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Feature and review paper
Quality of life assessments in advanced breast cancer:

should there be more consistency?
ecc_1370
565..580
E. REED, bsc, mphil, Research, Breast Cancer Care, London, UK, I. KSSLER, ba, msc, Swedish Breast Association,
Sundbyberg, Sweden, & J. HAWTHORN, bsc, phd, Oxshott, UK
REED E., KSSLER I. & HAWTHORN J. (2012) European Journal of Cancer Care 21, 565580
Quality of life assessments in advanced breast cancer: should there be more consistency?
Quality of life (QOL) measures have assumed increasing importance in assessing the impact of therapeutic
drugs and interventions on patients and in making judgements about their cost-effectiveness. Important
treatment decisions and crucial funding strategies involve QOL data and, for patients with a disease such as
advanced breast cancer that impinges on their life expectancy, QOL can become a hugely important consideration. Yet, despite this, there is a lack of consensus on what defines an appropriate QOL measure, and
inconsistency in the instruments that are chosen to measure it. The National Institute for Health and Clinical
Excellence (NICE) is seen as a model for appraising the value of new treatments and NICE approval is required
for treatments to be funded in the UK. In order to compare different disease conditions they use a generic
measure, preferring the EQ-5D. We have performed a literature search of clinical trials in advanced breast
cancer to establish which QOL measures have been used. Our findings show marked heterogeneity in terms
of which QOL tools are used. It is suggested that there should be more consensus on which QOL instruments
are used, not only between researchers, but between them and the bodies that approve funding.
Keywords: breast cancer, quality of life.
INTRODUCTION
Quality of life (QOL) is a concept that has, over the past
few decades, become increasingly important in health
care. Quality of life first appeared as a term in the
medical literature in the 1960s, but it took some 30 years
before it was recommended as a robust end-point in cancer
clinical trials by the American Society of Clinical Oncology. There is no universally accepted definition of the
term QOL (Muldoon et al. 1998), but there is now general
agreement that quality of life is a term describing a multifactorial measure that encompasses peoples emotional,
Correspondence address: Elizabeth Reed, Research Manager, Breast Cancer

Care, 5-13 great suffolk street, London se1, UK (e-mail: Liz.Reed@
breastcancercare.org.uk).
Accepted 30 April 2012

DOI: 10.1111/j.1365-2354.2012.01370.x
European Journal of Cancer Care, 2012, 21, 565580
2012 Blackwell Publishing Ltd
social and physical well-being and their ability to function

in the ordinary tasks of daily living (Leplge & Hunt 1997;
Muldoon et al. 1998).
Health-related quality of life (HRQOL) measures the
impact of treatments and disease processes on these holistic aspects of a persons life. The World Health Organisation (WHO) defined HRQOL as
An individuals perception of their position in life in
the context of the culture and value systems in which
they live and in relation to their goals, standards and
concerns. It is a broad ranging concept affected in a
complex way by the persons physical health, psychosocial state, level of independence, social relationships, and their relationship to salient features of the
environment. (WHO 1993)
The rising importance of QOL reflects the move to more
patient-focused health care. Especially in oncology, the
approach of healthcare professionals has shifted from
REED et al.
considering the underlying disease as a challenge to their

professional skills, to a more empathetic approach to the
patient as an individual whose care must encompass the
whole person. The idea that the patients perspective is as
valid as that of a clinician when it comes to evaluating
outcome has a great deal of legitimacy (Leplge & Hunt
1997).
The QOL measures are the means of providing valuable
insight into whether a treatment is meeting patients real
needs, rather than just considering the objective clinical
end-points of the effects of treatment. For people living
with chronic diseases, or where the prognosis is poor, this
is profoundly important. QOL measures can help patients
and clinicians to decide between different treatments, to
monitor treatment success from the patients perspective
and to plan and coordinate care packages. QOL data may
also be used to support licensing applications for drugs. A
treatment therefore might be recommended based on
QOL improvement even without an improvement in survival. This is especially relevant in the advanced disease
setting, when treatment is unlikely to be curative.
Another area in which the use of QOL measures has
increased in recent years is health economics. Advances in
drug development and medical technology now make a
vast array of treatments open to the clinician, sometimes
with very different costs between new and older drugs for
the same condition. With a finite budget to spend on
health care, service providers have to have a measure of
cost-effectiveness or value-for-money and increasingly,
QOL considerations are also encompassed, alongside
clinical efficacy when assessing the value of a treatment.
With important treatment decisions and crucial funding
strategies involving QOL data, it might be expected that
QOL instruments have been carefully evaluated to be fit
for purpose. Yet, despite the increasing importance of
QOL, there is a lack of consensus on what defines QOL,
and a very wide range of instruments have been designed
to measure it.
The search for instruments that are specific to particular diseases has led to the development of numerous QOL
tools. In breast cancer there is now a large number of
instruments, but even within this one disease area there
is no gold standard instrument and no indication of
whether the instruments are suitable for all stages of
disease. This may be an important consideration in breast
cancer where patients with advanced disease often have
different needs from those diagnosed at an early stage.
The National Institute for Health and Clinical Excellence (NICE) is seen as a model for appraising the value of
new treatments. NICE recommends that health benefits
should be valued in terms of gains in quality-adjusted life
566
years (Dolan et al. 2009). In order to be able to compare

