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2190
Concomitant Chemoradiotherapy for Patients with
Nonmetastatic Breast Carcinoma
Side Effects, Quality of Life, and Daily Organization
Geneviève Macquart-Moulin, M.D.1
Patrice Viens, M.D.2
Dominique Genre, M.D.2
Marie-Laure Bouscary, M.D.1
Michel Resbeut, M.D.2
Gwenaëlle Gravis, M.D.2
Jacques Camerlo, M.D.2
Dominique Maraninchi, Ph.D.2,3
Jean-Paul Moatti, Ph.D.1,3
1
INSERM Research Unit 379, “Epidemiology and
Social Sciences Applied to Medical Innovation,”
Marseilles, France.
2
Paoli-Calmettes Institute, Regional Hospital for
Cancer Care, Marseilles, France.
3
University of the Mediterranean, Aix-Marseilles II,
Marseilles, France.
Supported by the Association for Cancer Research.
The authors thank all of the members of the
medical staff of the outpatient clinic of the PaoliCalmettes Institute for their assistance and their
interest in quality of life research.
Address for reprints: Geneviève Macquart-Moulin,
INSERM U 379, Institut Paoli-Calmettes, 232, Boulevard de Sainte-Marguerite, 13273 Marseilles Cedex 9, France.
Received May 26, 1998; revisions received September 21, 1998 and January 6, 1999; accepted
January 28, 1999.
© 1999 American Cancer Society
BACKGROUND. This study was designed to investigate the personal experience of
patients with nonmetastatic breast carcinoma who were treated with the concurrent administration of radiotherapy and chemotherapy in terms of side effects and
quality of life (QL).
METHODS. One hundred nine patients with nonmetastatic breast carcinoma, recruited between May 1995 and February 1997, were included in a protocol combining chemotherapy with mitoxantrone and cyclophosphamide, administered
intravenously in 4 cycles of 21 days, and concomitant radiotherapy. Side effects of
treatment and its impact on patients’ daily lives were measured using ad hoc
questionnaires; QL was measured by the European Organization for Research and
Treatment of Cancer QLQ-C30 QL questionnaire, and pain was measured by a
visual analogue scale (VAS).
RESULTS. All patients agreed to participate. The mean number of chemotherapy
and radiotherapy symptoms per cycle were: 7.2 6 2.5 and 2.4 6 1.8, respectively.
Chemotherapy symptoms generally were more frequent and distressing than those
of radiotherapy. The average pain score reported on the VAS by patients during
treatment was 3.0 6 2.0. Multidimensional QL assessment showed that treatment
mainly affects physical functioning and global QL. Multivariate analysis showed
that the main determinants of QL at the end of treatment were fatigue, pain, and
loss of appetite experienced during treatment. Moreover, 62.8% of patients required specific help for transportation to the hospital and/or home upkeep.
CONCLUSIONS. The concurrent administration of chemotherapy and radiotherapy
deteriorates patients’ QL but in a proportion similar to sequential administration
while presenting the advantage of a shorter duration of treatment. However,
increased fatigue, pain, and loss of appetite as well as difficulties in patients’ daily
lives have to be taken into account in therapeutic decision-making analysis.
Cancer 1999;85:2190 –9. © 1999 American Cancer Society.
KEYWORDS: nonmetastatic breast carcinoma, chemotherapy, radiotherapy, physical
symptoms, quality of life, daily life.
I
n the current adjuvant treatment of breast carcinoma, chemotherapy frequently is added to radiotherapy. However, the sequencing
of radiotherapy and chemotherapy has been a matter of debate.1,2 A
recent randomized study compared chemotherapy followed by radiotherapy with radiotherapy followed by chemotherapy.3 Results
showed that local relapse was more common when chemotherapy
was administered first, but distant relapse was more common when
chemotherapy was administered after the completion of radiotherapy. In conclusion, the authors suggested the administration of che-
Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al.
2191
motherapy first for those patients who have a high risk
of distant recurrence.
To avoid the potential risks of sequencing radiotherapy and chemotherapy, we developed a program
of radiotherapy and chemotherapy in which both
treatments are administered together. In addition to
the potential clinical benefits, this approach could be
of value for the patient, because it reduces the overall
duration of treatment. However, concurrent administration of radiotherapy and chemotherapy also could
be expected to have negative consequences in terms
of side effects and quality of life (QL) during treatment. We therefore explored the psychosocial impact
of such concomitant treatment to provide additional
information about the modalities of administration of
chemotherapy and radiotherapy in the adjuvant treatment of nonmetastatic breast carcinoma.
This study was designed to investigate the personal experience of patients with breast carcinoma
who submitted to an adjuvant concomitant chemoradiotherapy protocol. Data obtained encompassed
both chemotherapy and radiotherapy side effects as
well as patients’ QL during treatment and the impact
of treatment on patients’ daily lives.
receptors and was started after the completion of the
chemoradiotherapy sequence.
