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Recommendations for staging and managing the axilla

Summary of trial or study results

AXILLARY STAGING

SURGICAL STAGING

Optimal extent of axillary dissection for staging

The findings of several non-randomised studies41, 67, 79-80 suggest that the optimal number of nodes examined by the pathologist to achieve maximal accuracy was approximately 20. Conflicting findings were reported by 13 studies27-28, 31-32, 41-43, 76, 79, 82, 89-90, 94 that investigated the association between the number of nodes excised during dissection and clinical outcomes, including survival and axillary recurrence.

Sentinel node biopsy

Sentinel node biopsy is an accurate and suitable alternative to axillary dissection and is recommended for women with unifocal breast cancer tumours that are three centimetres or less in diameter and with clinically negative nodes. The significance of micrometastases in the sentinel node is yet to be established. For comprehensive guidelines on sentinel node biopsy, please refer to the NBOCC Recommendations for use of sentinel node biopsy in early (operable) breast cancer, 2008.2 Relevant recommendations from this guideline include:

If the sentinel node is identified at the time of sentinel node biopsy:

  • For a positive sentinel node – axillary dissection is recommended (with due consideration of the risks and benefits to the individual woman)
  • For a negative sentinel node – clinical follow-up of the axilla is recommended.

If the sentinel node is not identified at the time of sentinel node biopsy:

  • axillary dissection should be performed.

New evidence published since 2008
Positive sentinel nodes

A recent randomised trial of 891 patients (with 446 patients randomised to no further surgery after a positive sentinel node was detected) reported results in 2011.18* Results indicate that for a select group of women (those with clinical T1-T2 invasive breast cancer, no palpable lymphadenopathy and 1 to 2 positive sentinel lymph nodes, who are treated with breast-conserving surgery, whole-breast irradiation and adjuvant systemic therapy) 5-year overall survival was not significantly different between groups randomised to axillary lymph node dissection (ALND) or to sentinel lymph node dissection (SLND) alone.18 It should be noted that accrual to this trial closed earlier than anticipated due to lower than expected accrual and event rates. Due to the select group of women enrolled in the trial, the applicability of these results should be considered.

There were no significant differences between the groups in 5-year disease-free survival, in 5-year rate of local recurrence or in locoregional recurrence-free survival at 5 years.  Surgical morbidities were higher for the group undergoing ALND than for the SLND-alone group (rate of wound infections, axillary seromas and paresthesias; p<0.001), and lymphoedema was significantly more common in the ALND group by subjective report (p<0.001). It should be noted that this study refers only to women who had lumpectomy and whole-breast irradiation.18 

Positive non-sentinel nodes

In the Z0011 trial, 27.3% of women in the ALND group had additional metastasis in non-sentinel lymph nodes removed by ALND, including 10% of women with sentinel node micrometastasis who had macroscopically involved non-sentinel nodes.18

A meta-analysis of 56 studies to June 2009, where patients had positive sentinel node/s and underwent ALND, reported the proportion of patients with positive non-sentinel nodes ranged from 24 to 65.7% (median 38%).124* The meta-analysis identified eight clinicopathological variables most predictive of non-sentinel node metastases when the sentinel node is positive: SLN metastases >2mm in size, extracapsular extension in the SLN, >1 positive SLN, ≤1 negative SLN, tumour size >2cm, ratio of positive sentinel nodes >50% and lymphovascular invasion in the primary tumour and method of detection.124

Negative sentinel nodes

Further results of a randomised controlled trial confirm that in patients with negative sentinel nodes, sentinel node biopsy alone with no further axillary dissection, is an appropriate, safe and effective therapy for patients with clinically negative lymph nodes.33* Sentinel node biopsy was found to be statistically equivalent to axillary dissection for overall survival, disease-free survival and regional control in node-negative patients.

