Download Management of the axilla in women with breast

Management of the axilla
in women with breast cancer
First edition
This document addresses the issue of management of the axilla in early stage breast cancer. It has been
compiled with multidisciplinary input from the Faculty of Radiation Oncology of the Royal Australian
and New Zealand College of Radiologists (FRO, RANZCR), the Breast Section of the Royal Australasian
College of Surgeons, the Medical Oncology Group of the Royal Australasian College of Physicians and the
Breast Cancer Network of Australia.
Principal authors:
Dr Susan Pendlebury, Radiation Oncologist
Mr David Speakman, Breast Surgeon
Contributing authors:
Professor Alan Rodger, Radiation Oncologist
Dr Martin Borg, Radiation Oncologist
Dr Graeme Morgan, Radiation Oncologist
and other members of the National Breast Cancer Centre/FRO, RANZCR Advisory Group
Mr Michael Henderson, Breast Surgeon
Mr James Kollias, Breast Surgeon
Mr Owen Ung, Breast Surgeon
Dr Raymond Snyder, Medical Oncologist
Ms Lyn Swinburne, Consumer Representative, Breast Cancer Network of Australia
National Library of Australia Cataloguing-in-Publication data:
Management of the axilla in women with breast cancer
First Edition
ISBN 1 876319739
616.99449
© 2001
iSource National Breast Cancer Centre
PO Box 572
Kings Cross NSW 1340
phone: +61 2 9334 1700
fax:
+61 2 9326 9329
email: [email protected]
website for publications: http://www.nbcc.org.au/pages/info/resource/nbccpubs/nbccpubs.htm
The iSource National Breast Cancer Centre is funded by the Australian Commonwealth Government
Management of the axilla in women with breast cancer
Important Notice
This document is a guide to appropriate practice, to be followed subject to the
clinician’s judgement and the woman’s preference in each individual cases.
The guidelines are designed to provide information to assist decision making and
are based on the best evidence available at the time of publication.
Important notice
Management of the axilla in women with breast cancer
i
Important notice
ii
Management of the axilla in women with breast cancer
Contents
page
Important notice
i
List of abbreviations
1
Foreword
3
Executive Summary
5
Management of the Axilla in Women with Breast Cancer
7
Aims of this document
7
Balancing the risks and benefits of axillary dissection
and axillary irradiation
8
The impact of treating the axilla on survival and axillary
recurrence: the evidence
10
Staging the axilla: advantages and alternatives
16
Clinical practice recommendations
21
Appendix
Appendix I
Axillary surgery: definitions
25
Appendix II
Risks of axillary dissection and irradiation
29
Appendix III
Sentinel node biopsy in breast cancer
33
Appendix IV
Technical aspects of radiation therapy
to the axilla
37
References
39
Contents
Management of the axilla in women with breast cancer
iii
Contents
iv
Management of the axilla in women with breast cancer
List of abbreviations
BMI
Body mass index
DCIS
Ductal carcinoma in situ
FDG
Fluoro deoxy glucose
FRO
Faculty of Radiation Oncology
Gy
Gray
ICBN
Intercostobrachial nerve
ICRU
International Commission on Radiation Units and Measurements
MRI
Magnetic resonance imaging
NBCC
iSource National Breast Cancer Centre
NHMRC
National Health and Medical Research Council
NSABP
National Surgical Adjuvant Breast and Bowel Project
PET
Positron emission tomography
RANZCR
Royal Australian and New Zealand College of Radiologists
List of abbreviations
Management of the axilla in women with breast cancer
1
List of abbreviations
2
Management of the axilla in women with breast cancer
Foreword
This document has been developed to support recommendations about the
management of the axilla in women with early stage breast cancer. It encompasses
recommendations on both axillary surgery and axillary irradiation and the need to
consider axillary management within a multidisciplinary framework in order to
optimise treatment decisions. The document grew out of a need identified by the
NHMRC National Breast Cancer Centre (NBCC) Consumer Advisory Group for
recommendations for clinicians about surgery and radiotherapy to the axilla in
relation to lymphoedema. The information contained within this document is
evidence-based. Recommendations for practice supported by the evidence were
agreed at a multidisciplinary consensus conference in 1998. Representatives
involved in the consensus conference included radiation oncologists, surgeons,
medical oncologists and consumers.
The resulting document provides women and clinicians with information
about indications for axillary surgery and axillary irradiation, and is aimed at both
minimising the risk of recurrence and limiting the impact of such interventions
on the occurence of lymphoedema and other morbidities.
The project team involved in the preparation of this document reflects the interest
of the NBCC and its Consumer Advisory Group in the development of axillary
recommendations – an interest shared by the many oncological disciplines involved
in the treatment of breast cancer. Representatives nominated from the Royal
Australasian College of Surgeons Breast Section, from the RANZCR Faculty of
Radiation Oncology and from the Royal Australasian College of Physicians
(Medical Oncology Group) have made significant contributions.
The Centre is grateful to all those who have contributed their time and advice.
The document will, in time, be updated to incorporate new evidence on the
optimal management of the axilla in the treatment of breast cancer.
Foreword
Management of the axilla in women with breast cancer
3
Foreword
4
Management of the axilla in women with breast cancer
Executive summary
Based on a review of the available literature, there is evidence that:
•
Management of the axilla should be determined by a multidisciplinary
team in discussion with the woman (Level III).54
•
For women with early breast cancer, a minimum Level I and II axillary
node dissection should be offered as the standard procedure to reduce
the risk of regional recurrence (Level II).5,7
•
•
Axillary dissection can be omitted for some women:
-
women diagnosed with DCIS55 (Level III); and
-
selected patients (Level IV).
Axillary irradiation will be the preferred method of treatment for some
women (Level III): 6,36,56
•
-
elderly patients or those with other serious health problems; and
-
women who do not wish to have surgery.
Some women will require axillary irradiation following axillary
surgery (Level IV):
-
women who have surgical or pathological evidence of remaining
axillary disease following dissection; and
-
who have undergone less than axillary dissection, eg formal sample
or sentinel node biopsy, which is positive for malignancy.
•
Coordination of trials of sentinel node biopsy across Australia should
be undertaken as a matter of priority (Level IV).
There is currently no Level I or II evidence to confirm or refute a benefit of:
•
axillary dissection in prolonging survival;
•
an impact of axillary irradiation on mortality from breast cancer; or
•
axillary irradiation in women with breast cancer based solely on reported
extranodal spread.
There are no Level I or II studies which compare sentinel node biopsy with
formal axillary dissection.
Executive summary
Management of the axilla in women with breast cancer
5
Executive summary
6
Management of the axilla in women with breast cancer
Management of the Axilla in Women
with Breast cancer
Aims of this document
This document has two aims: to examine critically the evidence governing
management of the axilla; and to provide a guide to current optimal practice
and the way in which new practices may be incorporated. The literature was
examined up until mid-2000. This document has been informed by reviews of
the available evidence and recommendations by expert groups, and the evidence
has been rated according to the system developed by the US Preventive Services
Task Force (see Appendix 2).
Level I evidence (where evidence is obtained from a systematic review of
all relevant randomised controlled trials) represents the gold standard. However,
Level I evidence is not available for all areas of practice and for some
recommendations the working party considered it appropriate to base
recommendations on other levels of evidence.
Most women diagnosed with invasive breast cancer currently undergo axillary
dissection.1,2,3 Some of these women will also receive axillary irradiation.
Axillary dissection is used to stage the cancer to determine further treatment.4
The current rationale for axillary treatment, by dissection or irradiation, is that it
is used to reduce the risk of axillary recurrence5 and possibly increase survival.6,7
Definitions and technical descriptions of these techniques are provided in
Appendices II and IV.8
However, these techniques have a number of side effects with particular
concern focusing on lymphoedema – both together and separately. It is clear
that the lymphoedema of the arm is more prevalent in women who have had both
axillary dissection and axillary irradiation following a diagnosis of breast cancer.9
Management of the axilla in women with breast cancer
Management of the axilla in women with breast cancer
7
There is considerable confusion among women about the role of axillary
dissection and axillary irradiation. There is also evidence of considerable variation
in practice across Australia.1
The recommendations about optimal practice contained in this document are
intended to both assist clinicians and form the basis of information for women.