All radiotherapy was administered in 2 Gy fractions through a linear accelerator. 46 Gy (4 to 6 mv
photons) were delivered to the mammary gland with a
boost of 14 Gy (electrons) on tumoral bed in the case
of free margins and a boost of 14 Gy or 19 Gy (electrons) in the case of involved margins. After mastectomy, when indicated, 46 Gy were delivered on chest
wall with a boost of 10 Gy (electrons) in the case of
tumor size of more than 5 cm or of more than 4
involved axillary nodes. The axillary lymph node area
was never irradiated. The supraclavicular area and
internal mammary area received a total dose of 50 Gy
(mixed photons and electrons for internal mammary
gland) in case of internal tumors or in case of histologically involved axillary lymph nodes. The supraclavicular fossa and the internal mammary lymph nodes
were irradiated effectively in, 89.9% and 94.9% of patients, respectively. Radiotherapy started 1 week after
the beginning of chemotherapy and lasted 5 weeks.
PATIENTS AND METHODS
Chemotherapy side-effect questionnaire
Study Patients
The questionnaire, which was tested in a previous
study,4 was comprised of 19 items corresponding to
symptoms commonly associated with chemotherapy
of breast carcinoma: nausea, vomiting, loss of appetite, change in taste, diarrhea, weight loss and gain,
mouth sore, stomach pain, headache, hair loss, skin
rash, articular and muscular pain, cystitis, hot flush,
fever, conjunctivitis, and fatigue. For each symptom,
patients were asked three questions: 1) whether they
had experienced this symptom, at least once, during
the previous 3 weeks (yes or no); 2) what was the
duration of such a symptom (using a four-point scale:
,2 days, 3– 6 days, 1–2 weeks, all the time); 3) to what
extent the symptom had been distressing for the patient (using a four-point Likert scale: not at all, a little
bit, quite a bit, very much). Because duration was not
relevant for three symptoms (hair, weight loss/gain),
severity was evaluated instead.
Patients who were suffering from breast carcinoma
with no metastases and less than nine involved axillary lymph nodes received an adjuvant treatment associating polychemotherapy and concomitant radiotherapy. They were recruited at the Paoli-Calmettes
Institute (Regional Hospital for Cancer Care) in Marseilles between May 1995 and February 1997.
Chemotherapy doses were based on ideal body
weight. The protocol was comprised of mitoxantrone
(12 mg/m2) and cyclophosphamide (600 mg/m2) administered in four cycles of 21 days in outpatient
clinic. Mitoxantrone was administered as a 15-minute
intravenous (I.V.) infusion, and cyclophosphamide
was administered as a 30-minute I.V. infusion. Antiemetic prophylaxis consisted of granisetron (Kytril®)
administered in 1-mg tablet form 1 hour before the
start of each cycle of chemotherapy and within 12
hours after the first administration.
Complete blood count was performed on Day 1 of
each cycle, and chemotherapy was administered if the
neutrophil count was .1.5 3 109/L and the platelet
count was .100 3 109/liter. If a patient did not meet
these criteria, then chemotherapy was delayed until
hematological recovery. No dose reduction was
planned. Tamoxifen (20 mg once a day for 3 years) was
given to menopausal patients with positive estrogen
Instruments for Measurement of Side Effects and QL
The instruments described below were used in the QL
form presented to patients.
Radiotherapy side-effect questionnaire
This questionnaire was developed on the model of the
chemotherapy questionnaire. It included eight items:
breast pain, loss of nipple sensitivity, altered skin pigmentation, breast redness, breast lesion(s), problems
with arm (edema, difficulty in elevation), difficulty
swallowing, and cough. Breast pain, problems with
arm, difficulty swallowing, and cough were measured
2192
CANCER May 15, 1999 / Volume 85 / Number 10
in terms of duration and distress, and other radiotherapy symptoms were measured in terms of severity and
distress. Duration, severity, and distress levels were
evaluated on a four-point-scale, as in the chemotherapy questionnaire.
Visual Analogic Scale
Patients were asked to evaluate pain by using a Visual
Analogic Scale (VAS).5 For the pretreatment period,
patients had to report present pain, whereas, for the
other measures that were evaluated prior the start of
each cycle of chemotherapy, they were asked to evaluate maximal pain experienced during the previous
cycle.
European Organization for Research and Treatment of
Cancer QLQ-C30 (version 1)
This 30-item questionnaire is a cancer specific, patient-based measure designed for self administration.
