ann Oncol 8:617-618, 1997 4. Ganz PA, Rowland J, Meyerowitz B, et al: Breast cancer survivors (BCS): Sexuality and intimacy concerns. Breast Cancer Res Treat 37:35, 1996 (suppl, abstr 10) 5. Ganz PA: Sexual functioning after breast cancer: A conceptional framework for future studies. Ann Oncol 8:105-107, 1997 6. Ganz PA, Rowland JH, Desmond K, et al: Life after breast cancer: Understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 16:501-514, 1998 7. Schover LR: The impact of breast cancer on sexuality, body image, and intimate relationships. CA Cancer J Clin 41:112-120, 1991 8. Jonath W, Kaufmann M, Blamey RW, et al: A randomised study to compare the effect of the 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 9. Care Program Group, Breast Cancer: Stockholm adjuvant breast cancer trials 5-8. Stockholm-Gotland, Sweden, Onkologiskt Centrum, 1992 10. Statsoft: Statistica (ed 4): Tulsa, OK, Statsoft, 1994 11. Howell DC: Statistical Methods for Psychology (ed 3). Belmont, CA, Duxbury Press, 1992 12. 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 9:1317-1333, 1998 13. 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 Stock-
holm 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) 14. Davidson N, O’Neill A, Vukov A, et al: Effects 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) 15. 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 the Austrian Breast Cancer Study Group (ABCSG) Trial 5. Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 250) 16. Schover LR, Yetman RJ, Tuason LJ, et al: Partial mastectomy and breast reconstruction: A comparison of their effects on psychosocial adjustment, body image and sexuality. Cancer 75:5464, 1995 17. Ganz PA, Rowland JH, Meyerowitz BE, et al: Impact of different adjuvant therapy strategies on quality of life in breast cancer survivors. Recent Results Cancer Res 152:396-411, 1998 18. Kaplan HS: The sexual side effects of current treatments for breast cancer. J Sex Marital Ther 18:3-19, 1992 19. Scherwin BB, Gelfand MM: The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 49:397-409, 1987 20. Scherwin BB: The psychoendocrinology. Ann Rev Sex Res II:181-198, 1991 21. Fornander T, Rutquist LE, Wilking N: Effects of tamoxifen on the female genital tract. Ann N Y Acad Sci 622:469-476, 1991 22. Nystedt M, Berglund G, Bolund C, et al: Adjuvant endocrine therapy in premenopausal breast cancer: Somatic and psychosocial consequences. Acta Oncol 39:959-968, 2000 23. Dorval M, Maunsell E, Descheˆs L, et al: Long term quality of life after breast cancer: Comparison of 8-year survivors with population controls. J Clin Oncol 16:478-494, 1998
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Zoladex and ZT produced a significantly higher level of dysfunction from 1 to 2 years after inclusion, as compared with those who received no endocrine treatment. Tamoxifen alone did not produce side effects. After termination of endocrine treatment, sexual dysfunction began to diminish. Those with chemotherapy had high and frequently increasing levels of dysfunction even after 2 to 3 years of independent of endocrine treatment. Zoladex had a negative effect on sexual fear, which was reduced by the addition of tamoxifen. Conclusion: Zoladex increased sexual dysfunction during treatment among patients without chemotherapy, but the disturbances of sexual functioning were reversible. The use of adjuvant chemotherapy was associated with continued sexual problems, even at 3 years after randomization. J Clin Oncol 19:2788-2796. © 2001 by American Society of Clinical Oncology.
ETERMINANTS OF sexual problems among healthy women seem to be multifactorial,1 and the relationship between the hormonal changes associated with menopause and sexuality is unclear.2 Chemotherapy (Ch) has been found to lower sexual activity during and after cancer treatment.3 Prior use of Ch has also been shown to be a predictor of poor sexual functioning at all ages4 and especially among young women who were made menopausal prematurely as a result of Ch.5 On the other hand, adjuvant tamoxifen does not seem to affect sexuality negatively in women older than 50 years,6 and women who received tamoxifen did not differ in this respect from those who had no systemic therapy.7 However, in a randomized study, the effect of adjuvant treatment with a luteinizing hormone-releasing hormone agonist, goserelin (Zoladex [Zeneca AB, So¨derta¨lje, Sweden]), administered to obtain a
chemical castration, was investigated with and without additional tamoxifen.8 The proportion of patients experiencing an adverse effect on sexual activity during treatment was 15% in the Zoladex group and 10% in the combined (ZT) group.8 To summarize, Ch has a negative effect on breast cancer patients’ sexuality both during and for some time after treatment, especially among premenopausal women.5 Tamoxifen does not seem to affect sexuality negatively among postmenopausal women,6 whereas there is little data available concerning younger women. The aims of the present study were to compare overall sexual functioning of groups of premenopausal breast cancer patients with and without Ch in a controlled clinical trial comparing treatment with Zoladex alone, tamoxifen alone, and the ZT combination versus endocrinologically untreated controls. The groups were monitored for 3 years after primary treatment, ie, 1 year after termination of the adjuvant endocrine treatment.