Balancing the risks and benefits of axillary dissection
and axillary irradiation
There are two reasons for undergoing axillary dissection and/or axillary irradiation:
1.
Treating disease in the axilla
Cancer cells can travel from the breast through the lymph system to the axillary
nodes. If the cancer has already spread to the axillary lymph nodes at diagnosis,
surgery and radiotherapy to the breast alone may not control the disease in the
axilla. The woman’s chances of survival are reduced and there may be recurrence
of the disease in the axilla.6
Axillary dissection and axillary irradiation are used to treat any disease that may
have potentially spread to the axilla.
2.
Staging the disease
Axillary dissection is also used to assess whether the disease has spread to the
axillary lymph nodes and, if so, to how many nodes. This information may be used
to determine what type of systemic therapy is indicated, whether irradiation is
indicated and to what extent. It also allows the most accurate prognosis.4
There is something of a paradox in the current approach to axillary dissection.
Only women who transpire to have positive lymph nodes have required treatment
of the axilla. However, at this time, the best strategy for determining complete
lymph node status is through axillary dissection. This means that some women
with negative lymph nodes and who will not benefit directly from treating the axilla
will receive axillary dissection for staging purposes only.
Management of the Axilla in Women with Breast Cancer
8
Management of the axilla in women with breast cancer
The consequence of uncontrolled disease
in the axilla
Regional axillary recurrence
A recurrence of breast cancer in the axilla carries significant risks to the woman.
Risks include a mass in the axilla that may be difficult to treat; brachial plexus
infiltration; lymphoedema; and, rarely, axillary skin ulceration. The risk of such
problems in the untreated axilla varies with tumour size, from about 10% for
tumours less than 1 cm to 33% for tumours greater than 2 cm.10 A large trial of
early breast cancer estimated that expectant management of the axilla would result
in an incidence of uncontrolled axillary disease in about 20% of cases.6 Both this
trial and another11 have demonstrated the importance of treating the axilla. Where
the axilla was selectively excluded from treatment, both trials showed an increased
risk of locoregional recurrence.
Lymphoedema is an important side effect of axillary treatment and of axillary
recurrence. Although rarely simple to manage, it is easier to manage in an axilla
where the disease is controlled rather than uncontrolled.
Side effects of axillary dissection and
axillary irradiation
There are a number of major side effects of axillary dissection and axillary
irradiation. These are described in detail in Appendix II. Risks associated with
axillary dissection include seromas; wound infection; damage to motor nerves;
numbness and paraesthesia; reduced shoulder mobility and stiffness; and
lymphoedema. The side-effects of axillary irradiation include lymphoedema;
reduced shoulder mobility or arm movement restrictions; and, much more rarely,
rib fracture, brachial plexus damage, pneumonitis, axillary blood vessel damage and
sarcoma formation.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
9
Lymphoedema is one of the most common and therefore significant side effects
of an intervention to the axilla, with either radiotherapy or surgery. The incidence
of ‘clinically obvious’ lymphoedema associated with axillary dissection alone is
approximately 7%.9 The incidence of lymphoedema associated with axillary
irradiation alone is similar. However, when both dissection and irradiation are
given, more recent studies report rates of around 30%. There is randomised trial
evidence that lymphoedema rates for axillary sample plus irradiation are not
different from those for either modality alone.12
The impact of treating the axilla on survival and
axillary recurrence: the evidence
Does axillary dissection increase survival from
breast cancer?
The benefits of axillary dissection in prolonging survival are unclear. Studies
have reported different effects on survival, and most have some methodological
flaws. For example, the NSABP B-04 trial5 found that there was no difference in
survival between women who had simple mastectomy and those who had radical
mastectomy (including axillary dissection). However, 33% of women in the nondissected group had undergone some form of limited axillary surgery and the
power of the study may have been insufficient to demonstrate a clinically
significant difference between the groups.
Other studies have found overall long term benefits in survival when axillary
dissection was carried out.7,13,14 For example, a study by Cabanes7 et al. – of
lumpectomy plus breast and axillary irradiation without axillary dissection, versus
lumpectomy and breast irradiation with axillary dissection – showed a small but
significant improvement in survival in women who had axillary surgery (92.6%
versus 96.6%, p = 0.014).7 However, interpretation of these results is difficult since
a significant proportion of the axillary dissection group received adjuvant systemic
therapy based on their nodal status.
Management of the Axilla in Women with Breast Cancer
10
Management of the axilla in women with breast cancer
Two other studies, the Guys Hospital breast conservation study13 and the
Edinburgh study comparing a radical mastectomy with a total mastectomy plus
radiotherapy,14 found significantly decreased survival for treatment groups that had
a higher rate of locally uncontrolled disease. Both concluded overall long-term
benefits in survival when axillary dissection was compared to no intervention or
radiotherapy to the axilla.
In summary, the data suggest that axillary dissection may have an impact on
survival, although the evidence remains insufficient.
Does axillary dissection reduce axillary reccurence?
Axillary dissection reduces the risk of axillary recurrence (Level II). The best
evidence for this comes from the NSABP B-04 trial,5 which reported 10–year
axillary recurrence rates of only 1% (node negative) and 3% (node positive) for
women who had undergone axillary lymph node dissection at mastectomy,
compared to more than 17% in women who had not (Level II). Other studies
have shown that axillary recurrence is inversely related to the number of nodes
removed from the axilla.15,16
Does axillary irradiation influence survival from
breast cancer?
The impact of axillary irradiation on mortality from breast cancer remains
unclear. Although Overgaard17,18 showed a survival benefit for postmastectomy
radiotherapy which included the axilla, the patients included in that study were
high risk T 3-4 and node positive. The surgical management of the axilla in that
trial was also different from most Australian centres, in that the mean lymph node
yield was less in the Danish trial. Another trial has shown a trend towards
improved survival19 (Level II). However, in these three trials the postmastectomy
radiotherapy included chest wall, axillary, supraclavicular and internal mammary
node irradiation. Indeed, given that all nodal areas were irradiated in these trials,
it is impossible to isolate one area of treatment as being solely responsible for their
identified survival improvements.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
11
However, no other trial, overview20 or meta-analysis has demonstrated a
survival benefit.
At this time there is therefore no Level I evidence to conclude that post-operative
radiotherapy to the axilla provides a survival benefit.
Does irradiating the axilla reduce
axillary recurrence?
Axillary irradiation reduces axillary recurrence (Level I)20 and can therefore be
considered an alternative to axillary dissection.
In an overview of randomised trials, the Early Breast Cancer Trialists'
Collaborative Group20 demonstrated that radiotherapy reduced the locoregional
relapse rate by about two-thirds, from 19.6% to 6.7%. This was independent of the
type of axillary surgery or nodal status, and included breast-conserving surgery and
mastectomy.
Axillary irradiation may be added to axillary dissection in some cases where women
are identified as being clearly at risk of axillary recurrence, especially where there is
evidence of disease remaining after dissection. In these situations, axillary
irradiation may confer additional benefits over dissection alone, in controlling
axillary disease and preventing ensuing symptoms.
The benefit of axillary radiotherapy in different subgroups needs to be carefully
considered, as the extent of the benefit for various subgroups will differ depending
upon their risks and must be balanced against potential morbidity.
Management of the Axilla in Women with Breast Cancer
12
Management of the axilla in women with breast cancer
Axillary irradiation following dissection in women with
limited nodal involvement
Relevant data is provided by extrapolating results from several large randomised
trials21,22,23 which compared breast-conserving therapy and mastectomy. The trial
findings suggest that there may be little benefit from adding axillary irradiation
among women who have had axillary dissection and have only a small number of
involved lymph nodes.
For example, the NSABP B-06 trial21 reported that 90% of patients had less than
four lymph nodes positive in a dissected axilla. Local axillary relapse in this entire
series is low, at around 1–3%. It is unlikely that the addition of radiotherapy will
confer much benefit where rates of relapse are already very low.