It is comprised of five functioning scales (physical,
role, emotional, cognitive functioning, and social
functioning). There are three symptoms scales (fatigue, nausea and vomiting, and pain) and six single
items (dyspnoea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties). The questionnaire also includes two global questions about the
patient’s health status and overall QL, allowing a
global QL scale to be obtained. All scores obtained
from scales and single items range from 0 to 100. A
high score for a functional scale and for the global QL
scale represents a high level of functioning or global
QL, whereas, inversely, a high score for a symptom
scale/single item corresponds to a high level of symptoms or problems. The reliability of the European
Organization for Research and Treatment of Cancer
(EORTC) QLQ-C30, as measured by Cronbach’s alpha
coefficient,7 ranged from 0.61 for nausea/vomiting to
0.90 for fatigue at the first evaluation (pretreatment)
and from 0.46 for physical functioning to 0.91 for
fatigue at the last evaluation (21 days after the last
cycle of chemotherapy).
Questionnaire about organization of daily life
This detailed questionnaire was study specific and
contained 16 self-report questions that were related
principally to the pursuit or not by the patient of her
occupational activity and the assistance needed during treatment: by whom (family, friend[s], partner,
employee), how (looking after by a parent or a friend
at his/her home, staying in a convalescent home or
therapeutic apartment), and/or for what motive (daily
care, transportation to hospital, children’ care, shopping, walks), and use of ambulatory care services.
Sociodemographic questionnaire
This questionnaire contained ten items related to sociodemographic data: date of birth, place of residence,
distance from residence to hospital, marital status, life
style (alone or with spouse/partner), education, occupation, employment status before disease, number of
children, and number of children living at home.
Administration of the QL Form
All patients who met eligibility criteria were asked to
participate in the survey. Oral information was provided for patients on the objectives and the constraints of the study. From the first cycle of chemotherapy (pretreatment), each patient was asked by a
nurse or a physician to complete the QL form prior to
the start of each session of chemotherapy. The last
form, which assessed the impact of the last cycle of
chemotherapy, was filled out by the patient at home
and returned to the medical team during a follow-up
consultation or was sent by mail with a prestamped
return envelope.
The content of the five QL forms presented to
patients varied according to the moment of the evaluation, and special attention was given to minimize
patients’ stress (Table 1). The chemotherapy side-effect questionnaire was presented at each cycle beginning at cycle 2, and the radiotherapy side-effects questionnaire was presented at cycles 2 and 3 only
(because radiotherapy started about 1 week after the
beginning of chemotherapy and lasted 5 weeks). Both
questionnaires at each evaluation measured the treatment side effects experienced by patients during the
previous cycle of chemotherapy. The EORTC QLQ-C30
was proposed prior the start of chemotherapy (pretreatment) and 21 days after the start of the fourth
cycle of chemotherapy. Pain was assessed on VAS in
the pretreatment period and at each cycle. Sociodemographic data were included in the first QL form
(pretreatment), and the questionnaire that evaluated
the organization of daily life during treatment was
included the last QL form. According to its length,
each QL form could be filled out by patients in an
average of 10 –20 minutes.
Statistical Analysis
The statistical software program, SPSS PC for Windows (version 6.0; SPSS, Inc., Cary, NC) was used for
statistical analyses.8 We used nonparametric tests to
analyze QL data. The use of nonparametric tests was
based on the ordinal measures (answers to items of
the ad hoc chemotherapy questionnaire and of the
EORTC QLQ-C30 were obtained by using Likert
scales), and the nonnormality of distributions was
Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al.
2193
TABLE 1
Content of the Quality of Life Form
QL form
Questionnaires/scales
Sociodemographic questionnaire
Chemotherapy side effect questionnaire
Radiotherapy side effect questionnaire
Visual analogic scale
EORTC QLQ-C30
Questionnaire of daily organization
No. 1,
pretreatment
No. 2,
cycle 1
No. 3,
cycle 2
No. 4,
cycle 3
No. 5,*
cycle 4a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
QL: quality of life; EORTC: European Organization for Research and Treatment of Cancer.
a
Completed by the patient at home 21 days after the start of the fourth cycle of chemotherapy.
used to limit assumptions and maintain consistency.
Spearman’s rank-correlation coefficients and the
Kruskall–Wallis test were used to investigate correlations between QL data as well as between QL data and
sociodemographic or clinical data. McNemar, Cochran, and Friedman nonparametric tests were used to
test for significant changes over time. For the multivariate analysis, a linear regression model (using ordinary least-squares regression) was performed to determine explanatory variables of patient’s QL at the
end of treatment, measured by the EORTC global QL
score (depending on variables). A “stepwise regression” approach was chosen. The linear regression
model included the International Union Against Cancer (UICC) stage of disease, the level of occupational
activity of women before disease, the EORTC global
quality of life score reported in the pretreatment period, the mean number of physical symptoms, the
average maximal pain experienced by patients during
the entire course of treatment, and the most significant physical symptoms experienced by patients during the last cycle of chemotherapy (symptoms expressed in terms of duration/severity and/or distress
by the chemotherapy questionnaire). All P values
quoted are two-sided.
