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Reviews

Variations in treatment and survival in


breast cancer
AD Purushotham, SJ Pain, D Miles, and A Harnett

To achieve optimum quality of care for women with


breast cancer in the UK, uniformity of care in
accordance with consensus guidelines is needed. This
review highlights variations in provision of care for
women with breast cancer, with particular emphasis
on care received in the UK, examines differences in
survival, and discusses the factors that may underlie
these differences. Strong variation in treatment was
identified, which appeared to affect survival
significantly. These findings reinforce the need for
women with breast cancer to be treated by dedicated
specialists working within a multidisciplinary team to
provide a high standard of care.
Lancet Oncol 2001; 2: 71925

The treatment of breast cancer is multidisciplinary


(Figure 1). Much media attention has focused on
recent correspondence published in The Lancet, which
highlighted the decrease in deaths from breast cancer
in the UK during the past decade (Figure 2).1 This decline
has been hailed as a demonstration of the success of breastcancer treatment in this country. Although such positive
reporting is welcome, these data should not be allowed to
engender a false sense of security. In fact, the UK has long
been known to have poor survival for cancer patients,
including women with breast cancer. The EUROCARE
project, published in 1998, highlighted discrepancies in
breast-cancer survival within Europe.2,3 Cancer-registry data
were used to assess survival after treatment for breast cancer
in 15 European countries. Between 1978 and 1985, 5-year
survival was 64% in England and Wales and 61% in
Scotland. In Switzerland and Finland, however, 5-year
survival was 74% and 78%, respectively. When analysis was
extended to 1989, England and Wales had made a 3%
improvement to 67%, and Scotland showed a slightly better
increase of 4% to 65%. However, the European average from
the study was then 73%, with some countries, including
France and Italy, achieving proportions of 7781%. There
were differences across all age-groups, with a relative risk of
not surviving for 5 years in the UK of 1.071.32 compared
with the pooled data for the rest of Europe.
These findings should be interpreted with caution,
because a possible contributing factor is the completeness of
data collection in the UK. England, Scotland, and Wales
accounted for more than 50% of the cases analysed in the
EUROCARE study. Scotland (along with Denmark, Estonia,
and Finland) submitted data from a single national cancer
registry covering the whole country, and the submitting
registries from England and Wales covered more than 50%
of the population. In the other European countries, no more
THE LANCET Oncology Vol 2 December 2001

Figure 1. The multidisciplinary management of breast cancer.

than 13% of the populations were covered by the


participating registries. There also seemed to be variation in
criteria for entry onto the registry, with the proportion of
registrations that were histologically verified ranging from
76% (in England) to 100% (in excess of 90% in most
countries). Nevertheless, there remains concern that there is
a genuine disparity in breast-cancer survival between the UK
and our European neighbours.
Further analysis of the EUROCARE data revealed that,
for some countries, there is strong variation in survival
between regions.3 Spain and Italy, for instance, showed
differences of 16% and 22% in 5-year survival between the
ADP and SJP are at the Cambridge Breast Unit, Addenbrookes
Hospital, Cambridge. DM is at the Department of Oncology, Guys
Hospital, London. AH is at the Beatson Oncology Centre, Western
Infirmary, Glasgow, UK.
Correspondence: Mr A D Purushotham, Cambridge Breast Unit,
Box 97, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ,
UK.Tel: +44 (0) 1223 586627. Fax: +44 (0) 1223 586932.
Email: amy.byrtus@addenbrookes.nhs.uk

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Review

Survival variation in breast cancer

best and worst regions, in both cases the affluent northern


regions faring better than the less well-off south.
Here we review published evidence on variations in
delivery of care and survival. Treatment is considered in
terms of variation in surgery, pathological reporting,
radiotherapy, and adjuvant systemic therapy, including
factors that influence their provision. Variations in breastcancer survival within the UK are presented, with discussion
of the factors that underlie such differences.

