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Clinical Update - Breast Cancer

Clinical Update Issue 24 - July 2006 - ISSN 1328-9454

RANDOMIZED MULTICENTER TRIAL OF SENTINEL NODE BIOPSY VERSUS STANDARD AXILLARY TREATMENT IN OPERABLE BREAST CANCER: THE ALMANAC TRIAL

Commentary by Mr Andrew Spillane

The article:

Mansel RE, Fallowfield L, Kissin M et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC Trial. J Natl Cancer Inst 2006;98:599–609

Reviewer:

Mr Andrew Spillane is a surgical oncologist at the Royal Prince Alfred and Mater Hospitals in Sydney. He has a special interest in breast cancer.

In this issue...

• Article summary
• What does this article add to existing clinical evidence in this area?
• How adequate was the methodology used in addressing the aims of the study?
• What are the implications of the study for clinical practice in Australia?

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Summary

Abbreviations

Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC); Confidence Interval (CI); Functional Assessment of Cancer Therapy – Breast + 4 (FACT-B+4); Relative Risk (RR); Spielberger State/Trait Anxiety Inventory (STAI); Trial Outcome Index (TOI)

Study design

This article describes a randomised trial comparing sentinel lymph node biopsy with standard axillary clearance in women with early-stage breast cancer with clinically negative nodes. Between November 1999 and October 2003, 1031 patients were recruited from 11 centres in the UK and were randomly assigned to undergo sentinel lymph node biopsy or standard axillary surgery. Of these, 954 patients were eligible for intention-to-treat analysis. The primary outcome measures were postoperative arm and shoulder morbidity and quality of life. Postoperative arm and shoulder morbidity were assessed by measuring levels of lymphoedema, sensory deficit and shoulder function. Quality of life was assessed using the FACT-B+4 questionnaire (FACT-B plus four additional arm morbidity items) to give TOI and arm functioning subscale scores. STAI scores were also measured to assess anxiety of the patients. Other efficacy assessments were also identified. Assessments were made at 1, 3, 6 and 12 months after surgery.

Findings

Postoperative arm morbidity assessments

The following arm morbidity assessments were reported less often by patients in the sentinel lymph node biopsy group than by those in the standard axillary treatment group:

• lymphoedema (RR at 12 months: 0.37; 95% CI: 0.23 to 0.60; p<0.001)
• sensory deficit (RR at 12 months: 0.37; 95% CI: 0.27 to 0.50; p<0.001).

Other than shoulder flexion and abduction being more impaired in the standard axillary treatment group at 1 month after surgery (p=0.004 and 0.001, respectively), there were no statistically significant differences in shoulder function between the two groups.

Quality of life assessments

After surgery, quality of life decreased in both patient groups; however it decreased less in patients in the sentinel lymph node biopsy group than in those in the standard axillary treatment group. The following quality of life assessment scores were higher in the sentinel lymph node biopsy group compared to those in the standard axillary treatment group (higher scores indicate a better quality of life):

• TOI scores (1 month p<0.001; 3, 6 and 12 months p=0.001)
• arm functioning subscale scores (p<0.001 at all assessment points)
• overall FACT-B+4 scores (1 month p<0.001; 3 months p=0.001; 6 months p=0.003; 12 months p=0.002).

There was no difference in the STAI scores between the treatment groups.

Other efficacy assessments

The following endpoints were lower in the sentinel lymph node biopsy group than the standard axillary treatment group:

• length of hospital stay (4.1 days vs 5.4 days, p<0.001)
• axillary drain usage (17% vs 79%, p<0.001)
• time to resumption of normal day-to-day activities (p<0.001).

Conclusion

The authors found that for women with early-stage breast cancer with clinically negative nodes, sentinel lymph node biopsy was associated with reduced arm morbidity and better quality of life compared to standard axillary treatment, with no increase in anxiety.

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What does this article add to existing clinical evidence in this area?

Over the past 10 years, sentinel node biopsy (SNB) has progressively become the standard of care for clinically node negative early breast cancer (EBC) around the world. In the United Kingdom the inception of SNB was slower than in many other countries. The ALMANAC trial enabled a quality assured mechanism for the wider introduction of the technique and has acted as a foundation for the ongoing ‘New Start’ quality assurance program.