RESULTS
Patients’ Sociodemographic and Clinical Characteristics
From May 1995 to February 1997, 109 patients were
included in the chemoradiotherapy protocol. Patients’
sociodemographic characteristics are listed in Table 2.
The mean age of patients was 50.8 years (range, 23–73
years). Table 2 shows that nearly half of the patients
lived in an area no farther than 20 kms from the
outpatient clinic. A high proportion of women (73.3%)
lived with a partner, and 50% had children living at
home. Because some women were older than 60 years
TABLE 2
Patients’ Sociodemographic Characteristics (n 5 109)
Characteristic
Valuea
Age (yrs)
Distance from residence place to hospital
,20 kms
20 to 100 kms
.100 kms
Marital status
Married
Not married
Living as a couple
Yes
No
Children at charge
None
One
Two or more
Level of education
Lower level of education
Secondary school/university graduat
Occupational activity before disease
Yes
No
Occupation of active women
Executive/middle management
Professional/teacher
Employee/worker
50.8 6 11.8
53
31
19
51.5
30.1
18.4
67
42
61.5
38.5
77
28
73.3
26.7
49
22
27
50.0
22.4
27.6
68
40
63.0
37.0
58
48
54.7
45.3
6
17
32
10.9
30.9
58.2
Number and percentage excepted for age (mean 6 standard deviation). Incomplete numbers correspond to missing data.
a
of age (29 patients), only 54.7% of patients had an
occupational activity before their disease.
Forty-four percent of women were menopausal.
Thirty-nine patients (35.8%) had no axillary lymph
node involved, and only 13 patients (11.9%) had more
than three axillary lymph nodes involved. The majority of women (78.9%) had undergone a tumorectomy.
Seventy-eight percent of patients had a ductal carci-
2194
CANCER May 15, 1999 / Volume 85 / Number 10
noma, and American Joint Committee on Cancer stage
of disease was 0 for 14 patients (12.8%), Stage I for 34
patients (31.2%), Stage II for 51 patients (46.8%), Stage
III for 5 patients (4.6%), and not applicable or not
done for 5 patients (4.6%).
Patients’ Participation and Compliance
All patients included in the clinical protocol were
asked to participate in the QL study. All of the patients
agreed to participate (participation rate, 100%). A total
of 524 QL forms were available for statistical analysis,
respectively, 109, 107, 106, 105, and 97, from the pretreatment period to the fourth cycle of chemotherapy.
The average rate of missing values was 2.1% for the
chemotherapy questionnaire (1.5% for the items of the
duration/severity dimension and 2.8% for that of the
distress dimension), 2.6% for the EORTC QLQ-C30
questionnaire, 4.5% for sociodemographic data, 5.5%
for the radiotherapy questionnaire (5% for the items of
the duration/severity dimension and 6% for that of the
distress dimension), 10.9 % for the pain VAS, and 11%
for the patient daily life organization questionnaire.
Frequency and Characteristics of Symptoms
The mean number of symptoms associated with the
chemotherapy treatment was 7.2 6 2.5 (range, 0 –17).
Table 3 summarizes the patients’ declared frequency
of chemotherapy symptoms, their duration/severity,
and the degree of distress that patients associated with
them during 415 cycles of chemotherapy. In 50% of
cycles or more, patients experienced nausea, hair loss,
change in taste, headaches, and hot flushes. Furthermore, long term hot flushes, change in taste, conjunctivitis, articular pain, skin rash, and stomach pain were
present in more than 45% of cycles. The four most
distressing symptoms were vomiting, cystitis, stomach
pain, and hot flushes. Surprisingly, the least distressing symptom was weight loss.
The frequency trend of chemotherapy symptoms,
measured by the self-report questionnaire, was tested
in a subgroup of 91 patients who completed this questionnaire at each cycle of chemotherapy. A significant
increase (P , 0.05) in the frequency of some symptoms was observed across cycles. It was the case for
vomiting, change in taste, hair loss, and hot flushes.
The results also show a statistically significant increase
in duration/severity of nausea, loss of appetite,
change in taste, headache, and hair loss. However,
distress associated with each symptom remained constant across cycles, with the exception of muscular
pain, which tended to be associated with a higher
distress in the latter cycles.
The mean number of specific radiotherapy symptoms experienced within 213 cycles in which radio-
therapy was concomitant to chemotherapy was low:
2.4 6 1.8 (range, 0 –7). Thirty-four percent of patients
did not report any symptoms. Table 3 shows the relatively low frequency of most radiotherapy symptoms
(l,40% of cycles, except for breast redness), with a
weak percentage of long term and distressing symptoms (,20% of cycles) except for arm problems.