Extensive studies published in the early and mid 1980s


showed that, combined with postoperative radiotherapy,
breast-conserving surgery is as effective as mastectomy in
controlling disease.49 Low rates of breast-conserving surgery
have no influence on survival, but they may reflect a
reluctance to incorporate new treatment modalities into
clinical practice. A 1987 Canadian study appeared to
support this possibility.10 It showed that surgeons who still
preferred mastectomy to breast-conserving surgery were just
as well informed as colleagues were about results of clinical
trials, but they were more sceptical about their application in
practice. Various other factors seem to influence surgical
management. Several studies from the USA have reported
associations between rates of breast-conserving surgery and
teaching status of hospital,11 major urban centres, and
patients educational attainment and income.12,13 Similar
trends have been observed in Italy14 and Japan.15 There were
also pronounced differences relating to geographical region,
which remained with time.16,17 Reports of two Australian
series noted low rates of breast-conserving surgery in rural
areas (presumably because of problems of access to
radiotherapy facilities), but also found differences within
and between States that could not be explained by
urban/rural demographics.18,19
In the UK, successive postal questionnaires have
reflected the increasing rates of breast-conserving surgery
nationwide over the years but have also shown much
variation in practice.2022 One extensive study examined
treatment patterns of patients with breast cancer in
Yorkshire.23 In the period 197892, the overall rate of breastconserving surgery increased from 30% to 56%, but the
range across districts was very wide (1387%). Though rates
in all districts increased with time over the study period,
relative differences persisted. Teaching status of hospitals
did not seem to influence the proportion of breastconserving surgery. The Scottish Breast Cancer Focus
Group, which audited breast-cancer management
throughout Scotland for the years 1987 and 1993,24 found
that rates of breast-conserving surgery increased from 40%
to 52% during this 6-year period, but no variation in
practice was identified when surgeons were grouped by
caseload. By contrast, Moritz and colleagues25 found that
surgeons with a higher caseload were consistently more
likely to carry out breast-conserving surgery.
Axillary surgery provides essential information for
staging of disease and subsequent selection of adjuvant
therapy, reduces the risk of locoregional recurrence, and
may also improve survival, although this issue is
controversial.26 In comparison of practices, analysis can be
720

50
UK

Death rate, age standardised

Surgery

50

40

40
USA

30

30

20

20

10

198889

10

0
1950

1960

1970

1980

1990

2000

Year
Figure 2. UK/US, 195099: decrease in breast-cancer mortality at ages
2069 (mean of annual death rates per 100 000 women in component
5-year age-groups).

made of both the presence or absence of an axillary


procedure, and the extent of clearance, if this is the
procedure undertaken, as judged by number of nodes
retrieved (although this number will also be influenced by
the completeness of histological identification and
reporting). If axillary sampling is done, the number of
inadequate samples, in which fewer than four nodes are
reported on, can also be analysed.
A UK regional survey conducted between 1984 and 1988
found that the proportion of axillary procedures undertaken
was two times higher in teaching hospitals than in nonteaching hospitals (65.0% versus 32.5%).27 Rates in teaching
hospitals did not change during the study, whereas those in
the non-teaching units fell significantly (42% in 1984, 27%
in 1988; p < 0.0003). Over the same period, rates of breastconserving surgery increased by similar amounts in both
teaching and non-teaching hospitals. Another study in a
similar time period had conflicting findings: 71% of patients
treated in a non-teaching hospital underwent some form of
axillary procedure compared with 51% in a teaching
centre.28 A more recent study comparing centres grouped by
numbers of new cancers seen per year showed increasing
rates of axillary clearance, greater numbers of nodes taken,
and fewer inadequate samples with increasing caseload.29
Differences between the units with the highest and lowest
volumes were particularly large. In all, 51% of patients in the
highest-volume units received some form of axillary
THE LANCET Oncology Vol 2 December 2001

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Review

Survival variation in breast cancer

clearance compared with 8% in the lowest-volume units;