different disease conditions NICE advises using a generic
measure of QOL, and it prefers the EQ-5D.
The EQ-5D describes health in terms of three levels of
severity for each of five dimensions (mobility, self-care,
usual activities, pain or discomfort, and anxiety or depression). This therefore generates 243 (35) possible health
states defined by a five number code from 11111 to 33333.
So 11121 describes a health state without problem for the
majority of dimensions (the 1s), but with moderate pain or
discomfort (the 2 that appears in the fourth state). NICE
have used a time trade-off system to assign average tariff
values to each of the 243 EQ-5D health states. Around
3000 members of the UK general public were asked to
describe their health using EQ-5D and to consider how
many years of life in full health x, are equivalent to a
longer time, t, in a poorer health state. If full health is
assigned a value of 1 then the value of the poor health
state is x/t.
Thus the EQ-5D questionnaire has been developed
using the healthy general public giving answers about how
they think they might feel in hypothetical situations of
poor health. Healthcare professionals and patients alike
are increasingly questioning the appropriateness of using
an instrument defined in a healthy population to assess a
population of people who have different degrees of illness.
Patient needs and attitudes may even change as a disease
progresses and responses to questionnaires may change
markedly, depending on the persons mood or medical
condition at the time (Hawthorn 1993; Carr & Higginson
2001).
This review was conducted therefore to discover what
QOL tools are used in randomised clinical trials of chemotherapy or hormonal therapy in treating advanced
breast cancer patients and to identify the most commonly used instruments. This study was not designed,
nor intended to, evaluate individual QOL instruments,
nor assess how appropriate they are to patient needs; the
study was aimed at examining the consistency with
which QOL instruments are (or are not) used. QOL in
breast cancer has been reviewed previously (Bottomley &
Therasse 2002; Goodwin et al. 2003; Fossati et al. 2004;
Montazeri 2008). This current review provides an up-todate summary.
METHODS
Literature searches were performed using the PubMed
database, and the Medline database using search terms as
given in Tables 1 and 2. The searches were carried out at
the end of October 2011. The abstracts of papers were then
Quality of life assessment in advanced breast cancer
Table 1. Medline search

A Medline search was carried out using the following procedure:
Query No. Search
1
Results
[Breast and (neoplasm* or tumour* or

235 458
tumor* or cancer*)].mp. [mp=titlt,
original title, abstract, name of
substance word, subject heading word]
1 AND (random or controlled
6 760
trials).mp.[mp=title, original title,
abstract, name of substance word,
subject heading word]
Quality of life
147 498
2 AND 3
513
4 and (advan* or metasta*).mp. [mp=title,
186
original title, abstract, name of
substance word, subject heading word]
Limit 11 to yr=19942009
169
3
4
12
Table 2. PubMed search

Search term
Results
Breast cancer
Breast cancer AND Clinical trials
Breast cancer AND Clinical trials AND quality
of Life
Breast cancer AND clinical trials AND quality
of life. Limit 19942009
Advanced breast cancer AND clinical trials
AND quality of life.
235 807
25 167
1 869
1 725
285
reviewed and inappropriate studies excluded. Studies were

excluded on the grounds that they:
were not about breast cancer

were early breast cancer
were reviews of studies captured elsewhere
were considering bisphosphonate treatment of metastatic disease
were not randomised controlled trials
did not include QOL measurements
were cost-effectiveness studies
were methodological considerations of missing data in
QOL studies
were prevention studies
only a summary was available in English
The resulting papers were reviewed in conjunction with

the overviews provided by the Cochrane Library, Bandolier and Health Technology Assessments to provide the
database used for this literature review. Abstracts presented at meetings were not included.
RESULTS
These searches revealed 169 and 284 papers respectively
that matched all search criteria. Manual selection from
these papers, plus papers located from searching the other

