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JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Adjuvant Chemotherapy Followed By Goserelin Compared
With Either Modality Alone: The Impact on Amenorrhea,
Hot Flashes, and Quality of Life in Premenopausal
Patients—The International Breast Cancer Study Group
Trial VIII
From the International Breast Cancer
Study Group (IBCSG); IBCSG Coordinating Center, Swiss Group for Clinical
Cancer Research (SAKK), Department
of Medical Oncology, Bern; Bürgerspital
and Kantonsspital, St Gallen; Oncology
Institute of Southern Switzerland, Bellinzona, Switzerland; IBCSG Statistical
Center, Dana-Farber Cancer Institute,
Frontier Science and Technology
Research Foundation, Harvard School
of Public Health, Boston, MA; Australian New Zealand Breast Cancer Trials
Group and Newcastle Mater Misericordiae Hospital, Newcastle; Department
of Surgery, The Royal Melbourne
Hospital, Melbourne; the University of
Sydney, Sydney, Australia; Groote
Schuur Hospital and University of Cape
Town, South Africa; and the European
Institute of Oncology, Milan, Italy.
Submitted October 8, 2005; accepted
October 17, 2006; published online
ahead of print at www.jco.org on
December 11, 2006.
Supported by Swiss Group for Clinical
Cancer Research (SAKK), Frontier
Science and Technology Research
Foundation, The Cancer Council Australia, Australian New Zealand Breast
Cancer Trials Group, Australian National
Health and Medical Research Council
(project 920876), National Cancer Institute Grant No. CA-75362; Bethesda,
MD, Swedish Cancer Society, Cancer
Association of South Africa, and Foundation for Clinical Research of Eastern
Switzerland (OSKK). Astra-Zeneca
provided the Zoladex free of charge.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Address reprint requests to Jürg
Bernhard, PhD, International Breast
Cancer Study Group Coordinating
Center, Effingerstr 40, 3008 Bern,
Switzerland; e-mail: juerg.bernhard@
ibcsg.org.
© 2007 by American Society of Clinical
Oncology
0732-183X/07/2503-263/$20.00
DOI: 10.1200/JCO.2005.04.5393
Jürg Bernhard, David Zahrieh, Monica Castiglione-Gertsch, Christoph Hürny, Richard D. Gelber,
John F. Forbes, Elizabeth Murray, John Collins, Stefan Aebi, Beat Thürlimann, Karen N. Price,
Aron Goldhirsch, and Alan S. Coates
A
B
S
T
R
A
C
T
Purpose
The purpose of this article is to compare quality of life (QOL) and menopausal symptoms among
premenopausal patients with lymph node-negative breast cancer receiving chemotherapy, goserelin, or their sequential combination, and to investigate differential effects by age.
Patients and Methods
We evaluated QOL data from 874 pre- and perimenopausal women with lymph node-negative
breast cancer who were randomly assigned to receive six courses of classical cyclophosphamide,
methotrexate, and fluorouracil (CMF) chemotherapy, ovarian suppression with goserelin for 24
months, or six courses of classical CMF followed by 18 months of goserelin. We report QOL data
collected during 3 years after random assignment in patients without disease recurrence.
Results
Overall, patients receiving goserelin alone showed a marked improvement or less deterioration in
QOL measures over the first 6 months than those patients treated with CMF. There were no
differences at 3 years after random assignment according to treatment except for hot flashes. As
reflected in the hot flashes scores, patients in all three treatment groups experienced induced
amenorrhea, but the onset of ovarian function suppression was slightly delayed for patients
receiving chemotherapy. Younger patients (⬍ 40 years) who received goserelin alone returned to
their premenopausal status at 6 months after the cessation of therapy, while those who received
CMF showed marginal changes from their baseline hot flashes scores.
Conclusion
Age-adjusted risk profiles that consider patient-reported outcomes enable patients to adapt to their
disease and treatment, such as considering the trade-offs between delayed endocrine symptoms,
but higher risk of permanent menopause with chemotherapy, and immediate but reversible
endocrine symptoms with goserelin, in younger premenopausal patients.
