Chapter 11
192
still an overall recurrence rate of between 3% and
13%13,55,66 at 5 years, and research into the use
of additional adjuvant therapies for women with
‘high-risk’ DCIS remains important.
In this trial, 30% of women were younger than
50 years at diagnosis and the effect of tamoxifen
was largely due to a 40% reduction in this younger
age group, with only a 20% reduction in the age
group greater than 50 years. On this basis adjuvant
tamoxifen after wide local excision for DCIS could
be discussed in this younger (under 50) age group;
however, current NICE guidelines indicate that
tamoxifen should not be used in DCIS.52 A retro-
spective review of the NSABP-B24 results showed
that tamoxifen was only beneficial in oestrogen
receptor-positive cases, as one would expect. The
relative risk of recurrence of any breast cancer in
the oestrogen receptor-positive cohort was 0.41
(95% CI 0.25–0.65, P = 0.0002), whereas there was
little benefit in the oestrogen receptor-negative cases
(relative risk 0.80, P = 0.51).80 The UK/ANZ DCIS
trial found that adjuvant tamoxifen reduced overall
DCIS recurrence (0.70, 0.51–0.86; P = 0.03) and
contralateral tumours (0.44, 0.25–0.77; P = 0.005)
but had no effect on ipsilateral invasive disease67
(see Table 11.3). The UK/ANZ DCIS trial has not
published a breakdown of tamoxifen response in
relation to oestrogen receptor status, but tamoxi-
fen was found to be more effective in low- and in-
termediate-grade compared with high-grade DCIS
and this is likely a surrogate (though not completely
accurate) reflection of oestrogen receptor status;
low-grade DCIS tends to be nearly 100% oestro-
gen receptor positive, compared with only 60% of
high-grade cases expressing oestrogen receptor.81
The UK/ANZ DCIS trial authors suggested that the
variation in findings, as to the benefit of tamoxi-
fen in preventing ipsilateral invasive recurrence
between the two trials, may have been a product of
the American B24 trial having approximately 34%
of women aged under 50, whereas in the UK trial
>90% of participants were older than 50.67 No sig-
nificant effects were seen on mortality with the use
of tamoxifen in either trial.
In the randomised controlled trials, the rate of con-
tralateral breast cancer after DCIS is 0.5% per year
for 10 years. As tamoxifen can halve the risk of
breast cancer in the contralateral breast, its effects
in part are as a chemopreventive agent. This may
possibly justify its use in some women with oestro-
gen receptor-positive disease. Approximately 60%
of DCIS cases express HER-2. Oestrogen receptor-
positive tumours that also express HER-2 are con-
sidered to be more often resistant to tamoxifen but
do respond to aromatase inhibitors. The ERISAC
trial showed that exemestane, at a dose of 25 mg/
day, inhibits epithelial proliferation in DCIS by 39%
(hazard ratio 0.61, 95% CI 0.41–0.91, P = 0.016)
compared with placebo.82 This suggests that aroma-
tase inhibition of oestrogen receptor-positive DCIS
could potentially be used to prevent local recurrence.
The use of aromatase inhibitors is currently be-
ing investigated in the IBIS II DCIS trial, which
is a comparison of tamoxifen with anastrozole
or placebo, after complete excision of oestrogen
receptor-positive DCIS. The NSABPB35 trial is
comparing anastrozole with tamoxifen for patients
with DCIS after lumpectomy and radiation therapy.
The NSABP P-1 chemoprevention trial83 compared
tamoxifen to placebo in patients at high risk of
breast cancer. The study reported a 49% reduction
in incidence of invasive cancer and a 50% reduction
of DCIS in the tamoxifen-treated group. The reduc-
tion in contralateral breast cancer was only seen in
oestrogen receptor-positive cases, with no benefit
being seen for oestrogen receptor-negative patients.
The recent MAP.3 trial looked at exemestane in a
prevention setting in postmenopausal women and
showed a reduction in both new cases of DCIS and
further breast events in women with a prior diagno-
sis of DCIS, though numbers were small.17
Follow-up and prognosis
Following confirmation that there has been complete
excision of all suspicious microcalcifications with clear
margins, patients should be given the opportunity to
participate in clinical trials. One trial is investigating
The NSABP-B24 trial compared breast-
conserving surgery and radiotherapy with or
without adjuvant tamoxifen. The study found that
tamoxifen following breast-conserving surgery and
radiotherapy was of benefit in reducing recurrence.
There were 43% fewer invasive breast cancer
events and 31 % fewer non-invasive events in the
tamoxifen-treated group.59 The main advantage was
in reducing invasive recurrence in the ipsilateral
breast, although there was a significantly lower
cumulative incidence of all breast cancer-related
events in the tamoxifen group.
Treatment of ductal carcinoma in situ
193
the role of boost radiotherapy in DCIS. Follow-up in
outpatient clinics, after the initial postoperative re-
views, should be by annual bilateral two-view mam-
mography to detect recurrence. Most DCIS recurrence
is impalpable and the only role for clinical examina-
tion may be in detecting invasive recurrences in pre-
menopausal women. Breast cancer-specific mortality
following breast-conserving surgery for DCIS is low
at less than 2% at 10 years and is not influenced by
adjuvant radiotherapy. This figure is similar to that
following mastectomy for DCIS.
Management of recurrence
In situ recurrence
Patients with an in situ recurrence where the primary
was treated initially with breast-conserving surgery
alone can be offered re-excision (ensuring clear mar-
gins) followed by postoperative radiotherapy. Patients
who have already received radiotherapy following
their primary excision are usually advised to have com-
pletion mastectomy unless recurrence is many years
later. A skin-sparing mastectomy with a myocutane-
ous flap breast reconstruction gives excellent results.
Implant based reconstructions have an increased rate
of complications if there has been prior radiotherapy.
Invasive recurrence
The management of invasive recurrence is depen-
dent on the initial therapy for DCIS. If the patient
did not receive radiotherapy after initial DCIS exci-
sion, then wide local excision and radiotherapy may
be an option depending on the size and location of
the invasive tumour. If wide local excision is not an
option, then mastectomy and axillary staging is the
treatment of choice, with adjuvant therapy dictated
by standard protocols for primary invasive cancers.
Studies following salvage treatment for both in situ
and invasive recurrences of DCIS have shown over-
all cause-specific survival rates in excess of 90% at
8 years after recurrence.57
DCIS of the male breast
DCIS accounts for approximately 5% of breast can-
cers in men.84 It usually presents clinically with symp-
toms of a retro-areola cystic-type mass or bloody
nipple discharge. Clinical, rather than mammo-
graphic, detection possibly accounts for the different
incidence of DCIS between men and women. The
predominant histological subtypes of DCIS in men
are papillary and cribriform. Standard treatment is
total mastectomy with excision of the nipple–areola
complex but wide excision and radiotherapy is being
used more frequently.85 Pure DCIS in men is usually
of low or intermediate grade; less than 3% of cases
are high grade. In a series of 114 patients, 84 with
pure DCIS and 30 with DCIS and invasive cancer,
there were no cases of high-grade comedo DCIS in
men without an invasive tumour.86 The percentage of
men with DCIS that eventually develop an invasive
cancer is not known.
The future
Ongoing trials
The IBIS II and NSABP B-35 trials (as discussed pre-
viously) are in active follow-up. The NSABP B-43
trial is currently recruiting patients to compare
trastuzumab given during radiotherapy or radio-
therapy alone in women with HER-2-positive DCIS
treated with lumpectomy. The ICICLE trial is try-
ing to identify genes that increase women's risk of
developing DCIS, and also trying to identify which
women with DCIS are at risk of developing an inva-
sive recurrence if left untreated. A more novel treat-
ment is being investigated in a phase I/II trial looking
at vaccine therapy, where vaccines made from a pa-
tient's white blood cells mixed with peptides may
help the body build an effective immune response to
kill tumour cells. Neoadjuvant therapy with aroma-
tase inhibitors in postmenopausal women with oes-
trogen receptor-positive cancers is showing promise
as a short-term treatment to reduce tumour extent
and as long-term treatment for some patients with
low- and intermediate-grade DCIS.
UK National DCIS audit (Sloane
Project)
The Sloane Project is a prospective audit that is
collecting data on all screen-detected DCIS, LCIS,
ADH and ALH in the UK. For each case the clinical,
pathological, radiological and treatment character-
istics are documented. It currently has over 10 000
Chapter 11
194
cases submitted by participating UK breast screen-
ing units. The aim is to correlate initial characteris-
tics with clinical outcomes – specifically recurrence
and invasive cancer development. Data from this
study to inform clinical management and restrict
treatment to at-risk groups are awaited eagerly.
DCIS stem cell therapy
Breast cancers have been shown to consist of a mix-
ture of stem cells and proliferating cells.19 The stem
cells appear to be more resistant to both chemother-
apy and endocrine therapy than proliferating cells.
Stem cells evade death and subsequently may re-grow
and may be a source of breast recurrence. Farnie
et al.19 showed that primary cultures of DCIS using
a mammosphere technique identified Notch and the
epidermal growth factor receptor/HER-1 as key re-
ceptors that stem cells use to avoid death. Thus strat-
egies aimed at inhibiting both stem cell self-renewal
and proliferating progeny may increase the DCIS cure
rate. HER-2-amplified DCIS has an increased stem
cell population and this population is targeted by
lapatinib, trastuzumab and other anti-HER-2 thera-
pies but not by chemotherapy. In vitro lapatinib (an
HER-1/2 inhibitor) has been shown to reduce stem
cell renewal by 70% in HER-2-amplified DCIS.87
Therapies that target cancer stem cells may pre-
vent recurrence of DCIS. There is concern that, in
some patients with DCIS, there may be stem cells
that are not identified by the standard methods of
assessing margins. Treatment with anti-stem cell
therapy given perioperatively or in combination
with endocrine therapy should theoretically reduce
the rate of recurrence. Additionally, new data utilis-
ing dual HER-2 inhibition with combinations of
trastuzumab with either lapatinib or pertuzumab
show complete response in up to 60% of oestrogen
receptor-negative, HER-2-positive invasive cancers
in association with chemotherapy and suggest that
dual anti-HER-2 treatment might be effective in
oestrogen receptor-negative, HER-2-positive DCIS
at reducing disease burden and could avoid mas-
tectomy in some women. This strategy is also an
effective anti-stem cell strategy and so may have
long-term benefits in reducing recurrence rates for
women with HER-2-positive DCIS.
Optimising treatment
Controversies regarding the optimum management
of this heterogeneous preinvasive lesion still reign.
Surgeons should ensure complete pathological and
radiological excision of DCIS and discuss the ap-
propriateness of adjuvant therapy (radiotherapy or
endocrine) with the patient in a multidisciplinary
setting in order to minimise recurrence without
over-treatment.
Key points
• DCIS is a preinvasive breast tumour; the proliferation of malignant epithelial cells is confined within
an intact basement membrane. The developmental pathway for low- and intermediate-grade DCIS
appears different from that for high-grade DCIS.
• DCIS accounts for approximately 20% of new screen-detected cancers.
• Small localised areas of DCIS (normally <4 cm) should be treated with breast-conserving surgery
with or without radiotherapy. Larger lesions are usually treated by mastectomy and sentinel node
biopsy unless they can be excised using oncoplastic techniques. Axillary surgery should be
avoided after breast-conserving surgery.
• We are potentially over-treating a number of ‘low-risk’ cases of DCIS that may never progress to
invasive disease.
• There are current controversies in management of DCIS with respect to over-treatment and in
particular the widespread use of radiotherapy in this condition.
• Up to 13% of cases recur at 5 years following breast-conserving surgery and radiotherapy, 50% of
which (i.e. up to 6.5% of all cases) are invasive disease.
• The key factor for decreasing tumour recurrence is to excise the lesion to clear margins at the time
of surgery.
Treatment of ductal carcinoma in situ
195
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fen and radiotherapy in women with locally excised
ductal carcinoma in situ: long-term results from the
UK/ANZ DCIS trial. Lancet Oncol 2010;12(1):21–9.
68. Rodrigues N, Dillon D, Parisot N, et al. Differences
in the pathologic and molecular features of intra-
ductal breast carcinoma between younger and older
women. Cancer 2003;97:1393–403.
69. Silverstein MJ, Lagios MD. Choosing treatment for
patients with DCIS: fine tuning the University of
Southern California/Van-Nuys Prognostic Index.
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markers that predict clinical recurrence in duc-
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2003;39:622–30.
71. Witton CJ, Reeves JR, Going JJ, et al. Expression of
the HER 1–4 family of receptor tyrosine kinases in
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72. Barnes NLP, Khavari S, Boland GP, et al. Absence
of HER4 expression predicts recurrence of ductal
carcinoma in situ of the breast. Clin Cancer Res
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73. Lari SA, Kuerer HM. Biological markers in DCIS
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74. Goodwin A, Parker S, Ghersi D, et al. Post-
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75. Emdin SO, Granstrand B, Ringberg A, et al.
SweDCIS: radiotherapy after sector resection for
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76. Bijker N, Meijnen P, Peterse JL, et al. Breast-
conserving treatment with or without radiotherapy
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77. Wong J, Kaelin C, Troyan S, et al. Prospective
study of wide local excision alone for ductal
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78. Hughes L, Wang M, Page D, et al. Local exci-
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199
12
Rosalie Fisher
Ian Smith
The role of adjuvant systemic therapy in
patients with operable breast cancer
Introduction
The mortality from breast cancer has fallen by over
15% in the UK over the last 15 years, despite a
rising incidence. The improvement in survival co-
incides with the widespread uptake of adjuvant
systemic therapy and increasing evidence of its
survival benefit. The rationale for this treatment is
that over half of women with operable breast can-
cer who receive local regional treatment alone will
die from metastatic disease, indicating the presence
of micrometastases at the time of initial clinical
presentation. Traditionally, the major risk factors
for recurrence have been the involvement of axil-
lary nodes, poor histological grade, large tumour
size and histological evidence of lymphovascular
invasion around the tumour site. The absence of
oestrogen and progestogen receptor and the over-
expression of human epidermal growth factor re-
ceptor 2 (HER-2) also carry an adverse prognosis.
The only way to improve survival for these women
is to administer effective systemic medical treat-
ment, using endocrine therapy, chemotherapy and
targeted biological therapies, along with surgery
and radiotherapy. It is now recognised that breast
cancer comprises a number of subtypes, each with
a distinct biological behaviour and prognosis, and
increasingly molecular factors rather than classical
histopathological features are being used to deter-
mine the degree of residual risk after breast can-
cer surgery, and all the judicious use of potentially
toxic treatments.1 Gene expression profiling has
emerged as a new determinant of recurrence risk
and a major current challenge is to assimilate this
new technology into treatment planning.
Adjuvant endocrine therapy
Approximately 75% of invasive breast cancer pa-
tients present with hormone-receptor positive
disease.2 As the oestrogen receptor (ER) pathway
is key to the growth of these cancers, modulation
of ER activation is an essential component of treat-
ment for these women. Since the observation by
Beatson more than 100 years ago that oophorec-
tomy could induce regression of advanced breast
cancer,3 endocrine treatment has proved one of the
most valuables therapies in cancer medicine.
Tamoxifen
Until recently tamoxifen was the standard adju-
vant endocrine therapy. The results of the most re-
cent overview of tamoxifen trials involving around
21 000 women carried out by the Early Breast Cancer
Trialists' Collaborative Group (EBCTCG) have
shown that tamoxifen given for about 5 years reduces
the risk of death by around one-third (relative risk
(RR) = 0.71 ± 0.07).4 The proportional reduction
is not significantly affected by age, nodal status or
use of chemotherapy; the absolute benefit of course
Chapter 12
200
relates to the absolute risk. The reduction in the risk
of recurrence is seen both during the 5 years of treat-
ment (RR = 0.53 ± 0.03) and extends into years 5–9
(RR = 0.70 ± 0.06), but there was no further reduction
in risk beyond 10 years. The benefits were similar and
highly significant in both ER-positive/progesterone
receptor (PgR)-positive and ER-positive/PgR-negative
disease. The reduction was greater in strongly posi-
tive ER disease (RR = 0.51 ± 0.07) than in marginally
ER-positive disease (RR = 0.65 ± 0.07).
Tamoxifen is associated with a small but signifi-
cantly increased risk of developing uterine carcinoma
and of thromboembolism; when combined these two
conditions result in a 10-year mortality of 0.2%.
