University of Groningen
Long-term side effects of adjuvant breast cancer treatment
Buijs, Ciska
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15
Chapter 2
Prospective study of long-term
impact of adjuvant high-dose
and conventional-dose
chemotherapy on health-related
quality of life
C. Buijs1, S. Rodenhuis2, C.M. Seynaeve3, Q.G.C.M. van Hoesel4, E. van der Wall5,
W.J.M. Smit6, M.A. Nooij7, E. Voest5, P. Hupperets8, E.M. TenVergert1, H. van
Tinteren2, P.H.B. Willemse1, M.J.E. Mourits1, N.K. Aaronson2, W.J. Post1, E.G.E. de
Vries1
1University
Medical Center Groningen and University of Groningen, Groningen, 2The Netherlands Cancer
Institute, Amsterdam, 3Erasmus Medical Center/Daniel den Hoed Cancer Center, Rotterdam, 4University
Medical Center Nijmegen, Nijmegen, 5University Medical Center Utrecht, Utrecht, 6Medical Spectrum
Twente, Enschede, 7Leiden University Medical Center, Leiden, 8University Hospital, Maastricht, the
Netherlands
J Clin Oncol 2007; 25:5403-5409
16 |
Long-term side effects of adjuvant breast cancer treatment
ABSTRACT
Purpose
To evaluate and compare Health Related Quality of Life (HRQoL) after
conventional- and high-dose adjuvant chemotherapy in patients with high-risk
breast cancer.
Patients and methods
Patients were randomized between a conventional and high-dose chemotherapy
regimen; both followed by radiotherapy and tamoxifen. HRQoL was evaluated
until disease progression, using the Short-Form (SF-36), Visual Analogue Scale
(VAS) and Rotterdam Symptom Checklist (RSCL) and assessed every 6 months for
5 years following randomization. For the SF-36 data from healthy Dutch women
with the same age distribution served as reference value.
Results
804 patients (405 conventional-dose, 399 high-dose chemotherapy) were
included.
Median
follow-up
was
57
months.
Directly
after
high-dose
chemotherapy HRQoL decreased more compared to conventional chemotherapy
for all SF-36 subscales. After 1 year the reference value of healthy women was
reached in both groups. Small differences were observed between the two
groups in the subscale role-physical and role-emotional, but 1 year after
treatment these differences were minor and not clinically relevant. During
follow-up, patients with a lower educational level and many complaints before
chemotherapy experienced a worse HRQoL.
Conclusion
Shortly after high-dose chemotherapy, HRQoL was more affected than after
conventional-dose chemotherapy. One year after randomization differences
were negligible. Identifying patients who have a higher chance of persistent
impaired quality of life after treatment, in the present study those with a lower
educational level and many complaints before chemotherapy, is important and
may open the way for better patient-tailored prevention strategies.
HRQoL of high-dose versus conventional dose
| 17
INTRODUCTION
Adjuvant therapy is administered increasingly to women with breast cancer,
resulting in delayed disease recurrence and improved survival. Because of the
dismal prognosis of patients with extensive axillary nodal involvement, over the
last 10 years a variety of new treatment regimens has been tested. These include
adjuvant dose-dense, as well as high-dose chemotherapy with hematopoietic
stem-cell reinfusion. A number of randomized studies have been performed.1 A
recent meta-analysis shows a significant benefit in event-free survival for the
high-dose group at 3 and 4 years. Overall survival rates were not significantly
different, but most studies are still immature.1
Relatively little is known about the long-term effects of adjuvant therapy on
patients’ well-being. Long-term data concerning health-related quality of life
(HRQoL) in breast cancer patients following chemotherapy, particularly after
high-dose chemotherapy, are limited.2-10 Most studies used cross-sectional
follow-up.
In a Dutch randomized, multi-center study, high-dose chemotherapy improved
relapse-free survival of stage II and III breast cancer patients with 10 or more
positive axillary lymph nodes.11 An update showed a trend for a better relapsefree survival in the high-dose arm. For the 621 patients with HER2/neu-negative
disease there was a relapse-free survival and survival benefit of high-dose
therapy.12 HRQoL was included as a secondary endpoint. In this paper we report
the longitudinal HRQoL results of this trial.