Fatigue, which may be associated with chemotherapy as well as radiotherapy, was present globally
in 89.4% of cycles (Table 3). This symptom lasted more
than 1 week in 61.8% of cycles and was distressing for
patients in more than two-thirds of cycles. Furthermore, the duration and the distress associated with
this symptom increased significantly across cycles
(P , 0.001 for both statistics). The percentage of cycles
with persistent and distressing fatigue was significantly higher in the last two cycles (cycles 3 and 4),
although chemotherapy was administered alone, than
in the first two cycles, in which radiotherapy and
chemotherapy were concomitant: 71.7% versus 51.9%,
respectively (P , 0.0001) and 74.7% versus 62.4%,
respectively (P 5 0.01). The average maximal pain
reported on VAS by patients during their treatment
was 3.0 6 2.0 (range, 0 – 8.7) and was constant across
cycles.
Impact of the Treatment on Patients’ QL
Results from the EORTC QLQ-C30 core questionnaire
completed by patients are listed in Table 4. This questionnaire reports patients’ experience during the week
before interview, except for physical functioning and
global QL, which refer to patient status at the time of
interview. The analysis was performed on patients
who had completed both the pretreatment questionnaire and the final questionnaire (n 5 97).
Of six functional scales, two were found to be
significantly lower after the completion of treatment.
They related to physical functioning and global quality
of life (P 5 0.001 for both statistics). For other functional scales, no statistically significant differences
were observed. However, compared with the pretreatment period, mean scores of these scales were lower.
Of nine symptom scales/items, five were found to be
significantly higher 21 days after treatment completion. They related to fatigue, nausea/vomiting, and
dyspnoea (P , 0.001 for all statistics) as well as appetite loss and sleep disturbance (P 5 0.02 for both
statistics). Because patients were asked to describe
their symptoms the week prior to the completion of
the questionnaire, these results demonstrate that
some symptoms last 15 days or more after the last
cycle of chemotherapy. Furthermore, we must note
that global QL in the pretreatment period did not
depend significantly on sociodemographic or clinical
Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al.
2195
TABLE 3
Frequency and Characteristics of Symptoms
Cycles with symptoms
Symptom
Chemotherapy symptom (415 cycles)
Nausea
Hair loss
Change in taste
Headache
Hot flush
Lack of appetite
Stomach pain
Muscular pain
Articular pain
Vomiting
Sore mouth
Weight gain
Weight loss
Skin rash
Conjunctivitis
Diarrhoea
Cystitis
Fever
Radiotherapy symptom (213 cycles)
Breast pain
Loss of nipple sensitivityc
Breast pigmentationc
Breast rednessc
Breast lesionsc
Problems with arm
Difficulty for swallowing
Cough
Chemotherapy/radiotherapy symptom
Fatigue
Entire treatment (415 cycles)
Chemo 1 radiotherapy (213 cycles)d
Chemotherapy alone (202 cycles)e
No.
%
Percent of cycles
with long term/
severe symptomsa
348
307
223
214
207
205
165
158
130
118
102
95
89
84
53
44
40
37
83.9
73.9
53.7
51.6
49.9
49.4
39.8
38.1
31.3
28.4
24.6
22.9
21.4
20.2
12.8
10.6
9.6
8.9
28.9
25.1
64.3
25.9
71.4
36.8
49.0
39.8
54.0
8.6
41.6
14.7
16.8
53.1
64.1
15.9
23.7
20.0
57.4
54.1
56.6
55.4
61.3
36.2
63.2
52.0
50.8
71.3
49.5
35.3
13.5
51.3
58.0
48.8
71.1
25.8
69
63
63
82
14
72
72
66
32.4
37.7
37.7
49.1
8.4
33.8
33.8
31.0
19.0
8.9
14.6
15.6
3.7
23.1
18.6
18.6
15.2
8.9
6.5
11.5
6.1
21.0
19.1
14.5
371
187
184
89.4
87.8
91.1
61.8
51.9
71.7
68.5
62.4
74.7
Percent of cycles with
distressing symptomsb
a
Symptoms that persisted more than 1 week.
Symptoms that were declared to be quite a bit or a lot distressing by patients.
c
Only for women who did not undergo mastectomy.
d
Cycle 1 1 cycle 2, because radiotherapy covered only the two first cycles of chemotherapy.
e
Cycle 3 1 cycle 4, in which chemotherapy was administered alone.
b
variables. However, it appears that women with an
occupational activity before disease had higher global
quality of life scores than women without an occupational activity. Similarly, women with UICC Stage I or
Stage II disease exhibited higher global QL scores than
others.
Results of the multivariate analysis are displayed
in Table 5. They show that QL life at the end of treatment is associated with the average maximal pain
reported by patients during the entire treatment and
with the duration of articular pain, loss of appetite,
and fatigue experienced during the last cycle of chemotherapy.