J Clin Oncol 25:263-270. © 2007 by American Society of Clinical Oncology
INTRODUCTION
The International Breast Cancer Study Group
(IBCSG) trial VIII for pre- and perimenopausal
women with lymph node-negative breast cancer
compared sequential chemotherapy followed by the
gonadotropin-releasing hormone agonist goserelin
with either modality alone. Disease-related outcomes have been reported.1 Patients with estrogen
receptor (ER) -negative tumors achieved better
disease-free survival (DFS) if they received treatments that included cyclophosphamide, methotrex-
ate, and fluorouracil (CMF) than if they received
goserelin alone. In contrast, for patients with ER–
positive disease, chemotherapy alone and goserelin
alone provided similar outcomes, whereas sequential therapy provided a statistically nonsignificant
benefit compared with either modality alone, due
largely to the results for the younger patients. In this
report, we compare the impact of the randomized
treatments on quality of life (QOL). Similar adjuvant trials have been reported.2,3 The trade-offs between early (first 6 months), intermediate (months 6
to 24), and late (month 36) QOL effects require
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Bernhard et al
patients and physicians to balance different impacts of treatment at
different time points, making individual decision making more challenging.4 However, minor differences in the toxicity profiles may be
important for a patient’s choice.3,4
Age may influence a patient’s perception of fertility, body image,
and sexuality. Younger women are especially vulnerable for physical
and emotional sequelae of breast cancer, with an early menopause as a
main concern.5-10 We expanded the QOL analysis by investigating the
time course of amenorrhea and patient-rated hot flashes, a key symptom of estrogen deprivation, between treatments and by patient age.
PATIENTS AND METHODS
Trial
From March 1990 through October 1999, 1,111 pre- and perimenopausal patients were randomly assigned to receive either no adjuvant systemic
treatment, six 28-day courses of classical CMF chemotherapy (in which one
course, every 28 days, consisted of cyclophosphamide at 100 mg/m2 on days 1
through 14, orally; methotrexate at 40 mg/m2 on days 1 and 8, intravenously;
and fluorouracil at 600 mg/m2 on days 1 and 8, intravenously), 24 monthly
subcutaneous implants of a gonadotropin-releasing hormone analog (goserelin at 3.6 mg every 28 days), or six 28-day courses of classical CMF followed by
18 implants of goserelin. Systemic adjuvant therapy was to begin within 6
weeks of primary surgery. For the sequential treatment arm, the first goserelin
implant was scheduled to be given on day 28 of the sixth course of CMF.
Informed consent was required according to the criteria established within the
individual countries. The protocol was approved by institutional review
boards as required by national and local law.
The details of the trial protocol and conduct are described elsewhere.1 In
April 1992, after accrual of 205 patients, random assignment to the noadjuvant treatment control arm (46 patients) was discontinued because of
results from other trials. This report concerns QOL comparisons among the
three active treatment arms.
For the first 36 months of treatment, patients received a calendar
to record their menses. These data were checked by the medical staff at
visits and transmitted to the menstrual status form with 1 ⫽ normal;
2 ⫽ scanty; 3 ⫽ no menses.
QOL Analysis
The IBCSG QOL core questionnaire11-13 comprised single-item linear
analog self-assessment (LASA) indicators for physical well-being, mood,14
coping effort,15 appetite, tiredness, hot flashes, nausea/vomiting, perceived
social support, restrictions in arm movement, and subjective health estimation16 referring to the last 2 weeks. Patient self-assessments were obtained at
the beginning of treatment (baseline), at month 3 (ie, day 1 of cycle 3 or 8 weeks
after goserelin start), and at each 3 months for the first 2 years, and again at year
3. We report QOL data for the first 36 months in patients without recurrence
within this time.