Tamoxifen duration
The overview data indicate that 5 years of tamoxi-
fen is more effective than shorter durations. Until
very recently, there was no convincing evidence that
more than 5 years of tamoxifen had a further ad-
vantage. Indeed, the largest published trial so far of
tamoxifen for more than 5 years (National Surgical
Adjuvant Breast and Bowel Project (NSABP) B14)
showed that tamoxifen for more than 5 years had an
unexpected adverse influence on disease-free survival
(DFS) (78% vs. 82% with placebo, P = 0.03) and
was also associated with higher rates of endometrial
cancer, ischaemic heart disease and cerebral vascular
disease.5 Recently a much larger international trial
involving 11 500 patients, the Adjuvant Tamoxifen
Longer Against Shorter (ATLAS) trial, has ad-
dressed the question of long-term tamoxifen du-
ration. Results have so far been presented only in
abstract form, but showed a small but significant re-
duction in recurrence comparing 5 years with more
than 5 years treatment (hazard ratio (HR) = 0.88).6
Preliminary results from a similar UK trial (aTTom:
adjuvant Tamoxifen – To offer more?) involving
8000 patients are reported to be consistent with
those of ATLAS, but mature data are awaited.7
Aromatase inhibitors
First line
In the ATAC (Arimidex, Tamoxifen, Alone or in
Combination) trial involving over 9000 women, an-
astrozole was compared with tamoxifen and with
a combination of the two drugs, and was shown to
be superior to both in terms of DFS. With a median
follow-up of 120 months, a 5-year DFS benefit of
4.3% (HR = 0.86) emerged in hormone receptor-
positive patients.10
The aromatase inhibitors anastrozole and
letrozole have each been shown to improve DFS
compared with tamoxifen when given as first-
line adjuvant therapy for a planned 5 years in
postmenopausal women with hormone receptor-
positive early breast cancer8,9 (Fig. 12.1).
ATAC
Surgery
Randomise
Tamoxifen 20 mg
Anastrozole 1 mg
Tamoxifen 20 mg +
anastrozole 1 mg
5 years
BIG-98
Surgery
Randomise
Tamoxifen 20 mg
Letrozole 2.5 mg
Tamoxifen 20 mg Letrozole 2.5 mg
Letrozole 2.5 mg Tamoxifen 20 mg
2 years
3 years
Figure 12.1 • The ATAC and BIG1-98 trial schemes.
Adjuvant systemic therapy in patients with operable breast cancer
201
In the BIG1-98 trial involving more than 8000
women, letrozole was compared with tamoxifen in
a four-arm trial as follows: letrozole monotherapy;
tamoxifen monotherapy; sequential tamoxifen then
letrozole; sequential letrozole then tamoxifen; all
for a total of 5 years. With a median follow-up pe-
riod of 8.7 years, letrozole was significantly better
than tamoxifen in terms of both DFS (HR = 0.82,
95% confidence interval (CI) 074–0.92) and overall
survival (OS) (HR = 0.79, CI 0.69–0.90).11 This is
in contrast to the ATAC trial, where no overall sur-
vival benefit was seen for anastrozole over tamoxi-
fen. The results of these two trials are summarised
in Table 12.1.
First-line aromatase inhibitors: bad prognosis
subgroups
ER-positive, PgR-negative breast cancers are recog-
nised as having a poorer outcome.12 In the EBCTCG
analysis, patients with PgR poor tumours had a
worse prognosis but nevertheless had a similar pro-
portional benefit to adjuvant tamoxifen compared
with control.4
The relative gain with anastrozole and letrozole
respectively over tamoxifen is similar in both the
ATAC and the BIG 1-98 trials,13 but in both in-
stances the absolute gain is greater in patients with
PgR-negative cancers, because of the greater risk of
recurrence.
HER-2-positive tumours have a worse prognosis
than HER-2-negative cancers and in a neoadju-
vant endocrine therapy trial comparing letrozole
with tamoxifen, a large and highly significant ben-
efit was seen for letrozole over tamoxifen in terms
of clinical response in this small subgroup (88
vs. 21%, P = 0.0004).14 In a similar neoadjuvant
trial comparing anastrozole with tamoxifen, the
IMmediate Preoperative Arimidex Compared with
Tamoxifen (IMPACT) trial, a numerical although
non-significant difference was again seen in favour
of the aromatase inhibitor for HER-2-positive tu-
mours (58% vs. 22%, P = 0.09).15
These results were not, however, confirmed in the
equivalent adjuvant trials. In the ATAC trial there was
no evidence of a proportionately greater benefit for an-
astrozole over tamoxifen in HER-2-positive tumours
compared with other subtypes.13 A similar finding was
true when letrozole was compared with tamoxifen in
the BIG1-98 trial.16 Invasive lobular cancers appear to
benefit more from letrozole than tamoxifen.17
Comparative toxicities of front-line anastrozole/
letrozole and tamoxifen
The ATAC and BIG1-98 trials have both shown that
tamoxifen is associated with a small but significant
increase in the incidence of hot flushes compared
with anastrozole or letrozole (4.5–5% increase), vag-
inal bleeding (3.3–3.7% increase), vaginal discharge
(8.6% increase), endometrial carcinoma (0.2–0.4%
increase) and venous thromboembolism (1.4–2% in-
crease). The ATAC trial has likewise shown a small
but significant increase in ischaemic cerebral vascu-
lar disease (1.1% increase) with tamoxifen compared
with anastrozole, but this has not been confirmed in
the BIG1-98 trial with letrozole. In contrast, anas-
trozole and letrozole have been shown to be asso-
ciated with a statistically significant increase in the
incidence of musculoskeletal problems (6.5–8% in-
crease) and fractures (1.7–2.2% increase).
Of note, tamoxifen is associated with a significant
increase in gynaecological surgery compared with
either of the aromatase inhibitors. In the ATAC trial
5.1% of women had hysterectomies compared with
1.3% on anastrozole.18 In the BIG1-98 trial 288
women (9.1%) have required endometrial biopsies
compared with 77 (2.3%) with letrozole.9
Sequential therapy with aromatase
inhibitors after tamoxifen
Until recently, there was considerable interest in tri-
als assessing the benefit of sequential adjuvant aro-
matase inhibitors given 2–3 years after tamoxifen.
For example, in the Intergroup Exemestane Study
(IES), 4274 patients who had already been on
tamoxifen for around 2 years were randomised
double-blind to continuing on tamoxifen or switch-
ing to exemestane to complete 5 years of treat-
ment. Updated results with a median follow-up
of 91 months have shown a significant reduction
ATAC*
BIG1-98*
No. of patients
6241
8010
Median follow-up (years)
10
8.7
DFS (hazard ratio)
0.91
0.82
5-year DFS difference (%)#
2.7
3.1
OS (hazard ratio)
0.97†
0.79
Table 12.1 • Results from the ATAC and BIG1-98 trials
*Monotherapy groups only.
†Non-significant. #Absolute difference
Chapter 12
202
in the risk of relapse and an improvement in OS
(HR = 0.86, 95% CI 0.75–0.99) with the switch.19
Three other sequential trials involving anastrozole
have shown similar results.20–22
These results suggested possible superiority with
sequential switching over the benefit achieved with
first-line aromatase inhibitor therapy in ATAC and
BIG1-98.
Two trials have addressed this issue directly,
however, and recently reported results. Two of
the arms in BIG1-98 compared tamoxifen for
2 years followed by a switch to letrozole with
letrozole alone for 5 years and found no signifi-
cant benefit of the switch compared with letro-
zole up front (8-year DFS 85.9% vs. 87.5%).11
Likewise, in the TEAM (Tamoxifen Exemestane
Adjuvant Multinational) trial, 9779 patients were
randomised to tamoxifen for 2–3 years followed
by exemestane to complete 5 years or to exemes-
tane up front for 5 years. No significant difference
was found in DFS (85% vs. 86%) with a median
follow-up of 5.1 years.23
Extended adjuvant therapy with
aromatase inhibitors
The risk of recurrence of early breast cancer con-
tinues for at least 10 years after diagnosis and is
greater in patients with hormone receptor-positive
cancers.24 In the EBCTCG overview analysis more
than half of breast cancer recurrences occur after
the 5-year mark.4
Against this background, the results of the MA17
trial evaluating the benefit of extended adjuvant
therapy with letrozole in women still in remission
after 5 years of tamoxifen were of great importance
in that they demonstrated a significant DFS benefit
in favour of letrozole.25 This benefit has continued,
and indeed increased with time, with an initial HR
of 0.52 (95% CI 0.40–0.64) 12 months after ran-
domisation, increasing to 0.19 (0.04–0.34) after
48 months. Recently a similar and perhaps even
greater benefit has been reported for the subgroup
of 889 younger women <50 and premenopausal at
the time of diagnosis but who subsequently became
postmenopausal during their 5 years of tamoxifen,
with an absolute gain in 4-year DFS of 10%.26
This represents a risk reduction of 75% with ex-
tended adjuvant endocrine therapy compared with
33% in the much larger group who were postmeno-
pausal from the outset.
In two similar but smaller trials, extended adju-
vant anastrozole (ABCSG-6a) and extended adju-
vant exemestane (NSABP-B33), both after 5 years
of tamoxifen, showed that extended therapy with
an aromatase inhibitor reduces the risk of recur-
rence significantly.27,28
The optimal duration of adjuvant aromatase in-
hibitor therapy has not yet been established. It is
possible that for some women very lengthy or even
lifelong treatment might be the most appropriate
but this has to be balanced against the potential
risks of very-long-term usage. Clinical trials are es-
sential in this area. In this context, the MA17 trial
is now running a second randomisation for women
still in remission after 5 years of letrozole. Other
trials are also addressing this key issue, includ-
ing NSABP B-42 (5 vs. 10 years letrozole) and the
ABCG-16 Secondary Adjuvant Long-term Study
with Arimidex (SALSA) comparing a further 2 years
versus a further 5 years of adjuvant treatment with
anastrozole after an initial 5 years of adjuvant en-
docrine therapy.
Other aromatase inhibitor issues
Aromatase inhibitors are contraindicated in pre-
menopausal women. Likewise, caution must be
observed in their use in younger women following
chemotherapy-induced amenorrhoea. In an audit
carried out at the Royal Marsden Hospital 12
of 45 younger women (27%), median age 47,
treated with an aromatase inhibitor following
chemotherapy-induced amenorrhoea (27%) de-
veloped clinical or biochemical return of ovarian
function (including up to the age of 53 years).29
Aromatase inhibitors should therefore be used with
great caution in this group of women and ideally
serum oestradiol should be monitored using a high
sensitivity assay.
Vaginal dryness, atrophy and dyspareunia are sig-
nificant issues in women on aromatase inhibitors.
In a small study, six of seven women given vaginal
oestradiol (Vagifem®) while on an aromatase inhibi-
tor developed a significant rise in serum oestradiol
from less than 5 pmol/L to a mean of 72 pmo/L
(maximum 219 pmol/L) at 2 weeks.30
Current evidence therefore suggests that it is
easier and at least as effective to give aromatase
inhibitors up front rather than after 2–3 years of
tamoxifen.
Adjuvant systemic therapy in patients with operable breast cancer
203
Endocrine therapy in
premenopausal women
A key question is whether ovarian suppression in
addition to tamoxifen (and chemotherapy where
appropriate) is superior to tamoxifen alone in the
management of premenopausal breast cancer. In
the INT-101 trial, the addition of goserelin and
tamoxifen to standard adjuvant therapy with CAF
(cyclophosphmide, adriamycin and fluorouracil)
significantly improved DFS; 9-year DFS rates were
57% for CAF, 60% for CAF plus goserelin, and
68% for CAF plus goserelin and tamoxifen.31 An
unplanned retrospective analysis of these data sug-
gested that the addition of goserelin to CAF was
most beneficial in those women under the age of 40.
A prospective trial, SOFT (Suppression of Ovarian
Function), is currently addressing this question and
has recruited 3000 premenopausal women with
hormone receptor-positive disease randomised to
tamoxifen alone for 5 years or ovarian suppression
with either tamoxifen or exemestane for 5 years in
women post-chemotherapy who are still menstru-
ating, or who have not received chemotherapy. It
is currently in active follow-up. In a randomised
trial involving 927 premenopausal women, no
significant differences in risk reduction were seen
after 12 years of follow-up between tamoxifen alone
(27%) or a combination of tamoxifen with the
luteinising hormone-releasing hormone (LHRH)
analogue goserelin (24%).32
The SOFT trial also addresses the important ques-
tion of whether an aromatase inhibitor is superior
to tamoxifen in premenopausal patients who have
undergone ovarian suppression. The only trial to
present data on this so far is ABCSG-12 and the
Austrian Group reported no significant difference
in outcome for 1803 women randomised to tamoxi-
fen or anastrozole, both given with goserelin, with a
median 62 months follow-up.33
Obesity and adjuvant endocrine
therapy
An increase in body mass index is associated with
an increased risk of breast cancer recurrence34,35
and this was recently confirmed in patients in the
ATAC trial.36 Moreover, the benefit of anastrozole
over tamoxifen in terms of distant recurrence was
lost in patients with a body mass index of 25 kg/m2
or greater, and a similar trend was seen for all re-
currences. The Austrian ABCSG-6 and -6a trials in
which patients who had maintained a continued re-
mission on tamoxifen for 5 years were randomised to
a further 3 years of anastrozole or not have reported
similar findings. Outcome was not influenced by
body weight during tamoxifen therapy, but during
extended adjuvant therapy an exploratory analysis
found that women with normal body weight ran-
domised to anastrozole had a significant gain in DFS
The majority of vaginal oestrogen preparations
should not be used in women on aromatase
inhibitors unless serum oestradiol levels can be
monitored with a high sensitivity assay. Estring®
releases very low levels of oestrogen continuously
and appears to have very low levels of absorption
when compared to oestrogen creams or pessaries.
This may well be a better option, although
confirmatory studies have not yet been done. The
other option is to switch to tamoxifen, which is
likely to be of similar efficacy except for high-risk
cancers.
The 2011 EBCTCG overview analysis shows
no significant difference in the reduction in the
risk of recurrence or mortality with tamoxifen in
women less than 45 compared with older women
(Table 12.2).4
Age
<45 years 45–54 years 55–69 years
Risk
reduction
for
recurrence
0.63
0.72
0.54
Risk
reduction
for breast
cancer
mortality
0.71
0.82
0.63
Table 12.2 • Outcomes for oestrogen receptor-positive
patients with ~5 years tamoxifen, by age at
trial entry
Given the potential long-term morbidity of early
treatment-induced menopause, the authors do not
believe there is currently a strong evidence base for
recommending ovarian suppression in addition to
tamoxifen.
Chapter 12
204
(HR = 0.46, P = 0.02) and OS (HR = 0.37, P = 0.02),
whereas no gain was seen in patients with a body
mass index of greater than 25 kg/m2.37 This raises
the intriguing possibility that anastrozole, a rela-
tively weak aromatase inhibitor, is unable to inhibit
fully the excess aromatase associated with adipos-
ity. In contrast, in the BIG 1-98 trial, the benefit of
letrozole, a much more potent aromatase inhibitor
than anastrozole, over tamoxifen was maintained
whatever the body mass index.38 Further data are
required, but these results suggest that anastro-
zole may not be the optimal aromatase inhibitor in
women with higher body mass indices.
See Table 12.3 for a summary of recommenda-
tions for adjuvant endocrine therapy.
Adjuvant chemotherapy
Age and chemotherapy
In general, the absolute gain from chemotherapy is
higher for younger than older women.39 It is likely,
however, that this difference relates mainly to the
biological characteristics of breast cancer being
more favourable to chemotherapy response (ER
negativity, for example) in younger women, rather
than an intrinsic adverse interaction between age
and chemotherapy efficacy.41
Elderly women with breast cancer have been
under-represented in clinical trials to date, but this
is changing. The Cancer and Leukaemia Group B
(CALGB) 49907 trial demonstrated that standard
adjuvant chemotherapy was superior to single-agent
oral chemotherapy with capecitabine in women
over the age of 65, and suggested that the benefit
was more pronounced in women with hormone
receptor-negative tumours.42 However, it is also clear
that older women experience significantly greater
toxicity with adjuvant cytotoxic treatment,43–46 and
there are a number of trials under way that aim to
define those elderly patients for whom chemother-
apy is most appropriate.