49% of these had more than eight nodes retrieved and
reported on in the high-volume group compared with 17%
in the lowest. The proportion of inadequate axillary samples
was 25% in the smallest units and only 3% in the largest.
Gillis and Hole examined treatment patterns of patients
with breast cancer in the west of Scotland between 1980 and
1988.30 Surgeons were labelled specialist or non-specialist
on the basis of local perception and whether they met several
criteria: establishment of a dedicated breast clinic, a defined
association with pathologists and oncologists, organisation
and facilitation of clinical trials, and maintenance of
separate records for all patients with breast cancer. The
investigators found no mention of nodal status in
histopathology reports of 17% of cases treated by specialist
surgeons compared with 39% of non-specialists. Fewer than
four nodes were reported on in 10% of patients treated by a
specialist, compared with 38% for non-specialists. The audit
by the Scottish Breast Cancer Focus Group had similar
findings; among patients treated by surgeons with larger
caseloads there were fewer inadequate samples than among
those treated by surgeons with small caseloads,24 as well as a
higher frequency of axillary surgery and a greater mean
number of nodes in both sample and clearance specimens. A
study in Norway found the median number of lymph nodes
taken in a cancer centre was double that of patients treated
in a municipal hospital (14 versus seven nodes),31 and that
for T1 tumours excision of more than nine nodes more than
doubled the rate of detection of lymph-node metastases.
Inadequate nodal information may result in understaging of
disease, potentially leading to too little or inappropriate use
of adjuvant systemic therapy, increased regional recurrence,
and possibly reduced survival.

Pathological reporting
Provision of appropriate adjuvant therapy depends on
accurate staging of disease. Such staging is influenced not
only by adequate initial surgery, but also by completeness of
subsequent histopathological reporting. In 1993, 45% of
pathologists reporting on breast-cancer specimens had a
special interest in the disease.32 This issue is becoming
increasingly relevant as clinicians become more aware of the
importance of hormone-receptor status (for both oestrogen
and progesterone), as well as special stains such as c-ERBB2.
In a review covering years 198488, Richards and colleagues
found a report of non-specific morphology in 26% of
cases.27 On further analysis, this proportion was 17% for
teaching hospitals, 20% for non-teaching hospitals seeing
more than 50 new cases per year, and 38% for those seeing
fewer than 50 new cases. A similar study looking at care
provided in 1992 found that reporting of tumour grade and
of excision margins improved with caseload of the unit
involved.29 Dey and co-workers similarly found that caseload
was the major determinant of completeness of reporting,
noting no significant difference between teaching and nonteaching hospitals of equivalent size.33 The 1987/1993
Scottish audit found pathological reports in 87% of 1987
case-notes and 90% of those from 1993, with wide variation
between Health Boards (66100%).24 Information on
tumour size and grade improved over the study period,
THE LANCET Oncology Vol 2 December 2001

although reporting of oestrogen-receptor (ER) status


declined from 61% to 54%. More recently, the authors of a
review in Australia of 1600 cases that were reported on
during a 2-month period in 1995 devised a scoring system
for histological reports of breast-cancer specimens based on
guidelines yet to be published.34 Information on tumour size
was absent in 6% of cases, excision margins in 13%, and
tumour grade in 16%. Analysis for association with caseload
by individual pathologist showed significant variation in
reporting on vascular invasion only, although numbers were
small (392 pathologists issued 1500 reports over the 2
months, with 69% reporting on fewer than two cancers per
month). By laboratory, inadequate reporting of tumour size,
vascular invasion, and excision margins was significantly
associated with caseload.
Availability of ER status significantly influences
decision-making on adjuvant systemic therapy; in a study in
which consensus management plans were made with and
without availability of ER status, management decisions
were changed in 57% of cases in one subgroup.35 A recent
postal survey found that 84% of UK breast-cancer units had
access to facilities for investigating receptor status, 60% on
site. Thus, 16% of units never obtained ER status, whereas a
selective policy was adopted in a further 46%.36 In all, 12.5%
of lead clinicians did not believe that knowledge of receptor
status was important in the management of their patients.