PATIENTS AND METHODS
Patients
Patients with stage II-III breast cancer were eligible for the trial if they had ≥ 4
positive axillary lymph nodes, an ECOG-Zubrod performance status of 0 or 1,
and if they were younger than 56 years. Prior to randomization, patients were
stratified according to age (< 50 years versus ≥ 50 years), menopausal status
(pre- or postmenopausal), number of lymph node metastases (4-9 or ≥ 10) and
tumor size (pT1, pT2, or pT3).11,12
Chapter 2
designs with small and heterogeneous patient samples, and relatively short
18 |
Long-term side effects of adjuvant breast cancer treatment
Treatment regimens
Patients received 5 cycles of 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2),
and cyclophosphamide (500 mg/m2) (FEC) or 4 cycles FEC followed by one cycle
of high-dose chemotherapy consisting of cylophosphamide 6 g/m2, thiotepa
480 mg/m2 and carboplatin 1600 mg/m2 over 4 days and autologous
peripheral-stem cell re-infusion. The original protocol included tamoxifen, 40
mg daily for 2 years. During the trial, it became clear that 5 years tamoxifen was
superior to 2 years. Patients with hormone-receptor-positive cancer therefore
continued to receive tamoxifen for, in total, 5 years.11
The Medical Ethical Committee of the participating hospitals approved the study
and all patients gave informed consent.
Health Related Quality of Life measures
HRQoL was assessed by means of a Visual Analogue Scale (VAS) for general
health perception, the Short-Form 36 Health Survey (SF-36), and the Rotterdam
Symptom Checklist (RSCL). The VAS scale ranged from 0 (worst imaginable
health state) to 100 (best imaginable health state).
The SF-36 is organized into 8 scales assessing physical functioning, rolephysical, bodily pain, general health, mental health, role-emotional, social
functioning, and vitality.13 Scale scores range from 0-100, with higher scores
representing a higher level of functioning. Reference data for healthy Dutch
women, mean age 47 years (range 16-96) were available for comparison.14 The
outcome of the SF-36 is age dependent. The age distribution in this study is
skewed (range 24-56 years). Therefore, six age-categories were identified.
Within each age category one “reference healthy woman” could be sampled for
every four breast cancer patients. This way 199 reference women were identified
and their data on the 8 scales of the SF-36 were used. The calculated mean
values were used as references values.
The RSCL is a cancer-specific tool to measure psychological and physical
distress in cancer patients. Patients indicated the degree to which they have
been bothered by the 30 indicated symptoms in the past week.15 The
distribution of the RSCL item scores was highly skewed. Therefore, the 4-point
Likert-type response scales were collapsed into the presence/absence of each
symptom. Socio-demographic characteristics including age, education, marital
status, number of children living at home and employment status were collected
at baseline.
Follow-up
Patients received the questionnaires by mail before randomization, after
chemotherapy completion, after radiotherapy completion and thereafter every 6
HRQoL of high-dose versus conventional dose
| 19
months. The data reported cover a maximum of 5 years post-randomization
(maximum of 12 assessments).
Statistical analysis
The planned sample size was based on the primary endpoints: disease-free and
overall survival. The HRQoL data were analyzed according to the intention-totreat principle. Data of patients that had not yet reached the 5-years follow-up
were included in the analysis until their last follow-up. Questionnaires of
patients who relapsed or died within 5 years after randomization, were included
in the analyses until disease relapse or death. Statistical analysis was performed
using SPSS (11.0) and Multi Level-wiN (ML-Win) version 1.10.16
Student’s t-test for independent samples and chi-square test were used to
compare sociodemographic and baseline HRQoL scores of the two arms. At one
year follow-up, Student’s t test was used to compare mean SF-36 scores of the
two arms with those of the age-matched reference group from the general
Dutch population.
Mixed-effects analysis of variance models for repeated-measures was used to
randomization there was no difference in HRQoL between the two groups. This
information was put into the mixed-effects analysis. Age (> 50 and ≤ 50 years)
and menopausal status were separately included as covariates. A P value of <.05
was considered statistically significant.