This conclusion is supported by a strong body of retrospective data.6,22,23 Data
from the Mayo Clinic suggest isolated locoregional recurrences (ie recurrences on
the chest wall or lymphatic areas) of only around 8% with less than four lymph
nodes involved.24 Similarly, Fowble et al.25 suggest that isolated locoregional
recurrences occur in 7% of women with limited nodal involvelment. Of the 634
patients analysed by Fowble et al.,25 only 1.3% recurred in the axilla alone and
another 1.3% in multiple sites that included the axilla – that is, the total axillary
recurrence rate was only 2.6%.
Fisher15 et al. analysed patterns of recurrence in 320 patients who had been treated
for Stage II or III breast cancer with surgery and chemotherapy without
locoregional radiation therapy. They found 21 isolated axillary recurrences (6.6%)
at a median follow-up of 77 months, and concluded that the number of axillary
nodes involved was not predictive of recurrence.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
13
Axillary irradiation following dissection in women
with greater lymph node involvement or remaining
disease in the axilla
While the above data suggest that there is little to be gained by axillary irradiation
in women with only a small number of involved lymph nodes, it seems that there
may be benefit from the addition of radiotherapy when it is likely that there is
remaining disease in the axilla. This included cases where the surgeon believes
that macroscopic disease was left behind or transected, or where the pathologist
indicates positive margins.
The addition of axillary irradiation with greater nodal involvement is more
controversial than with limited nodal involvement.15,16,26,27 When there is
greater nodal involvement, local relapse rates will be increased where surgery
is the sole treatment. For example, data from the Mayo Clinic23 suggest isolated
locoregional recurrences at three years of 14% among women with 4–7 positive
nodes and 22% for women with eight or more positive nodes. Similar data have
been reported by Fowble et al.25 However, not all of these relapses are axillary.
Most studies have shown at least 50% to be on the chest wall. These studies are
non-randomised.15,16,26,27
The three randomised trials17,18,19 noted above, showing an improvement in
survival in high risk disease for patients irradiated to the entire lymphatics and
chest wall, also showed a reduction in locoregional relapse from 32% to 9% at
10 years. Although the distribution of local relapses was not given, more than half
were on the chest wall. Even in patients with heavy nodal involvement, axillary
recurrences remain uncommon. Not all analyses have demonstrated increased
axillary relapse rates with increasing numbers of involved nodes.15
However, it is important to consider the role of axillary irradiation in patients at
high risk of local recurrence. Not all axillary recurrences can be salvaged. It is
particularly difficult to salvage axillary recurrence with radiotherapy where the
axilla has been previously selectively excluded from the chest wall and
supraclavicular fossa volume. The prevention of recurrence may therefore be a
preferable option, albeit carrying the cost of increased risks of lymphoedema.
Management of the Axilla in Women with Breast Cancer
14
Management of the axilla in women with breast cancer
Axillary irradiation following dissection in women
with extranodal spread
The significance of axillary extranodal spread in breast cancer has been a
controversial issue.28-35 Studies have examined the effects of extranodal spread on
both survival and local recurrences compared with patients in the same series who
have no extranodal spread. All are retrospective reviews of single institution data.
Most have demonstrated significant reductions in overall survival in patients with
extranodal spread of disease, 30,32,33,34 and one study35 showed a non-significant
trend (Level III).
In examining the risks of locoregional recurrence, some of these studies have
demonstrated increased relapse rates. They looked specifically at any differences
between focal and extensive extranodal spread and found no difference in rates
of local relapse.28,30,32,34 Only two studies have examined the sites of local relapse in
patients with axillary extranodal spread.30,34 Both have demonstrated increased
chest wall recurrences but no significant increase in axillary recurrence rates.
The axillary recurrence rate in both studies was 7%. While this figure is higher than
reported axillary relapse rates in patients with comparable numbers of involved
lymph nodes without extranodal spread, it was not significantly higher
in the studies reported. There remains no Level I or II evidence to support
axillary irradiation in patients with breast cancer based solely on reported
extranodal spread.
Is axillary irradiation as effective as axillary
dissection in local control?
There are data6,36 (Level II) reporting no difference in outcome between
axillary dissection and radical radiotherapy to the undissected axilla in clinically
node negative axillae. Patient factors such as individual preference, performance
status and age should be taken into account. Differences in morbidity patterns
should be also considered.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
15
Staging the axilla: advantages and alternatives
Surgical staging of the axilla is currently the usual practice for the majority
of women, as it provides prognostic information and data upon which major
treatment decisions are made. Although several prognostic indices have been
developed to date, most rely on knowledge of the nodal status.37,38 Axillary
lymph node status is the most powerful single variable in the estimation of
prognosis for primary breast cancer. Prognosis is related to the number
of axillary nodes which contain metastases; this relationship applies to both
disease-free interval and to survival.4,39
The absolute benefit that any individual patient will derive from adjuvant systemic
therapy depends on an accurate assessment of her individual risk of relapse.
Currently, the best indicator of this is lymph node status. For women considering
entry to systemic therapy clinical trials, some require minimum numbers of lymph
nodes to have been examined.
Systemic adjuvant therapy can provide a survival benefit.40-44 However,
chemotherapy in particular is associated with major side effects. For those women
in whom it is unlikely that the disease has spread, there will be little advantage in
systemic adjuvant therapy but the potential for considerable morbidity from the
side effects.
The number of nodes involved is an important selection factor for adjuvant
systematic therapy, since the benefits of systemic therapy are expressed as a
reduction in risk. The probability of lymph node involvement is related directly
to the size of the primary tumours. Larger tumours are more likely to have
metastasised to axillary lymph nodes than smaller ones. However, even in small
primary tumours (up to 10 mm), the risk of nodal metastases is in the order of
10%,10,45 and for these patients identification of the involved lymph nodes will alter
both their prognosis and the adjuvant therapy offered. It is important to note that
there is an increase in the proportion of women with breast cancer who may not
benefit from systemic adjuvant therapy. Screen-detected cancers, which tend to be
small and associated with an excellent prognosis, are becoming increasingly more
common. Adjuvant systemic chemotherapy has little role in this group of patients.
Management of the Axilla in Women with Breast Cancer
16
Management of the axilla in women with breast cancer
There is evidence that chemotherapy will not substitute for inadequate local
treatment21 (Level I) and so may not be effective against all the cells that may have
spread to the axilla.
Alternatives to axillary dissection for staging
At this time, axillary dissection remains the best available technique for staging the
axilla to provide full qualitative and quantitative information.
Non-operative approaches
Surgical staging of the axilla has remained the gold standard because no reliable
non-operative alternative has yet proven as effective. Clinical examination misses
30–75% of involved lymph nodes and even when lymph nodes are palpable at the
time of presentation, nodal metastases will be confirmed on histological
examination in less than 50% of cases.46,47 Mammography is a sensitive method of
detecting large axillary lymph nodes, but it’s specificity is severely limited. Careful
ultrasound of the axilla supplemented with colour Doppler improves both
sensitivity and specificity, but not to an extent that justifies its routine use. Other
nodal imaging techniques which have been investigated with limited success
include nuclear scanning and labelled antibody scanning. Magnetic resonance
imaging (MRI) examination of the axilla has not confirmed its initial promise and
cannot be considered at the present time to be sufficiently sensitive and specific.
Fluoro deoxy glucose (FDG) positron emission tomography (PET) has shown
promising early results, with a sensitivity of 75% and specificity of 90%. However,
small volume nodal disease is unlikely to be accurately staged using present PET
technology, which is expensive and not widely available.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
17
Axillary sampling
A formal axillary sample, as described by Steele et al.48 and which provides
a minimum of four nodes, is an adequate means of qualitatively establishing
whether the axilla is involved. Many argue that it is not an easily reproducible
technique. It does not provide total quantitative data in patients with involved
axillae. A randomised trial of axillary clearance versus a four-node lower axillary
sample (with axillary irradiation in the case of a positive sample) shows comparable
axillary control rates (Level II).48
Axillary sampling may be adopted by those comfortable with the technique where
the patient is known to be least likely to have involved nodes (eg small low grade
tumours) and the extent of nodal involvement is unlikely to influence the choice
of systemic therapies (especially in the elderly). If the sampled lymph nodes
contain tumour deposits, further treatment of the axilla (ie radiotherapy, further
surgery) is indicated. Axillary sampling carries a low rate of arm morbidity.12
Sentinel node biopsy
Although no formal clinical trial results are yet available, the most promising
alternative to axillary dissection for staging is sentinel node biopsy. This technique
can detect a positive axilla but does not represent adequate treatment of it.