D
From the Departments of Oncology, Karolinska Hospital and Huddinge University Hospital, Stockholm; and Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. Supported by the Stockholm Cancer Society, Stockholm, Sweden. Submitted October 28, 1999; accepted March 1, 2001. Address reprint requests to Gunilla Berglund, PhD, Department of Public Health and Caring Sciences, Uppsala University, Uppsala Science Park, S-75183 Uppsala, Sweden; email: [email protected] or [email protected]. © 2001 by American Society of Clinical Oncology. 0732-183X/01/1911-2788
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PATIENTS AND METHODS
Patients The present study is part of a randomized clinical trial9 evaluating the effects of adjuvant endocrine treatment in premenopausal women with breast cancer (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients)(Fig 1). The inclusion criteria for the trial were (1) histologically verified invasive breast cancer, (2) premenopausal menstrual status (last menstruation ⬍ 6 months ago), (3)
Journal of Clinical Oncology, Vol 19, No 11 (June 1), 2001: pp 2788-2796
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2789
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY
axillary lymph nodes were also offered radiation therapy to the breast chest wall and the regional lymph nodes (50 Gy/5 weeks). Between 1990 and 1994, patients in the Stockholm area who agreed to participate in the randomized clinical trial (Fig 1) were asked to participate also in the present study. A total of 293 (72%) potentially eligible trial patients (149 with no Ch [NCh] and 144 with Ch) agreed to participate in the present study. Noninclusion was due to administrative failure (n ⫽ 40), language difficulties (n ⫽ 20), declined participation (n ⫽ 21), and concurrent disease (n ⫽ 7). There were no statistically significant differences between participants and nonparticipants concerning allocated endocrine therapy, type of surgery, or age (data not shown). Demographic and medical characteristics of the 293 included patients are listed in Table 1. Only the proportion of unmarried patients differed significantly (Table 1) between the ZT and the Zoladex groups (P ⬍ .05).
Procedure Fig 1. Study design: All patients treated with breast conservation were offered radiotherapy to the breast parenchyma (50 Gy/5 weeks). Abbreviations: pT, pathologic tumor; pN, pathologic node; CMF, cyclophosphamide, methotrexate, and fluorouracil.
primary surgery consisting of a modified radical mastectomy or a sector resection plus axillary dissection, (4) histopathologic tumor size ⱖ 10 mm with or without node-positive axillary nodes, and (5) no clinical evidence of distant metastases. Exclusion criteria were (1) inoperable breast cancer, (2) prior radiotherapy, and (3) prior Ch and/or current hormonal therapy. Patients were thus eligible irrespective of their hormone receptor status. The trial design was prospective, including four randomization groups: (1) Zoladex, (2) ZT, (3) tamoxifen, and (4) control. The duration of endocrine treatment was 2 years. All patients with node-positive disease were offered six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil–type Ch. Patients with four or more positive
Table 1.
In conjunction with providing information about the clinical trial, a research nurse informed the patients about the present study. The voluntary nature of the study was emphasized and confidentiality was guaranteed. The Karolinska Institute Regional Ethics Committee approved the randomized clinical trial as well as the present study. There were seven points of assessment (the numbers and percentages of NCh and Ch patients, respectively, are listed): (1) baseline, occurring after surgery but before randomization and before decisions about adjuvant systemic treatment (n ⫽ 149 [100%]/142 [99%]), (2) 3 to 4 months after randomization (n ⫽ 143 [95%]/139 [97%]), (3) 12 months after randomization (n ⫽ 136 [91%]/128 [89%]), (4) 18 months after randomization (n ⫽ 132 [89%]/118 [82%]), (5) 24 months after randomization (n ⫽ 125 [84%]/115 [80%]), (6) 30 months after randomization (n ⫽ 120 [81%]/106 [74%]), and (7) 36 months after randomization (n ⫽ 129 [87%]/115 [80%]). Patient attrition during the 3 years was due to medical reasons (mainly disease recurrence varying between zero and 9% at different points of assessment), administrative failures (⬍ 1% to 4%), declined
Demographic and Medical Characteristics of the Study Sample Randomization Group
ZT Characteristic
No.
No. Age, years Stages pT ⬎ 10 (pN0) pN 1-3 pN 4 ⫹ Additional treatment Chemotherapy Chemo- and radiotherapy No additional treatment Surgery Radical mastectomy Partial mastectomy Civil status Married/cohabitant Single
Z %
80
27
No.
74
45.3
T %
25
No.
67
45.7
C %
23
No.
%
73
44.9
25 45.1
39 28 13
49 35 16
38 25 11
51 34 15
35 21 11
52 31 16
38 24 11
52 33 15
20 21 20
25 26 25
17 18 20
23 24 27
16 16 15
24 24 22
13 21 17
18 29 23
48 32
60 40
41 33
55 45
36 31
54 46
39 34
53 47
68 12
85 15
48 25
65 34
49 17
73 25
51 22
70 30
Abbreviations: Z, Zoladex; T, tamoxifen; C, control; pT, pathologic tumor; pN, pathologic node.
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2790
BERGLUND ET AL Table 2.