Nodal status
Initially adjuvant chemotherapy tended to be re-
served for patients with axillary node involvement
Menopausal status*
Recommendation
Premenopausal
Tamoxifen 5 years
Postmenopausal†
Anastrazole 5 years
or
Letrozole 5 years
Women who are
menopausal after 5 years
of tamoxifen
Consider:
Anastrazole
Letrozole
Exemestane
in high-risk patients
Women who have
completed 5 years of
aromatase inhibitor
Currently no data
Consider option of continuing
in high-risk patients
Table 12.3 • Summary of recommendations for adjuvant
endocrine therapy
*Based on pre-chemotherapy menopausal status.
†Caution in women under the age of 50; return of ovarian
function on aromatase inhibitor is possible.
Adjuvant chemotherapy is effective in the
treatment of early breast cancer. The 2011 Oxford
Overview meta-analysis39 included outcome
data from more than 100 polychemotherapy
trials (including the oldest of 25 years) and for
approximately 100 000 randomised women,
and reported that combination chemotherapy
reduces the annual risk of recurrence by almost
25% and reduces the risk of death by around
14%. Furthermore, greater reductions in breast
cancer and overall mortality were shown in
comparisons between trials of more modern and
older chemotherapy regimens. Most of the effect
of adjuvant chemotherapy on the risk of recurrence
is seen within the first 5 years after randomisation.
Patient selection is critical to the effective and safe
use of adjuvant chemotherapy; for some subgroups,
the benefit is very much larger than the average and
for others smaller. Adjuvant chemotherapy began
in women with involved axillary lymph nodes for
whom recurrence risk was highest. It is now clear
that many women with node-negative disease also
benefit; conversely it is likely that some with node-
positive disease do not. The most recent Oxford
meta-analysis suggests that the proportional risk
reductions associated with taxane- or anthracycline-
based chemotherapy regimens are not influenced
by age, nodal status or tumour characeteristics.39
Currently, a great deal of research is focused
on identifying with more precision than in the
past which patients are likely to benefit from
chemotherapy, and particularly those women with
oestrogen receptor-positive cancers who benefit,
as in these women adjuvant endocrine therapy also
improves outcome. Indeed, a poll of international
breast cancer specialists indicated that this was the
top priority in breast cancer research.40
Adjuvant systemic therapy in patients with operable breast cancer
205
on the basis of higher risk. It is now clear that the
proportional reduction in the risk of recurrence is
similar for those with node-negative as for node-
positive disease.39 Nevertheless, since the absolute
risk is greater with nodal involvement, so is the ab-
solute benefit. Although nodal involvement carries
a worse prognosis, this does not necessarily imply
chemotherapy benefit and we are now in an era
when molecular markers are at least as important
as nodal status in determining chemotherapy ben-
efit (see below).
ER status
There has been considerable controversy over
the years as to whether patients with ER-positive
disease gain as much from adjuvant chemotherapy
as those whose tumours are ER negative. The 2011
Oxford Overview data indicate that the propor-
tional benefits are very similar, both in older and
younger women.39
The Overview also indicates an additional ben-
efit for combination chemotherapy over tamoxifen
alone for ER-positive tumours, but again more so
for younger than for older women. Recent evidence,
however, suggests that the major chemotherapy ben-
efit in ER-positive breast cancer is in selected sub-
groups and that for many patients with ER-positive
cancers there is little or no benefit for chemotherapy
(see below).
Anthracycline-based
chemotherapy
Anthracyclines have been used widely for the last de-
cade or more, and have largely replaced older CMF
(cyclophosphamide/methotrexate/fluorouracil) regi-
mens. The 2005 Overview data (including trials in-
volving a total of around 40 000 women) established
clearly the efficacy of anthracycline-based adjuvant
regimens in early breast cancer, and indicated an ad-
ditional proportional risk of recurrence of around
11% and a proportional reduction in mortality of
around 16%.47
Dose of anthracyclines
The two main anthracyclines in current use are adri-
amycin (doxorubicin) and epirubicin. The Cancer
and Leukaemia Group B (CALGB) 9344 trial ran-
domised women with node-positive breast cancer to
receive four courses of anthracycline chemotherapy
to one of three different adriamycin dose levels (60,
75 or 90 mg/m2), followed by four cycles of paclitaxel
or not.52 This important dose escalation trial showed
no benefit for adriamycin doses above 60 mg/m2 and
this dose should now be considered standard.
The French Adjuvant Study Group (FASG)-05
trial randomised lymph node-positive women with
poor prognosis and found a dose effect in favour of
six cycles of FEC100 (epirubicin 100 mg/m2) over
six cycles of FEC50 (epirubicin 50 mg/m2).53 A sig-
nificant improvement in the DFS (66.3 months vs.
54.8 months) and 5-year OS (77.4% vs. 65.3%) was
seen in the FEC100 group but there were signifi-
cantly more side-effects in the FEC100 group. These
included neutropenia, anaemia, nausea and vomit-
ing, stomatitis, alopecia and grade 3 infections. It is
important to note that this trial does not determine
that an epirubicin dose of 100 mg/m2 is optimal. All
that can be concluded is that 50 mg/m2 is suboptimal
and that a dose between the two is likely to achieve
the best balance between efficacy and toxicity.
In the 2011 Oxford meta-analysis, four cycles of
anthracycline chemotherapy appeared equivalent to
six courses of standard CMF, but there was a clear
improvement in recurrence and mortality when
regimens with a cumulative anthracycline dosage
of more than 240 mg/m2 adriamycin or 360 mg/m2
epirubicin (for example, fluorouracil/adriamycin/
cyclophosphamide (FAC) or FEC) were compared
with CMF (risk ratio 0.89 and 0.84 for recurrence
and mortality respectively).39
Higher doses of anthracylines are related to long-
term complications such as an increased incidence
of acute myeloid leukaemia (AML)/myelodysplasia.
In the EBC-1/MA.5 study by the NCIC CTG, which
used the very high epirubicin dose of 120 mg/m2,
a disturbingly high incidence of AML/myelodys-
plasia was reported (2% at 10-year follow-up).50
Likewise, in a study that analysed the toxicity of ad-
juvant chemotherapy treatment in elderly patients,
there was a linear increase in the incidence of AML/
myelodysplasia with advancing age (P < 0.001) with
a reported incidence of 1.8% for the group of age
>65 years.43
Since this Overview, other studies have
confirmed the greater benefits with anthracycline-
based therapy,48–50 including, in the UK, the
National Epirubicin Adjuvant Trial (NEAT) trial.51
Chapter 12
206
Cardiotoxicity is a further concern with the an-
thracyclines. Symptomatic congestive heart failure
(CHF) is a rare but very serious complication in
patients receiving an anthracycline-based chemo-
therapy regimen with an incidence that relates to
the cumulative dose received.54,55 As with secondary
AML, there is an association between the risk of
cardiotoxicity and increasing age. Recent long-term
data on cardiac safety in more than 40 000 early
breast cancer patients of an older age treated with
adjuvant anthracycline regimens have shown an in-
creased risk of cardiotoxicity compared with non-
anthracycline chemotherapy treatment. This was
statistically significant in the group of patients aged
66–70 with a 26% increased risk of developing
CHF. This difference in rates of CHF continued to
increase through more than 10 years of follow-up.45
For all these reasons, therefore, it is important
to determine whether high doses of epirubicin
(90 mg/m2 and above) really are more effective
than moderate doses of around 75 mg/m2 to justify
the additional toxicity, and trials addressing this
issue are indicated.
Anthracyclines and HER-2-positive
disease
The CALGB 8541 trial reported in 397 node-positive
patients that high expression of HER-2 was asso-
ciated with benefit from standard doses of doxo-
rubicin (60 mg/m2) but not from lower doses of
anthracyclines.56 In contrast, this dose–response
effect was not seen in the majority whose tumours
did not overexpress HER-2. An additional cohort
of 595 patients showed an even stronger correla-
tion between HER-2 overexpression and CAF dose
efficacy with further follow-up.57 No significant
interaction was observed in the CALGB 9344 study
between HER-2 status and the use of doses of doxo-
rubicin >60 mg/m2.58
In a retrospective study of 639 formalin-fixed
paraffin-embedded specimens obtained from 710
premenopausal women with node-positive breast
cancer who had received either cyclophosphamide,
epirubicin and fluorouracil (CEF) or CMF, HER2
amplification or overexpression was associated
with a poor prognosis regardless of the type of
treatment. In patients whose tumours showed am-
plification of HER2, CEF was superior to CMF in
terms of recurrence-free survival (RFS) (HR = 0.52,
95% CI 0.34–0.80; P = 0.003) and OS (HR = 0.65,
95% CI 0.42–1.02; P = 0.06).59 Similarly, a retro-
spective evaluation of patients in the Southwest
Oncology Group study (SWOG) 8814 trial,
which randomised postmenopausal patients with
node-positive hormone receptor-positive tumours
between tamoxifen and tamoxifen plus CAF che-
motherapy, showed that CAF offered a substantial
advantage for patients with HER-2-positive cancers
but little, if any, advantage for those with HER-2-
negative tumours.60
Recently, the Breast Cancer International Research
Group (BCIRG)-006 trial published results of a
non-anthracycline regimen combined with trastu-
zumab in patients with HER-2-positive early breast
cancer.61 This prospective study randomised 3222
women to one of three treatment arms: doxorubi-
cin and cyclophosphamide followed by docetaxel
(AC-T), the same regimen plus 52 weeks of trastu-
zumab (AC-TH), or docetaxel and carboplatin
plus 52 weeks of trastuzumab (TCH). Predictably,
both trastuzumab-containing regimens improved
DFS and OS significantly compared to the AC arm,
but there were no significant differences between
AC-T and TCH in these outcome measures (DFS
at 5 years 75%, 84% and 81% for AC, AC-T and
TCH respectively, and OS 87%, 92% and 91% re-
spectively). Anthracycline-based treatments resulted
in significantly higher rates of cardiotoxicity and
leukaemia, and TCH was better tolerated overall.
This trial raises the critical question of whether
adjuvant chemotherapy regimens should always in-
clude an anthracycline. There has been much interest
in defining the biological mechanism that underlies
the anthracycline sensitivity of HER-2-positive
breast cancers, and a number of studies have impli-
cated alterations in topoisomerase II-α (TOP2A) in
this process. The TOP2A gene regulates DNA rep-
lication and RNA transcription and is considered
a target of anthracyclines. It is located on chromo-
some 17, in close proximity to the HER2 gene, and
the two are frequently co-amplified. However, de-
spite a number of pre-clinical and clinical studies,
BCIRG-006 was not designed as a non-
inferiority trial, but it is reasonable to conclude
that TCH is an acceptable standard of care in the
adjuvant treatment of HER-2-positive early breast
cancer, and should be considered for those patients
who have a higher baseline risk for cardiac and
other toxicities.
Adjuvant systemic therapy in patients with operable breast cancer
207
(including a sub-study of the BCIRG-006 trial
described above) suggesting a predictive role for
TOP2A amplification and benefit from anthracy-
clines, other studies disagree, so at present there
is no indication to look for TOP2A amplification
when considering treatment selection.62,63
Taxanes
Paclitaxel (Taxol) and docetaxel (Taxotere) have
emerged as two of the most active cytotoxic agents
against breast cancer. In the metastatic setting,
these compounds have been shown to be active
in anthracyline-resistant breast cancers.64 Several
randomised trials have evaluated the benefit of
taxanes combined with anthracyclines in the ad-
juvant treatment of early breast cancer,52,65–69 but
their exact role remains controversial. The ma-
jority have shown a DFS benefit, but some have
failed to show a benefit in OS65,70 and in endocrine
receptor-positive tumours.52,70 A meta-analysis of
13 randomised trials involving more than 22 000
patients assessing the addition of a taxane to an
anthracycline-based regimen71 showed an absolute
improvement at 5 years of approximately 5% for
recurrence and 3% for death. This benefit is pres-
ent irrespective of the number of lymph nodes in-
volved (N1–3 vs. N4+), ER status (ER positive vs.
ER negative) or age/menopausal status (≤50 years/
premenopausal vs. >50 years/postmenopausal).
The most recent Oxford meta-analysis of poly-
chemotherapy included data from 44 000 women
in 33 taxane studies.39 A significant reduction in
breast cancer mortality (15–20%) was found when
trials that added four separate cycles of a taxane
to anthracycline chemotherapy (thereby prolonging
adjuvant chemotherapy duration) were compared
with anthracycline chemotherapy alone, but this
benefit was much smaller (though still significant)
when studies in which the number of anthracycline
cycles was increased to balance treatment duration
were analysed. The results of this meta-analysis
suggest that the benefit from taxanes is independent
of age, nodal status or hormone receptor status. It
should also be noted, however, that results from the
largest adjuvant taxane trial, the UK Taxotere as
Adjuvant Chemotherapy Trial (TACT), involving
4162 patients, did not show a significant benefit for
the addition of docetaxel to standard anthracycline
chemotherapy.70
Adjuvant docetaxel has also been tested instead
of an anthracycline in patients with early breast
cancer. In a prospective US Oncology phase III
trial, a total of 1106 patients were randomised to
received either four cycles of standard AC (doxo-
rubicin 60 mg/m2 and cyclophosphamide 600 mg/
m2) or four cycles of TC (docetaxel 75 mg/m2 and
cyclophosphamide 600 mg/m2) as adjuvant treat-
ment for early breast cancer.72 Treatment with
TC achieved a significant improvement in 5-year
DFS compared with AC (86% vs. 80% respec-
tively, HR = 0.67; P = 0.015). With further follow-
up a significant overall survival benefit has also
emerged.73 There was significantly more nausea
and vomiting in patients receiving AC compared
with TC, whereas patients receiving docetaxel ex-
perienced more oedema, myalgia, arthralgia and
a higher rate of fever and neutropenia compared
with AC (5% vs. 2.5%; P = 0.07).
Which taxane and which schedule?
The optimal schedule is determined by the type of tax-
ane selected, as demonstrated by the pivotal ECOG
1199 trial.74 Nearly 5000 women with node-positive
or high-risk node-negative disease were enrolled and
received standard AC chemotherapy for four cycles,
followed by paclitaxel or docetaxel, either given
every 3 weeks for four cycles or weekly for 12 cycles.
Progression-free survival was superior in those treated
with 3-weekly docetaxel (HR = 1.23), or weekly
paclitaxel (HR = 1.27), when compared with the
standard treatment of paclitaxel given 3-weekly. A
survival gain was demonstrated in patients treated
with weekly compared with 3-weekly paclitaxel
(HR = 1.32). On the basis of these results, weekly
Our interpretation of all these data is that the
most convincing evidence of benefit for adjuvant
taxanes is in patients with ER-negative and/or HER-
2-positive disease. In a retrospective analysis of
the CALGB 9344 trial, in which patients with node-
positive breast cancer were randomised to receive
paclitaxel (175 mg/m2) or observation after four
cycles of AC at doses of 60, 75 and 90 mg/m2,58
patients who gained from the addition of paclitaxel
were those with HER-2-positive disease (including
those with ER-positive and ER-negative disease)
and those with HER-2-negative and ER-negative
disease. In contrast, patients whose tumours were
HER-2 negative and ER positive (by far the largest
group) achieved no benefit from the addition of
paclitaxel.
Chapter 12
208
paclitaxel or 3-weekly docetaxel are considered stan-
dards of care in adjuvant breast cancer treatment.
Duration of chemotherapy
The optimum duration of chemotherapy remains
uncertain. The 1998 EBCTG meta-analysis assessed
five CMF-based trials and found no survival benefit
for more than 6 months treatment,75 but the most
recent data suggest that regimens utilising chemo-
therapy regimens longer than four cycles of AC
(more cycles or higher cumulative dose) are more
effective.39 A French FASG-01 trial showed a sig-
nificant benefit in DFS of six cycles of FEC50 over
three cycles of FEC50 or 75, and improved OS with
six cycles of FEC50 over three cycles.76
Preliminary results of the CALGB 40101 trial
were presented recently in abstract form77 and indi-
cate that for women with early breast cancer and no
or limited lymph node disease (0–3), four cycles of
3-weekly AC or weekly paclitaxel were equivalent
in efficacy to six cycles of either. Further trials of
chemotherapy duration are needed.