Radiotherapy
Recent work has suggested that postoperative radiotherapy
of the breast can affect survival as well as local recurrence.37
It should be offered to virtually all patients who undergo
breast-conserving surgery for invasive disease, as well as a
proportion of those undergoing mastectomy. In a 1993
postal survey of UK oncologists, only 70% reported an
agreed local policy for provision of radiotherapy.32 Two UK
audits of treatment provided in the 1990s reported that the
overall proportions for patients undergoing breastconserving surgery who were not subsequently referred for
radiotherapy were 10% and 25%, respectively.38,39 Significant
association between caseload and likelihood of referral for
radiotherapy was observed: 32% referral from surgeons with
the lowest caseload compared with 86% from those having
the highest caseload (p < 0.0001 for trend).38 Basnett and
colleagues found that referral for radiotherapy was more
likely in teaching than in non-teaching hospitals,28 and the
Yorkshire group noted wide variation in referral between
different districts within the county, unrelated to variations
in use of breast-conserving surgery.23 The Scottish Audit
noted an increase in rates of referral for radiotherapy after
breast-conserving surgery from 55% in 1987 to 75% in 1993,
but they found no variation by surgical caseload.24 The
actuarial rate of local recurrence for the 1987 patients was
6% for those who had received radiotherapy and 25% for
those who had not, with overall rates ranging from zero to
20% when analysed by Health Board of initial referral.
Studies in the USA have found age and stage of disease, in
addition to type of institution, lack of local facilities, and
urban location, to be significant determinants of provision
of radiotherapy after breast-conserving surgery,12,16,40 as well
as noting broader regional variations.41
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Review
Adjuvant systemic therapy
Adjuvant systemic therapy can be in the form of endocrine
manipulation or chemotherapy. Previous surveys have
revealed wide variation in provision of systemic treatment,20
with apparently greater use in teaching than in non-teaching
hospitals.28 Sainsbury and colleagues review of management
of breast cancer throughout Yorkshire showed that patients
under the care of a surgeon with a special interest in breast
cancer were more likely to receive both endocrine-based
therapy and chemotherapy.23 Along with consultant
caseload, use of chemotherapy was the characteristic most
closely associated with survival.42 These findings may well
relate to the increased likelihood of involvement of an
oncologist by specialist breast surgeons, because referral to
an oncologist influences the ultimate provision of adjuvant
therapy.43 Unfortunately, the UK has fewer cancer specialists
per head of population than any other European country.44
The advent of the multidisciplinary team, with regular
discussions between surgeons, oncologists, radiologists, and
pathologists, should reduce the variability of provision of
adjuvant systemic therapy. However, in a postal survey of
UK oncologists in 1993, only 20% of those who replied were
involved in multidisciplinary discussion before surgery;32 the
proportion is likely to have changed since that time.
Furthermore, only 56% reported an agreed policy for
provision of adjuvant systemic therapy, with great variation
noted between different policies.
For patients receiving inadequate adjuvant therapy, the
inadequacy seems to apply over a range of modalities. A
199596 audit in the South Thames region showed that
patients who received radiotherapy after breast-conserving
surgery had a greater chance of being prescribed tamoxifen
than those who did not (95% versus 25%).38 In 1987,
Twelves and co-workers reviewed breast-cancer
management for the whole of Scotland in a single year to
limit the effect of changes in practice over time.45 They found
that the treating health board was an independent predictor
of use of adjuvant systemic therapy, supporting the notion
that the problem is as much one of service organisation as of
differences between individuals.46

Survival
Gillis and Holes review of breast-cancer management in the
west of Scotland for the years 198088 compared survival for
patients treated by specialist and non-specialist surgeons.30 At
5 years, overall survival was 67% and 58%, respectively, and
that at 10 years 49% compared with 41%. The study period
predates the introduction of mammographic screening, and
differences were observed across all patients and disease
subgroups; the largest difference was 19%. The relative
hazard ratio for women under the care of a specialist surgeon
compared with those treated by a non-specialist was 0.83
(95% CI 0.740.92) after adjustment for age, deprivation
index, and tumour size. If nodal involvement was also taken
into account, the hazard ratio was 0.84 (0.750.94) . The
actual treatment received was not included as part of the
analysis, though the noted differences seem to exceed any
discrepancy that could be attributed to use of adjuvant
systemic therapy.47 In the review by Twelves and colleagues of
patterns of breast-cancer care throughout Scotland in 1987,
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Survival variation in breast cancer