The ALMANAC trial involved comparison of the new SNB technique with the old axillary dissection or axillary sampling techniques. It is the first of the three larger randomised controlled trials to be published [1–3] after earlier publication of the smaller randomised study from Milan [4]. 

This study substantially confirms the significantly lower morbidity of SNB compared to alternative axillary surgery. The analysis of morbidity/quality of life (QOL) data in the SNB group included the 26% of cases that were positive and went on to have further axillary dissection or radiotherapy. This further emphasises the lesser morbidity of SNB alone. 

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How adequate was the methodology used in addressing the aims of the study?

This is a pragmatically structured trial. Well-validated tools were used to assess morbidity and QOL endpoints. However there are methodological issues and other details worthy of emphasis.

These include:

1. There were only 13 contributing surgeons from 11 centres.
2. There was no SNB in the control arm. Thus false negative rate can’t be calculated.
3. The inclusion of 4 node sampling in the standard treatment arm (n=123) may have led to an underestimate of the benefit of SNB. This technique is not widely used outside the UK.
4. Pathological assessment of the lymph nodes involved simple bisection if the nodes were <5 mm while nodes ≥ 5 mm had 3 mm intervals with H&E staining only. There was no frozen section or immunohistochemistry. This is a less thorough examination than would be performed at most Australian centres.
5. The group of 121 patients with positive SNB had completion axillary dissection (n=83), axillary radiotherapy (n=33) or no further treatment (n=5).  In Australia, almost all patients with a positive sentinel node receive axillary dissection. Radiotherapy is not commonly used instead of surgery. This comparison of surgery to radiotherapy after a positive SNB is being examined in EORTC Study 10981/22023 (AMAROS).
6. The tumours were ≤ 2 cm in 72% of cases in the SNB group compared to 78% in the control group. This seems to be an unusual imbalance in the randomisation favouring the standard treatment arm with lower risk patients. The high prevalence of smaller tumours indicates the patient population has a good prognosis/low risk, despite the trial being open to all size tumours. Larger tumours are under-represented, so the low risk of recurrence may not be generalisable to all tumours. This has relevance when considering the value of the SNAC2 trial.
7. 92% of patients in both arms of the study had breast conservation. Again this confirms the good prognosis for this patient group. However, this does not represent the case mix of most Australian breast cancer centres.
8. Axillary local recurrence events favoured the study group (1 in SNB vs 4 in standard treatment - not statistically significant).

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What are the implications of the study for clinical practice in Australia?

The ALMANAC trial provides further evidence of the lower morbidity rate and improved QOL for SNB in early breast cancer with at least equivalent information about axillary staging. There are too few breast cancer recurrences to determine if regional control is as good with SNB as it is with axillary clearance.

The Royal Australasian College of Surgeons SNAC trial will report on 1 year outcomes later this year. SNAC is a more stringently designed study and is likely to have a cleaner data set with greater relevance to local practice patterns. SNAC2 will determine if SNB is more suitable for women with tumours that are larger or multifocal. Already it is clear that SNB is a reasonable alternative to other axillary surgery for EBC when the surgeon has audited his/her performance and shown it to be satisfactory.

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References

1. Mansel RE, Fallowfield L, Kissin M et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC Trial. J Natl Cancer Inst 2006;98:599–609
2. Krag DN, Julian TB, Harlow SP et al. NSABP-32: Phase III, randomized trial comparing axillary resection with sentinel lymph node dissection: a description of the trial. Ann Surg Oncol 2004;11(3 Suppl):208S–10S
3. Wetzig NR, Gill PG, Ung O et al for the RACS SNAC Group. Participation in the RACS sentinel node biopsy versus axillary clearance trial. ANZ J Surg 2005;75(3):98–100
4. Veronesi U, Paganelli G, Viale G et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546–53

Disclaimer:
Clinical Update is produced by the National Breast Cancer Centre (NBCC) and is intended to provide health professionals with timely expert commentary on new research in breast cancer. Commentaries included in Clinical Update do not replace recommendations included in NBCC clinical practice guidelines.
Information contained in Clinical Update is not intended to be used as substitute for an independent health professional's advice. The NBCC does not accept any liability for any injury, loss or damage incurred by use of or reliance on the information contained in Clinical Update. The NBCC develops material based on the best available evidence however cannot guarantee and assumes no legal liability or responsibility for the currency or completeness of the information.

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