Dose density
Recently interest has developed in accelerated (also
called dose-dense) chemotherapy in which treat-
ment is given at 2-week rather than 3-week inter-
vals with G-CSF (granulocyte colony-stimulating
factor) support to overcome the risk of neutrope-
nic sepsis. The CALGB 9741 trial has shown that
accelerated 2-weekly AC × 4 followed by acceler-
ated paclitaxel × 4 improved efficacy over the same
eight courses given conventionally at 3-weekly in-
tervals in women with node-positive breast cancer,
with 4-year DFS of 82% and 75% respectively.78
In addition, the accelerated arm was associated
with less neutropenic sepsis. Likewise, an Italian
trial, so far presented only in abstract form, has
shown a similar increase in efficacy with reduced
risk of neutropenic sepsis when six courses of FEC
chemotherapy were given in accelerated fashion
compared with the conventional approach.79
A recent systematic review and meta-analysis of dose-
dense chemotherapy for early or locally advanced breast
cancer reported improved outcomes with this approach,
but included a number of trials with heterogeneous
study designs and treatments, and for this reason did not
provide meaningful conclusions.80
Which patients really benefit from
adjuvant chemotherapy? The role
of molecular markers
The EBCTCG Overview shows that, overall, the
survival of patients with hormone receptor-positive
disease is significantly improved by chemotherapy
over and above tamoxifen, with an HR of 0.66.39
The important question, however, is to identify those
women for whom the gain is large enough to be of
real clinical benefit when balanced against toxicity.
Various guidelines for chemotherapy decision-making
have been proposed; one of the best recognised is
the St Gallen Consensus. In the most recent update,
the 2011 St Gallen panel suggested that subtypes of
breast cancer can be defined by gene array profiles,
and that each subtype differs in its epidemiological
risk factors, natural history, and response to systemic
and local therapies.1 Surrogate immunohistochemi-
cal markers of gene expression array information
allow an approximate and simplified classification
system of intrinsic subtypes (see Table 12.4). This
latest consensus demonstrates a paradigm shift from
the use of traditional clinico-pathological features to
determine the risk of recurrence, towards an assess-
ment of the underlying biology of the tumour. This
is also evidenced by the fact that most of the panel
supported further research into the role of molecular
profiling techniques (discussed below) as prognostic
and predictive tools in early breast cancer.
Intrinsic subtype
Clinico-pathological
definition
Luminal A
ER positive
HER-2 negative
Ki67 low (<14%)*
Luminal B
ER positive
HER-2 negative
Ki67 high
HER-2 overexpression
HER-2 overexpressed
ER absent
Basal-like
‘Triple negative’
ER, PgR absent
HER-2 negative
Table 12.4 • Intrinsic subtypes of breast cancer and
approximation by immunohistochemistry
(St Gallen 2011)
*Definition of Ki67 low established by comparison with PAM50
intrinsic subtyping.119
Adjuvant systemic therapy in patients with operable breast cancer
209
Further insight into this issue comes from an
analysis of the SWOG 8814 trial, in which post-
menopausal women with node-positive hormone
receptor-positive tumours were randomised to
tamoxifen alone or tamoxifen with anthracycline-
containing chemotherapy (cyclophosphamide, adri-
amycin and 5-fluorouracil).81 Overall, there was a
significant benefit in favour of those receiving che-
motherapy concurrently with tamoxifen but in a
retrospective subset analysis, patients with a high
ER score (Allred score 7 or 8) showed no benefit
from the addition of chemotherapy even in the pres-
ence of involved nodes. Likewise, women whose
tumours were HER-2 negative showed no benefit
from the addition of chemotherapy unless they had
four or more nodes involved. This analysis should
be considered by hypothesis generation rather than
being definitive, but emphasises the need to identify
molecular markers to predict which patients really
benefit from chemotherapy.
Multiple gene expression assays
including Oncotype DX
DNA micro array analysis has classified breast
cancers according to gene expression signatures, to
quantify more accurately the likelihood of breast
cancer recurrence and predict the magnitude of
chemotherapy benefit. Currently, the most widely
used of these is a 21-gene assay now offered as a
commercial reference laboratory test (Oncotype
DX Genomic Health Inc.). This is based on for-
malin-fixed material from which the level of gene
expression is used to determine a recurrence score
predicting the likelihood of distant recurrence.82
The Oncotype DX assay has been applied to a
subset of patients in the NSABP B-20 trial, ran-
domising women with node-negative disease to
tamoxifen and chemotherapy (CMF or MF) ver-
sus tamoxifen alone. It was found that women
with a low recurrence score had no significant
benefit from chemotherapy, whereas those with a
high recurrence score had a major and significant
benefit with an absolute decrease in the 10-year
rate of distant recurrence of 28% (88% vs. 60%
free of distant recurrence).83 Patients with an in-
termediate recurrence score had a relatively small
benefit and such patients are now being included
in a trial randomising women with cancers with
intermediate scores to chemotherapy or not in
addition
to
endocrine
therapy
(TAILORx).
Oncotype DX has also been validated in ER-positive
patients in the ATAC trial84 and in node-positive
patients in SWOG 8814;85 the key message from
these data is that many patients, even those with
node-positive disease, may not benefit from chemo-
therapy. The question with regard to Oncotype DX
is its additional benefit over standard immunohis-
tochemistry. This was addressed in a study where
proliferation as measured by Ki67, were combined
with ER, PgR and HER-2 to form the IHC4 score.86
The score appeared to further risk-stratify those
patients deemed intermediate risk by the Adjuvant
Online and Nottingham Prognostic Index (NPI)
and correlated closely with Oncotype DX. The
main issue with the IHC4 is quality control; mea-
suring Ki67 in a reproducible manner continues to
be a problem in many laboratories.87 Similarly, a
70-gene signature has also shown strong correla-
tion with outcome88,89 and identifies a good and a
poor prognosis group. A second trial, MINDACT,
is assessing the value of this signature, in predicting
which patients with hormone receptor-positive tu-
mours might also benefit from chemotherapy.
Bisphosphonates
Two of three early trials indicated a benefit for the
use of oral clodronate compared with placebo in
the adjuvant setting in early breast cancer.90–93 Both
positive trials observed a reduction in bone me-
tastases and improvement in overall survival. The
NSABP B-34 study is the largest trial to compare
clodronate with placebo in addition to adjuvant
chemo- or hormone therapy and results were pre-
sented recently. The trial's primary end-point of su-
perior disease-free survival was not met, but there
appeared to be distinct benefits of clodronate for
women over the age of 50, including a trend toward
improved overall survival.94
The results of two large trials of a much more po-
tent bisphosphonate, zoledronic acid, have been pub-
lished recently. The Austrian Breast and Colorectal
Cancer Study Group trial-12 (ABSCG-12) ran-
domised premenopausal women with hormone
receptor-positive early breast cancer to anastrazole
or tamoxifen, with or without zoledronic acid.33 All
patients received goserelin for ovarian suppression.
Chapter 12
210
The investigators reported that disease-free survival
was improved with the addition of zoledronic acid
(HR = 0.68), although zoledronic acid did not sig-
nificantly affect overall survival. More recently, the
AZURE trial randomising pre- and postmenopausal
women to receive standard adjuvant systemic ther-
apy with or without zoledronic acid produced com-
plex results.95 Overall, no difference in disease-free
survival was observed between these two groups,
but in a pre-planned analysis of AZURE, post-
menopausal patients (similar to the premenopausal
population of ABSCG-12 who were rendered
‘postmenopausal’ with goserelin) had a small but
significant disease-free survival advantage, which
was apparent early after diagnosis. The results of
ABSCG-12 and AZURE suggest that there may be
an interaction between menopausal status and effect
of bisphosphonates. This hypothesis was supported
by the results of two further studies of adjuvant
bisphosphonates presented in late 2011. In an un-
planned analysis of the ZO-FAST study, disease-free
survival and overall survival were improved by the
addition of zoledronic acid to adjuvant endocrine
therapy in women who were established to be post-
menopausal,96 while the GAIN (German Adjuvant
Intergroup Node-Positive) study,97 although nega-
tive overall, suggested a beneficial effect of bisphos-
phonates in older women.
The weight of evidence increasingly favours a ben-
efit for adjuvant zoledronic acid in women whose
ovarian function has ceased or been suppressed, but
further confirmatory data are required.
Trastuzumab (Herceptin)
Trastuzumab is a recombinant humanised monoclo-
nal antibody specific to the human HER-2 receptor.
HER-2 is amplified in 15–20% of breast cancers.
It plays a critical role in tumour development, and
is an independent marker of survival, with ampli-
fication/ overexpression carrying an adverse prog-
nosis.98,99 Trastuzumab was developed as targeted
therapy against HER-2100 and has established
efficacy, including a significantly improved survival
benefit in metastatic breast cancer.101,102
Four large, multicentre randomised adjuvant tri-
als involving more than 12 000 women have as-
sessed whether trastuzumab given concurrently
with a taxane after anthracycline chemotherapy
(adriamycin/cyclophosphamide, AC) (NSABP B-31;
Intergroup N9831; BCIRG 006)61,103 or concur-
rently with a non-anthracycline regimen of taxotere
and carboplatin (BCIRG 006),61 or sequentially af-
ter any standard chemotherapy schedule (Herceptin
in Adjuvant Breast Cancer (HERA) trial),104 or
sequentially after AC and a taxane (Intergroup
N9831)105 can improve disease-free survival and
overall survival (Table 12.4). In all these trials
trastuzumab was given for 1 year; in the HERA
trial a third arm is also evaluating treatment for
2 years (Fig. 12.2).
NSABP-B31
(n=1960)
1 year
NCCTG N9831
(n=3046)
1 year
HERA
(n=5090)
1 year
1 year
2 years
BCIRG 006
(n=3222)
1 year
1 year
Docetaxel + Carboplatin
Trastuzumab
AC
‘Standard’
Paclilaxel
Figure 12.2 • Schematic of the main trials testing
trastuzumab in the adjuvant setting.
The most recent results from these trials
confirm that, with longer follow-up, there is a
consistent disease-free and overall survival benefit
from the addition of trastuzumab to adjuvant
chemotherapy, establishing adjuvant trastuzumab
as improving survival in women with HER-2-
positive breast cancer.61,103,104 The hazard ratios for
disease-free survival range from 0.52 to 0.76, and
for overall survival range from 0.61 to 0.77, in these
large trials. A much smaller trial, FinHer, randomised
232 HER-2-positive patients to adjuvant docetaxel
or vinorelbine with or without trastuzumab for
three cycles, followed by FEC in both groups for
three cycles.106 The initial results of this trial also
indicated a significant disease-free survival benefit
in favour of trastuzumab. There was no difference
in outcome for 2 years vs 1 year trastuzumab in the
HERA trial.107
Adjuvant systemic therapy in patients with operable breast cancer
211
Chemotherapy and trastuzumab:
concurrent or sequential?
Indirect comparisons of these trials suggest improved
benefit when trastuzumab is given concurrently with
chemotherapy (NSABP B-31; Intergroup N9831;
BCIRG 006; FinHer) rather than when it is admin-
istered sequentially (HERA) (Table 12.5). Likewise,
a much smaller French PACS 004 trial involving 540
women also assessed trastuzumab given sequentially
after chemotherapy and so far this is the only negative
trial.108 The inferior results of the PACS trial raises
the important issue of whether trastuzumab given
sequentially after chemotherapy may be inferior to
concurrent administration. The definitive answer to
this question comes from the N9831 trial, in which
patients were randomised to control (AC followed
by weekly paclitaxel, arm A), versus AC followed
by weekly paclitaxel and thereafter trastuzumab se-
quentially (arm B), versus AC followed by weekly
paclitaxel with concurrent trastuzumab (arm C).
Duration of trastuzumab
The optimal duration of adjuvant trastuzumab ther-
apy is unknown. Results of the 2-year treatment arm
from the HERA trial showed no benefit over 1 year.
The preliminary results of the FinHer randomised
study suggested similar results with only 9 weeks of
trastuzumab treatment combined with nonanthra-
cycline chemotherapy,107 with an increase in 3-year
RFS compared with those receiving chemotherapy
alone (89% vs. 78%, HR = 0.32; P = 0.02).78 This
effect lost statistical significance with longer follow-
up, but results may have been influenced by cross-
over in the control arm once the first results were
announced.109 A confirmatory trial, the Synergism
or Long Duration (SOLD) study, is currently ran-
domising 3000 patients with HER-2-positive early
breast cancer to 9 or 52 weeks of adjuvant trastu-
zumab in an attempt to clarify this issue.
Small HER-2-positive breast
cancers
It is becoming clear that small (less than 10 mm)
HER-2-positive cancers have a worse prognosis
than similarly small HER-2-negative tumours.110–112
The adjuvant trials of trastuzumab largely excluded
Trial
Treatment
Number
HR for DFS
HR for OS
Median follow-up
(years)
Concurrent
Combined US
(NSABP B-31
and N9831)
NSABP:
AC-T vs. AC-TH
N9831:
AC-T vs. AC-T-H vs. AC-TH
3968
0.52
0.61
4
BCIRG-006
AC-T
2147
0.64
0.63
4
TCH
2148
0.75
0.77
4
FinHER
TH-FEC vs. T-FEC
232
0.65
(NS)
0.42
(NS)
5
Sequential
HERA
Standard adjuvant
chemotherapy then
trastuzumab
3501
0.76
0.85
(NS)
4
PACS 004
FEC100-T
Epirubicin/docetaxel-T
540
0.86
(NS)
1.27
3
Table 12.5 • Adjuvant trastuzumab trials: concurrent and sequential
DFS, disease-free survival; HR, hazard ratio; NS, not significant; OS, overall survival.
After 6 years of follow-up, comparison of arms B
and C revealed that trastuzumab given concurrently
with chemotherapy resulted in a significant
improvement in disease-free survival, compared
to sequential chemotherapy and trastuzumab
(HR = 0.77).105
Chapter 12
212
patients with tumours of this size, but in the HERA
trial patients with small (1.1–2 cm) node-negative
breast cancers had a very similar benefit to those
with larger tumours from the addition of trastu-
zumab (HR = 0.53),113 and it is reasonable to expect
that this group would derive a similar reduction in
risk from adjuvant chemotherapy and trastuzumab.
The issue of whether to give a modified, shorter che-
motherapy regimen with trastuzumab in this situa-
tion remains controversial: a US group has recently
carried out a non-randomised phase II study of
single agent paclitaxel with trastuzumab in 400 pa-
tients with small HER-2-positive breast cancer and
results are awaited (clinical trials NCT 00542451).
Cardiotoxicity with trastuzumab
The only significant toxicity associated with trastu-
zumab (and one that was quite unexpected from
preliminary experimental studies) is cardiotoxicity,
particularly when given concurrently with or after
anthracyclines. Updated cardiac safety data from
three of the adjuvant trastuzumab trials were pre-
sented in 2010. Independent retrospective review of
the NSAPB B-31 and N9831 trials reported that the
risk of symptomatic CHF from trastuzumab was
low, but that it increased from 0.45% for patients
treated with chemotherapy alone to 2% when
trastuzumab was added to chemotherapy.114 The
majority of patients (86.1%) experienced complete
or partial recovery. A second, similar analysis of the
HERA trial confirmed a low incidence of cardiac
end-points; severe CHF occurred in 0.8% versus
0% and significant decreases in left ventricular
ejection fraction (LVEF) occurred in 3.6% versus
0.6% in the trastuzumab and control arms respec-
tively.115 Approximately 80% of patients who suf-
fered a cardiac event achieved ‘acute recovery’,
defined as two or more sequential LVEF measure-
ments of 50% or more, after the initial low ejection
fraction.
Triple-negative breast cancer
Triple-negative breast cancers are defined as lacking
expression of the ER, PgR, and HER-2 receptors.116
They are usually associated with a high histologi-
cal grade117 and are recognised to have a more ag-
gressive natural history than other breast cancer
subtypes. Although considered as one group, they
consist of basal cancers, metaplastic cancers and a
heterogeneous mixture of other true tumour types.
Some triple negatives have low levels of expression
of ER rather than being true ER zero. Standard ad-
juvant anthracycline chemotherapy results in poorer
outcomes for triple-negative patients,118 and retro-
spective data from CALGB 9344 suggest that triple-
negative breast cancers specifically benefit from
adjuvant taxanes.58 New therapies for this subtype,
including the angiogenesis inhibitor bevacizumab,
are also being investigated. The value of bevaci-
zumab in breast cancer is, however, far from clear
and its use outside clinical trials cannot be justified.
Conclusion
Adjuvant medical therapy after surgery repre-
sents the most important advance in the treatment
of breast cancer over the last four decades and is
largely responsible for the very significant improve-
ment in mortality.