sources, resulted in 51 papers. For trials involving chemotherapy, there were 36 papers which covered 34 studies
involving 11 251 patients (Table 3). A total of 12 studies
involving 5972 patients concerning hormonal therapy
(Table 4). (Not all patients involved in these trials were
included in the QOL assessments.) In addition, two papers
were located that outlined the methodology for ongoing
studies (one was still recruiting at the time of publication).
(Wapnir et al. 2008a,b; Twelves et al. 2010). Three further
papers evaluated QOL as a predictor of outcome (Table 5).
For two studies, although QOL data were mentioned in
the study report a separate publication also covered the
QOL data in more detail (for the Paridaens study, QOL
data were published in Kramer et al. 2000; for the Biganzoli study the QOL data were published in Bottomley
et al. 2004). All the publications have been included in
Table 3.
It is acknowledged that searching databases electronically is an imprecise science and it is never possible to be
sure that all relevant papers have been located, or that all
the papers located are actually relevant, so manual selection is essential. However, within these constraints, it
was of interest to see what percentage of papers on clinical
trials in breast cancer was also indexed under the term
QOL.
Based on these search terms, the two searches suggest
that 513/6760 or 7.6% (Medline) and 1725/25176 or 6.8%
(PubMed) of clinical trials in breast cancer included QOL
measures. These figures are similar to those of Fossati
et al. (1998), who reported only 9% of the patients to be
involved in any assessment of QOL in a previous review of
medical interventions in the treatment of breast cancer
between 1975 and 1997. The Fossati study reported on
data from 189 studies treating 31 510 patients.
It is worth bearing in mind that for some papers
(Paridaens et al. 2000; Howell et al. 2002; Nabholtz et al.
2003; Keller et al. 2004; Chia et al. 2008), QOL was not
mentioned at all in the abstract, even though QOL measurements were made. This raises issues of whether
studies will be missed in searches. (Nabholtz was included
in the Pub/Med search Keller and Paridaens were not.
These papers were located since they were mentioned in
earlier review articles.)
Conversely, a detailed account of QOL measures in the
EG100151 study was published in 2009 (Zhou et al. 2009),
yet there was no mention of QOL at all in the full paper
reporting final outcome of the study (Cameron et al.
2010). Another paper did not report QOL in the full paper
although the authors did present the QOL data at a
meeting (Ackland et al. 2001a,b), but this study was not
567
568
179
Vinorelbine vs. melphalan
648
Tamoxifen vs.
toremifine 60 mg vs.
toremifine 200 mg
390
FEC at two doses of
epirubicin
249
CAF vs. CNF
303
Combination (CEF plus
MV) vs. single agent
therapy epirubicin
followed by M
392
Docetaxel vs.
mitomycin plus
vinblastine
116
CMF vs. methotrexate
mitozantrone
209
Previously untreated
patients with metastatic
breast cancer.
Paclitaxel 200 mg/m2 iv or
CMFP
2. Hayes et al.
(1995)
3. Brufman
et al. (1997)
4. Stewart
et al. (1997)
5. Joensuu
et al. (1998)
6. Nabholtz
et al. (1999)
7. Harper-Wynne
et al. (1999)
8. Bishop et al.
(1999)
Investigation
1. Jones et al.
(1995)
Study/reference
Patient number
QOL LASA scales

completed by patients
(physical well-being,
mood, nausea and
vomiting, appetite, QOL
and physician-rated
QOL)
Spitzer QOL index
completed by Physician
HADS, RSCL
EORTC-QLQ C-30
(patients)
KPS (physicians)
RSCL
PriestmanBaum QOL
(VAS)
FLIC
ECOG VAS (mood, pain,

enjoyment of life)
ECOG Analgesic
Requirement for
tumour-specific
symptoms
Modified SWOG (patients)

KPS (physicians)
QOL instrument
Table 3. Studies of chemotherapy including quality of life (QOL) measures
Yes
Yes
Yes
Yes
No
Yes
No
Data reported
in detail
Medically paclitaxel associated with increased

OS
QOL measures slightly better in the taxane
group
Overall QOL was similar in both groups.
Alopecia, peripheral neuropathy, myalgia/
arthralgia more severe with paclitaxel
No difference in TTP, RR or OS. MM likely to

be less active than CMF
No statistically significant differences in QOL.
Association of QOL with toxicity; worsening
psychological state with greater toxicity.
Small number of patients who were able to
complete QOL study
OR, TTP and OS better with docetaxel

No difference in HRQOL; docetaxel better for
nausea and vomiting and appetite; worse for
role and social functioning
Single agent E followed by M showed similar

survival but less treatment-related toxicity
and better QOL compared with those treated
with CEF followed by MV
Physical functioning worse at 6 m with
combination therapy
Medically CAF better TTP, OS, RR

No statistically significant differences in QOL
Higher epirubicin dose more effective but more

toxic, with no increased survival
Poor compliance for QOL so no analysis
performed
No clinical differences in three arms. No

differences in QOL between three arms
Medically TTP, TTF, OS significantly better

with vinorelbine
No differences in QOL, KPS or cancer-related
symptoms
Outcome
QOL was considered

carefully but patient
numbers were low
(n = 59)
No
Limited interpretation
because of attrition rate
Yes
Supports use of epirubicin
plus mitomycin
Supports use of CAF

despite more alopecia
No
Yes
Supports toremifine as a
viable alternative to
tamoxifen
No
More QOL data to be
published at a later date
Comments
QOL considered in relation

to clinical decision
REED et al.
412
Mitozantrone vs. FEC
331
Single agent paclitaxel vs.
doxorubicin for
first-line treatment of
advanced breast cancer
331
Single agent paclitaxel vs.
doxorubicin for
first-line treatment of
74
12. Heidemann
et al. (2000)
13. Paridaens
et al. (2000)
14. Kramer et al.

(2000)
15. Riccardi
et al. (2000)
16. Jassem et al.

(2001)
303
Vinorelbine plus
doxorubicin vs.
doxorubicin
11. Norris et al.

(2000)
267
Doxorubicin and
paclitaxel vs. FAC
120 FEC G-CST vs. 60

FEC
283
Docetaxel vs.
methotrexate, 5-FU
(MF)
326
Docetaxel vs. doxorubicin
10. HakamiesBlomqvist
et al. (2000)
9. Chan et al.
(1999)
EORTC-QLQ- C30 and

QLQ BR23
EORTC-QLQ-C30 and
QLQ- BR23 (patients)
Spitzer QL-index
(physicians)
EORTC-QLQ-C30
RSCL
EORTC-QLQ-C30
RSC
WHO scale
Brunners score
EORTC-QLQ C-30
EORTC-QLQ C-30
EORTC-QLQ-C30
completed by patients
KPS completed by
physician
Yes
Yes
Yes
No
No
Yes
Yes
Yes
Yes
Study closed early due to
inability to demonstrate
improved RR and QOL
with higher dose
treatment
Yes
Doxorubicin more active
but may have more side
effects, but items such
as better pain control
compensated
Discussed in Kramer et al.