The protocol required that all patients participate in the QOL study. As a
primary hypothesis, based on experience in patients with node-positive disease11 we predicted worse QOL during chemotherapy (months 3 and 6) as
compared with goserelin but no residual effects in treatment groups after
completion of chemotherapy, using coping effort as primary end point. As a
secondary hypothesis, we expected a smaller adverse effect of CMF on mood at
baseline for patients with ER-negative tumors than for those with ER-positive
tumors.17 We considered a change of 8 points or more on a scale of 0 to 100 as
clinically significant.18
Of the 1,065 patients randomly assigned to one of the three adjuvanttreatment arms, 1,043 were deemed eligible and assessable. Of these, 874
patients were included in the QOL analysis (Table 1). We expected the QOL
assessment at month 36 from all patients randomly assigned at a time point less
than 3 years before June 1, 1995, resulting in a total of 746 (85%) of the 874
patients for this assessment. To identify reasons for the lower submission rate
at month 36, we investigated the association between missing data and baseline
264
Table 1. Description of Patients Excluded From the QOL Analysis of Trial VIII
No. of Patients
Patient Group
Goserelin
CMF
CMF
Followed by
Goserelin
Total eligible and assessable
patients
Exclusions from QOL analysis
Relapsed or died within
first 3 years
Completed no QOL
assessments
Completed assessments
in multiple languages
Undefined culture
Included in the QOL analyses
341
350
352
1,043
45
46
28
119
9
10
16
35
4
4
6
14
0
283
0
290
1
301
1
874
Total
Abbreviations: QOL, quality of life; CMF, cyclophosphamide, methotrexate,
and fluorouracil.
characteristics, treatment assignment, participating center, and toxicity, and fit
a logistic regression model to examine the relative importance of these factors.
For a sensitivity analysis, two imputation techniques were used. Missing values
at month 36 were replaced by the previous assessment score, and the lower
quartile from the compliant cases at month 36 was applied to the noncompliant cases.
The indicators were scored between 0 and 100 and analyzed separately;
higher values represented better QOL or less severe symptoms/adverse effects.
QOL scores were transformed to reduce skewing. The statistical significance of
treatment differences at each time point was assessed with analysis of variance,
adjusting for country/language group.11 The figures show the results in the
original scores from 0 to 100.
We also tested for differences in QOL scores between baseline and month
3 of the within patient changes in an analysis of variance model that included
assigned treatment and country/language group. Similarly, we analyzed
changes from baseline to month 6 and month 36.
Differential treatment effects by age were analyzed post hoc using the hot
flashes indicator with the anchors of none and a lot, with age categorized as 39
years or younger and 40 years or older. Treatment-covariate interactions were
studied by use of the nonparametric Subpopulation Treatment Effect Pattern
Plot (STEPP) methodology.19,20 STEPP involves defining overlapping subgroups of patients on the basis of a covariate of interest and studying the
resulting pattern of the treatment effects estimated within each subgroup.
Patient age at study entry was the covariate of interest. The treatment effects
estimated within each subgroup were calculated as mean of the square root of
the hot flashes scores, then transformed back for visual display.
Probability values are two sided. P ⱕ .05 was deemed statistically significant. No adjustment was made for multiple testing.
RESULTS
The submission rates of the QOL forms were similar across treatment
groups and decreased as follow-up went on, from 90% at baseline, to
77% at month 12, to 74% at month 24, and to 62% at month 36.
Participants and nonparticipants at month 36 were similar regarding
age, tumor size, tumor grade, and ER status at random assignment.
The toxicity profile of participants and nonparticipants at month 36
within the goserelin (submission rate, 65%) and CMF (60%) arms was
similar. Participating center was most strongly associated with missing
data at month 36 (P ⫽ .02; data not shown).
Table 2 presents characteristics of the 874 patients. Nineteen
percent of the patients were age 39 years or younger. The median
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Amenorrhea and Quality of Life
Table 2. Baseline Characteristics According to Treatment of the Patients Included in the QOL Analyses (N ⫽ 874)
Patients
Goserelin
CMF Followed by
Goserelin
CMF
Total
Characteristic
No.
%
No.
%
No.
%
No.