Axillary sampling

Pooled 15-year follow-up data34 showed that four-node sampling (a staging procedure comprising excision and biopsy of four lymph nodes) was associated with a significantly higher rate of axillary recurrence than axillary dissection in the subgroup of patients assessed as node-negative. However, randomised clinical trial outcome data for four-node sampling are only available from a single centre, and therefore must be interpreted with caution. Two non-randomised trials72,88 using axillary dissection as the reference standard reported that four-node sampling was an accurate method for staging breast cancer.

NON-SURGICAL STAGING (IMAGING)

There is insufficient evidence for the accuracy of imaging modalities (ultrasound, magnetic resonance spectroscopy, MRI or PET) in axillary staging in the absence of confirmatory pathology. Imaging alone remains unreliable as a diagnostic test for axillary lymph node involvement in early breast cancer due to its low sensitivity.

Ultrasound

The overall accuracy of ultrasound alone ranged from 70% to 82% in studies using axillary dissection and/or sentinel node biopsy as the reference standard.6, 9-10, 13, 36, 97, 99, 101 Accuracy approached 93% where ultrasound was performed in combination with either cytology fine needle aspiration or histology core biopsy.9, 36-38, 78, 96-97 These results suggest that preoperative ultrasound Ă‚± FNA/core biopsy may be useful in staging the clinically negative axilla. A preoperative finding of ultrasound-positive nodes confirmed by FNA or core biopsy might allow the patient to proceed to axillary clearance immediately, without initial sentinel node biopsy. However due to the low negative predictive value of ultrasound, a negative result on ultrasound plus FNA/core biopsy would not remove the need for surgical axillary staging.

Magnetic resonance imaging (MRI)

The utility of MRI is limited by technical difficulties and lack of standardised criteria for a positive lymph node.14, 39 Two small studies14, 39 in which patients underwent dynamic contrast-enhanced MRI prior to planned level I/II axillary dissection, reported positive predictive values of 38–83% and negative predictive values of 90–100%. Available data suggest that a positive finding on axillary MRI must be carefully interpreted and requires surgical confirmation.

Positron emission tomography (PET)

Reported results on the accuracy of PET must be interpreted with caution, due to wide variability and the small size of several studies.15-16, 103-106, 108 With findings on axillary dissection as the reference standard, the overall negative predictive value was low. Reported specificity was generally relatively high (80–100%), with the largest series107,110-111 (n > 230 for each) reporting specificity values of 80–98.5% and positive predictive values of 62–98.4%. Therefore, axillary lymph node dissection may be more appropriate than a confirmatory sentinel node biopsy for axillary staging in patients with PET-positive axillary nodes to minimise the number of procedures for the woman. Sentinel node biopsy may still be considered, however, to avoid unnecessary axillary dissection due to the possibility of false positives. The results of one small study suggest that a combination of PET and ultrasound may increase sensitivity and accuracy compared to either modality alone, however the difference was not statistically significant.101

* This paper was published after NBOCC systematic review was completed

TREATMENT

DISEASE-FREE SURVIVAL

Axillary dissection

Overall axillary recurrence rates are low following axillary dissection.1

Available evidence suggests there is no difference between level I/II axillary dissection and level III axillary dissection with respect to local recurrence. Two large randomised controlled clinical trials19-20 with median follow-up intervals of more than seven years reported no statistically significant difference in disease-free survival, axillary recurrence or local recurrence between patients who underwent level I dissection compared with level III dissection20 and between patients who underwent level II dissection compared with level III dissection.19

It may, however, be appropriate to perform a level III axillary clearance in certain clinical situations, in particular when obviously involved nodes are present in level III of the axilla.

The subgroup of patients at high risk of axillary recurrence following axillary dissection is not well defined due to limited data. Among older patients with clinically node-negative disease, at low risk of recurrence, two small randomised controlled clinical trials23-24  comparing axillary dissection with observation reported no difference in rates of overall survival or local control. In the single study with the longest follow-up (NSABP04),22 axillary dissection was not associated with a survival benefit, compared with mastectomy alone followed by observation or radiotherapy in clinically node-negative patients. However, local recurrence rates were high in this study population.22

Axillary radiotherapy

A randomised controlled clinical trial55 comparing breast-conserving surgery plus radiotherapy with two opposed fields (antero-posterior and postero-anterior) with surgery alone in clinically node-negative women aged over 45 years reported no significant difference in axillary recurrence rates between groups. However, the axillary recurrence rate was very low in both treatment arms.