(2000)
Yes
There is no evidence that
high-risk, advanced
cancer patients need
combination therapy. In
order to maintain their
QOL it may be wise to
treat them with a single
agent such as
mitozantrone
Yes
Because of the importance
of QOL outcome,
increased attention
needs to be paid to the
consistent performance
of the EORTCQLQ-C-30 and other
QOL instruments
Yes
Suggests that because QOL
was so similar the
choice of drug should be
made on clinical effect
Yes
The observed differences
in activity and toxicity
profiles provides the
basis for therapy choice
No statistically significant differences in changes

No
from baseline in functional scales for role,
emotional, cognitive, social global health status,
body image, sexual enjoyment or future
perspective. Differences favoured FAC for sexual
functioning and physical scales as well as pain,
fatigue, insomnia and diarrhoea
Improved TTP with higher dose, no difference

RR or OS. No statistically significant
differences in QOL
64% completed baseline QLQ-C30 and 61%

completed RSC. Dox was associated with
significantly more nausea and vomiting, loss
of appetite, burden of disease and treatment
but less bone pain and rash. Long term QOL
could not be assessed
Doxorubicin better for disease and symptom

control. QOL data will be reported separately
QOL significantly worse with FEC
No statistically significant differences in TTP,

TTF
No significant differences in QOL
Transient minor differences, favouring MF for

emotional and social functioning, No
significant differences in functional and
symptom scales
Clinically docetaxel was better than

doxorubicin
Compliance >80%, but high rate of attrition
No statistically significant difference in the 2
groups in mean decreases in global health
569
570
Investigation
400
Chemotherapy vs.
chemotherapy plus
Herceptin
739
Doxorubicin vs. paclitaxel
vs. doxorubicin plus
paclitaxel
260
Mitoxantrone vs. FEC
511
Capecitabine plus
docetaxel vs. docetaxel
275
Doxorubicin plus
paclitaxel vs.
doxorubicin and
cyclophosphamide first
line treatment for
275
Doxorubicin plus
paclitaxel vs.
doxorubicin plus
cyclophosphamide
525
First year after
marrow-supported
chemo with
cyclophosphamide,
thiotepa and carboplatin
(CTCb) or fluorouracil,
epirubicin and
cyclophosphamide (FEC).
17. Osoba et al.

(2002)
18. Sledge et al.

(2003)
19. Heidemann
et al. (2002)
20. O Shaughnessy
et al. (2002)
21. Biganzoli
et al. (2002)
22. Bottomley
et al. (2004)
23. Brandberg
et al. (2003)
Patient number
Study/reference
Table 3. Continued
EORTC-QLQ-C30 and
EORTC-BR-23
EORTC-QLQ-C30 (version
2)
QLQ-BR23
EORTC-QLQ-30 and QLQ

BR-23
EORTC-QLQ C-30 and

QLQ BR23
Brunners score
FACT-B
EORTC-QLQ- C30
QOL instrument
Yes
Yes
No
Yes
Yes
Yes
Data reported
in detail
Outcome
No statistically significant overall

differences between FEC CTCb
for any HRQOL parameters.
QOL showed steeper decrease
but faster recovery in CTCb
group than in FEC group.
Despite aggressive therapies
patient QOL returned to
baseline levels for most
parameters
No significant differences between the two

groups. Significant time effect. Fatigue
increased in both groups by >10 points.
Global QOL was maintained and showed
little or no change over study
QOL data not included in paper
No statistically significant differences.

Trend towards deterioration of global
Health Score over time less with
combination treatment
No clinical difference in terms of response,

remission rate, remission duration, time to
response or OS
Significant difference in gain using Brunners
score favouring single-agent treatment
No statistically significant difference in overall

QOL score or in any of the subscales
A statistically significantly higher proportion of

patients treated with a combination of
trastuzumab and chemotherapy reported
improved global QOL than did patients
treated with chemotherapy alone
Yes
Used to help clinicians and

patients make informed
treatment decisions.
QOL data reported in

Bottomley et al. (2004)
(see below)
No
Yes
Since toxicity and QOL
score favour the
single-agent this
treatment may be
offered to patients
preferring QOL to a
potential small
prolongation of survival
Despite superior OR and

TTF with AT, the
combination therapy did
not improve survival or
QOL
Yes
Comments

REED et al.
429
Doxorubicin (A) plus
docetaxel (T) vs.
docetaxel plus
cyclophosphamide (C)
327
Epirubicin/paclitaxel vs.
paclitaxel/carboplatin
301
Pegylated liposomal
doxorubicin (PLD) vs.
vinorelbine vs.
mitomycin plus
vinblastine
202
Epirubicin plus paclitaxel
(concomitant treatment)
vs. epirubicin followed
by paclitaxel
477
3 different doses of
paclitaxel
462
Capecitabine vs.
capecitabine +
bevacizumab
271
DPPE (tesmilifene)
plus doxorubicin
vs. doxorubicin
210
Chemotherapy
vs. BSC
336
Gemcitabine plus
paclitaxel vs. paclitaxel
24. Nabholtz
et al. (2003)
25. Fountzilas
et al. (2004)
26. Keller et al.