Patient Attrition at Seven Points of Assessment
Administrative Failure (n)
Change of Residence (cum n)
Declined Participation (n)
Medical Reasons (n)
Deceased (cum n)
No.
%
2 5 8 9 13 9 2
0 1 1 (2) 1 (3) 1 (4) 0 (4) 0 (4)
0 3 7 10 7 11 5
0 2 11 17 21 26 16
0 0 1 3 (4) 5 (9) 8 (17) 5 (22)
2 11 29 43 53 67 49
0.6 4 10 15 18 23 17
1
15
0-9
Baseline 3-4 months 12 months 18 months 24 months 30 months 36 months %
1-4
Total
8
Abbreviation: cum, cumulative.
further participation (15%), death (8%), or change of residence (1%) (Table 2). Patients completed the questionnaires in connection with their regular medical check-ups at outpatient clinics. At the first assessment, the research nurse was present in case the patient had questions regarding the questionnaire. Background data on stage of disease, type of surgery, additional treatment, marital status, and so on were collected at inclusion (Table 1). The Relationship and Sexuality Scale, a 19-item questionnaire developed for the assessment of patients’ relationships and sexuality, was used (Appendix 1). Patient perceptions were assessed concerning emotional closeness (or distance) in relationships, affection, sexual desire, arousal, orgasm, and frequency of sexual intercourse. Some aspects of the relationship and sexual activity were assessed for the period of the previous 2 weeks. Most response formats used ordinal category scales (0 to 3 or 0 to 4) (Appendix 1). Numbers indicate problem levels. A factorial analysis was performed on 13 items in this scale (varimax, oblique rotation, eigenvalues ⬎ 1). Six items were excluded because they did not concern sexuality or relationship (item 1), were completed only by a minority of patients (items 17 and 18), or because their scale was not ordinal (items 5, 14, and 19). Criteria for included items were at least one interitem correlation of ⱖ 0.40, and factor loading of ⱖ 0.40 (items 6, 7, and 15 omitted).10 Three factors explained 35%, 15%, and 12% of the variance, respectively. Interfactor correlations were 0.52 to 0.60. Factor 1 (alpha ⫽ 0.88) was sexual function (SFU) and included items 2, 3, 4, 11, and 12 (range, zero to 18). Factor 2 (alpha ⫽ 0.77) was sexual frequency (SFR) and included items 8, 13, and 16 (range, zero to 8). Factor 3 was sexual fear (SF) and included items 9 and 10 (range, zero to eight). Alpha could not be estimated for factor 3 because only two items were included. The interitem correlation was 0.34. Items 1, 5, 6, 7, 14, and 15 (single items), not included in any of the factors, were analyzed separately.
Statistical Methods 2 was performed to test the demographic comparability of groups (Table 1). Analyses of variance (repeated measures) were performed on a four-factor design involving (1) Ch versus NCh, (2) Zoladex versus no Zoladex (NZ), (3) tamoxifen versus no tamoxifen (NT), and (4) the points of assessment.11 Separate analyses were performed at 2 years (ie, at the end of endocrine treatment) including all previous assessments, and at 3 years including the baseline, 30-month, and 36-month assessments. These two points of analysis were chosen as a compro-
mise so as not to lose patients who dropped out after the 2-year completion of endocrine treatment and yet cover the treatment period as a whole. In case of significant interactions, between-group comparisons were performed using the Tukey honest significance difference test. T tests of independent samples were used for comparisons between the two means (Table 3). Missing values in the Relationship and Sexuality Scale were replaced by the individual scores recorded at the previous assessment,12 or as the mean of two adjacent scores. A two-sided P value of less than .05 was considered statistically significant. To test the reliability of the chosen substitution method, one variable (information at 2.5 years with 11 missing values) was chosen at random for comparison with an alternative method. Using the method described above, mean values for the control, tamoxifen, Zoladex, and ZT groups were 1.60, 1.67, 1.73, and 1.78, respectively. The substitution of missing values by group means yielded the values 1.61, 1.70, 1.75, and 1.80, respectively. The correlation between the resulting two distributions was 0.99. The number of substituted missing values varied between zero and 14 for different items and assessment points between them.
Table 3.
Factor Structure of the Relationship and Sexuality Scale Factor Loading, Oblique Rotation
Factor Item
Sexual function 2. Negatively affected 3. Disease–sexual arousal 4. Treatment–sexual arousal 11. Frequency of intercourse 12. Possibility to reach orgasm Sexual frequency 8. Hugs and kisses 13. Satisfied with frequency 15. Intercourse last 2 weeks Sexual fear 9. Afraid of intercourse 10. Partner afraid Variance explained, %
Factor 1
Factor 2
Factor 3
0.82 0.80 0.98 0.66 0.67
0.14 ⫺0.20 ⫺0.08 0.07 0.15
0.07 0.27 ⫺0.07 0.29 ⫺0.05
⫺0.07 0.32 0.08
0.69 0.80 0.62
0.28 ⫺0.15 0.21
0.22 0.22 35
⫺0.00 0.30 15
0.70 0.67 12
*Each factor includes underlined items below.
