Review question
This review aimed to compare the benefits of surgical removal of underarm lymph nodes with the potential harms associated with this surgical procedure. The review also aimed to learn whether complete removal of all underarm nodes could be replaced by procedures that remove only a small number of lymph nodes.
Background
Surgical removal of underarm (axillary) lymph nodes is often part of the initial surgical treatment for patients with operable breast cancer. If cancer has spread to these lymph nodes, patients are advised to undergo additional treatments, such as chemotherapy or radiotherapy, to help treat their disease. If cancer has not spread to these lymph nodes, patients are spared extra treatments (with extra side effects). Surgical removal of lymph nodes can lead to short-term surgical complications (such as infection and wound healing problems) and long-term problems (such as shoulder stiffness, pain and arm swelling (lymphoedema)) when fluid accumulation causes restricted function and discomfort.
Modern strategies use a stepwise approach by first removing a small number of nodes and removing the others only if cancer is found at the first stage. This first stage can consist of ‘random’ axillary sampling, whereby the surgeon removes a small number of nodes (typically four) that can be felt. Alternatively, surgeons can use sentinel node techniques to identify those nodes most likely to contain cancer, leading to removal of as few nodes as possible. For patients with cancer in the sentinel nodes (or sample), complete removal of all underarm lymph nodes (axillary lymph node dissection) is usually recommended; however, radiotherapy to the axilla can also be given to obliterate any cancer cells in the lymph nodes. Some studies have explored alternative approaches such as no surgical treatment to the underarm nodes.
Study characteristics
The evidence is current to March 2015. The review identified 26 randomised controlled trials that compared axillary lymph node dissection (ALND) with alternative approaches involving less axillary surgery. Patients in these trials had operable primary breast cancer, and some trials included patients with palpably enlarged axillary lymph nodes. Ten trials including 3849 patients compared ALND with no axillary surgery. Six trials including 1559 patients compared ALND with axillary sampling. Seven trials including 9426 patients compared ALND with sentinel lymph node biopsy (SLNB). Four trials including 2585 patients compared ALND (with or without radiotherapy) with radiotherapy alone.
Key results
Moderate-quality evidence suggests that patients treated with approaches involving lesser axillary surgery (such as axillary sampling or SLNB) do not have a reduced chance of survival compared with those treated with ALND. Moderate-quality evidence indicates that overall survival is slightly reduced in patients who receive radiotherapy (but no axillary surgery) when compared with ALND. If survival is assumed to be 81% five years after surgery with ALND, then the evidence suggests it would be between 77% and 81% after treatment with radiotherapy alone.
Moderate-quality evidence suggests that patients who have no axillary lymph nodes removed at all are at increased risk of locoregional recurrence (regrowth of cancer, in the breast, mastectomy scar area or underarm glands). If it is assumed that 86% of patients receiving ALND are free of locoregional recurrence five years after surgery, evidence suggests that the corresponding figure for patients who have no lymph nodes removed at all would be between 66% and 76%. For patients treated with axillary sampling, low-quality evidence suggests that between 73% and 87% would be free of locoregional recurrence at five years.
Axillary recurrence rates were reported only in SLNB versus ALND trials, and researchers remain uncertain about the best treatment for this outcome because rates were very low (occurring in less than 1% of patients).
Low-quality evidence suggests that patients treated with ALND are at increased risk of lymphoedema compared with those treated with SLNB or no axillary surgery. On the basis of this evidence, we would expect that out of every 1000 patients receiving ALND, 132 would experience lymphoedema at one year after surgery, compared with between 22 and 115 of those receiving SLNB. Other long-term harms such as pain, impaired arm movement and numbness were also more likely with ALND than with SLNB.
This review confirms the benefit of SLNB and axillary sampling as alternatives to ALND for axillary staging, supporting the view that ALND of the clinically and radiologically uninvolved axilla is no longer acceptable practice in people with breast cancer.
Axillary surgery is an established part of the management of primary breast cancer. It provides staging information to guide adjuvant therapy and potentially local control of axillary disease. Several alternative approaches to axillary surgery are available, most of which aim to spare a proportion of women the morbidity of complete axillary dissection.
To assess the benefits and harms of alternative approaches to axillary surgery (including omitting such surgery altogether) in terms of overall survival; local, regional and distant recurrences; and adverse events.
We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, Pre-MEDLINE, Embase, CENTRAL, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov on 12 March 2015 without language restrictions. We also contacted study authors and checked reference lists.
Randomised controlled trials (RCTs) including women with clinically defined operable primary breast cancer conducted to compare axillary lymph node dissection (ALND) with no axillary surgery, axillary sampling or sentinel lymph node biopsy (SLNB); RCTs comparing axillary sampling with SLNB or no axillary surgery; RCTs comparing SLNB with no axillary surgery; and RCTs comparing ALND with or without radiotherapy (RT) versus RT alone.