Adjuvant endocrine therapy is indicated for all but
the very best prognosis hormone receptor-positive
tumours. Tamoxifen remains the standard treat-
ment for premenopausal women with ER-positive
cancers, and current evidence suggests that there
may be some, if limited, additional benefit with con-
comitant ovarian suppression. Aromatase inhibitors
are marginally better than tamoxifen as first-line or
sequential treatment in postmenopausal women,
and in particular those at higher risk. Extended ad-
juvant therapy with an aromatase inhibitor beyond
5 years of tamoxifen is also an important new devel-
opment for women at prolonged risk.
Adjuvant chemotherapy is likewise of major im-
portance, particularly for women with hormone
receptor-negative disease. Many patients with hor-
mone receptor-positive disease undoubtedly also
benefit, but the challenge is to define these more
accurately using modern molecular marker tech-
nology to determine exactly who will benefit from
chemotherapy.
In summary, therefore, the risk of significant and/
or long-term cardiotoxicity is low with trastuzumab.
There is accumulating evidence that older patients
with borderline LVEF function and hypertension
might be at increased risk of cardiotoxicity, and
for this population it is appropriate to consider a
non-anthracyline-based chemotherapy regimen in
combination with trastuzumab.
Adjuvant systemic therapy in patients with operable breast cancer
213
Adjuvant trastuzumab has been a major break-
through for patients whose tumours amplify
or overexpress HER-2, and the likelihood is
that evidence will continue to accumulate in
the near future to support the use of adjuvant
bisphosphonates.
Key points
• Adjuvant treatment for breast carcinoma after surgery is responsible for significant improvements in
outcome.
• Tamoxifen remains the standard for premenopausal patients with oestrogen receptor-positive
early breast cancer and an aromatase inhibitor for postmenopausal patients, with tamoxifen still a
reasonable alternative if tolerability is poor.
• Adjuvant chemotherapy reduces the risk of recurrence and death from breast cancer, particularly
for oestrogen receptor-negative and/or HER-2-positive disease. A key current challenge is to
identify which patients with oestrogen receptor-positive disease also benefit from chemotherapy.
• Adjuvant trastuzumab in addition to adjuvant chemotherapy confers a very significant further
benefit in patients with HER-2-positive disease.
• The weight of evidence increasingly favours a benefit for adjuvant zoledronic acid in women whose
ovarian function has ceased or been suppressed, but this has not yet been approved as standard
treatment.
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97. Mobus V, et al. GAIN (German Adjuvant
Intergroup Node Positive) study: a phase III mul-
ticenter trial to compare dose dense, dose intense
ETC vs EC-TX and ibandronate vs observation
in patients with node-positive primary breast
cancer – first interim efficacy analysis. Cancer Res
2011;71(24):Suppl, abstract S2-4.
98. Slamon DJ, Clark GM, Wong SG, et al. Human
breast cancer: correlation of relapse and survival
with amplification of the HER-2/neu oncogene.
Science 1987;235(4785):177–82.
99. Slamon DJ, Godolphin W, Jones LA, et al. Studies of
the HER-2/neu proto-oncogene in human breast and
ovarian cancer. Science 1989;244(4905):707–12.
100. Finn RS, Slamon DJ. Monoclonal antibody therapy
for breast cancer: herceptin. Cancer Chemother
Biol Response Modif 2003;21:223–33.
101. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of
chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overex-
presses HER2. N Engl J Med 2001;344(11):783–92.
102. Marty M, Cognetti F, Maraninchi D, et al.
Randomized phase II trial of the efficacy and
safety of trastuzumab combined with docetaxel in
patients with human epidermal growth factor re-
ceptor 2-positive metastatic breast cancer admin-
istered as first-line treatment: the M77001 study
group. J Clin Oncol 2005;23(19):4265–74.
103. Perez EA, Romond EH, Suman VJ, et al. Four-year
follow-up of trastuzumab plus adjuvant chemo-
therapy for operable human epidermal growth fac-
tor receptor 2-positive breast cancer: joint analysis
of data from NCCTG N9831 and NSABP B-31.
J Clin Oncol 2011;29(25):3366–73.
104. Gianni L, Dafni U, Gelber RD, et al. Treatment
with trastuzumab for 1 year after adjuvant chemo-
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Chapter 12
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105. Perez EA, Suman VJ, Davidson NE, et al.
Sequential versus concurrent trastuzumab in adju-
vant chemotherapy for breast cancer. J Clin Oncol
2011;29(34):4491–7.
These three randomised trials (along with Ref. 60) of
adjuvant concurrent trastuzumab with chemotherapy
demonstrate a reduction in recurrence and death in
women with HER-2-positive breast cancer. All trials
published updated results in 2011, confirming that
these benefits are maintained with longer follow-up.
106. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al.
Adjuvant docetaxel or vinorelbine with or with-
out trastuzumab for breast cancer. N Engl J Med
2006;354(8):809–20.
107. Goldhirsch A, Piccart-Gebhart M.J, Procter M, et al.
HERA Trial: 2 years versus 1 year of trastuzumab
after adjuvant chemotherapy in women with HER2-
positive early breast cancer at 8 years of median fol-
low up. Cancer Res 2012;72(24 suppl):S5-2.
108. Spielmann M, Roché H, Delozier T, et al. Trastuzumab
for patients with axillary-node-positive breast can-
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109. Joensuu H, et al. FinXX final 5-year analysis: re-
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111. Park YH, Kim ST, Cho EY, et al. A risk stratification
by hormonal receptors (ER, PgR) and HER-2 status
in small (< or = 1 cm) invasive breast cancer: who
might be possible candidates for adjuvant treatment?
Breast Cancer Res Treat 2009;119(3):653–61.
112. Chavez-MacGregor M, Gonzalez-Angulo AM.
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2009;7(9):591–8.
113. Untch M, Gelber RD, Jackisch C, et al. Estimating
the magnitude of trastuzumab effects within pa-
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2008;19(6):1090–6.
114. Russell SD, Blackwell KL, Lawrence J, et al.
Independent adjudication of symptomatic heart
failure with the use of doxorubicin and cyclo-
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Bowel Project B-31 and the North Central Cancer
Treatment Group N9831 clinical trials. J Clin
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115. Procter M, Suter TM, de Azambuja E, et al. Longer-
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trial. J Clin Oncol 2010;28(21):3422–8.
116. Foulkes WD, Smith IE, Reis-Filho JS. Triple-
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117. Reis-Filho JS, Tutt AN. Triple negative tumours:
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118. Tan DS, Marchió C, Jones RL, et al. Triple negative
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219
13
Douglas J.A. Adamson
Alastair M. Thompson
Locally advanced breast cancer
Introduction
Locally advanced breast cancer (Fig. 13.1) includes
primary breast tumours with diameters of greater
than 5 cm, breast cancers with frank skin or chest
wall involvement, and any size of tumour with cer-
tain degrees of nodal involvement, but excludes
cancers that have spread further than local, supra/
infraclavicular and internal mammary chain nodes.1
Locally advanced breast cancer includes all cancers
of ‘TNM’ stage III, but also a subset of stage II can-
cers (Table 13.1). The definition of locally advanced
breast cancer includes inflammatory breast cancer
(Fig. 13.2), which is characterised by involvement
of the dermal lymphatic vessels by cancer cells that
produces an inflamed, erythematous appearance to
the whole breast. The management of locally ad-
vanced breast cancer should be multidisciplinary
in nature, and based on the extent of the disease,
as assessed with computed tomography (CT) scan-
ning of chest, abdomen and pelvis, and, if required,
isotope bone scanning, magnetic resonance imaging
(MRI) or positron emission tomography (PET) to
detect or confirm metastatic disease (Chapter 1).
Histological confirmation of the tumour type along
with appropriate immunohistochemistry for oestro-
gen receptor and human epidermal growth factor
(HER-2) receptor (supplemented by fluorescence
in situ hybridisation (FISH) analysis of HER-2
status) is required before embarking on therapy
(Chapter 2). Multimodal therapy is generally
needed and the timing and nature of treatments will
vary depending on whether the disease is confined
to operable areas, whether there is involvement of
internal mammary or supraclavicular lymph nodes,
and above all the general fitness of the patient.
The general principles of the oncological manage-
ment of locally advanced breast cancer are similar
to those for less advanced disease and draw on
appropriate use of surgery, including plastic and
reconstructive techniques, radiotherapy, chemo-
therapy, endocrine treatments, and therapy with
biological agents targeting specific cellular proteins.
The management of recurrent breast cancer in the
breast, chest wall and regional nodes is also guided
by these same principles.
Surgical management
Breast surgery
Pathological confirmation of the clinical diagnosis
of locally advanced breast cancer should be made
by core biopsy to distinguish invasive breast cancer
from ductal carcinoma in situ (DCIS) or metastatic
disease to the breast from another primary site. If
the patient is likely to be a candidate for neoadju-
vant therapy, placement of a radiological marker in
the tumour immediately following the core biopsy
is required to facilitate accurate surgical resection or
to localise the site of the cancer for the pathologist if
mastectomy is subsequently performed.2 However,
on occasion, excision of a skin nodule under local
anaesthetic may be useful to confirm the diagnosis
Chapter 13
220
and get tissue for receptor analysis. Resectional sur-
gery aims to secure clear surgical margins around
the cancer. There is a balance between the com-
pleteness of excision (margin involvement is linked
to recurrence) versus poorer cosmetic results from
more extensive surgery. If the cancer is not excisable
by conventional means then neoadjuvant therapy
or radiotherapy are the only treatment options.
Radical mastectomy (including excision of pectora-
lis major and level III axillary clearance) does not
improve survival over total mastectomy (odds ratio
of death 0.98 over 10 years3) and is rarely, if ever,
indicated even in locally advanced breast cancer.
Since survival following breast conservation is not
significantly different from that following mastec-
tomy, this has led most centres to use neoadjuvant
therapy for locally advanced breast cancer as initial
treatment followed by surgery, including the option
of breast conservation where appropriate. Where
neoadjuvant therapy has produced an excellent
clinical and radiological response, effective surgery
is possible only if a surgical marker was inserted
prior to commencing neoadjuvant treatment, as the
tumour may not be visible radiologically. As for all
breast conservation surgery (Chapter 4), complete
surgical excision with clear margins of at least 1 mm
on pathology review is required to reduce disease
recurrence. The term ‘toilet mastectomy’ has his-
torically been applied to mastectomy performed to
excise locally advanced breast cancer. Surgery alone
rarely controls such cancers and combination with
radiotherapy and/or systemic therapy is now stan-
dard. Excision of bulky disease in the breast previ-
ously led to difficulties in skin closure with the need
for split-skin grafting or application of an omental
flap to the chest wall but the widespread use of
skin-bearing autologous flaps, particularly the latis-
simus dorsi flap, has made primary closure possible
in all but a few patients.
Axillary surgery
Previously, level III axillary node clearance was the
axillary surgery of choice in patients with locally
advanced breast cancer due to the high probabil-
ity of axillary lymph node involvement. Given the
Figure 13.1 • Locally advanced breast cancer: still
operable by mastectomy.
Stage
TNM
IIB
T3
N0
M0
IIIA
T any
N2
M0
IIIA
T3
N1–2
M0
IIIB
T4a, b, c, d
N0–2
M0
IIIC
T any
N3
M0
Table 13.1 • Locally advanced breast cancer stage
and TNM
Figure 13.2 • Inflammatory breast cancer demonstrating
skin erythema (with indrawn nipple and skin tethering) and
a visible axillary nodal mass.
Locally advanced breast cancer
221
significant morbidity associated with level III axil-
lary clearance, for patients undergoing neoadjuvant
therapy who were node negative at diagnosis or
have a good clinical response this is being chal-
lenged. Sentinel lymph node biopsy of the post-
treatment axilla is now being used to guide therapy
and is of similar efficacy to that in patients who have
not received neoadjuvant therapy4 (see Chapter 7).
Although some advocate sentinel node biopsy prior
to neoadjuvant therapy this is illogical and denies
those whose nodes are cleared by this treatment
the option of sentinel node biopsy after completion
of their systemic therapy. It is useful, however, to
consider sentinel node biopsy prior to a definitive
surgical procedure in patients who are having mas-
tectomy and undergoing breast reconstruction, in
order to guide the extent of the axillary node dissec-
tion. Axillary nodes are converted to node negative
in approximately 35% of patients by neoadjuvant
chemotherapy. The rate of conversion from posi-
tive to negative relates to tumour type. Between
25% and 50% of involved nodes in triple negative
cancers, 40–60% in HER-2-positive patients who
receive trastuzumab but less than 10% of nodes
in patients with oestrogen receptor-positive breast
cancers are converted from positive to negative.
Breast reconstruction in locally
advanced breast cancer
For those patients undergoing mastectomy either
as primary treatment or following neoadjuvant
therapy, there remains controversy regarding imme-
diate breast reconstruction (Chapter 9). Although
there may be concerns that delayed wound healing
(on the chest wall or at donor sites for autologous
reconstruction) may delay the delivery of postop-
erative adjuvant chemotherapy or postoperative
radiotherapy5 and the need to avoid radiotherapy
following reconstruction with prostheses, few pa-
tients experience significant delays. Some surgeons
do not offer immediate reconstruction to patients
with locally advanced disease because of the likeli-
hood postoperative radiotherapy will be required.
Over the past 15 years, US practice has swung from
immediate reconstruction for patients with locally
advanced breast cancer to a more conservative ap-
proach of delayed breast reconstruction. There is
the option for patients wishing reconstruction of
a skin-sparing mastectomy and placement of a tis-
sue expander that is deflated during radiotherapy
and reflated shortly after completion of radiation.
Thereafter, an autologous reconstruction with a
myocutaneous flap utilises the preserved skin.
Autologous abdominal flap reconstruction at the
time of mastectomy has been reported by some to
produce unsatisfactory long-term outcomes follow-
ing radiotherapy, and with modern postoperative ra-
diotherapy techniques in the UK it does not appear
to prejudice the cosmetic outcome nor the oncological
management.6
Radiotherapy
Radiotherapy is thought to work mainly by caus-
ing damage to the DNA of tumour cells, which is
repaired more slowly than the damage caused in the
adjacent normal tissue. Tumour tissue is therefore
preferentially destroyed compared with the normal
tissue over a course of radiotherapy treatment. In
general, the chance of tumour control increases with
increasing total dose of radiotherapy given, but so
does the chance of permanent radiotherapy-related
side-effects, some of which have been implicated in
treatment-related mortality7 (Box 13.1).
Certain tissues (termed ‘late-responding tissues’)
such as nerves and, to some extent, lung can with-
stand a higher total dose of radiotherapy without
giving rise to symptomatic damage if the dose of
each separate radiotherapy treatment (or ‘fraction’)
is kept low. Traditionally, a course of radiotherapy
Sentinel lymph node biopsy after neoadjuvant
chemotherapy in patients with a good response
should be considered in place of axillary node
clearance.4
Acute skin toxicity: erythema, dry desquamation, moist
desquamation
Late skin toxicity: pigmentation, telangiectasia, fibrosis
Shoulder stiffness (if axilla treated)
Arm oedema (if lymphatics treated)
Pneumonitis (increasing likelihood with increasing lung
volume in treatment field)
Oesophagitis (uncommon, self-limiting)
Bone radionecrosis (rare with modern treatments)
Brachial plexopathy
Box 13.1 • Side-effects of breast cancer radiotherapy
Chapter 13
222
that was thought to give the best chance of long-
term tumour control comprised a relatively large
total dose given over several weeks by using small
daily fractions. Whilst shorter palliative courses of
treatment may be considered for less fit patients, the
total dose has to be reduced to minimise the toxicity
of the treatment, because the fraction size for such
short courses is by necessity large.8 The reduction in
the total radiotherapy dose for such short courses
often means that any benefit obtained from radio-
therapy is short-lived and may not be worth the
inconvenience to the patient of the treatment, and
so many oncologists advocate longer courses over
several weeks for advanced breast cancer. This
view is being challenged, partly because of the re-
sults of large randomised radiotherapy studies such
as the START trial,9 which has demonstrated that
shorter, ‘hypofractionated’ regimens using a lower
total dose than has been traditional produce good
outcome results with a trend towards fewer side-
effects. It remains to be seen whether further re-
search into much shorter hypofractionated courses
yields similar results.
Before considering radiotherapy, the patient
with locally advanced breast cancer should be as-
sessed to ensure she can comply with the treatment.