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2791
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY Table 4.
Sexual Activity Among Women at Baseline and 2 Years Later
2 Year Assessment
Activity Inactivity
Baseline Activity
Baseline No Activity
n ⫽ 145 67% n ⫽ 22 10%
n ⫽ 21 10% n ⫽ 29 13%
RESULTS
Sexual Activity At baseline, 77% of the patients considered themselves to be sexually active. Approximately 67% of the total patient group reported some degree of sexual activity (Appendix 1, item 5) at baseline and 2 years later, whereas 13% reported no activity. An additional 10% of patients were active at baseline and inactive 2 years later, whereas the reverse was true for another 10% (Table 4). Effects of Ch, Zoladex, Tamoxifen, and Assessment on SFU, SFR, and SF Ch/NCh, Zoladex/NZ, tamoxifen/NT, and assessments are listed for SFU in Table 5, for SFR in Table 6, and for SF in Table 7. Separate analyses were performed for sexually active patients and for all patients, including the sexually inactive. The latter group could not be analyzed separately due to its small size. Response patterns were similar in both analyses but somewhat more distinct when based only on the sexually active. Thus results are listed for this group only. Table 5.
For SFU during the first 2 years, there were significant main negative effects of Ch (Table 5) (F ⫽ 7.36 [1,168], P ⬍ .01), Zoladex (F ⫽ 4.73 [1,168], P ⬍ .05), and assessment (F ⫽ 3.60 [3,594], P ⬍ .05). In addition, the two-way interaction for Zoladex ⫻ assessment was significant (F ⫽ 2.69 [3,507], P ⬍ .05), ie, the negative effect of Zoladex increased with time, whereas the NZ groups (control and tamoxifen) were maintained at the same level. Likewise, the Ch ⫻ Zoladex interaction (F ⫽ 8.24 [1.168], P ⬍ .01) indicates that Zoladex had a negative effect on NCh patients and no effect on patients administered Ch. The three-way interactions among Ch ⫻ Zoladex ⫻ tamoxifen (F ⫽ 6.70 [1,168], P ⬍ .01) indicate that the effect of Zoladex was negative only among NCh patients and likewise when tamoxifen was added, whereas tamoxifen alone had no such negative effect. On the contrary, among patients administered Ch there was no additional effect from the use of Zoladex, ZT, or tamoxifen. The Ch ⫻ Zoladex ⫻ assessment interaction (F ⫽ 2.90 [3,507], P ⬍ .05) indicates that Zoladex had a negative effect only on NCh patients, that the effect increased by assessment, and that there was no negative effect on patients administered Ch. Finally, Zoladex ⫻ tamoxifen ⫻ assessment (F ⫽ 3.69 [3,507], P ⬍ .05) showed that tamoxifen had a negative effect only when added to Zoladex and not alone and that the effect worsened each assessment, whereas the control and tamoxifen did not deteriorate over assessments. Post hoc tests (honest significance difference) were computed between groups with and without Ch (eg, Zoladex with and without Ch), whereas
Mean Values for Sexual Function Among Sexually Active Patients With or Without Chemotherapy, Zoladex, and Tamoxifen at 7 Points of Assessment
Without chemotherapy Control T Z ZT With chemotherapy Control T Z ZT
CTX
Z
T
No.
Baseline/ Covariate
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0* 0 0 0
0* 0 1 1
0* 1 0 1
16-18 19-20 19-22 29-31
8.00 7.40 7.18 8.39
7.39 8.08 8.27 8.69
6.92 7.98 9.91 9.76
6.72 7.75 10.20 9.87
6.94 8.48 10.80 9.79
7.13 8.05 9.55 9.41
7.25 7.84 9.11 9.24
1 1 1 1
0 0 1 1
0 1 0 1
16-20 17-18 16-17 26-31
8.10 7.89 9.53 8.52
10.58 8.97 9.94 10.26
10.90 9.11 9.76 11.03
10.48 9.81 10.03 10.47
9.88 10.42 10.53 10.76
10.34 10.53 10.66 10.65
11.19 10.35 10.75 11.38
Abbreviations: CTX, chemotherapy; Z, Zoladex; T, tamoxifen. *Zero (0) indicates “with” the specified treatment, and one (1) indicates “without” the specified treatment. NOTE. Underlined mean values: Z (0 1 0) versus controls (0 0 0) and ZT (0 1 1) versus controls (0 0 0) at the same point of assessment are significantly different (Tukey’s HSD). Bold numbers indicate significant differences between controls with (1 0 0) and without (0 0 0) chemotherapy, and so on. Two years: main negative effects of chemotherapy (F ⫽ 7.36 [1,168], P ⬍ .01), Zoladex (F ⫽ 4.73 [1,168], P ⬍ .05) and assessments (F ⫽ 3.60 [3,594], P ⬍ .05). Two-way interactions: Zol ⫻ assessment, (F ⫽ 2.69 [3,507], P ⬍ .05); chemotherapy ⫻ Zol, (F ⫽ 8.24 [1,168], P ⬍ .01). Three-way interactions: chemotherapy ⫻ Zol ⫻ Tam, (F ⫽ 6.7 [1,168], P ⬍ .01); chemotherapy ⫻ Zol ⫻ assessment, (F ⫽ 2.90 [3,507], P ⬍ .05); and Zol ⫻ Tam ⫻ assessment, (F ⫽ 3.69 [3,507], P ⬍ .05). Baseline, 30, and 36 months: main negative effect of chemotherapy (F ⫽ 12.33 [1,149], P ⬍ .001).