Axillary radiotherapy versus axillary dissection

At 25-year follow-up of the NSABP04 trial,22 postmastectomy regional radiotherapy delivered to the internal mammary nodes,  the supraclavicular nodes and the chest wall was not associated with an overall improvement in local or systemic control, either in the clinically node-negative group (compared with total mastectomy and axillary dissection or radical mastectomy alone) or in the clinically node-positive group (compared with radical mastectomy). However, among the group with negative nodes at baseline, the cumulative incidence of local or regional recurrence was lowest (1% and 4% respectively) in the group who received total mastectomy and radiotherapy.22 The incidence of regional axillary recurrence was 4% for women who had radical mastectomy and axillary dissection; however this increased to 6% if surgery was delayed until recurrence.22 Interpretation of early results from randomised trials requires caution as after 25-year follow-up, 25% of all first distant recurrences and 50% of all contralateral breast cancers were detected after 5 years.22

Pooled 15-year follow-up data from two randomised controlled clinical trials34 reported that, for node-positive patients, axillary radiotherapy was associated with a non-significant trend towards reduced axillary recurrence, compared with axillary dissection alone. Fifteen-year follow-up data from a randomised trial in women with clinically uninvolved lymph nodes21 that compared axillary radiotherapy to axillary and internal mammary lymph nodes (n=332) with axillary dissection (n=326) reported no significant difference in disease-free survival between treatment groups. No improvement in axillary recurrence rates were reported in other recent non-randomised studies73-74, 117, 120 comparing axillary radiotherapy with axillary dissection.

Axillary radiotherapy post-axillary dissection

In subgroup analysis of 15-year follow-up data from the DBCG 82 b&c randomised controlled clinical trials25 conducted in high-risk patients, radiotherapy to the chest wall and regional lymph nodes (internal mammary nodes, peri-clavicular nodes, and the axilla) reduced the 15-year loco-regional failure rate from 51% to 10% (p<0.001) for patients with four or more positive nodes, and from 27% to 4% (p<0.001) for patients with one to three positive nodes.

In a small (n=76) randomised controlled trial54 comparing axillary radiotherapy with no radiotherapy in patients who had undergone mastectomy and axillary node sampling, axillary radiotherapy was associated with a significant reduction in loco-regional recurrence at 10 years post surgery (65% vs 25%, p<0.001) .

A non-randomised study45 reported that regional nodal irradiation reduced the rate of axillary relapse in patients with four or more positive lymph nodes at 8-year follow-up. No differences in survival or locoregional recurrence were reported in other non-randomised case series comparing axillary surgery plus radiotherapy with axillary surgery alone.

OVERALL SURVIVAL

Axillary dissection

Recent survival data are mainly derived from two randomised controlled clinical trials23-24 that compared axillary dissection with surgery alone in patients undergoing mastectomy or breast-conserving surgery. The IBCSG23 (n=473) compared surgery (either a total mastectomy or breast-conserving surgery) plus level III axillary dissection with surgery alone in women aged 60 years or older with clinically negative axillary nodes. At a median follow-up of 6.6 years, there was no significant difference in overall survival between groups. However, the findings must be interpreted with caution because approximately one third of patients in the non-axillary dissection group received breast radiotherapy.23 Another small (n=76) randomised controlled trial24 compared breast-conserving surgery plus axillary dissection with breast-conserving surgery alone in women aged 65–80 years with clinically negative axillary nodes who also received five years’ tamoxifen treatment. No significant difference in overall survival between groups was observed.24

