Management of the axilla in women with breast cancer · Important notice Management of the axilla in women with breast cancer i Important Notice This document is a guide to appropriate

in women with breast cancer Management of the axilla

First edition

M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r

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

I m p o r t a n t n o t i c e

M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r i

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.

I m p o r t a n t n o t i c e

ii M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r

Contents

M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r iii

Contents

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

page

C o n t e n t s

iv M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r

L i s t o f a b b r e v i a t i o n s

M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r 1

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

L i s t o f a b b r e v i a t i o n s

2 M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r

F o r e w o r d


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.

F o r e w o r d


E x e c u t i v e s u m m a r y


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.

E x e c u t i v e s u m m a r y


M a n a g e m e n t o f t h e a x i l l a i n w o m e n w i t h b r e a s t c a n c e r


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

M a n a g e m e n t o f t h e A x i l l a i n W o m e n w i t h B r e a s t C a n c e r


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.



The consequence of uncontrolled disease in the axilla

Regional axil lary 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.



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 non-

dissected 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.



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.



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.



Axillary irradiation following dissection in women with l imited 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.



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.



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.



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.



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.



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



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.



C l i n i c a l p r a c t i c e r e c o m m e n d a t i o n


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).54

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.



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



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).6,36,56

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.

• Patient choice: Some patients may not wish to have further surgery.

5 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.



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.

A p p e n d i x 1


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

A p p e n d i x I


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 costo-

clavicular (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

A p p e n d i x I


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.

A p p e n d i x I


A p p e n d i x I I


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.

A p p e n d i x I I


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.

A p p e n d i x I I


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

Lymphoedema9

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

A p p e n d i x I I


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

A p p e n d i x I I I


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.



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



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.



A p p e n d i x I V


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.



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.

R e f e r e n c e s


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Management of the axilla in women with breast cancer · Important notice Management of the axilla in women with breast cancer i Important Notice This document is a guide to appropriate