data were obtained from patients notes rather than cancer


registries.45 5-year survival rates ranged from 67% to 84% in
the various Health Boards. Type of surgery, use of adjuvant
therapy, and clinicians workload all significantly influenced
survival on univariate analysis, though significance was lost
on multivariate analysis. The only significant predictor of
survival on multivariate analysis was Health Board of
primary treatment (p = 0.02). The Yorkshire study analysed
survival by consultant surgeons caseload.42 Relative risk of
death at 5 years for patients treated by a surgeon seeing more
than 30 new cases per year compared with surgeons seeing
fewer than ten new cases was 0.85 (95% CI 0.770.93), very
similar to the findings from the west of Scotland.30 Again,
different treatment practices could not solely account for the
observed survival differences.
Basnett and co-workers found better survival for breastcancer patients treated in a teaching hospital than in those
treated in a non-teaching hospital.28 Relative odds of death at
the non-teaching centre were 1.46 (95% CI 1.161.84,
p = 0.0009) and 1.74 (1.342.27, p < 0.00001) after
adjustment for age and stage of disease. Similar findings
relating to hospital teaching status have been reported from
Finland48 and Japan.49 Studies in the USA have shown large
survival differences dependent on size of hospital,11,50 though
the particular organisation of health services in the USA
introduces several confounding factors.51 Similar studies in
the UK,27 Italy,52 Norway,31 and Australia53 found no
significant effect of size or teaching status of institution
on survival.
Adjuvant systemic therapy seems to be the treatment
modality with greatest influence on survival in breast cancer,
yet observed variations in survival exceed differences that
might be accounted for by its use. Furthermore, the
EUROCARE finding that survival from breast cancer within
the UK compares unfavourably with our European
neighbours suggests that such differences existed long before
the advent of adjuvant systemic therapy.2,3 Cancer-registry
data from the 1950s indicate 5-year survival in a sample
from England and Wales of 48%, whereas data from the
USA, Norway, and Finland show survival of 5257%.54 A
small study of patients treated in the UK, USA, and Japan
again showed significantly worse survival in the UK group,
which remained after crude adjustment for pathological
stage.55
Further analysis of the EUROCARE data, based only on
deaths during the first 6 months after diagnosis, shows an
even greater difference in survival between the UK and the
rest of Europe.2 The relative risk of death rises from
1.071.32 (at 5 years) across the age-group range to
1.443.75. Such variations in early deaths cannot be
explained by differences in treatment. Possible explanations
include more advanced disease at presentation and
biologically more advanced disease. These explanations need
not necessarily affect the validity of the data, because
treatment of a disease on a population basis should include
education of that population and ease of access to care.

Clinical trials
With continuing rapid advances in management of breast
cancer, there may be a problem in keeping up to date with
THE LANCET Oncology Vol 2 December 2001

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Review

Survival variation in breast cancer

the newest therapies. Dissemination of information is vital


for universal standards of care, although awareness of
consensus guidelines is not necessarily a guarantee of
compliance.10,14 Probably the most effective way of ensuring
adherence to guidelines and familiarity with latest
developments is participation in clinical trials. This factor
may well also improve survival, as was noted in a 1994
review on a range of cancers comparing clinical-trial versus
non-trial patients, teaching and non-teaching hospitals, and
specialist versus non-specialist clinicians.56 In all published
reports, there was either a survival advantage for the
specialist group or no difference seen, with no studies
reporting lower survival in patients treated by specialists. A
recent review of Canadian practice found that the rate of
provision of adjuvant systemic therapy in line with
consensus opinion increased with caseload for hospitals
participating in trials, whereas the reverse was shown in the
hospitals that were not involved in trials.57 As recently as
1993, however, less than 45% of UK oncologists were
entering patients into trials.32 Traditionally, trials have been
based mainly around teaching hospitals and other major
centres. A 1982 study in the USA compared such institutions
with small community hospitals and found no significant
difference in trial entry and compliance with protocols or of
outcome data.58