(2004)
27. Conte et al.

(2004)
28. Winer et al.

(2004)
29. Miller et al.

(2005)
30. Liu et al.

(2006)
31. Karamouzis
et al. (2007)
32. Hopwood
et al. (2008)
RSC and Brief Pain

Inventory
EORTC-QLQ-C30
and QLQ-BR23
Not stated
FACT-B
TOI
FLIC
SDS
EORTC-QLQ-C30
EORTC-QLQ C-30
Q TWiST
EORTC-QLQ-C30 (Greek
version)
EORTC-QLQ C-30
QLQ-BR23
Yes
Moderate
Yes
Yes
No
Yes
Yes
Improved QOL significantly associated with

reduced functional impairment, tumour
response and completing more cycles of
chemotherapy. QOL may be closely
associated with clinical efficacy of
chemo, functional status and
psychological well-being rather than
symptom outcome and toxicity
QOL statistically better in MBC patients

receiving chemo. Significant differences
in favour in functioning subscales,
symptom single-item questions and
sexual functioning
No significant difference sin QOL responses

except for nausea and vomiting. Patients
on DPPE/DOX were significantly worse
in terms of pain (DPPE causes nausea and
vomiting and hallucinations)
Time to deterioration in QOL did not differ

between treatment groups
No significant differences in the three arms

in change from baseline in overall score.
Physical functioning fell in the two
higher doses groups
Difference was only statistically

significantly different for
emotion al functioning (in
favour of concomitant
treatment). No clear differences
PFS and OS were similar for PLD

and comparators
Clinical benefit (physical
functioning, social functioning,
and global QOL was similar for
PLD and comparator groups)
TTF significantly longer in

paclitaxel/carboplatin
No significant difference in QOL
TTP and TTF significantly longer

with AT than AC. OS
comparable in both arms
QOL may be closely

associated with efficacy
of chemotherapy,
functional status and
psychological well-being,
rather than symptom
palliation and toxicity
Chemo more rational

approach than BSC
Detailed QOL analysis will

be reported separately.
No
No
No
QOL not considered in
discussion
Only 30% of patients

completed the QOL
study
No
571
572
408
Lapatinib plus capecitabine
(L + C) vs.
capecitabine
alone (C)
287
Epirubicin plus
paxitaxel (ET)
vs. epirubicin,
paclitaxel and
capecitabine
(TEX)
139
Weekly vs. 3-weekly
docetaxel-based
chemotherapy
34. Zhou et al.

(2009)
35. Svensson
et al. (2010)
36. Nuzzo et al.

(2011)
QOL instrument
EORTC-QLQ C30
Daily diary card
EORTC-QLQ C30
EORTC-QLQ-BR23
FACT-B
EQ-5D
EORTC-QLQ-C30
Yes
Paper was QOL data
Yes
Yes
Yes
Data reported
in detail
Outcome
Weekly schedule was inferior to 3-weekly

schedule in terms of QOL
No significant differences between TEX and

ET on any subscale 2 months after
randomisation. At 9 months the TEX group
scored significantly higher on global QOL
and physical functioning.
Adjusted mean changes form baseline in all

QOL scores for the L + C arm were
comparable to those for the C arm. The
between-group differences ranged from 0.7 to
2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D
visual analogue scale) and were consistently
in favour of the L + C arm (Not significant).
Patients with tumour response showed
meaningful differences in QOL
QOL not significantly

different between the
two groups. However,
the drugs had different
toxicity profiles
RR was 40% for AD and
42% for AP
Yes
Suggests weekly schedule
should not be the
preferred schedule
Not clear
Yes
The study concluded that
the lack of deterioration
in QOL confirmed the
clinical benefit in this
patient group
Comments

A, adriamycin (doxorubicin); AD, doxorubicin docetaxel; AP, doxorubicin, paclitaxel; CAF, cyclophosphamide, doxorubicin, fluorouracil, BSC, best supportive care; CEF,
cyclophosphamide, epirubicin, fluorouracil; CMF, cyclophosphamide, methotrexate, fluorouracil; CMFP, cyclophosphamide, methotrexate, fluorouracil, prednisone; CNF,
cyclophosphamide, mitoxantrone, fluorouracil; DOX, doxorubicin; ECOG, Eastern Co-operative Oncology Group; EORTC, European Organisation for Research and Treatment of
Cancer; EQ-5D, EuroQol Scale; FAC, fluorouracil, doxorubicin, cyclophosphamide; FACT-B, Functional Assessment of Cancer Treatment Breast; FEC, fluorouracil, epirubicin,
cyclophosphamide; FLIC, Functional Living Index Cancer; G-CST, granulocyte colony stimulating factor; HADS, Hospital Anxiety and Depression Scale; KPS, Karnovsky Performance
Status; LASA, Linear Analogue Self Assessment; M, mitomycin; MF, methotrexate, fluorouracil; OS, overall survival; QLQ, Quality of Life Questionnaire; RSCL, Rotterdam Symptom
Check List; SWOG, South Western Oncology Group; TOI, Trial Outcome Index; TTF, Time to Treatment Failure; TTP, Time to Progression; V, vinblastine; VAS, Visual Analogue Scale;
WHO, World Health Organisation.
Investigation
210
Doxorubicin plus
paclitaxel (AP) vs.
doxorubicin plus
docetaxel (AD)
33. Cassier et al. (2008)
Patient number
Study/reference
Table 3. Continued
REED et al.
400
Fulvestrant vs.
anastrozole
1021 patients.
Anastrozole vs.
tamoxifen
584
Fulvestrant vs.
tamoxifen
7. Osborne
et al. (2002)
8. Fallowfield
et al. (2004)
9. Howell
et al. (2004)
FACT-B
TOI
FACT-B
6-item oestrogen adverse
effect questionnaire
FACT-ES and TOI
QOL similar in both arms
The two doses of oestradiol were comparable in