%
Total
ER status
Negative
Positive
Unknown
Primary treatment
Total mastectomy
Breast conservation
With RT
With no RT
Tumor size, cm
ⱕ 1.0
1.1-2.0
ⱖ 2.1
Unknown
Tumor grade
1
2
3
Unknown
Age, years
ⱕ 39
ⱖ 40
283
32
290
33
301
34
874
100
83
189
11
29
67
4
85
198
7
29
68
2
88
206
7
29
68
2
256
593
25
29
68
3
118
42
128
44
123
41
369
42
155
10
55
4
150
12
52
4
160
18
53
6
465
40
53
5
28
148
105
2
10
52
37
1
31
143
112
4
11
49
39
1
47
155
97
2
16
52
32
1
106
446
314
8
12
51
36
1
49
131
102
1
17
46
36
1
39
137
108
6
13
47
37
2
73
126
100
2
24
42
33
1
161
394
310
9
18
45
35
1
53
230
19
82
48
242
17
83
64
237
21
78
165
709
19
81
Abbreviations: QOL, quality of life; CMF, cyclophosphamide, methotrexate, and fluorouracil; ER, estrogen receptor; RT, radiation therapy.
age within this cohort was 36 years (range, 22 to 39). The median
age within the cohort of patients age 40 or older was 46 years (range,
40 to 58). Sixty-eight percent of patients had primary tumors classified as ER–positive, 29% of patients had primary tumors classified
ER–negative, and 3% of patients had primary tumors classified
ER– unknown.
During the first 3, 6, and 36 months, we compared the change
(mean, SE) in QOL scores from baseline between patients receiving
Table 3. Changes in QOL Scores From Baseline to Months 3, 6, and 36 in Patients Receiving Goserelin Alone Versus CMF
Change From Baseline to Month 3ⴱ
Goserelin
Alone
CMF
QOL Indicator
Mean ⫾ SE
Mean ⫾ SE
Physical well-being
Mood
Coping effort
Appetite
Tiredness
Hot flashes
Nausea/vomiting
Perceived social
support
Restrictions in arm
movement
Subjective health
estimation
⫺1.4 ⫾ 3.5
⫺3.0 ⫾ 3.5
5.2 ⫾ 3.4
⫺1.2 ⫾ 3.3
⫺8.2 ⫾ 4.0
⫺43.8 ⫾ 4.5
⫺6.6 ⫾ 4.2
0.6 ⫾ 2.4
⫺1.6 ⫾ 3.3
1.5 ⫾ 3.2
1.4 ⫾ 3.2
⫺4.2 ⫾ 3.1
⫺12.2 ⫾ 3.5
⫺12.7 ⫾ 4.0
⫺22.5 ⫾ 3.8
0.8 ⫾ 2.1
8.7 ⫾ 3.7
13.4 ⫾ 3.3
⫺0.6 ⫾ 3.5
⫺4.1 ⫾ 3.1
Change From Baseline to Month 6ⴱ
Goserelin
Alone
CMF
P
Mean ⫾ SE
Mean ⫾ SE
.90
.04
.08
.14
.15
⬍ .0001
⬍ .0001
.93
⫺1.7 ⫾ 3.7
1.0 ⫾ 3.8
10.7 ⫾ 3.9
0.9 ⫾ 3.4
⫺8.0 ⫾ 4.2
⫺35.0 ⫾ 5.3
⫺1.2 ⫾ 4.2
⫺1.8 ⫾ 2.7
⫺4.7 ⫾ 3.4
2.2 ⫾ 3.5
2.8 ⫾ 3.6
⫺2.7 ⫾ 3.1
⫺13.1 ⫾ 3.7
⫺31.2 ⫾ 4.7
⫺18.0 ⫾ 3.7
0.5 ⫾ 2.4
.06
11.2 ⫾ 4.0
.17
0.8 ⫾ 3.3
Change From Baseline to Month 36ⴱ
Goserelin
Alone
CMF
P
Mean ⫾ SE
Mean ⫾ SE
P
.20
.60
.001
.10
.08
.30
⬍ .0001
.22
4.9 ⫾ 3.6
9.5 ⫾ 4.3
15.0 ⫾ 4.4
4.7 ⫾ 3.5
⫺0.7 ⫾ 4.4
⫺5.0 ⫾ 5.1
3.5 ⫾ 3.14
⫺2.9 ⫾ 3.1
8.8 ⫾ 3.2
14.8 ⫾ 3.8
18.7 ⫾ 3.9
6.6 ⫾ 3.1
1.8 ⫾ 3.9
⫺23.7 ⫾ 4.5
7.0 ⫾ 2.7
⫺1.0 ⫾ 2.7
.12
.08
.24
.46
.42
⬍ .0001
.11
.39
9.5 ⫾ 3.6
.54
13.1 ⫾ 4.6
13.1 ⫾ 4.0
0.99
⫺4.2 ⫾ 3.0
.03
9.5 ⫾ 3.4
10.1 ⫾ 3.0
0.80
Abbreviations: QOL, quality of life; CMF, cyclophosphamide, methotrexate, and fluorouracil.