Other factors
Studies from migrant populations have suggested that
differences in incidence of breast cancer among countries
are social and environmental, rather than genetic, in origin;
only about 5% of cases of breast cancer are due to highly
penetrant dominant genes.3 Though no convincing link has
ever been shown between incidence and survival, the
obvious association between breast cancer and external
influence supports the hypothesis that social and
environmental factors influence the biological behaviour of
the disease. A UK study of 5-year survival after treatment for
breast cancer showed rates of 70% and 57% for the most
affluent and least affluent tenths of the community studied.59
A small study from the Netherlands (271 patients in
total) compared the histopathological features of breast
cancers in laboratories serving two regions, in which 10-year
survival for breast cancer was 48% and 69%, respectively,
despite similar surgery and radiotherapy protocols (the
study predated the advent of mammographic screening and
of adjuvant systemic therapy).60 Age distribution of patients,
tumour size, and lymph-node status did not differ
significantly between the two cohorts, and nor did
histological and nuclear grade (according to World Health
Organisation criteria). However, the mitotic activity index
(the number of mitotic figures in a set number of
neighbouring fields) and mean nuclear area (area measured
at 2000 magnification) both showed significant differences
between the regions (p < 0.0001). At the time of another
study of the specimens from one of the regions 15 years
later, the features particular to that area were still present.
These differences could not be attributed to specific factors,
although one region was far more industrialised than the
other. In the USA, breast-cancer mortality has long been
known to be higher for women living in the northeastern
THE LANCET Oncology Vol 2 December 2001

Search strategy and selection criteria


Information was obtained from the MEDLINE database,
with cross-referencing from major articles. Search terms
used were breast cancer, survival, treatment, and
variation, and combinations of these. Only papers
published in English were included and there were no date
restrictions.

states than in southern areas, even after adjustment for


known risk factors.61 Incidence of breast cancer was only 3%
higher in the northeastern states than in the south, yet
mortality was 26% higher. On analysis of age-groups,
significant differences were restricted to postmenopausal
women.41

Discussion
There has clearly been great variation in management of
breast cancer within the UK, with poor adherence to
consensus guidelines, although the situation is improving.
Although data are sometimes confounding and
contradictory, such variation seems to affect survival
significantly. True comparisons between sets of data are
possible only if data-collection techniques and accuracy are
themselves comparable, which may call into question at least
the magnitude of some of the differences observed between
countries. A study of factors affecting breast-cancer survival
is inevitably retrospective in nature, such that better
understanding from future investigations depends on
application of the most rigorous standards to data
collection. However, studies cited here, in which methods of
data gathering have been uniform have shown significant
survival differences between individual clinicians,
institutions, and health-service organisations.
There is an increasing body of evidence in support of the
trend towards greater subspecialisation; patients fare best
when referred to a surgeon with a special interest in breast
cancer, seeing large numbers of new cases, and working as
part of an integrated multidisciplinary team. The large
differences in deaths within 6 months of diagnosis between
the UK and other European countries cannot be explained
by treatment differences alone, and are likely to reflect either
delayed presentation or biologically more virulent disease.
There is indirect evidence of the influence of socioeconomic
factors on survival, but the suggestion that provision of care
to women with breast cancer within the UK has been nonuniform and at times inadequate remains difficult to refute.
At the very least, we should aim to standardise care so as to
obtain maximum survival benefit, and strategies for
achieving this aim in the future are now being introduced.
In England, the Department of Health has overseen the
establishment of Regional Cancer Networks. Tumour-sitespecific groups, consisting of members of the
multidisciplinary teams from across the region, will
determine a pathway of care based on national guidelines
across the network. A similar system has been set up in
Scotland with the recently established Clinical Standards
Board, which will ensure that nationwide management is in
line with basic treatment protocols.
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Review

Survival variation in breast cancer

Acknowledgments

We thank Richard Peto for his assistance with the reproduction of


Figure 1.

24

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25

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