efficacy
Negative effects of 30 mg dose on QOL
No statistically significant differences in clinical

outcome
No difference in the two arms

outcome
No significant differences in TOI between the two
groups
Overall QOL improved over 2 years in both groups.

No statistically significant differences in trial
outcome index or endocrine scale
FACT-B + endocrine
subscales
FACT-B
No differences in clinical outcome

Two treatments not statistically different
No differences in clinical outcome

No statistically significant differences in
QOL reporting limited no data presented
OR higher in and median survival longer with

exemestane group
Similar or better improvements in pain, TRSS
and QOL with exemestane

outcome
No differences in FLIC scores. Vorozole better
psychological well-being
No statistically significant differences
Patients with partial or complete response had

better QOL
No differences clinical response Better physical

scores with 1 mg anastrozole and better
psychological scores with 10 mg anastrozole
Transiently better with anastrozole
Outcome
FACT B
EORTC-QLQ C-30
EORTC-QLQ C-30
FLIC
Likert scales
VAS QL indicators
RSC
QOL instrument
No
Since no differences seen
Yes
Yes
QOL was included in the abstract and supported
the equivalence of the two treatments
No
This was a specific study of QOL
Yes
QOL was maintained in fulvestrant treated
patients, supporting the use of this agent as an
alternative to anastrozole
No
Yes
Supports use of exemestane
Supports use of vorozole
No
Yes
Supporting treatment use. Patients subjective
perspective should be taken into account
Yes
No
Comments
QOL considered in relation to clinical decision
EORTC, European Organisation for Research and Treatment of Cancer; FACT-B, Functional Assessment of Cancer Treatment Breast; FLIC, Functional Living Index
Cancer; RSC, Rotterdam Symptom Checklist; TOI, Trial Outcome Index; TRSS, Tumour-Related Signs and Symptoms; VAS, Visual Analogue Scale.
736
Fulvestrant 250 mg vs.
500 mg
602
Letrozole vs.
megestrol acetate
6. Buzdar
et al. (2001)
12. Di Leo
et al. (2010)
769
Exemestane vs.
megestrol acetate
5. Kaufmann
et al. (2000)
66
6 mg vs. 30 mg
oestradiol
452
Vorozole vs.
megestrol acetate
4. Goss et al.
(1999)
11. Ellis et al.

(2009)
90
Maintenance Megace
vs. no maintenance
3. Kloke et al.
(1999)
693
Fulvestrant vs.
exemestane
177
Formestane vs.
megestrol acetate
2. Bernhard
et al. (1999)
10. Chia et al.

(2008)
382
Anastrozole (1 mg and
10 mg) vs. megace
Investigation
Patient number
1. Buzdar
et al. (1997)
Study
Table 4. Studies of hormonal therapy including quality of life (QOL) measures
573
REED et al.
Table 5. Studies using quality of life (QOL) to predict outcome

Study
QOL instrument
Comments
Coates
et al. (2000)
QOL assessments for

physical well-being,
mood, appetite
and coping.
EORTC-QLQ-C30
DFS not significantly predicted by QOL score at baseline or month 18. After relapse,
QOL scores were predictive for subsequent overall survival. Prognostic significance
of QOL in adjuvant setting is minimal or obscured by chemotherapy effects. Strong
significance after relapse.
Performance status and number of sites involved were the most significant clinical
predictors of outcome.
Substantial loss of appetite was the only independent HRQOL factor predicting poor
survival and was strongly correlated with fatigue, role and physical functioning.
Physical well-being (PWB), mood, appetite and overall QOL were significant
univariate predictors of overall survival. PWB and appetite were predictors of
chemotherapy response and toxicity as well as overall survival. QOL should be
routine clinical assessment to guide patient selection for chemotherapy and for
stratification in clinical trials.
Efficace
et al. (2004)
Lee et al.
(2010)
LASA
DFR, Disease Free Survival; EORTC, European Organisation for Research and Treatment of Cancer; LASA, Linear Analogue Self
Assessment.
included in this survey as studies appearing only as

meeting abstracts were not, by definition, valid for this
survey.
Health Technology Assessments carry out detailed literature searches and identify the studies that are relevant to a particular topic. Five Health Technology
Assessments were identified that were relevant to breast
cancer; three addressed advanced breast cancer. The following numbers of studies and studies including QOL
data are summarised.
Report
Jones et al. (2004),
Volume 8, No. 5
(Capecitabine in
metastatic breast
cancer)
Lewis et al. (2002),
Volume 6, No.
14 (Vinorelbine
for breast cancer)
Lister-Sharp et al.
(2000), Volume
4, No. 17
(Taxanes in
advanced breast
cancer)
Number
of studies
identified
Number of
studies
including QOL
% studies
including
QOL
23
4.3%
QOL instruments used

7
14%
25%
A number of studies that included QOL measurements

in the study design failed to report the data (Tables 3 and
4). In some cases a separate publication reported the
QOL data, but in other cases, for example the study of
Brufman et al. (1997) the small number of people completing the questionnaire (30%) weakened the data, or
made analysis not viable (Brufman et al. 1997). Other
authors commented on the high attrition rate (Chan
574
et al. 1999; Harper-Wynne et al. 1999; Nabholtz et al.