It constitutes a very focused sample based on identifying the sentinel node, ie the
first node that drains the site of the primary lesion. If this node does not contain
any evidence of cancer, then the likelihood that other nodes in the breast are
involved is extremely small (approximately 5–7% in experienced hands).49
Sentinel node biopsy is discussed in detail in Appendix III. There is some evidence
(see Appendix III) that as currently practised, it may not always be possible to find
the sentinel node and that in a small number of cases (5–7% in experienced hands)
other positive nodes will be present with a negative sentinel node. In well reported
larger series, however, sensitivity, specificity and accuracy are all in excess of
90%.49,50,51 The technical difficulty and the considerable learning curve of the
procedure cannot be underestimated. A recent report has found a significant
reduction in the accuracy of the procedure when inexperienced versus experienced
operators were analysed.52
Management of the Axilla in Women with Breast Cancer
18
Management of the axilla in women with breast cancer
There is currently no randomised data available comparing sentinel node
biopsy with formal axillary dissection. Those trials are still in progress
internationally. However, there is a recent report53 prospectively comparing sentinel
node biopsy and four-node positive sampling. The Nottingham Breast Unit
examined 150 routine axillary node samples to see whether the sentinel node was
removed. In 76% of cases, the sentinel node was excised as part of a routine
axillary node sample. In 14 cases, the sentinel node was not identified. In five
patients, the sentinel node was found to be false negative. However, no patient was
found to be under- or down-staged by the routine axillary node sample. It was
concluded that the sentinel node biopsy was an acceptable alternative to sampling,
but of no significant advantage over a routine sample.
As with the four-node axillary sampling, a positive sentinel node biopsy simply
denotes a positive axilla – it does not represent adequate treatment of the axilla.
Further treatment to the axilla is required for patients with positive sentinel nodes.
This can be with formal axillary dissection or with radiation therapy. The choice
will almost certainly depend upon local treatment protocols and patient selection
factors (eg age). The lymphoedema rates for radiotherapy following a positive
sampling procedure are equivalent to those of a dissected axilla without
radiotherapy.12 It would be expected to be similar for radiotherapy following
a positive sentinel node biopsy.
Management of the Axilla in Women with Breast Cancer
Management of the axilla in women with breast cancer
19
Management of the Axilla in Women with Breast Cancer
20
Management of the axilla in women with breast cancer
Clinical practice recommendations
These recommendations are derived both from the previous discussion of the
evidence and from a multidisciplinary consensus conference in which draft
evidence-based statements were prepared and discussed. It was agreed that the
recommendations represent both the evidence and best practice in relation to the
management of the axilla.
1
Management of the axilla should be
determined by a multidisplinary team in
discussion with the patient (Level III). 5 4
Patient management is optimal in clinical situations where multidisciplinary
communication is greatest. There are several reasons why multidisciplinary
communication is particularly important in the management of the axilla.
For example, in determining whether axillary irradiation is required following
axillary dissection, the surgical description of the operative findings is critical.
A description of lymph nodes being enmeshed around axillary blood vessels and
needing to be dissected free, almost always denotes macroscopic residual disease.
This may not be evident from the pathology report. The nature of pathological
handling of the axillary contents makes orientation of the axillary specimen and
description of margins extremely difficult.
Likewise, for some patients, the preferred method of treatment may be
radiotherapy alone or no treatment. Close communication between the surgeon
and the radiation oncologist is required to manage such patients. For example, in
an elderly frail patient with a purely tubular carcinoma, the decision to ‘observe’ the
axilla rather than use surgery or radiation therapy should be made jointly between
the woman, her surgeon, her radiation oncologist and her medical oncologist.
Clinical practice recommendation
Management of the axilla in women with breast cancer
21
Given that the management of the axilla always involves a balance of the potential
costs and benefits of treatment, the woman must always be fully informed of and
participate in the decision. She should be provided with information about the
benefits of axillary dissection and irradiation in reducing the risk of local
recurrence and possibly increasing survival. She should also be advised about the
value of staging information in determining the best systemic adjuvant treatment if
required. She should also be fully informed about the potential side effects of
axillary dissection and irradiation, particularly lymphoedema.
2
For women with early breast cancer,
a minimum level I and II axillary node
dissection should be offered as the
standard procedure to reduce the risk
of regional recurrence (Level II). 5 , 7
There is evidence that axillary dissection reduces the risk of regional recurrence.5,7
3
Axillary dissection can be omitted for
some women.
The omission of axillary dissection can be considered for women in whom
it is likely that the risks will outweigh the benefits; however, the decision to
omit axillary dissection should be discussed fully with the woman. These
patients include:
•
Women diagnosed with ductal carcinoma in situ:
A number of studies have demonstrated that the rate of axillary
metastases in women with DCIS is less than 1%.55 Axillary dissection
should be omitted in these patients (Level III).
•
Selected patients:
In selected patients in whom the result of axillary dissection would be
unlikely to influence the decision to use adjuvant systemic therapy,
axillary dissection may be omitted. This may include frail, elderly
women. Although not subjected to any completed formal controlled
trial, management without axillary surgery may be appropriate in such
Clinical practice recommendation
22
Management of the axilla in women with breast cancer
patients with small low grade tumours, no palpable axillary disease and
very close clinical follow-up (Level IV).
4
Axillary irradiation will be the preferred
method of treatment for some patients
(Level III). 6 , 3 6 , 5 6
Evidence suggests that axillary irradiation is as effective as axillary dissection in
preventing local recurrence (Level III).6,36,56 For some patients, axillary irradiation
will be the preferred method of axillary management. These patients include:
•
Elderly patients or those with additional serious health problems:
Radiotherapy is the appropriate alternative for these women in whom
additional surgery should be avoided.
•
5
Patient choice: Some patients may not wish to have further surgery.
Some patients will require axillary irradiation
following axillary surgery (Level IV).
Some women at high risk of axillary recurrence will require both axillary dissection
and axillary irradiation. This particularly includes women who have surgical or
pathological evidence of remaining axillary disease following dissection.
Where women have undergone less axillary surgery than a dissection (a formal
sample or sentinel node biopsy, for example) and this procedure is positive for
axillary malignancy, they will require further axillary treatment and may elect for the
treatment to be with radiotherapy rather than further surgery.
6
Coordination of trials of sentinal node biopsy
across Australia should be undertaken as a
matter of priority (Level IV).
Ideally, only those women with positive nodes should receive axillary dissection.
However, there are currently no established alternatives for determining lymph
node status other than axillary dissection.
Clinical practice recommendation
Management of the axilla in women with breast cancer
23
The most promising alternative is sentinel node biopsy. This is currently available
in Australia only on an experimental basis; different approaches are being used and
a number of problems with the technique have been identified. The proposed
schema for a clinical trial in Australia is that patients be randomised to either a
standard axillary dissection or to a sentinel node biopsy. If the sentinel node were
negative, they would not receive further axillary treatment. A positive sentinel node
biopsy would be followed by a formal axillary dissection.
A nationally coordinated, controlled trial would provide information about the
possible role of sentinel node biopsy relatively quickly. It would ensure that women
are not provided with this treatment outside of clinical trials and that appropriate
quality assurance is achieved.
Clinical practice recommendation
24
Management of the axilla in women with breast cancer
Appendix 1
Axillary surgery – definitions
Definitions of axillary dissection
There is a wide variation in the extent of axillary dissection in the management of
breast cancer. It ranges from no surgical intervention at all, to the sampling
removal of a few lower nodes, to a specific sentinel node biopsy, to an exhaustive
complete clearance to the apex of the axilla. This variation has largely been due to
a number of differing beliefs about the amount of nodal tissue required for
staging, and about the benefits of a clearance procedure.