Radiotherapy is generally given with the patient
lying flat: patients with severe orthopnoea, for ex-
ample (whether due to breast cancer metastasis or
cardiorespiratory comorbidities), may not be able
to cope with this position. During radiotherapy, the
patient will be left on her own in the planning and
treatment room, and will be raised off the concrete
floor by several feet. If there is any chance she may
fall off the treatment couch, for example if she has
dementia, then the treatment cannot be given safely.
In additon, if the locally advanced disease prevents
abduction of the ipsilateral arm to less than 90°,
then it is difficult to give conventional radiotherapy
treatment to breast and axilla.
Adjuvant (postoperative)
radiotherapy
When treating locally advanced breast cancer, what-
ever surgery is performed on the breast, postopera-
tive radiotherapy significantly reduces locoregional
recurrence and improves overall survival for both
premenopausal10 and postmenopausal11 women, and
modern techniques do not have the cardiac morbid-
ity of older treatments.12 Postoperative radiotherapy
(which may be given after adjuvant chemotherapy)
reduces local recurrence from 35% without radio-
therapy to 8% with radiotherapy and improves
disease-free survival at 10 years from 24% to 36%.
Radiotherapy following the surgical treatment of
locally advanced breast cancer is given in the same
way as treatments for early breast cancer, the aim
being to reduce local relapse by about two-thirds
and improve survival.13 Locally advanced breast
cancer, by definition, has many features that pre-
dict for local relapse (large tumour size, lymph node
involvement, close or positive margins despite ad-
equate surgery). Thus, postoperative radiotherapy
is usually given,14 even if there has been a good re-
sponse to neoadjuvant treatment, as the risk of lo-
cal relapse in larger tumours is higher than for less
advanced cancers.15 The chest wall or residual con-
served breast is treated and the peripheral lymphat-
ics are irradiated as appropriate16 (see Chapter 15).
It is unusual to irradiate the internal mammary
chain nodes, as evidence for the efficacy of this
treatment is lacking, although much of the data re-
lates to trials that are decades old.17
Primary radical radiotherapy
If the patient is not fit for or declines surgery, and
is fit for radiotherapy, then radiotherapy may be
used as the principal local treatment. It is unusual
to ‘cure’ a locally advanced breast cancer without
surgery, but sometimes excellent local control can
be obtained (Figs 13.3 and 13.4) and unpleasant
symptoms of the tumour, such as pain, discharge,
bleeding and odour, can be partially or completely
removed following radiotherapy treatment.
While there is little evidence to support the use
of routine radiotherapy prior to definitive surgery,
radiotherapy has been used as an alternative to
surgery following neoadjuvant chemotherapy. In
women with stage III disease given neoadjuvant
chemotherapy, disease control, median survival
(39 months) and relapse rates appear similar in
studies that randomised patients to radiotherapy or
Postoperative radiotherapy following surgery
for advanced breast cancer reduces locoregional
recurrence and improves survival.10,11
Locally advanced breast cancer
223
surgery.18,19 For patients with disease suitable for
breast-conserving surgery, the combination of exci-
sion and radiotherapy improves local control com-
pared to radiotherapy alone.
Systemic treatment
If the patient has locally advanced disease and is
fit for treatment, then systemic therapy is usually
considered, as the risk of relapse in locally ad-
vanced breast cancer is high. In addition, neoad-
juvant treatment is often needed to ‘downstage’
some patients with locally advanced breast cancer
to allow surgery to be completed successfully and
sometimes thereafter breast conservation can be
achieved. Although cancer that has spread to the
ipsilateral supraclavicular lymph nodes was for-
merly considered ‘metastatic’ disease, patients with
isolated supraclavicular disease as the only site of
distant disease do just as well in terms of survival as
those patients with lesser stages of locally advanced
breast cancer.20
Neoadjuvant treatment
Treatment options include neoadjuvant chemo-
therapy ± trastuzumab (for HER-2-positive breast
cancer) and neoadjuvant endocrine therapy (for
oestrogen receptor-positive breast cancer).
Neoadjuvant chemotherapy
Neoadjuvant chemotherapy is as effective as adjuvant
chemotherapy in terms of survival in locally advanced
breast cancer. Randomised trials have shown a pos-
sible long-term advantage for neoadjuvant chemo-
therapy, particularly in young women (Fig. 13.5a,b).
Neoadjuvant chemotherapy is associated with a 31%
reduction in overall infective episodes compared to ad-
juvant chemotherapy.22 The choice of agents for locally
advanced breast cancer is determined by emerging
trial data and by local preferences, but is often similar
Figure 13.3 • Inoperable locally advanced breast cancer
prior to radiotherapy.
Figure 13.4 • Locally advanced breast cancer as in
Fig. 13.3 following radiotherapy.
Neoadjuvant chemotherapy is as effective as
adjuvant chemotherapy in terms of survival benefit
for locally advanced breast cancer.21
Chapter 13
224
or the same as the chemotherapy regimens given for
adjuvant therapy. There are no compelling data on
the optimum number of cycles of chemotherapy but
there may be some advantage in delivering the whole
chemotherapy course at once rather than in a periop-
erative fashion, as splitting it may give the worst of
both worlds, by exposing the patient to side-effects
both before and after their surgery with no evidence
of marked clinical advantage. It has been shown that
HER-2-positive tumours are more likely (by about
three times) to show a complete pathological response
after treatment with conventional neoadjuvant che-
motherapy compared to HER-2-negative cancers,
although the overall outlook for such tumours is
not as good as for those that are HER-2 negative.23
Neoadjuvant trastuzumab has been used in conjunc-
tion with chemotherapy and has shown improved
rates of complete pathological response compared to
chemotherapy alone, even in groups of patients that
include a significant proportion of more advanced
disease.24 Trials are underway, and showing promis-
ing results, from other inhibitors of this signalling
pathway, using the agents lapatinib, pertuzumab and
T-DM1 in different combinations with trastuzumab.
A combination of chemotherapy and trastuzumab to-
gether with either lapatanib or pertuzumab appears
superior to chemotherapy or trastuzumab alone.
The primary tumour should be assessed prior to treat-
ment, with documentation of its position in the breast,
accurate measurements of dimensions of the mass both
clinically and on imaging, and a description of the ap-
pearance of the lump and any changes associated with
it (Figs 13.1 and 13.2). A clinical photograph often
helps with future assessments if there is a visible mass
or abnormality and helps assess response to treatment.
Any palpable local lymph nodes that are thought to be
involved should be measured carefully in the same way.
Imaging,25 including ultrasonography, mammography,
Figure 13.5 • Disease-free survival in National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 from 0–5 and
5–15 years (a) and overall survival split into age groups (b) <50 and ≥50 (c) years of age. N = number of events;
Ev = Events; HR = hazard ratio. Overall, disease free survival is increased. This reaches significance beyond 5 years in patients
treated with neoadjuvant rather than adjuvant chemotherapy. However, the benefit may be confined to premenopausal women.
30
50
40
0
1
2
3
4
0
1
2
3
N
Ev
HR
P
Post 496 292
Pre
487 255 .81
0.05
4
5
6
7
8
9 10
100
90
80
70
60
a
30
40
50
60
70
80
90
100
< 50yrs
0 1 2 3 4 5 6 7 8 9 10111213141516
N
Ev
HR P
Post 388 167
Pre 381 139 .81 0.06
30
40
50
60
70
80
90
100
≥ 50yrs
0 1 2 3 4 5 6 7 8 9 10111213141516
N
Ev
HR P
Post 363 148
Pre 361 171 1.23 0.07
b
c
Post Adjuvant Chemotherapy Following Surgery
Pre-neoadjuvant Chemotherapy Prior to Surgery
Locally advanced breast cancer
225
MRI or PET/CT scanning, is required to obtain an
accurate assessment of the extent of disease before treat-
ment and assessment of response after chemotherapy
has been given if baseline images are obtained. Marker
placement can complement imaging by locating the
original position of the tumour, and facilitates tumour
site localisation following successful neoadjuvant ther-
apy. Some are now placing tumour markers in involved
lymph nodes to confirm that in patients with a negative
sentinel node biopsy after an excellent response to neo-
adjuvant therapy the node known to be involved prior
to therapy has been removed. There are some data sug-
gesting that MRI scanning after one cycle may yield
information about likely response to chemotherapy.26
There are also data to indicate that MRI is accurate in
most patients at assessing response, but in a significant
number can overestimate or underestimate the extent of
residual disease following neoadjuvant chemotherapy.27
Assessment is usually performed after two or three cy-
cles of treatment and if the tumour responds, then che-
motherapy should continue for up to eight cycles28 and
the patient then proceeds to definitive curative surgery.
When using adjuvant treatment, the clinician has no
idea whether the chemotherapy produces an effect on
micrometastatic disease. This is not the case for neo-
adjuvant chemotherapy. If the tumour fails to respond,
then the chemotherapy agents should be changed and
the assessment process repeated, unless the tumour is
deemed operable at that time, in which case it may be
better to stop neoadjuvant chemotherapy and proceed
directly to surgery. Lack of response to the first-line
neoadjuvant chemotherapy is a poor prognostic sign.
Despite much research into markers to predict prog-
nosis after neoadjuvant chemotherapy (Chapter 2),
the degree of involvement of axillary nodes follow-
ing neoadjuvant chemotherapy remains the best
predictor of subsequent relapse.29 Pathological com-
plete response is associated with improved overall
survival22 and is more likely to be seen in younger
women with higher grade invasive ductal car-
cinoma that is oestrogen receptor/progesterone
receptor negative and HER-2 positive.30 It is im-
portant to remember that both tumour grade and
receptor immunohistochemistry can change follow-
ing treatment31 when pre- and post-chemotherapy
pathological specimens are examined after neoadju-
vant chemotherapy for advanced breast cancer.
Neoadjuvant/therapeutic endocrine therapy
If the tumour is positive for oestrogen or pro-
gesterone receptor immunohistochemistry, then
the patient may be treated with neoadjuvant oes-
trogen blockade instead of with chemotherapy.
The side-effects are less with endocrine therapy
than with chemotherapy, although time to re-
sponse is generally slower and complete pathologi-
cal response less likely. The majority of patients
treated with neoadjuvant hormone therapy have
been postmenopausal. The pathological changes
seen following neoadjuvant treatment with an
aromatase inhibitor such as letrozole appear to
be different from those seen with neodjuvant che-
motherapy, with more ‘central scarring’ using this
type of oestrogen blockade, compared with more
cancers showing diffuse changes and a complete
pathological response rate with chemotherapy.32
Neoadjuvant therapy with oestrogen blockade can
potentially increase anxiety in patients (and clini-
cians) and could potentially lead to delay in switch-
ing to an effective treatment should the first agent
used be ineffective, as about 3 months of anti-
oestrogen treatment are needed before a true im-
pression of response can be obtained. Progression
during treatment is rare with endocrine therapy
and occurs in less than 5% of patients. The relative
lack of side-effects, and the potential for excellent
tumour response,33 make neoadjuvant endocrine
treatment an attractive prospect. Primary endo-
crine blockade also acts as a chemotherapy-sparing
treatment strategy, allowing more options in the
future as the patient is chemotherapy naive. Some
work has been done comparing neoadjuvant oes-
trogen blockade with neoadjuvant chemotherapy
in older women with hormone-sensitive breast can-
cers; the results of the two treatments, in one small
study, appeared to be equivalent for outcomes
such as response rate and time to response,34 with
a suggestion of a greater rate of conversion from
planned mastectomy to breast-conserving surgery
with endocrine therapy. The optimal duration for
endocrine therapy is a matter for debate, but it is
clear that treatments of around 9 months or more
are clinically acceptable and appear to produce bet-
ter results than treatments of shorter duration.35
For many years, it has been clear that postmeno-
pausal women with advanced disease, including
metastatic disease, respond to an aromatase inhibi-
tor at least as well36 or better37 than to tamoxifen.
In the treatment of locally advanced and metastatic
breast cancer in postmenopausal women, treatment
failure rate is lower with anastrozole (79%) com-
pared with tamoxifen (84%), with a median time
Chapter 13
226
to progression of 11.1 months for anastrozole and
5.6 months for tamoxifen.38 Letrozole is superior to
tamoxifen in terms of objective response rate (30%
vs. 20%) and treatment failure (85% vs. 75%).39
The difference could be related to a genuine differ-
ence between different classes of oestrogen blocking
drugs. In addition, it is known that tamoxifen metabo-
lism by the cytochrome P450 system varies in differ-
ent individuals according to genotype, adherence to
taking the medication and potential interaction with
other drugs, but the influence of individual variation
in the metabolism of tamoxifen (and indeed aromatase
inhibitors) and their subsequent efficacy is unclear.40
The pure oestrogen antagonist, fulvestrant, is as effec-
tive as anastrozole in postmenopausal women with
advanced breast cancer progressing after prior endo-
crine treatment,41 but the place of this drug, which
must be given parenterally, in the treatment of locally
advanced breast cancer is still under evaluation.
Adjuvant systemic treatment
Adjuvant systemic treatment for advanced breast
cancer that has been treated successfully by surgery
is very similar to that given for early-stage breast
cancer. Locally advanced breast cancer has a higher
risk of relapse than early-stage breast cancer, and
so it is likely that following surgery the patient will
be offered adjuvant oestrogen blockade, local radio-
therapy and therapies targeting specific signalling
pathways such as the HER-2/neu transmembrane
receptor, assuming that the tumour is found to be of
the correct biological type for the patient to poten-
tially benefit from such targeted agents (Chapter 2).
Certainly, adding chemotherapy or endocrine ther-
apy or both with radiotherapy for stage IIIB disease
reduces locoregional recurrence from 60% to 50%
but may not secure a long-term survival advantage.
Problems of locally recurrent
disease after previous treatment
Local recurrence of advanced breast cancer may
occur in isolation or in conjunction with overt
metastatic disease. Since histological confirmation
of disease recurrence is required and the oestrogen,
progesterone or HER-2 receptor status may change
between the primary and the recurrent disease for
one in six patients,42 biopsy of the locally recurrent
cancer should be performed. It is essential to know
what treatment a patient has received in the past
to be able to advise them on future treatment for
a recurrent cancer. For example, if the patient has
only had a sentinel node biopsy or axillary sampling
procedure, and further breast surgery is required to
treat recurrent disease, then an axillary clearance
should be considered.
The patient who has already been treated with ra-
diotherapy and who develops disease recurrence in
the treated area poses a problem. For the reasons
given above, there is a limit to how much radiother-
apy can be delivered to one area of the body. Accurate
written information on previous radiotherapy pre-
scriptions is therefore vital before further treatment
can be administered safely. Previous permanent skin
marks tattooed during radiotherapy planning may
help accurately delineate which areas may be irradi-
ated in the event of recurrence, but not if further local
surgery or reconstruction has been performed follow-
ing the tattoo, repositioning the markings.
A recent study has shown chemotherapy pro-
longs survival for isolated or regional recurrence
of breast cancer.43 The use of systemic treatment
for advanced, recurrent disease will depend on
what was given as adjuvant therapy at the time
of the original diagnosis. In general, different che-
motherapy agents are used to treat the recurrent
disease, on the basis that the ones used originally
did not sterilise the tumour completely, and also
because some, notably the anthracyclines, have
cumulative cardiac toxicity that can be serious.
Likewise, there may be some gain from rotating
oestrogen-blocking agents to palliate locally ad-
vanced cancers when there are no other treatment
options. Tamoxifen may work when aromatase
inhibitors start to fail and vice versa. Sometimes
older agents such as megestrol acetate or newer
agents such as fulvestrant are effective when other
agents fail to control the cancer.
The use of biological agents continues to evolve.
Trastuzumab in locally advanced disease typically
mimics the efficacy in metastatic disease (for inopera-
ble locally advanced cancers) or as adjuvant treatment
(in those advanced cancers amenable to more radical
treatment). However, trastuzumab is seldom used as
a single agent, as the response rates in combination
Aromatase inhibitors appear more effective
than tamoxifen in the neoadjuvant treatment of
locally advanced breast cancer.39
Locally advanced breast cancer
227
with chemotherapy are much better,44 although on-
going work on the use of other agents such as lapa-
tinib in combination with trastuzumab, pertuzumab,
T-DM1, chemotherapy and other biologicals may
provide new advances in the care of these patients.
There remains considerable uncertainty around
the optimum management of locally advanced
breast cancer. The accuracy of detecting systemic
disease, the value of data that are 20–30 years old,
and the relevance of agents and regimens in old tri-
als to the use of newer therapies and current radio-
therapy fractionation are unclear, and for operable
locally advanced breast cancer surgery remains a
good treatment option.