1999), which limited interpretation of the data. This
highlights the importance of selecting an assessment
tool that is appropriate for the study group. For women
with advanced cancer, a QOL questionnaire may be
more burdensome than for women with early disease,
and it may be that shorter instruments are more appropriate for women with progressive disease. To ensure
that meaningful data are obtained from future studies
using QOL instruments, Chan and colleagues recommend that particular attention is paid to compliance at
the time of progression or early study discontinuation
(Chan et al. 1999).
The QOL instruments chosen varied widely, with a total

of 21 different scales being used across the 56 papers
(some papers used more than one instrument) (Table 6).
By far the most popular instrument was the EORTCQLQ-C30, which was used in 24 studies. This was followed by the EORTC-QLQ-BR23 used in 10 studies and
the FACT-B scale used in eight studies. The hormonal
studies tended to use the FACT-B scale and this may be
because it has a specific endocrine subscale. Only one
study used the EQ-5D, despite it being available since
1990.
Such disparate approaches to trial design make it more
difficult to compare studies and for healthcare professionals to become familiar with the scales and therefore be
able to appreciate the data they produce. Moreover,
studies vary in the depth to which they report data. Meaningful comparisons across studies would require a group
mean difference and standard deviation. However, for
Table 6. Quality of life (QOL) instruments used in studies of

Instrument
No. of studies
EORTC-QLQ-C30
QLQ BR23
FACT-B
FLIC; Brunners score; TOI
QOL LASA
SWOG; ECOG VAS; ECOG Analgesia
requirements; Priestman- Baum QOL; HADS;
WHO; Q TWiST; Brief Pain Inventory; VAS
QL indicators; Likert scale; FACT-ES; SDS;
daily diary card; EQ-5D
24
10
8
4
2
1
ECOG, Eastern Co-operative Oncology Group; EORTC,

European Organisation for Research and Treatment of Cancer;
EQ-5D, EuroQol Scale; FACT-B, Functional Assessment of
Cancer Treatment Breast; FACT-ES, Functional Assessment
of Cancer Treatment Endocrine Treatment; FLIC, Functional
Living Index Cancer; HADS, Hospital Anxiety and Depression
Scale; LASA, Linear Analogue Self Assessment; RSC,
Rotterdam Symptom Checklist; SDS, Symptom Distress Scale;
SWOG, South Western Oncology Group; TOI, Trial Outcome
Index; TWiST, Quality-Adjusted Time. Without Symptoms and
Toxicity; VAS, Visual Analogue Scale.
many publications the QOL results comprise only a few

sentences of the top-line findings.
DISCUSSION
It is now widely accepted that the personal burden of
disease cannot be described fully by measures of disease
status, for example tumour load (Muldoon et al. 1998). In
advanced or recurrent breast cancer patients one of the
goals of treatment is to provide symptom palliation. It is
usually assumed that the number and severity of symptoms caused by the tumour burden will be decreased by
chemotherapy and that this will have a direct impact on
patients symptoms. Yet, there is no direct evidence that
tumour response can be directly correlated with palliative
benefit (Geels et al. 2000). This underpins the importance
of actually evaluating patients own perceptions of the
impact of treatment on them as an individual, rather than
just extrapolating from clinical efficacy and safety data
and assuming that decreased tumour load equals increased
QOL.
For example, when Geels and colleagues reviewed data
obtained from the women in the National Cancer Institute of Canada Clinical Trials Group MA-8 trial (Norris
et al. 2000) they showed that baseline cancer pain was
present in 38% of subjects if data from the case report
form (CRF) were used, but in 81% of patients according to
the QOL data. Similarly, tiredness was present in 26%
(CRF data) and 89% (QOL data). In fact, for any given
symptom the QOL questionnaires identified a much