In summary, the anatomical boundaries of the axilla are:57
Anterior wall
Pectoralis major and minor muscles subclavius,
clavipectoral fascia
Medial wall
Serratus anterior muscles/chest wall
Lateral wall
Humerus (medial side), brachialis muscle
Posterior wall
Latissimus dorsi, teres major and subscapularis muscles.
Base
Axillary fascia
Apex
Formed by outer border of first rib, clavicle and scapula
In order to facilitate communication and uniformity of approach, the axilla can be
conveniently divided into three levels based around the pectoralis minor muscle.
This leads to the definitions of level I, II and III clearance as outlined below.58
Appendix 1
Management of the axilla in women with breast cancer
25
Level I dissection: clearance from the lateral/lower
border of pectoralis minor
This may also be described as a ‘lower axillary dissection’. It includes all tissue
inferior to the axillary vein and extends laterally to the point where the axillary vein
crosses the tendon of latissimus dorsi. The rest of the dissection is limited by the
axillary fascia and the chest wall.
Level II dissection: clearance from the medial/upper
border of pectoralis minor
This dissection includes all of the level I tissue, plus those deep to the body of
the pectoralis minor muscle. Essentially, it simply extends a level I dissection to
the medial border of pectoralis minor.
The pectoralis minor muscle may be either divided or retracted to gain access
to this region. No significant difference in morbidity has been detected using
either technique.
Level III dissection: clearance from the axillary apex
This involves the complete removal of all nodal tissue from the axilla. The
dissection extends superomedially to the lateral border of the first rib and costoclavicular (Halsted’s) ligament.
Node retrieval
There is a wide variation in the number of glands harvested from any individual
nodal basin. For example, in the axilla, complete clearance has been reported as
yielding as few as eight nodes and as many as sixty in series from one institution.58
Appendix I
26
Management of the axilla in women with breast cancer
Average lymph node harvests:60,61,62,63
•
Level I alone
9–13
•
Level II alone
5–9
•
Level III alone
2–6
The median nodal retrieval in Australia is 14 lymph nodes.64,65
Axillary sampling
Axillary sampling is a non-anatomical dissection. This technique removes
significantly less nodal tissue than the clearances described above. However, there
are variations in the amount of nodal tissue retrieved. In its simplest form it can be
described as the removal of lymph nodes from the lower axilla. A limited resection
of the axillary tail of the breast and adjacent tissue containing lymph nodes is
performed.60,66 The more elaborate descriptions of this procedure sometimes
nominate the intercostobrachial nerve (ICBN) as a landmark of the superior extent
of an axillary sample. A more formally worded description runs:
‘The removal of tissue from below the axillary vein superiorly and the
lateral border of pectoralis minor medially. This differs from a formal
level I clearance in that the lateral aspect of the axilla and the subcapsular
fossa are not dissected. The nerves to latissimus dorsi and serratus are
not identified.’59
Given the differing appreciation of what an axillary sample involves, the number
of lymph nodes harvested from such procedures varies. Kissin demonstrated a
24% error rate when sampling was compared with complete axillary clearance.66 In
Forrest’s initial reports, sampling failed to retrieve any lymph nodes in 18% of
cases although the success rate improved substantially later.67 It is thus difficult to
interpret and compare the results of axillary sampling procedures in breast cancer.
However, the technique remains an accepted axillary approach in many
international centres.
Appendix I
Management of the axilla in women with breast cancer
27
Appendix I
28
Management of the axilla in women with breast cancer
Appendix II
Risks of axillary dissection and irradiation
Risks of axillary dissection
Seroma
Seromas are common following most types of axillary clearance,63,68 but are
reported to be less with axillary sampling. The ideal period of drainage is unknown
and the management of drain tubes and of seromas is very individualised.
Randomised trials have shown little difference in seroma formation, regardless of
the drainage technique employed. Even with prolonged periods of drainage, some
patients still require further aspiration of residual seroma.68
Wound infection
The rate of wound infection in axillary surgery has been reported at approximately
10%.63 Wound infection is more common in certain groups of patients: the elderly
and immuno-compromised; those who undergo repeated aspiration of seroma or
prolonged wound drainage; and those who have undergone recent surgery in the
vicinity of the axilla.
The prophylactic use of antibiotics has been shown to decrease the rate of wound
infection.69
Reduced shoulder mobility and stiffness
Shoulder stiffness is common immediately after axillary dissection.70 Patients may
be predisposed to this if they have pre-existing arthritis, or if the position of the
arm during the surgery is not carefully monitored. Early mobilisation and exercise
is important for retaining normal mobility post-operatively. There is little
documented evidence on the cause of this problem.
Appendix II
Management of the axilla in women with breast cancer
29
Damage to motor nerves
Although the frequency of injury appears to be low, three important motor nerves
are at risk during axillary lymph node dissection:
•
The medial pectoral nerve is at risk when dissecting around pectoralis
minor. This is particularly so if this muscle is divided, but the nerve
may also be damaged during dissection as it swings along the lateral
border of the pectoralis minor muscle. In up to one-third of patients,
it lies well lateral to the muscle and is at significant risk. Damage to the
nerve results in minimal morbidity, but will lead to wasting of the lower
fibres of pectoralis major. This will result in the loss of the anterior
axillary fold, and perhaps a less than desirable cosmetic result.
•
The long thoracic nerve of Bell or nerve to serratus anterior runs along
the chest wall in the posterior part of the axilla. Damage to this nerve
results in winging of the scapula.
•
The thoracodorsal nerve or nerve to latissimus dorsi may be divided in
the lateral aspect of the axilla. Although damage to this nerve may result
in minimal detectable disability, some reduction in the power may be
noticed, especially when the arm is raised above the head and in women
active in sports.
Numbness and paraesthesia
Various studies have looked at this common problem and estimated that
some numbness may be demonstrated in almost 80% of patients undergoing
axillary surgery.71 The frequency of more significant or disabling pain is in the
range of 5%. The alteration to sensory perception is assumed to result from
division of the ICBN.
The extent of any deficit is variable but may involve the inner aspect of the upper
arm, shoulder, axilla and anterolateral chest wall.
Appendix II
30
Management of the axilla in women with breast cancer
Although many surgeons preserve the ICBN, this is not necessarily reflected
in the preservation of normal sensation. Some units have demonstrated a better
outcome with ICBN preservation at 12 months; however, a recent report from
France failed to observe any difference regardless of whether the nerve was
divided.72 Importantly, preservation of the ICBN is not affected by the extent
of axillary clearance.
Lymphoedema
Lymphoedema is one of the most significant side effects of intervention to the
axilla with either radiotherapy and/or surgery.9 Research into lymphoedema is
made difficult by the varying definitions used and by the significant differences
between the subjective and objective appreciation of the problem. Various studies
have reported the incidence of lymphoedema to run between 10–25%.9 The
incidence of ‘clinically obvious’ lymphoedema associated with axillary clearance is
approximately 7%.9 However, the incidence of lymphoedema varies widely
depending upon the point post-treatment at which it is assessed. Some studies
suggest that its incidence increases with time following surgery, and certainly it
remains a difficult treatment problem. Patient size may be the best predictor of
lymphoedema risk, with those with a high body mass index (BMI) being at higher
risk. Other factors which may contribute to risk are hypertension, disruption of
sympathetic nervous input to the limb and anatomical situations where few
primary lymphatic channels exist.
Risks of axillary irradiation
Lymphoedema 9
The routine addition of radiotherapy to a fully dissected axilla increases the
incidence of lymphoedema to at least 30%.9 Management of the axilla with
radiation alone is reported to induce lymphoedema of the arm in rates similar to
that of surgery alone (3–8%).73
Radiation therapy to a conserved breast may include some level I of the axilla.
There is randomised trial evidence that the risk of lymphoedema is not increased
in this situation.74
Appendix II
Management of the axilla in women with breast cancer
31
Shoulder and arm movement restriction
This is relatively common (approximately 20%), even when the shoulder joint is
routinely excluded from the radiation beam.12 It may be due to the effects of
radiation on the pectoral and other muscles associated with shoulder movement.
Rib fracture
This is mostly due to the chest wall or breast fields. The risk of rib fracture in
those areas, based on several large reviews, is 1.8%.2,75 The risk of such fractures in
the axillary field areas is much less.