Key points
• Locally advanced breast cancer should be treated by a multidisciplinary team.
• Surgery is an option for operable locally advanced breast cancer but most patients are best
treated initially by systemic therapy.
• The surgeon removing the primary tumour as primary therapy or after neoadjuvant therapy should
aim for clear resection margins.
• Sentinel node biopsy is appropriate after successful neoadjuvant therapy.
• Immediate breast reconstruction can and should be considered following mastectomy for locally
advanced breast cancer.
• Postoperative radiotherapy significantly reduces local recurrence and improves survival in locally
advanced breast cancer.
• Neoadjuvant chemotherapy is as effective as adjuvant chemotherapy in prolonging survival for
patients with locally advanced breast cancer.
• After neoadjuvant chemotherapy, radical radiotherapy or surgery have similar efficacy.
• Neoadjuvant endocrine therapy with aromatase inhibitors is more effective than tamoxifen.
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230
14
John A. Dewar
Pamela Levack
Metastatic disease and palliative care
Introduction
Metastatic spread is defined as spread of breast
cancer beyond the breast and ipsilateral axillary
and/or internal mammary lymph nodes. With cur-
rent therapies, metastatic disease is incurable and
treatment is, by definition, palliative. Such patients
may, however, benefit considerably from treatment.
The principles and practice of treatment include a
combination of active disease management, active
symptom management, and appropriate support
for patient and family. A more detailed review of
the evidence is provided in the National Institute of
Health and Clinical Excellence (NICE) guideline.1
Historically, palliative care and terminal care were
one and the same. However, modern palliative care
includes symptom and supportive care for patients
‘upstream’ in their illness. As cancer advances, pa-
tients' symptom burden increases, and they need
the best of symptom control as well as the best of
cancer treatment. All surgeons should be able to
provide high-quality basic palliative care for their
patients, and specialist palliative care staff should
be available to support staff to manage the most
complex and persisting problems.
A frequent dilemma is how much and how in-
tensively to both treat and provide care aimed at
comfort. The issues faced by staff working at this
interface between intensive palliative surgical (or
medical) treatment and intensive symptom control
are demanding and complex.
Presentation and prognosis
A minority of breast cancer patients (<10%) present
initially with metastatic disease.2 Most metastatic
patients, however, present months or years after
their primary treatment (surgery and appropriate
adjuvant therapy). The natural history of breast
cancer can be very long – patients still die from
breast cancer 20 years and more after their initial
treatment.3
Most patients present with symptoms of metastatic
disease between follow-up visits;4 screening asymp-
tomatic patients is not worthwhile.5,6 The common
sites of metastatic spread are listed in Table 14.1;
among other sites is the peritoneum, to which infil-
trating lobular carcinoma, in particular, can spread
and cause non-specific abdominal symptoms and/
or obstruction.
Staging
All patients presenting with locally advanced, inop-
erable or locally recurrent breast cancer should un-
dergo a series of investigations to stage their disease
adequately. In addition, patients presenting with
metastatic disease at one site (e.g. bone) should have
investigations to assess the extent of spread to other
organs. The principal sites of spread are the tho-
rax, bone and liver. Thus, tests to assess the extent
of spread and organ function include a full blood
count, clinical chemistry (urea and electrolytes, bone
Metastatic disease and palliative care
231
chemistry and liver function tests), tumour markers
(carcinoembryonic antigen and carbohydrate anti-
gen 15-3, which can be useful to assess response7),
bone scintigram and computed tomography (CT)
scan of thorax abdomen and pelvis. Alternatives
are a liver ultrasound or magnetic resonance imag-
ing (MRI). Increased long bone activity identified
on bone scintigraphy should be further assessed by
plain X-ray, supplemented by MRI if necessary, to
assess degree of destruction and risk of pathological
fracture. The brain should be assessed (CT or MRI)
if the patient has symptoms suggestive of intracra-
nial metastases. Urgent MRI of the whole spine is
required if the patient has symptoms of spinal cord
compression.
Clinicians need to understand the limitations of
these investigations. Although bone scintigraphy is
more sensitive than plain X-ray, it will not detect
all bone metastases. If a patient has persistent bony
symptoms and a negative bone scan (or negative in
the symptomatic area) then an MRI should be re-
quested, since it is more sensitive than bone scintig-
raphy. Discrete liver metastases are well visualised
by most techniques, but diffuse infiltration may not
be apparent on liver ultrasound. Positron emission
tomography (PET)-CT cam be useful8 in resolving
whether lymph nodes or isolated lesions seen in the
lung or liver are indeed metastases (albeit infected
or inflammatory conditions can also be positive on
fluorodeoxyglucose PET).
Treatment
Management is palliative and the aim of treatment
is to give the patient the best quality of life with the
minimum of side-effects. Successful management of
symptoms will tend to prolong survival, but the em-
phasis of treatment is on the quality of the life lived
rather than its length. Patients need to understand
from their clinician the nature of their illness and
the aims of treatment before discussing treatment
options, likely side-effects and potential benefits.
Broadly speaking, systemic therapies control
breast cancer and specific therapies control specific
symptoms. The two are not mutually exclusive and
most patients will need both.
Systemic therapy
In general, a durable response to systemic therapy of-
fers the best quality of life (see guidance in Fig. 14.1).
Exceptions are patients with lymphangitis carcinoma-
tosa or extensive liver metastases – hormone-induced
response rates at both these sites are low, and one may
not be able to wait 6–8 weeks for a response, hence
chemotherapy is indicated. Endocrine therapy is in-
effective in ER-negative breast cancer. If patients re-
spond well to either endocrine or chemotherapy, then
they may respond to second-line agents on relapse.
Endocrine therapy
Premenopausal women
In 1896, Beatson10 demonstrated the endocrine
sensitivity of breast cancer for the first time, by un-
dertaking surgical oophorectomy for advanced breast
cancer. Current therapy (Table 14.2) aims to either
decrease levels of circulating oestrogen (ovarian ab-
lation) or block its effect on the oestrogen receptor
(anti-oestrogens). Ovarian ablation can be performed
either by surgical removal (usually laparoscopically),
by a short course of radiotherapy to the pelvis
(infrequent – because of gastrointestinal side-effects),
Site
Common symptoms
Pleura
Dyspnoea (due to effusion)
Bone
Pain
Pathological fracture
Nausea and thirst (due to associated
hypercalcaemia)
Lung
Dyspnoea
Cough (dry cough is often seen with
lymphangitis carcinomatosa)
Liver
Fatigue
Nausea
Anorexia
Pain over liver
Brain
Headache (often worse first thing in the
morning)
Unilateral weakness
Unsteady gait
Table 14.1 • Symptoms commonly associated with
metastatic spread to different organs
Most patients with oestrogen receptor (ER)-
positive tumours will be initially treated with
hormone therapy: it is generally less toxic than
chemotherapy, responses are of longer duration
and there is no evidence that patients with
ER-positive metastatic disease do better with
chemotherapy first.9
Chapter 14
232
or the use of a luteinising hormone-releasing hormone
(LH-RH) agonist, e.g. goserelin. The latter is given
by monthly injection into the anterior abdominal wall
and is reversible; thus, if there is no tumour response,
the patient's periods can be restored and menopausal
symptoms abolished. Tamoxifen is a partial oestrogen
agonist but its effects on breast cancer cells are to an-
tagonise oestrogen. It is effective in both pre- and
postmenopausal women.
Aromatase inhibitors (AIs; see next section) work in
postmenopausal but not in premenopausal women.
Particular caution should be taken with women who
have chemotherapy-induced amenorrhoea, as they
may still have some ovarian function, making AIs
ineffective.12 In premenopausal women, a combina-
tion of LH-RH agonist plus AI has shown responses.13
Progestagens (e.g. megesterol acetate, medroxy-
progesterone) at high dose have been used for
many years, for their anti-oestrogenic action.
Their main side-effects are significant weight gain
and increased risk of thromboembolic disease.
Suppression of glucocorticoid production has been
reported,14 so patients may need hydrocortisone to
cover physiological stress (e.g. pinning of pathologi-
cal fractures, infections, etc.).
Thus, first-line therapy would be tamoxifen ± ovarian
ablation, with an AI/LH-RH agonist as second line
and progestagens as third line. Choice will, however,
Metastatic disease
Staging
Bone metastases
Bisphosphonates
ER +ve
ER−ve
Hormone therapy
Cytotoxic chemotherapy
Failure of response
to hormonal agents
HER2−ve
Chemotherapy only
Chemotherapy
± trastuzumab
HER2+ve
Figure 14.1 • Outline of systemic therapy. Oestrogen receptor positive (ER +ve) includes all ER-positive and/or
progesterone receptor-positive patients. ER-positive patients with lymphangitis carcinomatosa or liver metastases would
normally be considered for chemotherapy in preference to hormone therapy.
Class of
agent
Examples
Main
side-effects
Ovarian ablation
Surgical
oophorectomy
Radiation
menopause
LH-RH agonists
Menopausal
symptoms
Anti-oestrogens
Tamoxifen
Fulvestrant
Menopausal
symptoms
Thrombo-embolism
Aromatase
inhibitors
Anastrozole
Letrozole
Exemestane
Menopausal
symptoms
Arthralgia
Osteoporosis
Progestagens
Megesterol
acetate
Weight gain
Increased appetite
Thrombo-embolism
Glucocorticoid
suppression
Table 14.2 • Endocrine agents used in breast cancer
Response to ovarian ablation is improved if
tamoxifen is added.11
Metastatic disease and palliative care
233
be influenced by prior adjuvant therapy, though
if it is >1 year since the last endocrine therapy (e.g.
tamoxifen), it may be worth retrying it.
Postmenopausal patients
Ovarian ablation has no role. Oestrogen in post-
menopausal women is produced by conversion of
androstenedione to oestrone by aromatase,15 mostly
in peripheral fat but also in liver, normal breast tis-
sue and some breast cancers. Aromatase inhibitors
(Table 14.2) reduce circulating oestrogen to nearly
immeasurable levels.
There are two types of AI: non-steroidal (anas-
trozole and letrozole) and steroidal (exemestane).
Their side-effects are, however, similar (Table 14.2),
implying that these are due to their reduction of cir-
culating oestrogen.
Fulvestrant is a pure oestrogen antagonist, as un-
like tamoxifen it has no agonist action. It binds to,
blocks and degrades the oestrogen receptor. Clinical
trials in postmenopausal women have shown it to be
as active as anastrozole.17 It is given monthly by in-
tramuscular injection – a potential advantage where
oral compliance is a problem. Studies with higher
doses, 500 mg instead of the standard 250 mg dose,
have shown that these higher doses appear effective.
Adding biological agents such as mTOR (mam-
malian target of rapamycin) inhibitors to endocrine
agents such as tamoxifen or aromatase inhibitors
appears to increase response rate, duration of re-
sponse and even overall survival (Fig. 14.2). Studies
with these agents are continuing, although as yet
they are not used outside clinical trials.
Chemotherapy
Chemotherapy is used to treat ER-negative breast
cancer, ER-positive breast cancer that is no longer sen-
sitive to endocrine agents, and advanced ER-positive
visceral disease. The main classes of drugs and their
side-effects are listed in Table 14.3. These drugs are
toxic and should only be prescribed by clinicians
(usually oncologists) experienced in their use.
AIs are more effective16 than tamoxifen
(appropriate second-line agent) and progestagens
(third line).
Probability of event (%)
100
80
90
70
60
40
30
10
50
20
0
0
12
24
36
48
60
78
72
6
18
30
42
54
66
Weeks
Hazard ratio, 0.43 (95% CI, 0.35–0.54)
P<0.001 by log-rank test
No. at Risk
Everolimus
Placebo
485
239
398
177
294
109
212
70
144
36
108
26
51
14
34
9
18
4
8
3
3
1
3
0
0
0
75
16
Everolimus plus exemestane
(median PFS, 6.9 mo)
Placebo plus exemestane
(median PFS, 2.8 mo)
Figure 14.2 • Progression-free survival on the basis of local assessment of radiographic studies. Reproduced from N Engl
J Med 2012; 366(6): 520–9.
Group of
drugs
Examples
Main
side-effects*
Anthracyclines
Doxorubicin
Epirubicin
Mouth ulcers
Cardiomyopathy
Alkylating agents
Cyclophosphamide
Antimetabolites
5-Fluorouracil
(capcitabine)
Methotrexate
Coronary spasm
Hand–foot
symdrome
Taxanes
Docetaxel
Paclitaxel
Peripheral and
autonomic
neuropathy
Mouth ulcers
Vinca alkaloids
Vinorelbine
Peripheral
neuropathy
Gemcitabine
Platinum
Carboplatinum
Cis-platinum
Neuropathy
Renal failure
Table 14.3 • Main cytotoxic chemotherapy drugs used
in breast cancer
*Nearly all these drugs can cause fatigue, nausea, vomiting,
myelosuppression, cessation of periods (premenopausal
women) and alopecia, so they are not listed individually.
Chapter 14
234
The drug groups with the highest activity are the
anthracyclines and the taxanes. The major limitation
to anthracycline use is cardiomyopathy – the risk
increasing as cumulative dose increases. A course of
anthracyclines cannot, therefore, usually be repeated.
Taxanes are active and more effective than some
other regimens.19 Capecitabine is an oral prodrug of
5-fluorouracil. It is metabolised into the active com-
ponent in the liver and possibly in the tumour itself.
As more agents are used in the adjuvant (or neo-
adjuvant) setting, the use of other active drugs such
as vinorelbine, gemcitabine and platinum agents
in metastatic disease is likely to increase. Platinum
salts may have particular activity in the treatment
of patients with basal-type tumours20 and are cur-
rently being studied in clinical trials.
The choice of chemotherapy agents is influenced
by prior therapy, the general health of the patient,
and what agent is most likely to produce useful pal-
liation with minimal side-effects.
Trastuzumab
A growth factor receptor gene, human epidermal
growth factor (HER-2), is amplified in about 14%
of breast cancers and is associated with a poorer
prognosis.21 Trastuzumab is a humanised mono-
clonal antibody that targets the HER-2 receptor
in patients whose tumours overexpress HER-2 as
assessed by immunohistochemistry and/or fluores-
cence in situ hybridisation (FISH) testing.
Trastuzumab is generally well tolerated except for
cardiac toxicity, so is not usually given concurrently
with anthracyclines. It should be used with caution
in patients with prior anthracycline exposure or
significant cardiac disease; patients require cardiac
monitoring by multiple-gated acquisition (MUGA)
scan or echocardiogram.
With these provisos, trastuzumab can be used in
HER-2-positive patients. It is generally given with a
course of taxane chemotherapy and continued as a
single agent whilst response is maintained. Response
may last months and even years. Trastuzumab is a
large molecule and does not pass the blood–brain
barrier, so patients who respond may develop brain
metastases as the sole site of active disease. The brain
metastases should be treated actively (see later), trastu-
zumab continued and the patient may regain remis-
sion. Other drugs targeting HER-2-positive breast
cancers including pertuzumab and T-DM1 are in
clinical trials. Combination of pertuzumab and trastu-
zumab looks particularly promising in patients with
metastatic breast cancer (Fig. 14.3).
Lapatinib inhibits the tyrosine kinases of HER-2
and has been shown to be active in combination
with capecitabine in patients who have relapsed on
trastuzumab.23
Assessment of response
The most important method of assessing benefit
is whether the patient's symptoms have improved.
Nevertheless, symptoms can improve independently of
systemic therapy (e.g. analgesics for pain). Thus, it is
also important to assess response to systemic therapy
objectively. Locally recurrent disease can be assessed
by regular photography and compared with previous
clinical photographs. Similarly, monitoring measurable
lesions on CT provides objective evidence of response.
Assessment of bony metastases can be difficult. Plain
Whilst it has some activity as a single agent
(response rates of 20–50% partly depending on
previous treatments), it increases the response
rate and survival of patients when added to taxane
chemotherapy.22
Progression-free survival (%)
0
10
20
30
40
50
60
70
80
90
100
0
5
10
15
20
25
30
35
40
Time (months)
Number of patients still at risk
Ptz + T + D 402
345
267
139
83
32
10
0
0
Pla + T + D 406
311
209
93
42
17
7
0
0
HR = 0.62
95% CI 0.51-0.75
P<0.0001
Ptz + T + D: median 18.5 months
Pla + T + D: median 12.4 months ∆ = 6.1 months
Figure 14.3 • Progression free survival in the CLEOPATRA
Trial of Docetaxel + Trastuzumab +/− Pertuzumab. Ptz =
pertuzumab; T = trastuzumab; D = docetaxel; Pla = placebo.