Effect size is defined as the mean HRQoL scores difference between high-dose
and conventional-dose group divided by the standard deviation of the HRQoL
scores of the total group at that measurement moment. A value of 0.2-0.5 is
considered indicative of a small effect, 0.5 a medium and 0.8 a large effect
size.18
RESULTS
Patients
From August 1993 to July 1999, 885 patients were enrolled in the clinical
trial.11,12 The HRQoL component of the trial began after 47 patients had been
entered. Of the remaining 838 patients, 34 (4%) did not participate (27 declined,
7 for logistical reasons). Of the 804 patients who participated in the HRQoL
study, 405 received conventional-dose and 399 high-dose chemotherapy.
Forty-one patients randomized to high-dose therapy did not receive this
treatment.11 According to the intention-to-treat principle, they were included in
Chapter 2
assess longitudinal HRQoL changes within and between treatment arms.17 At
20 |
Long-term side effects of adjuvant breast cancer treatment
the high-dose arm for analysis. None of the patients randomly assigned to
conventional-dose received high-dose chemotherapy.
Compliance with HRQoL questionnaires
HRQoL data collected up to 5 years post-randomization were included in the
analysis. The median follow-up was 57 months. Figure 1 shows response rates
for the HRQoL questionnaires at baseline and during follow-up. The overall
response rate was 86% (range 73-95%) at the various assessment points. No
significant differences in compliance were observed between the treatment
arms. 204 patients (25%, 100 in conventional-dose and 104 in high-dose group)
had not yet reached the 5-years follow-up. At the time of analysis 325 (40%)
patients (156 in conventional-dose and 169 in high-dose group) were diseasefree at 5 years follow-up.
Figure 1. Number of patients in the conventional-dose and the high-dose treatment group that
returned the HRQoL questionnaire during treatment and follow-up.
conventional dose completed
500
No. of patients
conventional dose not completed
high-dose completed
400
high-dose not completed
300
200
100
0
3
6
12 18 24 30 36 42 48 54 60
Months
Sociodemographic characteristics
Patient characteristics at randomization were well balanced between the
treatment arms (Table 1). At randomization 50% (n=400) of the patients were
employed and 80% (n=646) had children. There were no significant differences
between the arms in the percentage employed at randomization or at 1 or 3
years post-randomization, or in the number of hours per week worked. At
follow-up, 34% of all patients reported working less (≤ 4 hours/week) than at
trial entry, 48% indicated that this had not changed, and 18% worked more.
HRQoL of high-dose versus conventional dose
| 21
Table 1. Characteristics of the patients at randomization
Conventional-dose group
High-dose group
No. of patients
No. of patients
Mean
44.5
44.7
Range
26-56
24-56
Age (years)
Having a partner
Yes
356
359
No
34
25
Unknown
15
15
Having children
Yes
330
316
No
61
69
Unknown
14
14
Premenopausal
334
343
Postmenopausal
56
49
Uncertain
15
24
Menopausal status
None
1
Grammar school
16
17
High-school
281
273
Entered some college
76
60
Completed college
17
34
Unknown
15
14
Health Related Quality of Life outcomes
VAS
The results of the mixed-effects model analysis for VAS scores and effect sizes
over time for both arms are illustrated in Figure 2. At baseline, there was no
statistically significant difference in VAS scores between the treatment arms.
Until 24 months the conventional-dose group scored statistical significant
higher than the high-dose group. Just after chemotherapy there was a large
effect size (0.82) and until 24 months a small effect size (0.18 to 0.36) was
seen. Thereafter, no significant between group differences in VAS score were
observed over time.
SF-36
The results of the mixed-effects models for all subscales during follow-up in
both arms are presented in Figure 3, as well as the normal reference values and
Chapter 2
Education
22 |
Long-term side effects of adjuvant breast cancer treatment
Figure 2. Mean scores of the Visual Analogue Scale (VAS) by treatment group (high-dose (▲),
conventional-dose (■) randomization and during 5 years (higher scores represent better quality of
life) and the effect size (♦) The X-axis shows time in months. The left Y-axis represents the VAS
score while the second Y-axis represents the effect size. Significant difference between the highdose treatment group and the conventional-dose group is indicated with an asterisk (*)
VAS
100
1.0
* *
*
*
*
60
0.5
40
20
Effect size
Score
80
0.0
0
0
10
20
30
40
50
60
Months
the effect sizes. At baseline, there were no significant differences between the
arms in SF-36 scores. Both patient groups scored lower on two SF-36 scales,
role-physical and role-emotional, than the general population reference sample.