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BERGLUND ET AL Table 6.
Without chemotherapy Control Tamox Zoladex ZolTam With chemotherapy Control Tamox Zoladex ZolTam
Mean Values for Sexual Frequency Among Sexually Active Patients
CTX
Z
T
No.
Baseline
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0 0 0 0
0 0 1 1
0 1 0 1
15-18 17-21 20-22 28-31
5.06 4.71 4.41 4.87
4.72 4.88 5.59 4.84
5.44 4.76 6.16 5.02
5.03 3.97 6.36 5.32
4.64 4.92 6.77 5.02
5.53 4.50 6.40 5.46
5.80 4.94 5.80 5.36
1 1 1 1
0 0 1 1
0 1 0 1
15-20 17-18 16-17 26-31
5.40 5.39 5.24 5.39
5.90 5.50 5.82 5.35
5.95 5.14 5.82 6.32
6.13 5.83 5.65 5.48
6.18 6.50 6.09 5.68
6.10 6.59 6.06 6.08
6.00 7.00 6.00 6.69
NOTE. No significant main effects or interactions.
randomization groups were compared for groups with and without Ch separately (Table 5). In the analysis based on the baseline, 30-month, and 36-month assessments, there was a significant main negative effect of Ch only (F ⫽ 12.33 [1,149], P ⬍ .001). SFU problems among patients administered Ch did not decrease over the 3 years of assessment despite the fact that both Ch and endocrine treatment had been stopped. Thus, when added to Ch, endocrine treatment did not make sexual side effects worse. The negative effect of Ch or of the disease itself did not diminish with time or at the termination of Ch or endocrine treatment. To summarize, during endocrine treatment (at 12, 18, and 24 months) there were significant differences between the Zoladex and ZT groups and control group among those who did not receive Ch. However, patients administered the ZT combination did not differ significantly from the Zoladex group. Thus Zoladex had a negative effect on SFU during treatment that was not reduced by the addition of tamoxifen. However, all
Table 7.
Without chemotherapy Control Tamox Zoladex ZolTam With chemotherapy Control Tamox Zoladex ZolTam
endocrine treatment effects were reversible on cessation of treatment. Among patients administered Ch, endocrine treatment did not change dysfunction levels significantly. The control group with Ch had significantly major negative effects on SFU as compared with the NCh control group throughout the 3 years. At 36 months, all the NCh groups reported fewer negative effects than all the Ch groups. For SFR, there was no significant main effect or interaction, but there was a tendency for a Ch ⫻ Zoladex ⫻ assessment interaction (F ⫽ 2.52 [3,510], P ⬍ .06) in the 2-year analysis. Due to the absence of a significant difference, group means were not analyzed in a post hoc test. For SF, there was a main negative effect of Zoladex during endocrine treatment (baseline to 24 months) (F ⫽ 6.04 [1,181], P ⬍ .05) and afterward (baseline to 30 months and 36 months) (F ⫽ 4.44 [1,166], P ⬍ .05). There was a significant two-way interaction during the first 2 years for Zoladex ⫻ tamoxifen (F ⫽ 6.65 [1,181], P ⬍ .05), ie,
Mean Values for Sexual Fear Among Sexually Active Patients
CTX
Z
T
No.
Baseline Covariate
3-4 Months
12 Months
18 Months
24 Months
30 Months
36 Months
0 0 0 0
0 0 1 1
0 1 0 1
19-21 21-22 22-24 32-33
0.86 0.64 0.29 0.79
0.53 0.73 0.79 0.39
0.67 0.73 1.29 0.55
0.52 0.57 1.38 0.59
0.43 0.70 1.54 0.79
0.16 0.33 1.59 0.97
0.74 0.60 1.20 0.73
1 1 1 1
0 0 1 1
0 1 0 1
16-21 17-18 17-18 30-34
0.52 0.78 0.94 0.79
1.05 0.94 1.29 1.12
0.67 0.69 1.41 1.18
0.67 1.00 1.59 1.00
0.57 0.83 1.32 1.07
0.75 1.12 1.36 1.32
1.00 1.41 1.33 1.42
NOTE. Underlined mean values among patients without chemotherapy: Z (0 1 0) versus controls (0 0 0), ZT (0 1 1), and T (0 0 1) at the same point of assessment are significantly different (Tukey’s HSD), likewise indicated with italics among patients with chemotherapy. Bold numbers indicate significant differences between groups with and without chemotherapy. Two-years: main negative effect of Zoladex, (F ⫽ 6.04 [1,181], P ⬍ .05). Two-way interaction: Zol ⫻ Tam, (F ⫽ 6.65 [1,181], P ⬍ .05). Baseline, 30-, and 36 months: main negative effect of Zoladex, (F ⫽ 4.44 [1,166], P ⫽ .05). Two-way interaction: Zol ⫻ Assess, (F ⫽ 8.30 [1,167], P ⬍ .005).