higher number of patients with that symptom. This
underlines the very real differences seen in patients perception of symptoms and what assessors consider are the
patients symptoms.
It is also important to remember that patients expectations may change with time. If a person is confronting
an incurable condition their values will shift and, for
example, being able to continue to carry out certain tasks
may have a greater importance to them as their condition
progresses than it had previously. Patients certainly assign
different values to hypothetical health states than outsiders (De Wit et al. 2000).
This review of the literature has shown that only a
small proportion of studies of advanced breast cancer actually include QOL measurements in the trial. For those
that do, the EORTC-QLQ-C30 and EORTC-QLQ-BR23
are the most popular instruments for use in advanced
breast cancer studies, but their use is by no means universal. The EORTC-QLQ-C30 is arguably the most widely
used cancer questionnaire in Europe and is also widely
used around the rest of the world (Fayers & Sprangers
2002). The EORTC have substantial experience in QOL
research and this scale is becoming the preferred instrument for many studies. The EORTC-QLQ-C30 is a validated instrument that has been translated into 81
languages and is used in more than 3000 studies worldwide. Physical symptoms frequently reported by cancer
patients are assessed with a series of single items (for
limitation in work, pursuing hobbies, breathlessness,
pain, fatigue, sleeping, weakness, appetite, nausea and
vomiting) where each item can be rated on a 4-point scale.
Five functional scales (physical functioning, role functioning, cognitive functioning, emotional functioning, social
functioning) are similarly rated as well as global assessments of health and QOL on 7-point visual analogue
scales (VAS).
The QLQ-C30 is supplemented by disease-specific
modules, e.g. for breast, lung, head and neck etc. Thus the
EORTC-QLQ-BR23 is designed to be used as an extension
of the EORTC-QLQ-C30; however, some studies either do
not use the EORTC-QLQ-C30 or only report the EORTCQLQ-BR23 data.
Specific to breast cancer patients, the EORTC-QLQBR23 focuses on treatment-related side effects (dry mouth,
hair loss, hot flushes, headaches etc) as well as the psychological and emotional impact the disease and its treatment can have on a womans self-esteem, body image and
feelings of sexuality. It also seeks to obtain information on
possible treatment sequelae such as lymphoedema, local
breast changes and skin problems.
575
REED et al.
As this survey has shown, there does not seem to be a

QOL instrument that has been developed specifically for
women with advanced metastatic breast cancer. Women
with advanced disease may be moving towards more palliative treatment and receiving less therapy given with a
curative intent. This can have a profound effect on their
attitudes to life and to QOL. Perhaps it is time for a
specific QOL instrument for women with advanced breast
cancer; maybe the EORTC could develop a separate
module for advanced disease to complement its widely
used EORTC-QLQ-BR23?
The FACT-B scale addresses physical, social/family,
emotional and functional well-being in which different
aspects are rated on a 5-point scale. There is also a section
that covers treatment-specific side effects and feelings of
sexuality, appearance and attractiveness.
The NICE favours the use of the EQ-5D QOL instrument for making extremely important decisions about
cost-effectiveness of numerous treatments for a variety of
cancers and other diseases. However, this instrument may
not be appropriate for women with breast cancer, especially advanced disease. The EQ-5D does not, for example,
cover fatigue, which is a major problem for the majority of
cancer patients (Foubert 2006). Moreover, many patients
regard the management of fatigue as more important than
the treatment of pain, by contrast to the opinions of many
physicians (Engel et al. 2003; Browall et al. 2009). Fatigue
has also been shown to be an independent determinant of
well-being (Dolan 2007). In fact, Dolan and colleagues
argue that there is no good basis for giving special status
to the EQ-5D, particularly when other dimensions of
health may affect patients as much as those in the EQ-5D
(Dolan et al. 2009).
This literature review has revealed that only one clinical study in advanced breast cancer could be found that
actually used the EQ-5D. From the summary of scales
described above it can be seen that these scales focus far
more on cognitive and social functioning than the EQ-5D.
They assess disease-related and treatment-related physical
symptoms and have the potential to identify problems in
emotional attitudes and adjustment of sexual attitudes to
breast cancer and its treatment that would be completely
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Feature and review paper

Quality of life assessments in advanced breast cancer:

Keywords: breast cancer, quality of life.

Correspondence address: Elizabeth Reed, Research Manager, Breast Cancer

Accepted 30 April 2012

2012 Blackwell Publishing Ltd

social and physical well-being and their ability to function

considering the underlying disease as a challenge to their

years (Dolan et al. 2009). In order to be able to compare

Quality of life assessment in advanced breast cancer

Table 1. Medline search

[Breast and (neoplasm* or tumour* or

Table 2. PubMed search

reviewed and inappropriate studies excluded. Studies were

were not about breast cancer

The resulting papers were reviewed in conjunction with

these papers, plus papers located from searching the other

QOL LASA scales

ECOG VAS (mood, pain,

Modified SWOG (patients)

Table 3. Studies of chemotherapy including quality of life (QOL) measures

Medically paclitaxel associated with increased

No difference in TTP, RR or OS. MM likely to

OR, TTP and OS better with docetaxel

Single agent E followed by M showed similar

Medically CAF better TTP, OS, RR

Higher epirubicin dose more effective but more

No clinical differences in three arms. No

Medically TTP, TTF, OS significantly better

QOL was considered

Supports use of CAF

QOL considered in relation

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

14. Kramer et al.

16. Jassem et al.

11. Norris et al.

120 FEC G-CST vs. 60

EORTC-QLQ- C30 and

Discussed in Kramer et al.

No statistically significant differences in changes

Improved TTP with higher dose, no difference

64% completed baseline QLQ-C30 and 61%

Doxorubicin better for disease and symptom

QOL significantly worse with FEC

No statistically significant differences in TTP,

Transient minor differences, favouring MF for

Clinically docetaxel was better than

Quality of life assessment in advanced breast cancer

17. Osoba et al.

18. Sledge et al.

EORTC-QLQ-30 and QLQ

EORTC-QLQ C-30 and

No statistically significant overall

No significant differences between the two

QOL data not included in paper

No statistically significant differences.

No clinical difference in terms of response,

No statistically significant difference in overall

A statistically significantly higher proportion of

Used to help clinicians and

QOL data reported in

Despite superior OR and