ⴱ
Mean changes in QOL scores between baseline and months 3, 6, and 36 were obtained from an ANOVA model that included assigned treatment and
country/language group. Negative values indicate a worsening condition for all indicators.
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Bernhard et al
Median Hot Flashes Score
Better
Worse
100
90
80
70
60
50
40
Goserelin
CMF
CMF
goserelin
30
20
0
3
6
9
12 15 18 21 24 27 30 33 36
QOL Assessments (months)
No. of patients 570 518 511 494 489 446 464 465 471
P
.86 <.01 .03 <.01 .04 .01 .25 .85 <.01
437
<.01
Fig 1. Median hot flashes scores by treatment group during the first 36 months
for the 874 patients assessable for quality of life (QOL). The points indicate the
assessments when the patients were undergoing chemotherapy. Higher values
indicate fewer hot flashes. CMF, cyclophosphamide, methotrexate, and fluorouracil.
266
Better
100
90
Median Coping Score
goserelin alone with patients receiving CMF (Table 3). Significant
benefits were found for goserelin, with less impairment by nausea/
vomiting and an improvement in coping and subject health estimation. For the first 3 months, patients receiving goserelin reported a
bigger increase in hot flashes and a worse mood. There were no
differences at 36 months according to treatment in any of the indicators, except for hot flashes (Fig 1). The coping scores indicated a
rapid, clinically significant improvement after completing chemotherapy (Fig 2).
At baseline, patients receiving CMF reported more coping effort,
although this difference was not statistically significant (P ⫽ .12). Of
the patients who submitted a baseline QOL form, 43% completed the
form before random assignment (45% goserelin; 42% CMF); thus up
to 57% did so after knowing treatment assignment. When we excluded those patients who filled out their baseline assessment after
random assignment, the results were similar but slightly more pronounced on average for each indicator. At month 36, the results of
both imputation techniques were consistent with our main findings
(data not shown).
We tested for QOL differences among treatment groups at each
time point separately for both the ER–negative and ER–positive cohorts. Results were similar within both cohorts (data not shown).
Patients in all three treatment arms experienced induced amenorrhea, but the onset was delayed slightly for those patients who
received chemotherapy relative to those patients who received initial
goserelin—a pattern also reflected in the hot flashes scores (Fig 1).
After cessation of goserelin treatment, patients who received goserelin
alone indicated fewer hot flashes than those patients who had received
CMF (P ⬍ .01 at months 24 and 36).
The percentage of patients who reported no menses during each
month after random assignment according to treatment group is
shown separately for younger (age ⱕ 39; Fig 3A) and older patients
(age ⱖ 40; Fig 3B). For younger patients, goserelin induced amenorrhea within 2 months of study entry for 90% of the patients and within
80
70
60
50
40
Goserelin
CMF
CMF
goserelin
30
Worse
20
0
3
6
9
12 15 18 21 24 27 30 33 36
QOL Assessments (months)
No. of patients 774 705 687 676 674 627 649 647 641
P
.14 <.01 <.01 .44 .80 .93 .77 .38 .89
460
.57
Fig 2. Median scores of coping effort (Perceived Adjustment to Chronic Illness
Scale [PACIS]) by treatment group during the first 36 months for the 874 patients
assessable for quality of life (QOL). The points indicate the assessments when the
patients were undergoing chemotherapy. Higher values indicate less effort to cope.