Directly
after
chemotherapy
the
high-dose
group
scored
statistically
significantly lower for all subscales, with effect sizes all above 0.5. Only the
scores on general health did not differ between the two arms. For the scales:
mental health, role-emotional, social functioning and bodily pain, no significant
differences between the two arms were seen 6 months after randomization and
later and effect sizes were always below 0.20.
During 2.5 years after randomization, the high-dose group had lower scores for
role-physical compared to the conventional dose group but the effect sizes
during this period were below 0.20.
For the scales physical functioning and vitality a small, but significant difference
was observed between the two arms, during the 5 years follow-up. The effect
sizes of physical functioning were during those years just above 0.20 and for
vitality just below 0.20.
HRQoL of high-dose versus conventional dose
| 23
Figure 3. Mean scores of the SF-36 subscales in the high-dose treatment group (▲), conventionaldose treatment group (■), reference values from age corrected controls (---) and the effect size
(♦), at randomization and during 5 years thereafter (higher scores represent a better quality of
life). The X-axis shows time in months. The left Y-axis represents the VAS score while the right Yaxis represents the effect size. Significant difference between the high-dose treatment group and
the conventional-dose group is indicated with an asterisk (*).
Physical functioning
Role-physical
100
1.0
*
*
*
*
*
*
*
*
1.0
* *
80
0.5
40
20
*
*
*
60
0.5
40
0.0
20
0
0.0
0
0
12
24
36
48
60
0
12
24
Months
Bodily pain
1.0
80
20
60
Score
40
0.0
20
0
12
24
36
48
0.5
40
0.0
0
60
0
12
24
1.0
20
Score
0.5
40
0.0
48
0.5
40
20
0
36
60
0.0
0
60
0
12
24
Social function
48
60
Vitality
100
1.0
100
**
1.0
* *
0.5
40
20
0.0
0
*
*
*
*
*
*
*
* *
60
0.5
40
20
0.0
0
0
12
24
36
Months
48
60
0
12
24
36
Months
48
60
Effect size
60
Score
80
Effect size
Score
36
Months
Months
80
Effect size
60
Effect size
Score
1.0
*
80
24
60
100
*
12
48
Role-emotional
Mental health
100
0
36
Months
Months
Chapter 2
0.5
Effect size
Effect size
60
80
60
100
*
0
48
General Health
1.0
80
36
Months
100
Score
*
Effect size
60
Effect size
Score
*
Score
* *
80
100
24 |
Long-term side effects of adjuvant breast cancer treatment
For all subscales, except for role-physical in both arms and physical functioning
for the high-dose group, scores returned to normal or above reference values at
1 year. Thereafter, all HRQoL scores remained stable over the next 4 years.
Correlation between age, menopausal status in the SF-36 and VAS scores
The covariates age and menopausal status had significant effect on the
subscales physical functioning and role-physical. In both arms physical
functioning scores of younger women (< 50 years at randomization) were
significantly higher compared with older women at all time points. From 1 to 5
years after randomization, differences between younger and older women were
statistically significant, but effect sizes were small. Patients who were
Figure 4. Percentage of patients reporting symptoms by the RSCL (3 = quite a bit, 4 = very much) at
each assessment point for patients treated with conventional- or high-dose chemotherapy.
Tiredness
Conventional-dose
High-dose
80
70
60
50
% 40
30
20
10
0
0 3 6
12
18
24
30
36
42
48
54
60
230
243
211
220
177
194
158
159
129
134
Months
No. Responding Patients
Conventional dose
383 359 359 340
High-dose
380 360 345 340
308
311
274
285
255
263
Decreased sexual interest
Conventional-dose
High-dose
80
70
60
%
50
40
30
20
10
0
0 3 6
12
18
24
30
36
42
48
54
60
228
241
199
209
169
181
145
142
119
123
Months
No. Responding Patients
Conventional dose
379 353 354 340
High-dose
379 351 336 333
305
306
272
280
253
258
HRQoL of high-dose versus conventional dose
| 25
postmenopausal at randomization, scored significantly lower on the rolephysical scale, compared with patients who were pre-menopausal over the
whole 5 year period.