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EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY Table 8.
Sexually Active Patients Not Administered Chemotherapy Comparisons at the 24-Month Assessment Mean Values
Item
Z (n ⫽ 23-26)
Controls (n ⫽ 20-22)
P
Factor
Negatively affected Disease–sexual arousal Treatment–sexual arousal Frequency of intercourse Possibility to reach orgasm No. of hugs and kisses Satisfaction with intercourse Frequency (no.) of intercourse Fear of intercourse Partner’s fear
1.62 1.76 1.82 3.12 2.67 1.66 2.39 2.98 1.04 0.46
0.27 1.19 1.13 2.43 2.02 1.10 1.76 1.83 0.10 0.32
⬍ .001 ⬍ .05 ⬍ .0001 ⬍ .01 ⬍ .005 ⬍ .01 NS ⬍ .01 ⬍ .01 NS
Sexual func Sexual func Sexual func Sexual func Sexual func Frequency Frequency Frequency Fear Fear
Abbreviations: NS, not significant; func, function.
Zoladex alone was significantly more burdensome than in combination with tamoxifen among Ch and NCh patients, whereas the effects of tamoxifen alone were similar to the effects of the combination. During the follow-up period (baseline to 30 months and 36 months), the interaction was between Zoladex ⫻ assessment (F ⫽ 8.30 [1,167], P ⬍ .005), ie, negative effects increased with time for patients administered Zoladex, whereas it did not for the NZ groups (control and tamoxifen). Thus endocrine treatment for patients administered Ch had no negative impact on SFU and SFR but did have a negative impact on SF. In contrast, the negative impact of Zoladex as compared with control among NCh patients included both SFU and SF. Tamoxifen alone and in combination decreased SF among all patients independent of Ch/NCh. Comparisons of Zoladex and Control Groups on SFU, SFR, and SF at 24 Months
Vaginal Dryness
T tests were performed between the NCh Zoladex and control groups concerning the specific items included in SFU, SFR, and SF at the 24-month assessment, which was Table 9.
the assessment point of maximal differences (Table 8). The Zoladex group had a consistently higher dysfunction level concerning all SFU items than did the control group. These items included whether sexual life had been negatively affected after the onset of the cancer disease, the cancer disease affecting sexual arousal, cancer treatment affecting sexual arousal, the change of frequency of sexual intercourse, and the capacity to reach orgasm as compared with before the onset of breast cancer. Two of the SFR items differed in the same direction significantly between the Zoladex and the control groups, ie, frequency of intercourse and quantity of hugs and kisses during the last 2 weeks. Patients’ fear of intercourse was significantly higher in the Zoladex group than in the control group. This was not the case for the partners of these patients (Table 8).
Sexual activity was not related to vaginal dryness. Furthermore, among patients with moderate to severe problems, sexual activity was high (Table 9).
Vaginal Dryness and Its Relation to Sexual Activity and the Factors of Sexual Function, Sexual Frequency, and Sexual Fear at the Peak of Symptoms (24-month follow-up)
Control patients Tamoxifen patients Zoladex patients Zoldex ⫹ tamoxifen Sexually active Sexually inactive
Factor function Factor frequency Factor fear
Minor Problems With Vaginal Dryness (n ⫽ 221)
Major Problems With Vaginal Dryness (n ⫽ 32)
56 54 49 62 144 45
6 6 12 8 22 5
Mean
Mean
9.44 4.36 1.72
12.24 5.43 2.48
2
3.69 0.37
P
3,253
NS
1,216
NS
t
⫺3.74 ⫺2.35 ⫺2.28
P
201 206 204
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⬍ .0005 ⬍ .05 ⬍ .05
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BERGLUND ET AL
The majority (70%) of the women in the present study had lost their menses at the 2-year follow-up. Problems with SFU were significantly higher among these women (n ⫽ 132; mean, 10.17; SD, 4.03) as compared with women still menstruating (n ⫽ 31; mean, 8.37; SD, 3.30). The high number of patients with menses loss also among the tamoxifen and control groups suggests that many women were perimenopausal rather than purely premenopausal. Patient Information Analysis of variance (repeated measure) was used to analyze three-way interactions among Ch, Zoladex, tamoxifen, and assessment concerning patient satisfaction with information about possible effects of disease and treatment on sexuality. All patient groups rated their satisfaction with received information significantly higher with time, during the first 2 years (F ⫽ 79.64 [4,1044], P ⬍ .000) and from baseline to 30 months and 36 months (F ⫽ 123.30 [2,482], P ⬍ .000). There was a significant two-way interaction between Ch and assessment during the first 2 years (F ⫽ 4.16 [4,1044], P ⬍ .005) with groups in which patients were administered Ch generally more satisfied than NCh patients, whereas all groups improved significantly over time. At 24 months after inclusion, approximately 27% of patients stated that they had received insufficient information. DISCUSSION
The randomized trial that formed the basis for the current trial was closed for patient entry in 1996. All patients allocated to systemic treatment as part of the trial have thus had the opportunity to conclude their 2-year treatment schedule. A first analysis of treatment efficacy at a median follow-up of approximately 4 years was recently presented.13 There was a statistically significant benefit among patients allocated Zoladex in terms of event-free survival. Their relative hazards ratio (compared with patients not allocated Zoladex) was 0.77 (95% confidence interval, 0.66 to 0.90, P ⬍ .001), which corresponds to a relative reduction of events with 23% of patients. The benefit of Zoladex seemed to be somewhat less among those who received concurrent tamoxifen, but the difference compared with patients treated with Zoladex alone was not statistically significant. There was also a survival difference favoring the Zoladex-allocated patients (relative hazards ratio, 0.82; 95% confidence interval, 0.67 to 1.05), but this difference was not statistically significant (P ⫽ .12). Zoladex improves treatment outcome also when added to adjuvant cytotoxic Ch.14,15 The purpose of the Sex and Relationship Scale elaborated for the present study was to distinguish effects on sexuality of Zoladex, tamoxifen, and the combination of ZT among patients receiving Ch and NCh. Factor analysis was used for