Further survival data are available from the 25-year follow-up of the NSABP04 randomised clinical trial.22 A subgroup (n=1079) of women with clinically node-negative breast cancer, of whom 70% were aged over 50 years, were randomised to undergo either mastectomy plus axillary dissection, mastectomy alone (with axillary dissection if nodes became clinically positive; 68, or 18.6%, of the 365 in this group subsequently had positive ipsilateral nodes, removed by delayed axillary dissection), or mastectomy plus radiotherapy. Those in a second clinically node-positive subgroup (n=586) were randomised to undergo either mastectomy plus axillary dissection or mastectomy plus radiotherapy. Lymph nodes were found in a proportion of specimens removed in those designated mastectomy only, however no nodes were found in 65% of specimens in this group. In the mastectomy only group, the mean number of nodes removed was 2 (median 0), whereas in the mastectomy plus axillary dissection group, the mean was 18 (median 16).125 At 25 years follow-up, there were no significant differences in survival rates between those who underwent axillary dissection and those who did not, for both the node-positive and node-negative subgroups.22

Available evidence suggests there is no difference between level I/II axillary dissection and level III axillary dissection with respect to survival outcomes. Two large randomised controlled clinical trials19-20 with median follow-up intervals of more than 7 years reported no statistically significant difference in overall survival rates between patients who underwent level I dissection compared with level III dissection20 and between patients who underwent level II dissection compared with level III dissection.19

Axillary radiotherapy

A 2006 systematic review49 of randomised clinical trials concluded that optimal postmastectomy radiotherapy (targeting the chest wall, axillary lymph nodes, and the supraclavicular fossa with or without the internal mammary lymph nodes) was associated with a 2.9% absolute increase in survival at follow-up intervals of up to 10 years. An earlier systematic review (2000)52 reported that radiotherapy improved survival in the more recent trials and those which used current techniques.

A randomised controlled clinical trial55 comparing breast-conserving surgery plus axillary radiotherapy with breast-conserving surgery alone in clinically node-negative women aged over 45 years reported significantly higher overall survival among the radiotherapy group at 5-year follow-up.

However, other trials did not report survival benefits. Fifteen-year follow-up data from two SBCSG randomised trials58 comparing radiotherapy with adjuvant chemotherapy in high-risk patients (node-positive disease or a tumour diameter > 30 mm) showed no statistically significant difference in overall survival rates between groups. However, a non-significant survival trend in favour of chemotherapy was observed among premenopausal women (50% vs. 44%), and chemotherapy halved the risk of a second primary malignancy, compared with radiotherapy.58 Axillary radiotherapy was not associated with a survival benefit at 12-year follow-up in a small (n=76) randomised controlled trial54 comparing axillary radiotherapy with no radiotherapy in patients who had undergone mastectomy and axillary node sampling.

Axillary radiotherapy versus axillary dissection

Twenty-five year follow-up data are available from the NSABP04 randomised clinical trial,22 in which node-negative patients (n=1079) were randomised to receive either mastectomy plus axillary dissection, mastectomy alone (with axillary dissection if nodes became clinically positive), or mastectomy plus regional radiotherapy, and clinically node-positive women (n=586) were randomised to receive either mastectomy plus axillary dissection or mastectomy plus regional radiotherapy. Radiotherapy was not associated with a survival benefit in either the clinically node-negative or node-positive subgroup.22

Fifteen-year follow-up data from a randomised trial in women with clinically uninvolved lymph nodes21 that compared axillary radiotherapy (n=332) with axillary dissection (n=326) reported no significant difference in overall survival between treatment groups, despite an earlier difference in favour of axillary dissection. Other recent non-randomised studies118-120 comparing radiotherapy with axillary dissection did not report a significant survival benefit associated with axillary radiotherapy.

A number of studies reported in a systematic review4 demonstrated favourable survival rates among patients who underwent treatment regimens that included irradiation of the axilla. The degree to which the axillary radiotherapy component of therapy contributed to survival benefit is unclear.  Axillary radiotherapy does not appear to show significant survival advantage;22 however may be worthwhile in selected patients who are not candidates for axillary surgery.