Reproduced from N Engl J Med 2012; 366(2): 109–19.
Drug combinations appear more effective
than single agents partly because combinations
of drugs with different modes of action increase
efficacy and reduce the risk of drug resistance but
are associated with more toxicity.18 Nonetheless,
it is not uncommon in clinical practice to use
sequential single agents.
Metastatic disease and palliative care
235
X-ray changes are slow to develop with response, and
responding sclerotic lesions will show little change.
Bone scintigraphy can be misleading; 3 months after
starting therapy, there may be increased uptake at sites
of disease (‘flare’) indicating response and this can be in-
distinguishable from progression. Changes in the levels
of tumour markers at 3 months can predict response24
or individual lesions can be monitored by MRI.1
Surgery
For patients presenting with metastatic disease it was
formerly the case that surgery to the primary site was
contraindicated because it will not help symptoms nor
influence prognosis. This has now been questioned by
a series of studies that have shown improved outcome
in patients who have had surgery. Whether this im-
proved outcome is due to selection bias or is genuine
is not clear.25 Ongoing randomised trials will provide
the answers. In those patients who are responding
and have stable metastatic disease, surgery to control
local disease in the breast and on the chest wall and in
regional nodes should be considered.
Control of symptoms
Despite the absence of evidence, staff, patients and
families are often concerned that intensive symptom
management prevents further palliative treatment
of underlying cancer and that it inevitably causes
sedation and may even hasten death. Uncontrolled
symptoms affect quality of life and the ability of
the patient to make considered treatment decisions,
hence meticulous symptom control should be avail-
able as part of comprehensive cancer management.
Pain
Sixty-five per cent of patients with advanced cancer
suffer pain.27 One-third of those with pain have one
pain, another third have two different types of pain
and the remaining third have three or more types of
pain. Cancer-related nerve pain is common; 70–90%
of pain responds to potent opioids if properly pre-
scribed28 and the key to managing pain is careful
assessment using a simple structured tool such as
‘NOPQRST’ (Box 14.1).
Analgesic requirements are likely to increase as ill-
ness advances.
Other strong opioids are used when the transder-
mal route is preferred or the patient has unaccept-
able side-effects with morphine.
Non-oral routes (e.g. by a subcutaneous syringe
driver) are preferable when nausea and vomiting
are present and do not mean that the patient is
dying, merely that an alternative route to deliver
medication is needed – for example, a patient with
pain who is vomiting due to hypercalcaemia and
constipation. Morphine (10 mg given by intermit-
tent intravenous boluses) may lead to erratic pain
control and sleepiness, which can be avoided by
using lower doses by subcutaneous infusion, until
the situation has resolved and oral medications are
appropriate.
Common concerns over opioid analgesics
Whilst morphine is the drug of first choice, side-
effects or inadequate pain relief may limit benefit in
10–30% of patients. Switching opioids may reduce
side-effects (Box 14.2) but if the pain is not opioid
sensitive and toxicity is not a problem, switching
from one to the other alone will not solve uncon-
trolled pain.30
Pain flares
Transient flares of severe pain are common and
may be due to end of dose failure, a spontaneous
worsening of pain or incident pain. The first two
usually respond to an increased 24-hour dose of
opioid.
Patients with advanced malignancy can have
a high burden of distressing symptoms, frequently
under-reported by patients and underestimated and
undertreated by clinicians.26
N: Number of pains
O: Origin of pain
P: Palliate and potentiate
Q: Quality, e.g. is it neuropathic
R: Radiation
S: Severity or Suffering – 7–10 is a serious problem,
>10 overwhelming
Suffering is the impact pain has on the patient
T: Timing, including incident pain, for example moving or
dressing changes
Box 14.1 • NOPQRST tool for effective pain history
taking
Morphine is the strong opioid of choice for
cancer pain management.29
Chapter 14
236
Analgesia sufficient to manage an incident pain
peak may cause toxicity in relation to background
pain; therefore, a fast, short-acting rescue anal-
gesic such as transmucosal or intranasal fentanyl
may be more effective than breakthrough oral
morphine.
Liver capsule pain from liver metastases usually
responds to dexamethasone 4–12 mg p.o. daily or,
for speed and if pain is associated with nausea or
vomiting, 12 mg over 24 hours by subcutaneous
syringe driver for a few days until symptoms have
resolved. The dose should then be reduced to the
smallest effective oral maintenance dose.
Neuropathic pain
Patients often find it difficult to describe accurately
nerve pain that typically has burning, shooting,
stabbing, knife-like or tingling character and pa-
tients frequently accompany their description by
rubbing the dermatome where the pain is felt. It has
a distressing quality, which may not be adequately
reflected in a simple 0–10 scale; hence a simple
neuropathic pain screening tool has been recently
developed.32 It is critical to recognise neuropathic
pain, and to diagnose the underlying pathology, as
it usually represents new and potentially treatable
metastatic disease.
Neuropathic pain responds to opioids in approxi-
mately one-third of patients, but the remaining
two-thirds may be difficult to manage. Nerve root
involvement is most likely to result from brachial
plexus involvement or epidural disease as a result
of vertebral metastases and subsequent bony col-
lapse. Drugs used primarily for reasons other than
analgesia may help,33,34 such as low doses of anti-
depressants (amitriptyline or nortriptyline35), anti-
convulsants (gabapentin, pregabalin36) or specific
N-methyl-d-aspartate
antagonists
(ketamine37).
Methadone (specialist use only) is helpful when
pain consists of a mixture of neuropathic and non-
neuropathic pain, but there is insufficient published
evidence on its use in cancer-induced pain.38 Finally,
interventional procedures – cordotomy (unilateral
nerve root pain) or epidural followed by an intra-
thecal implant – may be considered following con-
sultation with the local pain or anaesthetic service.
Spinal cord compression
Patients with severe increasing back pain plus neu-
ropathic pain referred around the chest wall, abdo-
men or down one or both legs should be assessed
for the risk of spinal cord compression.
If spinal cord compression is suspected, then an
urgent MRI scan of the whole spine should be or-
ganised. If the diagnosis is confirmed, radiotherapy
or surgical intervention is indicated.40,41
Bony metastases
This is the commonest site of metastatic disease and
can cause significant pain and morbidity.
Bisphosphonates
Bisphosphonates inhibit osteoclast activity, leading
to decreased bone absorption.
The drugs used are most commonly the third-
generation drugs zoledronate and ibandronate.
Zoledronate is given intravenously every 4 weeks
(or 3-weekly with chemotherapy); ibandronate can
It is important to specifically ask these as the patient may
not volunteer it – for fear they are going a little mad.
1. Have you experienced any vivid dreams recently?
2. Have you woken suddenly with a start or had sudden
jerky movements?
3. Have you ever imagined that someone was sitting on
your bed and you came to with a start and found you had
imagined it?
Box 14.2 • Three questions to ask patient suspected of
being opioid toxic
Incident pain occurs in two-thirds of patients
with pain31 and is common in patients with bone
metastases. It is the result of an intervention such
as weight bearing, coughing or moving.
Waiting until the patient has neurological signs
of compression (loss of power and/or a sensory
level) will almost certainly be too late to institute
effective treatment.39
Specific treatment guidelines have been
published.24
There is good evidence42,43 that regular
treatment with bisphosphonates for 6 months
or longer reduces ‘skeletal morbidity’, namely
reduction in pathological fractures, need for
palliative radiotherapy and hypercalcaemia.
Metastatic disease and palliative care
237
be given orally (on an empty stomach 1 hour before
food). They are usually reasonably well tolerated
but can cause flu-like symptoms, gastrointestinal
disturbance and rarely osteonecrosis of the jaw.44
They should be given with caution in patients with
renal impairment. Intravenous bisphosphonates can
also reduce pain in patients with widespread bony
metastases.45 A monoclonal antibody against rank
ligand, denosumab, looks promising and is at least
as effective as zoledronate and can be administered
by subcutaneous injection.
Bone pain
Non-steroidal analgesics are helpful and are opioid
sparing. The most common drug used by palliative
medicine physicians is diclofenac (75 mg, slow re-
lease twice daily). A slow-release preparation reduces
early morning pain due to overnight immobility.
When pain is severe and distressing, immediate relief
may need a non-oral prescription, e.g. 48-hour sy-
ringe driver with, for example, an opioid and a non-
steroidal such as ketorolac, before returning to oral
medication.
Fractures
Pathological fractures cause severe bony pain.
Orthopaedic interventions can stabilise fractures
of long bones (commonly femur or humerus). The
results of orthopaedic interventions are usually
better if done prophylactically rather than as an
emergency. In either case, surgery will normally be
followed by palliative radiotherapy. Most vertebral
fractures are managed by palliative radiotherapy
but selected cases may benefit from surgical stabili-
sation and/or decompression, especially where there
is a risk of spinal cord compression.41
Effusions
Pleural spread is common, especially on the
ipsilateral side. The patient usually presents with
dyspnoea, and drainage with pleurodesis (using
talc47) gives good symptomatic relief. Ascites is less
common than pleural spread and is managed by re-
peated percutaneous drainage.
Cerebral metastases
This is typically a relatively late site of metas-
tases. Occasionally, it may be the sole site of
metastases. Presentation is usually with headache
(characteristically worst in the morning if the pa-
tient has raised intracranial pressure), weakness
and/or altered sensation, difficulty walking or se-
vere persisting nausea. Diagnosis is confirmed by
CT or MRI. A short course (five fractions) of pal-
liative radiotherapy to the whole brain may pro-
vide useful palliation for patients whose clinical
condition is reasonably well preserved. A patient
who is in good general condition and has a single
cerebral metastasis may get a more prolonged re-
mission from neurosurgical removal followed by
radiotherapy.
Nausea, vomiting and retching
These are common, distressing symptoms and
are reported in 50–60% of patients suffering
from advanced cancer. Numerous neurotransmit-
ters and receptor types are involved; thus, anti-
emetics are mainly neurotransmitter blockers
(Table 14.4).48
Constipation
Constipation is present in half of all patients
with advanced cancer. It causes pain, distension,
anorexia, nausea, malaise and embarrassment,
and diagnostic confusion if it results in ‘over-
flow’ diarrhoea. Contributory factors include
opioid use, reduced fluid and fibre intake, and
reduced mobility. A recent Cochrane systematic
review49 concluded that all laxatives assessed
were ineffective for a significant proportion of
patients, and some patients required multiple
‘rescue’ laxatives. Patients on opiates should be
routinely prescribed a stimulant and a softener.
Methylnaltrexone is a novel treatment for opioid-
induced constipation.50
Overall care of the patient
approaching death
On approaching the terminal phase, patient and
clinicians need to recognise that active treatment
becomes less appropriate, although active symptom
palliation remains paramount. The primary care
team and the hospital specialists involved in the
care of the patient will often have known the patient
for some considerable time and have some knowl-
edge of the family circumstances. But if the patient
does not understand the reality of their situation,
Palliative radiotherapy to painful bony
metastases can be very helpful in reducing pain and
single fractions are as effective as multiple fractions.46
Chapter 14
238
then important issues may not have been discussed.
For example, the young single mother will need to
address the future care of her children, an older
woman the care of a frail elderly spouse.
Patients may have survived many relapses over
the years, and they and their families may believe
that they will recover from the current episode.
Clinical staff need to recognise a patient's likely
prognosis – is she ill with very advanced metastatic
breast cancer and is she perhaps dying?
What does the patient understand? Although clin-
ical prediction of survival is a useful independent
predictor for survival, it tends to be over-optimistic
and for many patients it will be inaccurate. Broadly
speaking, when deterioration in health is noted
over months, survival is likely to be months, when
it has been over weeks, survival is likely weeks and
when it has been over days, survival is likely to
be days.
In
advanced
malignancy,
symptoms
rather
than test results may be more useful in predict-
ing survival. Patients with low performance status
(Palliative or Karnofsky Performance Scales) have
a poorer survival, although higher performance sta-
tus does not necessarily predict for longer survival.
Certain symptoms such as nausea, breathlessness
and weakness have independent value as prognos-
tic factors. Combining clinical prediction with other
factors to produce a prognostic score (Table 14.5)
gives simple and clinically more accurate useful bed-
side prognostic information.51
Anti-emetic
Metabolic, e.g. hypercalcaemia
Drug/toxin induced, e.g. opioid
Haloperidol 1.5 mg nocte/b.d.
Levomepromazine 6 mg tab nocte
Haloperidol 1.5 mg nocte/b.d.
Levomepromazine 6 mg nocte
Chemotherapy
Ondansetron
Dexamethasone
Radiotherapy
Ondansetron
Raised intracranial pressure (cerebral metastases, brain
stem or meningeal disease)
Cyclizine 50 mg t.d.s. or 150 mg/24 h s.c.
Dexamethasone 4–16 mg in morning
Bowel obstruction
(if surgery inappropriate)
Cyclizine 50 mg p.o. t.d.s./150 mg/24 h s.c.
Hyoscine butyl bromide 40–100 mg/24 h s.c.
Octreotide 300–1000 mg/24 h s.c.
Ondansetron 8–24 mg/24 h p.o., i.v., s.c.
Gastric stasis/outlet obstruction
Metochlopramide or domperidone 10–20 mg q.d.s. or
Metochlopramide 30–100 mg/24 s.c.
Vestibular disease (base skull tumour)
Cyclizine 50 mg p.o. t.d.s.
Levomepromazine 6 mg p.o.
Haloperidol 1.5 mg b.d.
Trial dexamethasone
Table 14.4 • Management of nausea/vomiting due to cancer or its treatment
Maximum possible
Palliative
Performance
Scale
10–20
30–50
≥60
4
2.5
0
4
Oral intake
Severely reduced
(≤ mouthfuls)
Moderately reduced
(> mouthfuls)
Normal
2.5
1
0
2.5
Oedema
Present
Absent
1
0
1
Dyspnoea at
rest
Present
Absent
3.5
0
3.5
Delirium
Present
Absent
4
0
4
Total
15
Table 14.5 • Palliative Prognostic Index (PPI; palliative.
info/teaching material/Prognosis.pdf)
If PPI >6, survival is less than 3 weeks.
Metastatic disease and palliative care
239
Recognition and
communication that the
patient may be dying
‘Is this a patient who could die
during this admission?’
Making and communicating a diagnosis that ‘this pa-
tient may be dying’ is the key to good end-of-life care,
but it is a difficult skill. It is not exclusively a nursing
responsibility – the doctor's role in diagnosis and prog-
nostication is vital. If there is no gap between aggres-
sive or interventional palliative treatments and terminal
care, the patient and family will be unprepared – a
change from ‘doing everything’ to ‘doing nothing’.
‘The physician does and does
not want to pronounce a death
sentence and the patient does and
does not want to hear it’
The patient and family value communication of
information and support that will come from a
variety of sources (e.g. doctors, specialist and gen-
eral nurses, palliative care staff) at different times
and stages.
Patients, families and professionals need to un-
derstand that death is a possibility before they can
discuss management options. Several consultations
may need to take place over a few days as people
psychologically edit what they are told.
Communication in difficult situations is difficult,
and easy for professionals to avoid. Some patients
prefer not to discuss these matters, as do some pro-
fessionals. Both patients and professionals may col-
lude to limit such discussions.52
There is usually more agreement about the most
appropriate approach when a patient is actively dy-
ing, i.e. the last few days or hours, and the use of
care pathways53 may be helpful in ensuring that all
pre-emptive medications for distress, pain, etc. are
prescribed and that the goals of care are clear to the
patient, family and staff. Requests for transfer to
hospice are common during this time, even when
the patient is comfortable and their needs are being
met. Other patients may wish to be at home and
many specialist palliative care services can help with
a swift, supported discharge.
Key points
• Metatastic breast cancer can be treated actively and many patients will survive with a good quality
of life for months and often years.
• Most of this time patients will be in the community and care will be shared between primary and
secondary care. Good communication between the two is vital.
• The patient will need considerable support from a multidisciplinary team during management of
metastatic breast cancer and will need help from many different members of the team that will vary
over time.
• Care will be a combination of active oncological management and meticulous symptom control.
• Metastatic breast cancer is ultimately a fatal condition and it is the duty of the staff looking after
the patient to optimise survival but also to recognise that the final phase of life needs to be actively
and sympathetically managed in line with the wishes of the patient and her family.
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