data reduction and scale construction. Three factors explained 62% of the variance and the scale differentiated between adjuvant treatments with and without Ch. Administration of endocrine treatment to patients receiving Ch had no significant impact on SFU and SFR. Although problem levels decreased after the cessation of endocrine treatment among patients not receiving systemic treatment, patients administered Ch maintained a high level of dysfunction throughout the study period. Their dysfunction levels during the first 2 years were comparable to those of the Zoladex group among patients with no Ch. These negative effects of Ch are in line with findings of other researchers eg, Schover et al16 and Ganz et al.6,17 One possible explanation is that Ch disrupts hormone production by the ovaries. Circulating levels of estrogens decrease, accompanied by elevated levels of follicle-stimulating hormone and luteinizing hormone. Also levels of androgens, which are assumed to promote sexual desire, decrease. These effects of Ch may be so strong that the effects of other systemic treatments (eg, Zoladex) are masked by Ch. Neither the present study nor that by Ganz et al17 found any effect of tamoxifen when added to Ch (except SF). Thus the present findings mainly contradict Kaplan’s suggestion18 that the addition of Zoladex or tamoxifen to Ch exacerbates its sexual side effects. Some studies19,20 have demonstrated the role of androgens in the maintenance of sexual interest after surgical menopause. However, Cawood et al1 found no evidence that hormonal parameters at baseline predict measures of sexuality. The differences in sexual function obtained by endocrine treatment and Ch in the present randomized study could be assumed to have been occasioned by differences in estrogens and androgens caused by Ch and Zoladex. Zoladex and ZT had a significant negative effect on most parameters of sexuality among patients not receiving Ch. Women treated with Zoladex or ZT perceived their sexuality as negatively affected by cancer treatment and their disease. Frequency of sexual intercourse also diminished for this patient group. Difficulty in attaining orgasm developed in all three endocrinologically treated groups but was worse among Zoladex-treated patients. The medical castration produced by Zoladex causes an endocrinologic postmenopausal status and, biologically, it could be expected that the addition of tamoxifen would produce the same effect as among initially postmenopausal women, ie, sexuality would not be negatively affected.6 The findings of the present study suggest that tamoxifen does not significantly ameliorate the negative effect of Zoladex in this respect (except with respect to SF). Generally, tamoxifen alone did not differ significantly from Zoladex, ZT, or control. However, tamoxifen had a decreasing effect on SF and a positive effect on sexual intercourse in the entire patient group. Fornander et al21
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2795
EFFECT OF ENDOCRINE TREATMENT ON SEXUALITY
suggested that tamoxifen has weak estrogenic effects on the vaginal epithelium and increases the bioavailable fraction of androgens. This may explain the positive effect of tamoxifen alone and the ameliorating effect of its combination with Zoladex on SF and frequency of sexual intercourse. Patients administered Zoladex indicated more fear of sexual intercourse as compared with control patients and with those administered tamoxifen and the combination ZT. An interpretation of this fear among the Zoladex patients is that it is due to pain during sexual intercourse, ie, an effect of the castration causing poor lubrication and vaginal dryness.22 However, we found that 69% of the patients with pronounced problems of vaginal dryness were sexually active; ie, retaining sexual activity does not imply an absence of sexual problems. Thus other reinforcements maintain sexual activity despite this fear. This indicates the high degree of complexity of several problems. For node-negative patients, SFU dysfunctions diminished after the termination of Zoladex treatment, ie, at the 30month and 36-month assessments. At 3 years, problem
levels were similar to those before the start of Zoladex treatment with the exception of SF. It is probable that SF decreases more slowly than other sexual problems. In a quality-of-life study of survivors 8 years after breast cancer treatment, Dorval et al23 found that these women still reported lower satisfaction with their sexual life in general than women in the same age group who never had cancer. In the present study, the control groups controlled for endocrine treatment among patients with and without Ch. However, our design did not include a noncancer premenopausal group. Thus it is possible that negative effects of the cancer disease continue at an elevated level compared with what occurs in a noncancer control group. In conclusion, an increased use of Zoladex in the adjuvant setting seems reasonable due to its clinical benefit in terms of event-free survival and reversibility of sexual problems induced by Zoladex. Also, when added to Ch, Zoladex does not contribute to the deterioration in sexual functioning resulting from Ch. There is, however, a need for more research about how to ameliorate sexual problems during treatment.