Axillary radiotherapy post-axillary dissection

In subgroup analysis of 15-year follow-up data from the DBCG 82 b&c randomised controlled clinical trials,25 radiotherapy significantly improved survival, compared with observation, in high-risk patients who had undergone axillary dissection. This benefit was observed for patients with 1–3 positive nodes (57% vs. 48%, p=0.03) and four or more positive nodes (21% vs. 12%, p=0.03).25

ADVERSE EVENTS

LYMPHOEDEMA

A significant potential side effect after surgery and/or radiotherapy is secondary lymphoedema, affecting approximately 20% of breast cancer survivors.126 Axillary dissection is associated with increased risk of lymphoedema.2, 127 In the IBCSG trial23 in patients aged 60 years and over, axillary dissection did not result in a significantly increased mean arm circumference or lymphoedema rate, compared with observation. Axillary dissection resulted in a numerically higher rate of early lymphoedema than four-node sampling (4% versus 2%) in a randomised controlled clinical trial53 for which 5-year follow-up data are available. Swelling resolved over time in the sampling group and, at 3 years after surgery, patients who had undergone sampling showed significantly smaller forearm girth than those who had undergone axillary dissection.53 The results of the axillary clearance arm of the RACS SNAC trial provide valuable information regarding lymphoedema rate noted prospectively and the timing of onset.128

Radiotherapy (administered as clinically indicated) resulted in a similar rate of lymphoedema as axillary dissection in the randomised controlled clinical trial8 comparing level III axillary dissection with axillary node sampling. Radiotherapy was associated with mild-to-moderate lymphoedema in 6% of patients in a small randomised controlled clinical trial54 that compared radiotherapy with observation following mastectomy and axillary node sampling in women with node-positive breast cancer. Some non-randomised comparative trials reported higher rates of lymphoedema among patients who received radiotherapy compared with those who underwent axillary dissection alone.44, 115, 120

SHOULDER MOVEMENT

Axillary dissection resulted in higher rates of arm restriction (39% versus 15%) and pain (23% versus 7%) at the first postoperative visit, compared with observation in the IBCSG trial.23

Axillary dissection, but not node sampling or radiotherapy, was associated with a slight reduction in shoulder movement at 3-year follow-up in a randomised controlled trial53 comparing level III axillary dissection with axillary node sampling, in which selected patients received radiotherapy (n=54).

Radiotherapy following axillary sampling was associated with a significantly greater reduction in range of shoulder flexion than node sampling alone in the same node-sampling randomised controlled trial.53 Radiotherapy also reduced lateral and medial shoulder rotation at 6 months, compared with no radiotherapy, but this improved over time. Patients who underwent radiotherapy also showed reduced shoulder muscle power persisting up to 1 year, but no effect persisted at 3 years.53

OTHER ADVERSE EVENTS

In one study,73-74 pneumonitis was reported in 4% of those who receive radiotherapy to the breast and regional lymphatics, with a numerically higher rate among those who also received chemotherapy. Brachial plexus neuropathy occurred in 1% of patients who received radiotherapy, but resolved completely within 30 months.73

LONG-TERM ADVERSE EVENTS

Findings from the IBSCG trial23 suggest that the increase in adverse effects associated with axillary dissection, compared with no dissection, do not persist long term.

Compared with level I or I/II dissection, level III dissection did not result in increased long-term morbidity such as oedema, arm pain, motor function, social functioning or pectoralis major muscle atrophy in two randomised clinical trials.19-20

QUALITY OF LIFE

Data on quality of life were not consistently reported in trials and studies of axilla management.

Axillary dissection

The IBCSG study23 reported a reduction in arm-related quality of life, compared with no axillary surgery. However, at 6-year follow-up, there was no significant difference in quality of life between patients who underwent axillary dissection and those who underwent breast surgery without axillary dissection.23

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