Brachial plexus damage
This can occur in breast cancer due to the effects of radiation, or due to tumour
recurrence in the brachial plexus or supraclavicular fossa. The major factors
responsible for radiation-induced plexopathy are a total radiation dose exceeding
50 Gray (Gy); high dose per fraction treatment; techniques delivering the dose
through a single anterior field; using orthovoltage radiation; and concurrent
chemotherapy. The risks range from 0–1.8%.75,76,77 The use of techniques that may
lead to field junction overlap increase the risk of this problem.
Pneumonitis
This complication occurs in up to 7% of patients.75 It is seen more
commonly where the volume irradiated is large, as when the supraclavicular
fossa and axilla are included in the field. The risk is as low as 0.5% for radiation
therapy alone to the breast or chest wall alone. This risk increases with the
addition of supraclavicular fossa and axillary radiation fields and with the
addition of chemotherapy.75
Sarcomas
The development of radiation-induced sarcomas is rare. They occur in bone or
soft tissue and most have involved orthovoltage therapy. A review of the evidence
in 1995 suggested an incidence of 1–2 per 1,000 treated patients who are alive
at 10 years.78,79
Appendix II
32
Management of the axilla in women with breast cancer
Appendix III
Sentinel node biopsy in breast cancer
The concept of sentinel node biopsy was first described by Cabanes in the
management of penile cancer.80 Previous to this it was assumed that drainage
of a primary tumour to the draining lymph nodes was a random phenomenon.
Morton et al. demonstrated that for cutaneous melanoma the first node that
drained the site of the primary lesion (ie the sentinel node) could be reliably
identified. They further demonstrated that the spread of disease within the
draining node basin followed in sequence from sentinel node to higher echelon
nodes; and that biopsy of the sentinel node could be used to stage the nodal basin.
Specifically, if the sentinel node did not contain any tumour then the likelihood
that any other nodes in that nodal basin would be involved was extremely small.81
The technique of sentinel node biopsy has been generalised from cutaneous
melanoma to a number of malignancies, including breast cancer, and a number of
groups have reported their experience. Three techniques usually in combination
have been used to identify the sentinel node/s in women with breast cancer.
Guilano et al. use only peritumoral injection with a vital dye (Patent Blue V in
Australia) to identify the sentinel node, which stains blue.82 This technique has the
lowest success rate although more recent results are much improved. Most groups
employ the technique of peritumoral injection with a radioactive labelled colloid
particle pre-operatively, and intra-operative use of a hand-held gamma probe to
identify the sentinel node taken up by the radio labelled colloid. Many of these
groups have also combined this technique with lymphoscintigraphy, which involves
imaging the woman after injection with the radio labelled colloid to visualise spread
among the lymphatics to the first or sentinel node. This technique not only
provides a guide as to the site of the sentinel node (which in a small number of
cases may not be the axilla) but also indicates if there is more than one sentinel
node. Uren et al. in a small series described lymphatic drainage in patients with
carcinoma of the breast.83 The ipsilateral axilla was involved in 85% of cases but in
nearly one-third of cases there was cross breast spread to axilla or internal
mammary nodes. Unexpectedly and potentially of considerable interest, 20% of
patients had spread to chest wall or clavicular nodes.
Appendix III
Management of the axilla in women with breast cancer
33
The most favoured technique – and that which is associated with the best result –
employs pre-operative lymphoscintigraphy and intra-operative use of hand-held
gamma probe after injection of a radio-colloid and use of the vital blue dye. The
optimal technique is still under evaluation. Such factors as the site of the injection
of the radio-colloid or blue dye have not yet been resolved. Most groups have
injected dye and colloid peri-tumourally, although there is some evidence that
subcutaneous injection in the skin over the tumour may be as accurate and clearly
has advantages for women with impalpable lesions.51 Regardless of the experience
of the operator, successful identification of the sentinel node appears to be less in
the elderly and in patients who have undergone a previous excision of the primary
tumour. At this time, it is therefore not possible to make any firm
recommendations about the optimal technique.
On the other hand, there is clear and emerging evidence of a considerable learning
curve for successful performance of this procedure.
There is no doubt that sentinel node biopsy in the reported series49,50,51
is highly accurate in predicting the status of the axillary nodal basin, but as
yet there is no information concerning the small proportion of patients in
whom the sentinel node is not in the axilla. As has occurred with melanoma,
the use of multiple histological sections through the sentinel node and of
immunohistochemistry to facilitate the identification of micro-metastases is
likely to increase the rate of node involvement.84 The significance of these
micro-metastases in patients with small and otherwise good prognosis tumours
is unknown, although previous studies suggest that micro-metastases are probably
associated with poorer long term survival.85 Whether this can be impacted by
current systemic therapies is not yet known.
In summary, the current data indicate that sentinel node biopsy is a highly effective
and accurate method of staging the axilla with little surgical morbidity. The
technical difficulty and the considerable learning curve of the procedure cannot be
underestimated. There are significant differences in accuracy reported in one series
that examined experienced versus inexperienced operators.52 Considerable
concerns remain about the optimal technique; the long-term safety of avoiding
axillary dissection in patients with good prognosis lesions; and the clinical
Appendix III
34
Management of the axilla in women with breast cancer
significance of micro-metastases and what should be done about them. Clinical
trials are currently under way to address these issues. At present, sentinel node
biopsy without complete axillary lymphadenectomy cannot be recommended as
standard management.
Appendix III
35
Management of the axilla in women with breast cancer
Appendix III
36
Management of the axilla in women with breast cancer
Appendix IV
Technical aspects of radiation therapy to the axilla
The axilla will not routinely be treated in isolation from the supraclavicular fossa.
The depth required to treat in the supraclavicular area should be considered. The
depth in the axilla must also be determined, and generally the dose should be taken
sufficiently posteriorly to include the posterior axillary area fully.
Radiation therapy for both areas is generally performed using unmatched anterior
and posterior portals. Generally, the supraclavicular portal will be irradiated from
the anterior surface only, and the axilla from the anterior and posterior surface.
The area of the axillary apex or the coracoid process is generally chosen to
determine the medial edge of the posterior field. If the axilla is to be excluded
from the treatment volume, the coracoid process forms the most lateral extent
of the field.
It may be desirable to angle the anterior portal away from the spinal cord. If a
direct portal is used, it is recommended to calculate dose to the spinal cord.
The potential for overlapping fields to produce areas of overdose or underdose
at the junctions should be addressed. Methods to minimise these include:
1
Using isocentric techniques to allow the use of asymmetric jaws on
all fields so that central axis rays are aligned at the junction. Half beam
blocking may also be used.
2
Using a calculated gap in the junction area to limit the dose to an
acceptable limit.
3
Avoiding turning the patient prone to deliver the posterior
axillary boost.
Supervoltage equipment (4, 6 or 8 MV or Cobalt-60) are preferred because of dose
homogeneity and skin sparing.
Appendix IV
Management of the axilla in women with breast cancer
37
The aim is to create a homogenous dose distribution throughout the treatment
volume (+ 5% variation). Factors to achieve this in axillary treatment include:
1
Choice of beam energy.
2
Lung correction should be used wherever possible.
3
Contours through the nodal areas should be given.
4
Dose should be recorded as per ICRU 50.
The prescribed dose is given in 1.8–2.25 Gy fractions at the rate of 9 or 10 times
per fortnight. In general, a dose of 45–52.5 Gy is prescribed. All fields should
be treated each day, although the posterior axillary boost is typically given in
fewer fractions.
Careful attention to the amount of lung included within the treatment volume will
decrease the risk of pneumonitis.
Appendix III
38
Management of the axilla in women with breast cancer
References
1
Hill D, Jamrozik K, White V, et al. Surgical management of breast cancer
in Australia in 1995. Woolloomooloo (NSW): National Breast Cancer
Centre, 1999.
2
Steering committee on clinical practice guidelines for the care and treatment
of breast cancer. A Canadian consensus document. Can Med Assoc J
1998;158 (3 suppl).