Patients’ Daily Lives
Analysis of data about organization of daily life was
performed on the subgroup of patients who completed both the pretreatment and the last QL form
(n 5 97). Among patients who had an occupational
activity before their disease (n 5 54), 85.7% had to
stop this activity during the treatment. Most patients
(83.1%) remained living in their home, whereas 16.9%
had to move to a convalescent home or a therapeutic
apartment. A total of 62.8% patients required specific
assistance for daily life during treatment. The majority
of people who provided this assistance were recruited
among close relatives (for 92.5% of patients who re-
2196
CANCER May 15, 1999 / Volume 85 / Number 10
TABLE 4
Patients’ Quality of Life in Pretreatment and 21 Days After the Last
Cycle of Chemotherapy (n 5 97)
TABLE 5
Linear Regression Model: Explanatory Variables of Patients’ European
Organization for Research and Treatment of Cancer Global Quality of
Life Score at the End of Treatment
Mean 6 SD score
Variable
Functional scalesa
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Global quality of life
Symptom scales/itemsb
Fatigue
Nausea and vomiting
Pain
Dyspnea
Sleep disturbance
Appetite loss
Constipation
Diarrhea
Financial difficulties
Pretreatment
21 days after the
last cycle of
chemotherapy
Variable
EORTC global quality of life
score at the end of treatment
(unstandardized regression
parameter estimate [B
parameter]a
P value
Pain during entire treatment (0–10)b
Muscular pain duration (1–4)c
Fatigue duration (1–4)c
Loss of appetite duration (1–4)c
Multiple R2
20.18 (0.08)
22.31 (0.99)
26.80 (1.24)
22.07 (1.00)
0.50
0.02
0.02
, 0.001
0.04
—
P value
77.8 6 23.7
54.7 6 43.6
63.5 6 25.8
74.4 6 27.2
67.4 6 31.7
62.2 6 19.0
69.2 6 22.9
51.6 6 35.7
59.7 6 29.1
68.2 6 32.8
63.6 6 31.5
52.8 6 19.5
0.001
NS
NS
NS
NS
0.001
39.3 6 26.9
9.7 6 17.6
28.6 6 28.9
14.5 6 22.2
35.1 6 34.2
17.0 6 25.1
23.5 6 32.9
5.0 6 16.2
13.6 6 24.2
56.5 6 30.9
25 6 26.7
28.5 6 28.7
30.5 6 28.8
45.9 6 38.3
26.2 6 33.5
29.8 6 36.1
7.8 6 21.5
18.8 6 28.7
,0.001
,0.001
NS
,0.001
0.02
0.02
NS
NS
NS
SD: standard deviation; NS: not significant.
a
Higher scores represent a high level of functioning.
b
Higher scores represent a high level of symptom/problem.
quired help). The need for assistance was due mainly
to transportation to hospital (57.7%) or/and home
upkeep (52.4%). Surprisingly, assistance did not depend significantly on patient age, education level, activity before disease, or number of children at home.
Finally, 29.4% of patients used ambulatory care services, such as nursing help, during treatment.
DISCUSSION
The purpose of this study was to evaluate side effects
and QL experienced by breast carcinoma patients during an adjuvant, concomitant chemoradiotherapy
protocol with the objective of exploring the potential
cumulative effects of the two treatments. Of course, a
limitation of this study is the lack of a comparative
group. However, comparisons with data from the literature about QL during breast carcinoma treatment
in which chemotherapy and radiotherapy are administered alone or in sequence can be of interest. Some
difficulties arise for these comparisons, because investigators usually evaluated toxicity of chemotherapy at
base of mitoxantrone using the World Health Organization (WHO) criteria9 or self-administered instruments that are not as detailed as our chemotherapy
EORTC: European Organization for Research and Treatment of Cancer.
a
A negative B indicates a negative, inverse correlation. The standard error of coefficient is noted in
parentheses.
b
Average maximal pain experienced by patients during entire treatment.
c
Symptom experienced by patients during the last cycle of chemotherapy.
side-effect questionnaire.10,11 Except for the study by
Sprangers et al.,12 similar problems exist with the assessment of radiotherapy side effects.13–15 Contrary to
The Breast Cancer Chemotherapy Questionnaire
(BCQ)16 and the Functional Assessment of Cancer
Therapy-Breast (FACT-B),17 also devised specifically
for breast carcinoma patients, the EORTC QLQ-BR,23
tested in the study by Sprangers et al.12 includes side
effects related to both chemotherapy and radiotherapy. Unfortunately, this module, which was developed
by the Study Group on Quality of Life of the EORTC to
be administered in conjunction with the EORTC QLQC30, was not available in French at the time of study.
This led us to adopt the EORTC core questionnaire to
measure multidimensional QL of patients and to develop specific instruments to measure treatment side
effects. The addition to the EORTC QLQ-C30 of the
two specific side-effect questionnaires (chemotherapy
and radiotherapy) permitted us to cover a broad range
of side effects addressed, by example, by the QLQBR23 module, notably in questions 32–35, 37, and 38
as well as in questions 47–50 and 53.