APPENDIX Relationship and Sexuality Estimate the situation during the last two weeks. Answer all questions even if you have no permanent partner or if you have not initiated your sexual life yet after disease and treatment. Put a cross in the square which is the most appropriate in your case. 1. I think I have received sufficient information about how disease and treatment (including surgery) might affect my sexual life. _ don’t agree at all _ slightly agree _ agree a lot _ fully agree 2. My sexual life has been negatively affected after the initiation of the cancer disease. _ not at all _ slightly _ rather much _ much _ very much 3. The cancer disease has affected my sexual desire. _ increased _ no difference _ decreased _ all gone _ inadequate question 4. The cancer treatment has affected my sexual desire. _ increased _ no difference _ decreased _ all gone _ inadequate question 5. Sexual intercourse whenever I want is. . . . _ impossible, I don’t _ I don’t think of sex. I _ impossible, my partner _ sometimes possible. _ always possible. have any partner. don’t want to. is not able to or doesn’t want any sex. 6. My partner and I have got emotionally separated during the course of the disease. _ unchanged _ slightly _ rather much _ much _ very much 7. My partner and I have come closer during the course of the disease. _ unchanged _ slightly _ rather much _ much _ very much 8. I am satisfied with the frequency of hugs and kisses between us. _ not at all _ slightly _ rather much _ much _ very much 9. I am afraid of sexual intercourse. _ never _ rarely _ sometimes _ often _ always 10. I feel my partner is afraid of sexual intercourse. _ never _ rarely _ sometimes _ often _ always 11. The frequency of sexual intercourse has changed now as compared to before my breast cancer disease. _ increased a lot _ somewhat increased _ no change _ somewhat decreased _ inadequate question 12. My possibility to reach orgasm has changed now as compared to before my breast cancer disease. _ increased a lot _ somewhat increased _ no change _ somewhat decreased _ inadequate question
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_ inadequate question
_ inadequate question _ inadequate question _ inadequate question _ inadequate question _ inadequate question
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BERGLUND ET AL
APPENDIX (Cont’d) 13. I am satisfied with my present frequency of sexual intercourse. _ not at all _ slightly _ rather much _ much _ very much 14. I use oestrogen ointment or sticks. _ yes _ no 15. My female identity has been negatively affected after the initiation of the cancer disease. _ not at all _ slightly _ rather much _ much _ very much 16. During the last two weeks I have had sexual intercourse _ no time. _ once. _ twice. _ three times. _ at least four times. SKIP THE FOLLOWING QUESTIONS IF YOU HAVEN’T HAD SEXUAL INTERCOURSE DURING LAST TWO WEEKS. 17. I have had an orgasm during sexual intercourse _ each time. _ mostly. _ about half of the times. _ rarely. _ never. 18. The sexual life is very pleasant for me. _ not at all _ slightly _ rather much _ much _ very much 19. The one taking initiative in sexual activity is mostly. . . _ me. _ my partner. _ both. _ don’t know. _ inadequate question
_ inadequate question
_ inadequate question _ inadequate question
_ inadequate question
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holm 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) 14. Davidson N, O’Neill A, Vukov A, et al: Effects 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) 15. 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 the Austrian Breast Cancer Study Group (ABCSG) Trial 5. Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 250) 16. Schover LR, Yetman RJ, Tuason LJ, et al: Partial mastectomy and breast reconstruction: A comparison of their effects on psychosocial adjustment, body image and sexuality. Cancer 75:5464, 1995 17. Ganz PA, Rowland JH, Meyerowitz BE, et al: Impact of different adjuvant therapy strategies on quality of life in breast cancer survivors. Recent Results Cancer Res 152:396-411, 1998 18. Kaplan HS: The sexual side effects of current treatments for breast cancer. J Sex Marital Ther 18:3-19, 1992 19. Scherwin BB, Gelfand MM: The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 49:397-409, 1987 20. Scherwin BB: The psychoendocrinology. Ann Rev Sex Res II:181-198, 1991 21. Fornander T, Rutquist LE, Wilking N: Effects of tamoxifen on the female genital tract. Ann N Y Acad Sci 622:469-476, 1991 22. Nystedt M, Berglund G, Bolund C, et al: Adjuvant endocrine therapy in premenopausal breast cancer: Somatic and psychosocial consequences. Acta Oncol 39:959-968, 2000 23. Dorval M, Maunsell E, Descheˆs L, et al: Long term quality of life after breast cancer: Comparison of 8-year survivors with population controls. J Clin Oncol 16:478-494, 1998
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