3
The Royal College of Radiologists’ Clinical Oncology Information
Network. Guidelines on the non-surgical management of breast cancer. Clin
Oncol (R Coll Radiol) 1999;11 Suppl 3:0–133.
4
Fisher ER, Sass R, Fisher B. Pathologic findings from the national surgical
adjuvant project (protocol no. 4). X. Discriminants for tenth year treatment
failure. Cancer 1984;53:12–23.
5
Fisher B, Redmond C, Fisher ER. Ten year results of a randomised clinical
trial comparing radical mastectomy and total mastectomy with or without
irradiation. N Engl J Med 1985;312:674–81.
6
Baum M, Haybittle JH, Berstock DA, et al. The Cancer Research Campaign
(King’s/Cambridge) Trial for Early Breast Cancer – a detailed update at the
tenth year. Lancet 1980;2(8185):55–60.
7
Cabanes PA, Salmon RJ, Vilcoq JR et al. Value of axillary dissection in
addition to lumpectomy and radiotherapy in early breast cancer. Lancet
1992;339:245–8.
8
Radiation Oncology Advisory Group. Radiotherapy and breast cancer.
Woolloomooloo (NSW): National Breast Cancer Centre, Royal Australian
and New Zealand College of Radiologists, Faculty of Radiation Oncology;
1999.
References
Management of the axilla in women with breast cancer
39
9
Browning C, Redman S, Pillar, C et al. Lymphoedema: prevalence, risk factors and
management: a review of research. Woolloomooloo (NSW): National Breast
Cancer Centre; 1997.
10
Baxter N, McCready DR, Chapman JA et al. Clinical behaviour of untreated
axillary nodes after local treatment for primary breast cancer. Ann Surg Oncol
1996;3:235–40.
11
Stewart HJ, Jack WL, Everington D, et al. South-east Scottish trial of local
therapy in node-negative breast cancer. Breast 1994;3:31–9.
12
Chetty U, Jack W, Presett RJ, et al. Management of the axilla in patients with
operable breast cancer being treated by breast conservation: a randomised
trial. Br J Surg 2000;87:163–169.
13
Hayward J, Caleffi M. The significance of local control in the primary
treatment of breast cancer. Arch Surg 1987;122:1244–7.
14
Langlands A, Prescott R, Hamilton T. A clinical trial in the management of
operable cancer of the breast. Br J Surg 1980;67:170–4.
15
Fisher BJ, Perera FE, Cooke AL, et al. Long-term follow-up of axillary
node-positive breast cancer patients receiving adjuvant systemic therapy
alone: patterns of recurrence. Int J Radiat Oncol Biol Phys 1997;38(3):541–50.
16
Vincini F, Horwitz E, Lacerna M, et al. The role of regional nodal
irradiation in the management of patients with early-stage breast cancer
treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys
1997;39(5):1069–76.
17
Overgaard M, Hansen PS, Overgaard J, et al. Post operative radiotherapy in
high risk premenopausal women with breast cancer who receive adjuvant
chemotherapy. N Engl J Med 1997;337(14):949–55.
18
Overgaard M, Hansen PS, Overgaard C, et al. Randomized trial evaluating
postoperative radiotherapy in high-risk postmenopausal breast cancer
patients given adjuvant tamoxifen. Results from the DBCG 82C Trial.
Abstract. Radiother Oncol 1998;48 Suppl 1:586.
References
40
Management of the axilla in women with breast cancer
19
Ragaz J, Stewart M, Jackson NL, et al. Adjuvant radiotherapy and
chemotherapy in node positive premenopausal women with breast cancer.
N Engl J Med 1988;6(7):1107–17.
20
Early Breast Cancer Trialists' Collaborative Group. Effects of radiotherapy
and surgery in early breast cancer. An overview of the randomized trials. N
Engl J Med 1995;333(22):1444–55.
21
Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomised
clinical trial comparing total mastectomy and lumpectomy with or without
radiation in the treatment of breast cancer. N Engl J Med 1989;320:822–8.
22
Veronisi U, Banfi A, Salvadori B, et al. Breast conservation is the treatment
of choice in small breast cancer: long term results of a randomised trial. Eur
J Cancer 1990;26:668–70.
23
Blichert-Toft M. A Danish randomised trial comparing breast conservation
with mastectomy in mammary carcinoma. Br J Cancer 1990;62 Suppl 12:15.
24
Pisansky TM, Ingle JN, Schaid DJ, et al. Patterns of tumour relapse
following mastectomy and adjuvant systemic therapy in patients with axillary
lymph node-positive breast cancer. Cancer 1993;72(4):1247–60.
25
Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of
patients with breast cancer and histologically positive axillary nodes
receiving adjuvant chemotherapy who may benefit from post operative
radiotherapy. J Clin Oncol 1988;6(7):1107–17.
26
Ung O, Langlands AO, Barraclough B, et al. Combined chemotherapy and
radiotherapy for patients with breast cancer and extensive nodal
involvement. J Clin Oncol 1995;13(2):435–43.
27
Diab SG, Hilsenbeck SG, de Moor C, et al. Radiation therapy and survival in
breast cancer patients with 10 or more positive axillary lymph nodes treated
with mastectomy. J Clin Oncol 1998;16(5):1655–60.
References
Management of the axilla in women with breast cancer
41
28
Fisher ER, Gregorio RM, Redmond C, et al. Pathologic findings from the
national surgical adjuvant breast project (protocol no. 4). III. The
significance of extranodal extension of axillary metastases. Am J Clin Pathol
1976;65(4):439–44.
29
Mambo NC, Gallagher HS. Carcinoma of the breast: the prognostic
significance of extranodal extension of axillary disease. Cancer
1977;39(5):280–5.
30
Fisher BJ, Perera FE, Cooke AL, et al. Extracapsular axillary node extension
in patients receiving adjuvant systemic therapy: an indication for
radiotherapy? Int J Radiat Oncol Biol Phys 1997;38(3):551–9.
31
Harviet F. The routine histological investigation of axillary lymph nodes for
metastatic breast cancer. J Pathol 1984;143(3):87–91.
32
Leonard C, Corkill M, Tompkin J, et al. Are axillary recurrence and overall
survival affected by axillary extranodal tumor extension in breast cancer?
Implications for radiation therapy. J Clin Oncol 1995;3(1):47–53.
33
Donegan WL, Stine SB, Samter TG. Implications of extracapsular
nodal metastases for treatment and prognosis of breast cancer. Cancer
1993;72(3):778–82.
34
Bucci JA, Kennedy CW, Burns J, et al. Implications of extranodal spread in
node positive breast cancer: a review of survival and local recurrence. 49th
Annual Scientific Meeting of the Royal Australasian College of Radiologists,
October 1998, Brisbane, Queensland.
35
Pierce LJ, Oberman HA, Strawderman MH, et al. Microscopic extracapsular
extension in the axilla: is this an indication for axillary radiotherapy? Int J
Radiat Oncol Biol Phys 1995;33(2):253–9.
36
Recht A, Pierce SM, Abner A, et al. Regional nodal failure after conservative
surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol
1991;9(6):988–96.
37
Du Toit RS, Locker AP, Ellis IO, et al. Evaluation of the prognostic value
of triple node biopsy in early breast cancer. Br J Surg 1990;77(2):163–7.
References
42
Management of the axilla in women with breast cancer
38
Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status,
and survival in 24,740 breast cancer cases. Cancer 1989;63(1):181–7.
39
Carter CL, Allen C, Henson DE, et al. Relation of tumour size, lymph node
status, and survival in 24,740 breast cancer cases. Cancer 1989:63(1):181–7.
40
Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of
early breast cancer by hormonal, cytotoxic or immune therapy: 133
randomised trials involving 31,000 recurrences and 24,000 deaths among
75,000 women. Lancet 1992a;339:1–15.
41
Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of
early breast cancer by hormonal, cytotoxic or immune therapy: 133
randomised trials involving 31,000 recurrences and 24,000 deaths among
75,000 women. Lancet 1992b;339:71–85.
42
Anonymous. Adjuvant systemic therapy for early breast cancer. Lancet
1992;339:27.
43
Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen
for early breast cancer: an overview of the randomised trials. Lancet
1998;351:1451–67.