Rotterdam Symptom Checklist (RSCL)
Tiredness, decreased sexual interest, sweating and painful muscles were the
most prevalent symptoms. The percentage of patients reporting tiredness and
decreased sexual interest over time is shown in Figure 4. Just after
chemotherapy, the percentage of patients with physical symptoms was higher
compared with baseline in both arms. Overall, the percentage of patients with
symptoms was higher in the high-dose group. This difference was already
largely reduced 6 months after randomization. During the follow-up period 10%
of the patients (n=78) experienced three or four of the most prevalent
symptoms for more than half of the time. Compared to patients without this
high frequency of complaints, these patients could only be distinguished by a
lower education level. The seven items indicating psychological distress
(irritability, worrying, depressed mood, nervousness, despairing about the
year later and remained constant over the next 4 years. After 5 years 244
Figure 5. Mean scores of the SF-36 subscales bodily pain for the patients with with many (≥ 4) (♦)
and few (≤ 3) symptoms (■) and the reference values from age corrected controls (---) at
randomization and during 5 years thereafter (higher scores represent a better quality of life). The
X-axis
shows
time
in
months.
The
left
Y-axis
represents
the
bodily
score.
Bodily pain
100
Score
80
60
40
20
many symptoms
few symptoms
0
0
12
24
36
Months
48
60
pain
Chapter 2
future, tension, anxiety) diminished in both arms from randomization up to 1
26 |
Long-term side effects of adjuvant breast cancer treatment
patients completed HRQoL questionnaires and 33% of them reported no
symptoms, 17% experienced one, 13% two, 9% three and 28% four or more
symptoms of the RSCL.
Decreased sexual interest was the most prevalent symptom (36%). Patients with
many (≥4) and few symptoms (≤3) showed no differences with regard to
treatment arm, age, employment status, number of working hours at
randomization, having children and children living at home, marital status,
menopausal status at randomization or education level. Patients with many
symptoms after 5 years scored significantly lower on all SF-36 subscales at
randomization and at the 11 measurement points thereafter compared with
other patients. The only exception was role-physical at randomization. In Figure
5 the scores over time for the subscale bodily pain for the patients with many
and few complaints is shown. The results for other subscales of SF-36 and VAS
are comparable and not shown. Eighty percent of patients scoring ≤3 symptoms
of the RSCL at randomization report ≤3 complaints after 5 years and half of all
patients scoring ≥4 items at randomization score ≥4 symptoms.
DISCUSSION
This prospective, longitudinal study describes HRQoL for 5 years following
randomization between conventional and high-dose chemotherapy in a large
group of disease-free, high-risk breast cancer patients. At randomization, their
HRQoL was only slightly different from an age- and gender-matched control
group obtained from the general Dutch population. During the immediate posttreatment period, HRoQL was worse in the high-dose than in the conventionaldose treatment group. However, 1 year after randomization, HRQoL in both
groups was again comparable to the general population reference values, and
these levels remained relatively constant over the next 4 years.
Comparison of HRQoL studies is relevant but can be hampered by differences in
study
designs
and
measures
used.19
In
the
future,
disease-specific
questionnaires like FACT-B, might be able to detect additional differences which
e.g. the SF-36 does not reveal.
A small cross-sectional study in 43 patients with 2 years median follow-up after
high-dose chemotherapy reported higher HRQoL scores compared to patients
with conventional-dose chemotherapy using the Functional Living Index Cancer
questionnaire (FLIC). This FLIC score differed, however, only marginally between
the two groups.20 Another study, comparing pre- and post treatment HRQoL,
observed that disease-free breast cancer patients (n=24) following high-dose
chemotherapy had higher HRQoL than prior to treatment.3 They excluded all
HRQoL of high-dose versus conventional dose
| 27
patients who relapsed or died during follow-up from the analysis. In order to
achieve an objective rating of HRQoL, data of all patients were included in our
study until disease relapse or death.