CMF, cyclophosphamide, methotrexate, and fluorouracil.
3 months for virtually all patients. Amenorrhea continued until the
end of goserelin treatment, when menses resumed in all but a few
patients. In contrast, chemotherapy-induced amenorrhea was
achieved more slowly and was observed in approximately 50% of
patients by the end of six courses of CMF. Among patients in whom
goserelin was not given after CMF, menses resumed in approximately
15%, but amenorrhea continued in approximately 35% to 40% of
such patients throughout the 36-month period of observation.
Among patients who received goserelin after CMF, virtually all reported amenorrhea during the 18-month goserelin treatment period.
Resumption of menses after cessation of goserelin was slower in patients who had received initial CMF than in those who did not.
The pattern of incidence of amenorrhea over time was different
for patients age ⱖ 40 (Fig 3B). Chemotherapy-induced amenorrhea
was observed sooner and in a larger proportion of patients than was
observed in the younger cohort. More than 90% of these patients who
received six courses of CMF reported amenorrhea by the end of
chemotherapy. Although menses resumed in a few patients who did
not receive goserelin after chemotherapy, nearly all cases had amenorrhea during the entire 36-month follow-up period, regardless of
whether goserelin was used.
We analyzed the hot flashes scores according to the same age
groups (Figs 4A and 4B). The same pattern seen for all patients across
time was observed within the cohort of older patients. However,
within the cohort of younger patients, patients on all three arms
eventually returned to their initial status after completing treatment by
CMF and/or goserelin, respectively. The patterns of changes were
similar: goserelin was associated with greater early deterioration, which
later recovered, whereas the effect of CMF, though slower in onset, was
persistent, especially among older patients (data not shown).
We performed a STEPP analysis at months 3, 6, and 36 for the hot
flashes indicator to evaluate the differences in treatment effects
according to age (Fig 5), limited to the 323 patients with complete
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Amenorrhea and Quality of Life
Goserelin
CMF
CMF
goserelin
0
10
Patients With Amenorrhea (%)
10
Patients With Amenorrhea (%)
B
Goserelin
CMF
CMF
goserelin
0
20
30
40
50
60
70
80
90
20
30
Fig 3. Percentage of randomly assigned
patients (n ⫽ 1,063) in the International
Breast Cancer Study Group trial VIII with
amenorrhea during each month from random assignment according to treatment. (A)
Shows the results for patients age 39 years
or younger, and (B) shows the results for
patients age 40 years or older. CMF, cyclophosphamide, methotrexate, and fluorouracil.
40
50
60
70
80
90
100
100
0
6
12
18
24
30
36
0
Months From Random Assignment
6
12
18
24
30
36
Months From Random Assignment
data for hot flashes at months 3, 6, and 36. For this sliding window
analysis, each subpopulation contained approximately 70 patients,
and each subsequent subpopulation was formed moving from left to
right by dropping approximately 45 patients with the lowest age and
adding approximately 45 patients with the next higher age. At month
3 (Fig 5A), significantly more hot flashes were observed at all ages for
patients randomly assigned to goserelin alone compared with CMF
(P ⬍ .01) and CMF followed by goserelin (P ⬍ .01). Patients in older
cohorts who were assigned CMF and CMF followed by goserelin
reported hot flashes scores similar to those for goserelin alone. By
month 6 (Fig 5B), the youngest cohort receiving CMF reported fewer
hot flashes than for patients assigned to goserelin alone, however, as
age increased there was no clear pattern of treatment differences as all
patients reported similar hot flashes scores. By month 36 (Fig 5C),
when all patients were no longer receiving treatment, the youngest
A
patients returned to the low or absent hot flashes scores reported at
baseline. This return to initial status was most striking in the goserelin
alone group. As the median age increased, fewer patients randomly
assigned to goserelin alone experienced hot flashes compared with
those randomly assigned to CMF (P ⫽ .03) or to CMF followed by
goserelin (P ⫽ .03).