44
Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for
early breast cancer: an overview of the randomised trials. Lancet
1998;352:930–42.
45
Kollias J, Murphy CA, Elston CW, et al. The prognosis of small primary
breast cancers. Eur J Cancer 1999;35:908–912.
46
Davies GC, Millis RR, Hayward JL. Assessment of axillary lymph node
status. Ann Surg 1980;192:148–51.
47
Fisher B, Wolmark N, Bauer M, et al. The accuracy of clinical nodal staging
and of limited axillary dissection as a determinant of histological nodal
status in carcinoma of the breast. Surg Gynaecol Obstet 1981;152:765–72.
References
Management of the axilla in women with breast cancer
43
48
Steele RJC, Forrest APM, Gibson T, et al. The efficacy of lower axillary
sampling in obtaining lymph node status in breast cancer: a controlled
randomised trial. Br J Surg 1985;72:368–9.
49
Krag DN, Ashikaga T, Harlow SP, et al. Development of sentinel node
targeting technique in breast cancer patients. Breast Journal 1998;4:67–74.
50
Turner RR, Ollila DW, Krasne DL, et al. Histopathologic validation of the
sentinel node hypothesis for breast carcinoma. Ann Surg 1997;226(3):271–6;
discussion 276–8.
51
Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy to avoid
axillary dissection in breast cancer with clinically negative lymph-nodes.
Lancet 1997;349:1864–7.
52
Kollias J, Gill P, Chatterton B, et al. Clinical and histological predictors
of sentinel node identification in breast cancer (poster presentation).
6th Nottingham International Breast Cancer Conference, September 1999,
Nottingham, UK.
53
Macmillan RD, Barbera D, Hadjiminas DJ, et al. Prospective comparison
study of sentinel node biopsy and four-node sampling to stage the axilla.
Abstract. 6th Nottingham International Breast Cancer Conference,
September 1999, Nottingham, UK.
54
Sainsbury R, Haward B, Rider L, et al. Influence of clinician workload
and patterns of treatment on survival from breast cancer. Lancet
1995;345:1265–70.
55
Silverstein MJ, Gierson ED, Colburn WJ, et al. Axillary lymphadenectomy
for intraductal carcinoma of the breast. Surg Gynecol Obstet 1991;172:211–4.
56
Wong JS, Recht A, Beard CJ, et al. Treatment outcome after tangential
radiation therapy without axillary dissection in patients with early stage
breast cancer and clinically negative axillary nodes. Int J Radiat Oncol Biol Phys
1997;39(4):915–20.
57
Gray H, Bannister L, Berry M, et al. (eds.). Gray’s Anatomy: the anatomical basis
of medicine and surgery. 38th edition. London: Churchill-Livingston, 1995.
References
44
Management of the axilla in women with breast cancer
58
Dunphy J, Way L (eds.). Current surgical diagnosis and treatment. 10th edition.
San Francisco: Paramount Publishing; Business and Professional, 1994.
59
Danforth DN Jr, Findlay PA, McDonald HD, et al. Complete axillary lymph
node dissection for stage I - II carcinoma of the breast. J Clin Oncol
1986;4:655–62.
60
Davidson T. Why I favour axillary node clearance in the management of
breast cancer. Eur J Surg Oncol 1995;21:5–7.
61
Bundred NJ, Morgan DA, Dixon JM. Management of regional nodes in
breast cancer. In: ABC of Breast Diseases, ed. J Dixon. London: BMJ
Publishing Group, 1995: 30–40.
62
Veronesi U, Rilke F, Luini A, et al. Distribution of axillary node metastases
by level of invasion. Cancer 1987;59(4):682–87.
63
Siegal BM, Mayzel KM, Love SM. Level I and II axillary dissection in the
treatment of early stage breast cancer: an analysis of 259 consecutive
patients. Arch Surg 1990;125:1144–47.
64
Boyages J, Langlands A. Postmastectomy radiation therapy: better late than
never. Aust NZ J Surg 1998;68(8):550–3.
65
Pendlebury SC, Ivanov OG, Renwick S, et al. Eighteen years of breast
conservation at Royal Prince Alfred Hospital: Results and trends over time.
Abstract. RANZCR Annual Scientific Meeting, 1999, Sydney, NSW.
66
Kissin MW, Thompson EM, Price AB, et al. The inadequacy of axillary
sampling in breast cancer. Lancet 1982;1:1210–12.
67
Forrest AP, Everington D, McDonald CC, et al. The Edinburgh randomised
trial of axillary sampling or clearance after mastectomy. Br J Surg
1995;82:1504–8.
68
Shaw JHF, Rumball EM. Complications and local recurrence following
lymphadenectomy. Br J Surg 1990;77:760–4.
References
Management of the axilla in women with breast cancer
45
69
Platt R, Zucker JR, Zaleznik DF, et al. Perioperative antibiotic prophylaxis
and wound infection following breast surgery. J Antimicrob Chemother 1993;31
suppl B:43–8.
70
Hladiuk M, Huchcroft S, Temple W, et al. Arm function after axillary
dissection for breast cancer: a pilot study to provide parameter estimates.
J Surg Oncol 1992;50(1):47–52.
71
Lin PP, Allison DC, Wainstock J, et al. Impact of axillary lymph node
dissection on the therapy of breast cancer patients. J Clin Oncol
1993;11(8):1536–44.
72
Salmon RJ, Ansquer Y, Asselain B. Preservation versus section of
intercosto-brachial nerve in axillary dissection for breast cancer – a
prospective randomised trial. Eur J Surg Oncol 1998;24:158–61.
73
Kissin MW, Querci-della-Rovere G, Easton D, et al. Risk of lymphoedema
following the treatment of breast cancer. Br J Surg 1986;73:580–84.
74
Liljegren G, Holmberg L. Arm morbidity after sector resection and axillary
dissection with or without postoperative radiotherapy in breast cancer stage
I. Results from a randomised trial. Uppsala – Orebro Breast Cancer Study
Group. Eur J Cancer 1997;33(2):193–9.
75
Pierce SM, Recht A, Lingos TI, et al. Long-term radiation complications
following conservative surgery and radiation therapy in patients with early
stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23(5):915–23.
76
Pierquin B, Mazeron JJ and Glaubiger D. Conservative treatment of breast
cancer in Europe: report of the Groupe Européen de Curietherapie.
Radiother Oncol 1990;18:213–20.
77
Bates T, Evans RGB. Report of the independent review commissioned
by the Royal College of Radiologists into brachial plexus neuropathy
following radiotherapy for breast carcinoma. London: Royal College
of Radiologists, 1995.
References
46
Management of the axilla in women with breast cancer
78
Pendlebury SC, Bilous M, Langlands AO. Sarcomas following radiation
therapy for breast cancer: a report of three cases and a review of the
literature. Int J Radiat Oncol Biol Phys 1995;1(2):405–10.
79
Doherty MA, Rodger A, Langlands AO, et al. Multiple primary tumours in
patients treated with radiotherapy for breast cancer. Radiother Oncol
1993;26:125–31.
80
Cabanes RM. An approach for the treatment of penile carcinoma. Cancer
1977;39:456–466.
81
Morton D, Wen D, Cochran A, et al. Management of early stage melanoma
by intraoperative lymphatic mapping and selective lymphadenectomy: an
alternative to routine elective lymphadenectomy or ‘watch and wait’ Surg
Oncol Clin N Am 1992;1:247–59.
82
Giuliano AE, Kirgan DM, Guenther JM et al. Lymphatic mapping and
sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391–401.
83
Uren RF, Howman-Giles RB, Thompson JF, et al. Mammary
lymphoscintigraphy in breast cancer. J Nucl Med 1995;36:1775–80.
84
Rogers CE, Chatterjee S, Mahapatra TK, et al. Improved axillary staging
with sentinel node biopsy. Abstract. 6th Nottingham Breast Cancer
Conference, September 1999, Nottingham, UK.
85
International (Ludwig) Breast Cancer Study Group. Prognostic importance
of occult axillary lymph node micrometastases from breast cancer. Lancet
1990;335:1565–68.
References
Management of the axilla in women with breast cancer
47