Although research on HRQoL in breast cancer patients has become increasingly
sophisticated, few longitudinal studies assessed patients before and after
treatment.7,9,10,21 Longitudinal HRQoL studies lay a considerable claim to the
compliance of patients, requiring frequent HRQoL questionnaires to be
returned.6 Objectively and compared with others, our overall response rate was
high (86%).7,9,10 Most longitudinal HRQoL studies are analyzed with repeated
measurement ANOVA, and one missing questionnaire will result in omitting all
data of that particular patient. Analysis by mixed-effect models as performed in
our study has the advantage that all data can be used and selection bias is
excluded.
One large randomized prospective study, with serial assessment points,
compared HRQoL of adjuvant high-dose (n=197) with “tailored” chemotherapy
(n=211). This study showed a larger decrease in HRQoL and faster recovery in
the high-dose group compared to the “tailored” group during the first year.7
after treatment. The faster HRQoL recovery in their high-dose group found can
be explained by the fact, that the tailored arm actually had received more
chemotherapy over a longer period of time.7 Another prospective study
compared HRQoL of breast cancer patients until 3 years after high-dose (n=106)
with intermediate-dose chemotherapy (n=104). HRQoL was compromised
transiently among patients in the high-dose but not in the intermediate-dose
group.10 One explanation for this finding could be the fact that the first
assessment took place 3 months after chemotherapy, thereby missing the
transient fall in the HRQoL in the intermediate-dose group. Availability of HRQoL
data of healthy women allowed us to interpret HRQoL in a more balanced
manner. HRQoL of our patients appeared to be comparable to that of healthy
women of the same age. With frequent assessments, others found a decrease in
HRQoL in both arms, similar to our observations.7 In another prospective
longitudinal breast cancer study in 52 patients after high-dose chemotherapy
HRQoL were measured repeatedly from baseline over 2 years. HRQoL decreased
but had returned to baseline 8 weeks post treatment.9 Although our and the
above studies differ in many aspects, 1 year after treatment no differences in
HRQoL between the treatment groups or baseline were found by all four.7,9,10
In our study patients generally reported a few (late) symptoms, but some
complaints persisted several years. Remarkably, single symptoms apparently did
not have a severe influence on the HRQoL. Decreased sexual interest was the
most prevalent symptom. Impaired sexual functioning represents a well-known
Chapter 2
Similar to our findings, HRQoL had returned to baseline in both groups 1 year
28 |
Long-term side effects of adjuvant breast cancer treatment
specific long-term sequel of breast cancer patients.4,9,22,23 This can be partly due
to chemotherapy causing premature ovarian failure.9 Tiredness, painful muscles
and sweating were also frequently reported. Interpreting these results is difficult
because healthy postmenopausal women also commonly mention these
symptoms. We have earlier shown that (lower) mental health was the strongest
predictor for tiredness in a sub-population of the current study.24 Patients with
repeated multiple complaints were in the current analysis, characterized by a
lower educational level. A few other studies also observed this relation.
Kornblith et al noticed that breast cancer survivors with a lower education level
had more problems adapting to posttraumatic stress 20 years after adjuvant
therapy.25 In a study of 2,208 women with breast cancer or at risk for breast
cancer detected that women with a lower educational level were more likely to
be bothered by symptoms.26 In our study the 10% of the patients with repeated
multiple complaints are characterized by a lower education level. We also
analyzed for 5 year disease free survivors whether complaints mentioned in the
RSCL at randomization predicted their HRQoL at 5 years. This revealed that half
of those with four or more symptoms at 5 years also had many complaints at
randomization. This indicates that having complaints before chemotherapy
predicts a worse HRQoL outcome.
HRQoL of breast cancer patients in our study, 1-5 years after treatment, is
comparable to healthy women. Only small, clinically irrelevant differences were
observed between the treatment groups. The impact of both chemotherapy
regimes on HRQoL is therefore clearly less severe than expected. HRQoL
recovers swiftly after adjuvant treatment. Women with poor prognosis breast
cancer, engaged in intensive treatment protocols, tend to adapt to their new
situation and to modify their reference points. The emotional and social support
of relatives, friends and medical staff, can contribute to their adaptation.27
Identifying patients who have a higher chance of persistent impaired quality of
life after treatment may open the way for better patient-tailored prevention
strategies.
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Chapter 2
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30 |
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