DISCUSSION
We compared the impact of the goserelin, CMF, and CMF followed
by goserelin on various QOL indicators measured during 3 years
after beginning of adjuvant therapy according to age, specifically
examining patient-rated hot flashes, a very common complaint of
peri- and postmenopausal women.21 The patterns of amenorrhea
B
Median Hot Flashes Score
Better
100
Better
90
80
70
60
50
40
Goserelin
CMF
CMF
goserelin
30
Worse
20
Median Hot Flashes Score
A
3
6
9
12 15 18 21 24 27 30 33 36
QOL Assessments (months)
No. of patients 107 100 99 102 99 89 93 85
P
.94 <.01 .07 <.01 <.01 <.01 <.01 .04
100
.01
90
80
70
60
50
40
Goserelin
CMF
CMF
goserelin
30
Worse
0
100
20
0
3
6
9
12 15 18 21 24 27 30 33 36
QOL Assessments (months)
81
.04
No. of patients 463 418 412 392 390 357 371 380 371
P
.77 <.01 .11 .05 .28 .07 .77 .49 <.01
356
<.01
Fig 4. Median hot flashes scores by treatment group during the first 36 months. (A) Shows the results for the 165 patients age ⱕ 39 years, and (B) shows the results
for the 709 patients age ⱖ 40 years. The points indicate the assessments when the patients were undergoing chemotherapy. Higher values indicate fewer hot flashes. CMF,
cyclophosphamide, methotrexate, and fluorouracil.
267
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Better 100
Median Hot Flashes Score
A
Worse
80
60
40
20
Goserelin
CMF
CMF
goserelin
0
37
42
44
46
48
50
52
70
53
Median Age (years)
No. of patients
70
70
70
70
Better 100
Median Hot Flashes Score
B
70
Worse
80
60
40
20
Goserelin
CMF
CMF
goserelin
0
37
42
44
46
48
50
52
70
53
Median Age (years)
No. of patients
70
70
70
70
Better 100
Median Hot Flashes Score
C
70
Worse
80
60
40
20
Goserelin
CMF
CMF
goserelin
0
37
42
44
46
48
50
52
70
53
Median Age (years)
No. of patients
70
70
70
70
70
Fig 5. Subpopulation Treatment Effect Pattern Plots (STEPP) showing the median
hot flashes scores in the original scale according to treatment and age subgroup (A)
3 months, (B) 6 months, and (C) 36 months after random assignment. Higher values
indicate fewer hot flashes. CMF, cyclophosphamide, methotrexate, and fluorouracil.
268
and patient-reported hot flashes were strikingly similar over time.
This correspondence supports the clinical validity of patientreported data by this type of simple single-item indicator.
Baseline assessment was required before adjuvant treatment but
allowed before or after random assignment. A substantial proportion
of patients, similar between those with versus without chemotherapy,
completed the QOL form after random assignment. To eliminate any
differential anticipatory effects on baseline scores in future studies, we
have since introduced a completed QOL form as an eligibility criterion. Firm conclusions at month 36 are hampered by incomplete
participation of patients. Those who did participate, however, were
representative of each treatment arm, and baseline characteristics were
balanced according to participants and nonparticipants. Participating
center, a stratification factor at random assignment, was the most
important predictor of forms submission at 36 months. Because we
recognize that missing data cannot be ignored in QOL studies, the
IBCSG has introduced a missing QOL form to collect reasons for
missing data.
Overall, patients treated with goserelin alone showed a more
pronounced improvement or less decline in various QOL indicators
during the first 6 months than those with CMF. A similar early benefit
in favor of goserelin was shown in the Zoladex Early Breast Cancer
Research Association (ZEBRA) and the Zoladex in Premenopausal
Patients (ZIPP) trials.2,3 In the ZEBRA trial, the same indicator for
coping was used and showed the same pattern: patients with goserelin
alone required less effort to cope reflecting less burden by adverse
effects. In agreement with both trials, in our trial there was no difference in mood and in physical domains at 3 years. Peri- or postmenopausal status per se is not an independent predictor of lower QOL.22
The improvement of these QOL domains over time, in particular
coping, confirms the pattern of adaptation described in our previous
trials,11,23,24 pointing to the major importance of a patient’s psychological adaptation for her QOL. Patients can be supported in their
adaptation by psycho-oncologic interventions. This is particularly
relevant to the age group of our trial, given that younger women are
more vulnerable for physical and emotional sequelae of a breast cancer
diagnosis. Contrary to our hypothesis, patients’ QOL under chemotherapy was not affected by the ER-status of their tumor.