Nausea frequency in our study (84%) was similar
with that reported in Bennett’s study10 (80% of cycles
for nausea/vomiting) in which cyclophosphamide,
mitoxantrone, and fluorouracil (CNF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF)
chemotherapy was administered after radiotherapy
(Table 6). Conversely, it was higher than in the study
carried out by Greene (25–55% of patients according
to the moment of the measure),11 in which breast
carcinoma patients received CNF chemotherapy
alone. Hair loss was severe for 25% of cycles in our
Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al.
TABLE 6
Literature Data: Comparison of Symptom Frequency Experienced by
Patients with Nonmetastatic Breast Carcinoma during Concomitant
Chemoradiotherapy with that Reported by Patients Receiving
Sequential Chemoradiotherapy
Study
Instrument for
measuring toxicity
Bennett et al., 198810
LASA
Alonso et al., 19959
Greene et al., 199411
WHO criteria
Self-care diary
Symptom(s)
Present study vs.
literature data
Nausea
Mouth sore
Alopecia
Alopecia
Nausea
Vomiting
Mouth sore
Change in taste
Loss of appetite
Fatigue
Alopecia
5
m
m
n
m
5
5
5
5
5
m
LASA: Linear analogue self-assessment; WHO: World Health Organization.
study, for 4% in the study by Bennett, and for 36%
(WHO Grade 3) in that of Alonso et al. (CNF vs. CAF
chemotherapy alone).9 Other symptoms, such as
mouth sore, change in taste, loss of appetite, and
fatigue, produced reports similar to that assessed in
Greene’s study, in which symptoms were measured by
using a self-care diary (Table 6). However, some long
term and/or distressing symptoms, such as hot flush,
stomach pain, and articular pain, were not assessed in
the studies discussed above.
Our results from the radiotherapy side-effects
questionnaire confirm a fact already known by clinicians, i.e., radiotherapy side effects are largely less
frequent, severe, and distressing than chemotherapy
side effects. It must be recognized that, among the
side effects assessed in our study, arm edema is due
more to surgery than to radiotherapy. Furthermore,
cough has to be more related to events such as mucitis
rather than to pneumonitis, which is unlikely to occur
acutely during radiation. Few studies to our knowledge have attempted to measure adverse effects and,
particularly, cosmetic effects of radiotherapy in breast
carcinoma patients as well as the associated distress.
One study15 has focused more on psychological symptoms than physical symptoms, except for fatigue,
which otherwise appeared as the most frequent side
effect of radiotherapy. However, Greenberg et al.14
found that, contrary to their hypothesis, fatigue, which
was evaluated during radiation treatment for breast
carcinoma, did not increase linearly with cumulative
radiation dose over time. In addition, compared with
other patients who received treatment, the fatigue
scores found in their study were lower. An interesting
2197
finding of our study is that patients experienced fatigue less often when they received chemotherapy and
radiotherapy simultaneously than when they received
chemotherapy alone. Because radiotherapy was concomitant with the two first cycles of chemotherapy,
this finding suggests, as in the other studies, that fatigue is due more to the duration of treatment than to
the effects of the current administration of chemotherapy and radiotherapy, per se. Regarding the cosmetic problems induced by radiotherapy, it is difficult
to compare our results with those of previous studies.
Indeed, Read et al.13 investigated morbidity and cosmesis after lumpectomy and radiotherapy in 184 patients with breast carcinoma, but the assessments
were performed only at 5–7 months after surgery. The
study by Sprangers et al.12 approached these effects by
means of the QLQ-BR23, but their results were not
analyzed and presented in the manner used in the
current report; therefore, comparison between the
two studies is not feasible. Another study published in
199618 evaluated the interaction of sequence and type
of chemotherapy and hormonal therapy given with
radiation therapy on the cosmetic outcome and the
incidence of complications of patients with Stage I
and II breast carcinoma who were treated with breastconserving therapy (79% of patients in our study).
That study demonstrated that cosmesis was not influenced detrimentally by the addition of chemotherapy
to radiation therapy in breast-conservation treatment.
Our results, which show few cosmetic problems in
study patients, and those of Markiewicz et al.18 are in
favor of the absence of deleterious effect on cosmesis
of the concurrent administration of chemotherapy
and radiotherapy.
The relatively high and constant pain intensity
reported by patients during treatment may be considered as the consequence of cumulative effects of disease, surgery, chemotherapy, and radiotherapy. For
example, one study that was performed in 1995 among
569 patients with breast carcinoma demonstrated that
pain was more common after breast-conserving surgery than after radical surgery.19 Surgical complications and postoperative radiotherapy and chemotherapy increased the risk of chronic pain and other
symptoms. Another paper by the same authors, which
was published the next year,20 investigated in more
depth the problem of pain in 93 patients with breast
carcinoma who submitted to different treatment modalities during the first year after radical and conservative surgery. The incidence of 1-month and
6-month posttreatment chronic pain in the breast
area and in the ipsilateral arm was significantly higher
after conservative surgery than after radical surgery. In
the posttreatment period, pain intensity in the ipsilat-
2198
CANCER May 15, 1999 / Volume 85 / Number 10
eral arm was significantly higher than the intensity of
pain before surgery. Pain-intensity scores in that study
were similar to ours both before treatment and 1
month after treatment.
