Axillary dissection in women with sentinel node metastasisBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2510 (Published 16 May 2011) Cite this as: BMJ 2011;342:d2510
- John Rescigno, MD1,
- Deborah Axelrod, MD
- 1Department of Radiation Oncology, Beth Israel Medical Center, New York, NY 10011, USA
- 3Department of Surgery, New York University School of Medicine, New York, NY, USA
Randomised trials published over 15 years ago established local excision, level I and II axillary lymph node dissection (ALND), and whole breast radiotherapy as appropriate locoregional treatment for women with early stage breast cancer. The recent publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial will reduce the use of ALND in women with positive sentinel lymph node biopsy (SLNB).1 The ACOSOG Z0011 trial compared ALND or no ALND in women with clinically negative axilla, no more than two sentinel lymph nodes affected (with no gross extracapsular extension), and primary tumour less than 5 cm who received lumpectomy, postoperative whole breast radiation, and appropriate systemic treatment.1 The trial was timely because about a third of women with a positive SLNB in the United States during the time of enrolment (1999-2005) did not undergo completion ALND after SLNB despite guidelines recommending it.2 As a non-inferiority trial, 1900 patients were needed to show with 90% confidence that the hazard ratio for overall survival did not include 1.3 in the patients who had no ALND, with final analysis after 500 deaths. Because the mortality rate in both arms was lower than expected, an independent data and safety monitoring committee recommendation resulted in only 891 patients being enrolled. Only 94 deaths occurred over a median follow-up of 6.3 years, which is a testament to the effectiveness of modern systemic treatments and radiotherapy, even in the absence of ALND. Factors such as patient withdrawal (35 patients), failure to receive the assigned treatment (43 patients), poor follow-up (166 patients), and poor study design or implementation will tend to negate the outcome of a superiority trial but artificially support a trial designed to show non-inferiority, so additional scrutiny of such trials is warranted.
Potential biases in enrolment could have been introduced during randomisation, because most patients were selected after final pathology results were available. Academic centres were less likely to enrol patients and 115 institutions participated, so many surgeons enrolled a small number of patients.3 It is therefore surprising that these patients’ clinical characteristics including age, T stage, oestrogen and progesterone receptor status, and tumour histology were not significantly different from those who had lumpectomy in the general US population (J Rescigno, unpublished; based on Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Limited-Use Data (1973–2004), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2007). However, the proportion of patients with grade 3 cancers enrolled in the trial was lower than in the general population (29% v 39%). Furthermore, non-significant imbalances in prognostic factors between arms—such as T1 stage, progesterone receptor positivity, low grade, and absence of lymphovascular space invasion—were consistently in favour of the SLNB alone arm. Tumour grade and lymphovascular space invasion were unknown in about a quarter of patients. Those in the SLNB arm were also more likely to have no lymph node involvement (7% v 1.2%), and it is unclear why such patients were randomised.
Although non-inferiority was not proved on the basis of initial statistical assumptions, the fact that these assumptions were incorrect does not negate the results. Only 3% of patients experienced locoregional recurrence. More than 75% of locoregional recurrences are expected to occur by five years, and such recurrences influence overall survival at 15 years when the difference is greater than 10% in absolute terms.4 Therefore, survival will not differ between the treatment arms at long term follow-up.
It is counterintuitive that disease left in the axilla in potentially more than 25% of the patients who received SLNB alone did not result in higher recurrence rates. Preoperative chemotherapy trials suggest that chemotherapy can eradicate disease in the lymph nodes in a third of node positive patients.5 Antioestrogen drugs are associated with low locoregional relapse in selected patients who do not undergo radiotherapy or ALND.6 Also, traditional tangential radiation to the whole breast treats a large portion of the axilla, and minor changes to tangential radiotherapy can allow full therapeutic dose to levels I and II.7 8
What does this all mean in practice? A two stage procedure of initial local excision and SLNB, followed by further discussion of ALND if the SLNB is positive is appropriate for most patients. Preoperative consent for ALND is no longer universally necessary, and neither is intraoperative assessment of the SLNB specimen. ALND remains necessary for women who have tumours larger than 5 cm, those who require mastectomy, or when partial breast radiation is planned. Completion ALND should be considered in women who on the basis of available nomograms are at particularly high risk of residual nodal disease, as well as those with high grade tumours, lymphovascular invasion, or extracapsular extension. Women who wish to avoid chemotherapy and those with comorbidities may also benefit from ALND, so that the absolute benefit of chemotherapy can be more accurately assessed on the basis of the number of axillary lymph nodes affected. Also, further research is needed to know if patients whose tumours respond well to preoperative chemotherapy can be spared ALND. Lastly, more than a fifth of women in the trial who underwent ALND had three or more axillary lymph nodes affected, in which case infraclavicular and supraclavicular radiotherapy would have been considered, but was prohibited in this trial. Given the excellent locoregional control demonstrated, it is reasonable to avoid infraclavicular and supraclavicular radiation in such patients. However, in the absence of specific information on radiotherapy field design, it is prudent to modify tangential breast fields to encompass levels I and II in node positive patients who undergo SLNB alone.
There is a now a new option for selected women with positive sentinel lymph node biopsy to avoid the morbidity of ALND. About 15% of all women diagnosed with invasive breast cancer are eligible for this new approach.
Cite this as: BMJ 2011;342:d2510
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.