Both CMF and goserelin induce amenorrhea. However, while it
is reversible in the majority of patients after cessation of goserelin, it is
often permanent after CMF. Patients in whom treatment results in
permanent amenorrhea have the short and long-term effects of an
early menopause. In the ZEBRA and the ZIPP trials, the hormonal
symptoms were worse in the goserelin group during the 2-year goserelin treatment period compared with the CMF group. One year after
the cessation of goserelin therapy, this trend was reversed.
The same pattern was seen for patient-rated hot flashes. Patients
randomly assigned to receive goserelin alone returned to baseline
values at 3 years, while patients who received CMF underwent early
menopause. However, there were substantial age-related differences
among patients who received CMF. Younger patients (ⱕ 39 years)
reported little change in hot flashes, while older patients (ⱖ 40 years)
showed a delayed onset of considerable hot flashes and remained at
this level. This differential effect by age was further illustrated by the
STEPP analysis, which showed consistent patterns. This finding of
differential symptom effects according to age underlines the importance of individual decision making.
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Amenorrhea and Quality of Life
For patients with ER-positive disease, CMF alone and goserelin
alone provided similar DFS outcomes.1 Hence, QOL considerations
become even more relevant to treatment choice. They have to be
balanced from patient’s individual perspective. In the younger
patients, this includes trade-offs between the early and a lower risk of
immediate symptoms but higher risk of permanent menopause by
chemotherapy, and initially greater but reversible endocrine symptoms with 2 years of goserelin. In the ZIPP trial, the effects on sexuality
of CMF were comparable with those of goserelin.25 After age 40, when
fertility becomes less important for many women, the perspective of
going once (chemotherapy) or twice (goserelin) through menopause
is an additional issue to consider.
Sequential therapy provided a statistically nonsignificant trend to
benefit in DFS compared with either modality alone, due largely to the
results among younger patients.1 CMF followed by goserelin showed
the same effect on all QOL indicators as CMF alone. The effects of
chemotherapy appear to mask those of endocrine therapy. This finding confirms those of the ZIPP trial, where no difference was found
regarding physical symptoms or sexual dysfunction between corresponding groups.3,25 Endocrine therapy had differential effects on
symptoms only in patients not treated with CMF. Those receiving
tamoxifen indicated milder menopausal symptoms than those with
goserelin, with the exception of vaginal discharge. Vasomotor symptoms and vaginal dryness were most troublesome. Differences in endocrine adverse effect profiles may assist in supportive care needs but
do not necessarily impact overall QOL.26,27
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The authors indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Jürg Bernhard, Christoph Hürny, Richard D.
Gelber, Alan S. Coates
Provision of study materials or patients: Elizabeth Murray, John
Collins, Stefan Aebi
Data analysis and interpretation: David Zahrieh, Richard D. Gelber
Manuscript writing: Jürg Bernhard, David Zahrieh, Monica
Castiglione-Gertsch, Christoph Hürny, Richard D. Gelber, John F.
Forbes, Elizabeth Murray, John Collins, Stefan Aebi, Beat Thürlimann,
Karen N. Price, Aron Goldhirsch, Alan S. Coates
Final approval of manuscript: Jürg Bernhard, David Zahrieh, Monica
Castiglione-Gertsch, Christoph Hürny, Richard D. Gelber, John F.
Forbes, Elizabeth Murray, John Collins, Stefan Aebi, Beat Thürlimann,
Karen N. Price, Aron Goldhirsch, Alan S. Coates
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Bernhard et al
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■ ■ ■
Acknowledgment
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials and
Rita Hinkle for data management.
Appendix
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version
(via Adobe® Reader®).
270
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