Multidimensional QL assessment in patients
with nonmetastatic breast carcinoma using the
EORTC QLQ-C30 shows that the impact of treatment is obvious; however, it affects mainly patients’
physical functioning and global QL, whereas, compared with the pretreatment period, emotional, cognitive, role, and cognitive functions remain unchanged. Several studies have attempted to evaluate
the impact of adjuvant treatment on QL before,
during, and after treatment.21–27 Among the most
recent, the study by Hürny et al.27 investigated QL
during therapy and after disease recurrence in patients with lymph node positive, operable breast
carcinoma who were included in two trials of the
International Breast Cancer Study Group. Those authors concluded that, although adjuvant chemotherapy had a measurable impact on patients’ QL,
this impact was transient and minor compared with
patients’ adaptation/coping after diagnosis and surgery. The conclusions of this study are similar to
those of Campora et al.,24 indicating that the majority of patients with breast carcinoma respond normally to adjuvant chemotherapy. QL assessments at
the end of the treatment period, in our study, suggest that the disappearance of a certain number of
physical symptoms due to treatment (and particularly to chemotherapy) will have as a consequence
further improvement of patients’ QL. However, pain
experienced by patients during treatment, duration
of articular pain, fatigue, and loss of appetite at the
last cycle of chemotherapy compromise global QL at
the end of treatment. Except when it is related to
chronic anemia, for which transfusions or erytropoietin (for treatment as well as for prevention)28 –30
can be offered, clinicians are not able to treat fatigue. Psychological support alone may represent a
possibility. Pain, which often is present already before surgery in the breast area and in the ipsilateral
arm, may be intensified by radiotherapy and also by
chemotherapy, which induces many other painful
symptoms. This should incite clinicians to relieve
pain before as well as during and after treatment.
Generally, physicians should attempt to detect
symptoms that persist and about which patients do
not necessarily complain.
We have not found references in the literature
concerning the organization of daily lives for patients
who underwent chemotherapy alone or chemotherapy plus radiotherapy. However, the study by Campora et al.24 indicated that, in 83–90% of cases, pa-
tients who received chemotherapy alone took care of
themselves. Our results are slightly less optimistic:
Although 83.1% of patients lived at home during treatment, about 63% have needed help (principally by
close relatives) for transportation to the hospital
and/or home upkeep. It is obvious that the addition of
chemotherapy and radiotherapy may complicate daily
life for patients who have to come to the hospital for
radiotherapy every day (weekends excepted) for 5
weeks. However, fatigue itself may complicate daily
life and incite women to seek help. An interesting
finding from a social point of view is that a high
proportion of active women (85.7%) had to stop their
occupation during treatment. This may have been due
to difficulties that were related directly to the disease
and its treatment. However, considering the minimum
symptoms identified, it is likely than other problems
exist. These problems may be difficulties for patients
to conciliate their work, their family lives, and the
constraints due to treatment and to obtain flexible
time management with employers. Another possibility
is the reluctance of patients to talk about their disease
and/or to reveal its effects as well as those of the
treatment to their colleagues.
In conclusion, this work shows that concomitant
administration of chemotherapy and radiotherapy induces certain side effects that deteriorate patients’ QL
but in a proportion similar to that observed with sequential protocols. Although some of these effects,
such as fatigue, pain, and loss of appetite, detract from
QL at the end of treatment, the results suggest that the
advantage of shortening the duration of treatment
compared with sequential protocols does not seem to
be offset by an increase in distress associated with side
effects. Moreover, concomitant chemoradiotherapy
may require that women have an adequate organization of their daily lives during treatment and will need
more assistance during this period. These results can
provide clinicians with adequate data to give to patients for obtaining their informed consent to undergo
such treatment. Moreover, this work demonstrates
that the psychosocial effects of treatments are measurable, and their recognition may be helpful to clinicians in routine care and even in the therapeutic decision-making process. However, the results of our
study probably are not directly generalizable. Indeed,
mitoxantrone is reputed to be less toxic, particularly in
terms of alopecia, than the most commonly used anthracyclin (adriamycin) and the equivalence of its efficacy is discussed. So, additional studies on concomitant radio-chemotherapy using adriamycin are
mandatory. Furthermore, long term outcomes of the
concurrent administration of radiotherapy and chemotherapy, such as cosmesis and late cardiac effects,
Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al.
would have to be evaluated before generalizing this
type of treatment.
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