Two review authors independently assessed each potentially relevant trial for inclusion. We independently extracted outcome data, risk of bias information and study characteristics from all included trials. We pooled data according to trial interventions, and we used hazard ratios (HRs) for time-to-event outcomes and odds ratios (OR) for binary outcomes.
We included 26 RCTs in this review. Studies were at low or unclear risk of selection bias. Blinding was not done, but this was only considered a source of bias for outcomes with potential for subjectivity in measurements. We found no RCTs of axillary sampling versus SLNB, axillary sampling versus no axillary surgery or SLNB versus no axillary surgery.
No axillary surgery versus ALND
Ten trials involving 3849 participants compared no axillary surgery versus ALND. Moderate quality evidence showed no important differences between overall survival of women in the two groups (HR 1.06, 95% confidence interval (CI) 0.96 to 1.17; 3849 participants; 10 studies) although no axillary surgery increased the risk of locoregional recurrence (HR ranging from 1.10 to 3.06; 20,863 person-years of follow-up; four studies). It was uncertain whether no surgery increased the risk of distant metastasis compared with ALND (HR 1.06, 95% CI 0.87 to 1.30; 946 participants; two studies). Low-quality evidence indicated no axillary surgery decreased the risk of lymphoedema compared with ALND (OR 0.31, 95% CI 0.23 to 0.43; 1714 participants; four studies).
Axillary sampling versus ALND
Six trials involving 1559 participants compared axillary sampling versus ALND. Low-quality evidence indicated similar effectiveness of axillary sampling compared with ALND in terms of overall survival (HR 0.94, 95% CI 0.73 to 1.21; 967 participants; three studies) but it was unclear whether axillary sampling led to increased risk of local recurrence compared with ALND (HR 1.41, 95% CI 0.94 to 2.12; 1404 participants; three studies). The relative effectiveness of axillary sampling and ALND for locoregional recurrence (HR 0.74, 95% CI 0.46 to 1.20; 406 participants; one study) and distant metastasis was uncertain (HR 1.05, 95% CI 0.74 to 1.49; 406 participants; one study). Lymphoedema was less likely after axillary sampling than after ALND (OR 0.32, 95% CI 0.13 to 0.81; 80 participants; one study).
SLNB versus ALND
Seven trials involving 9426 participants compared SLNB with ALND. Moderate-quality evidence showed similar overall survival following SLNB compared with ALND (HR 1.05, 95% CI 0.89 to 1.25; 6352 participants; three studies; moderate-quality evidence). Differences in local recurrence (HR 0.94, 95% CI 0.24 to 3.77; 516 participants; one study), locoregional recurrence (HR 0.96, 95% CI 0.74 to 1.24; 5611 participants; one study) and distant metastasis (HR 0.80, 95% CI 0.42 to 1.53; 516 participants; one study) were uncertain. However, studies showed little absolute difference in the aforementioned outcomes. Lymphoedema was less likely after SLNB than ALND (OR ranged from 0.04 to 0.60; three studies; 1965 participants; low-quality evidence). Three studies including 1755 participants reported quality of life: Investigators in two studies found quality of life better after SLNB than ALND, and in the other study observed no difference.
RT versus ALND
Four trials involving 2585 participants compared RT alone with ALND (with or without RT). High-quality evidence indicated that overall survival was reduced among women treated with radiotherapy alone compared with those treated with ALND (HR 1.10, 95% CI 1.00 to 1.21; 2469 participants; four studies), and local recurrence was less likely in women treated with radiotherapy than in those treated with ALND (HR 0.80, 95% CI 0.64 to 0.99; 22,256 person-years of follow-up; four studies). Risk of distant metastasis was similar for radiotherapy alone as for ALND (HR 1.07, 95% CI 0.93 to 1.25; 1313 participants; one study), and whether lymphoedema was less likely after RT alone than ALND remained uncertain (OR 0.47, 95% CI 0.16 to 1.44; 200 participants; one study).
Less surgery versus ALND
When combining results from all trials, treatment involving less surgery was associated with reduced overall survival compared with ALND (HR 1.08, 95% CI 1.01 to 1.16; 12,864 participants; 19 studies). Whether local recurrence was reduced with less axillary surgery when compared with ALND was uncertain (HR 0.90, 95% CI 0.75 to 1.09; 24,176 participant-years of follow up; eight studies). Locoregional recurrence was more likely with less surgery than with ALND (HR 1.53, 95% CI 1.31 to 1.78; 26,880 participant-years of follow-up; seven studies). Whether risk of distant metastasis was increased after less axillary surgery compared with ALND was uncertain (HR 1.07, 95% CI 0.95 to 1.20; 2665 participants; five studies). Lymphoedema was less likely after less axillary surgery than with ALND (OR 0.37, 95% CI 0.29 to 0.46; 3964 participants; nine studies).
No studies reported on disease control in the axilla.