Non-surgical management of the axilla.
BackgroundIn the context of early breast cancer, surgery has formed the cornerstone of the staging and treatment of the axillary lymph nodes. Historically, the standard of care was a full axillary lymph node clearance in keeping with the radical surgical philosophy of the time. This was then superseded by sampling of the lower-echelon lymph nodes of the axilla, with more selective use of axillary lymph node clearance if the sampled lymph nodes were positive on subsequent histological analysis. In the modern era, sentinel lymph node biopsy, with or without perioperative lymph node analysis, is now routine--providing the best compromise between sensitivity and specificity of lymph node analysis with a low surgical morbidity [1-61.
The current paradigm of surgical management of the axilla has evolved independently of advances in oncological interventions such as radiotherapy and more widespread use of more effective systemic therapies. Randomised trials exploring the integration of the different treatment modalities have until now been sparse, and the mature results of recent studies are awaited. This paper explores the pertinent issues, and current and potentially new practices for the future.
Previous clinical trials
Halsted pioneered surgery for early breast cancer with mastectomy and axillary clearance in keeping with the hypothesis that breast cancer spread contiguously to the regional nodes and so an extensive en bloc resection was advocated.
An alternative theory proposed by Fisher suggested that breast cancer was a systemic disease at presentation and hypothesised that local treatment had no effect upon survival.
This led the National Surgical Adjuvant Breast and Bowel Project (NSABP-B04) [7,8] to investigate alternative methods to lymph node dissection. Mastectomy was the treatment of choice for the management of the breast at this time and, within the trial, clinically lymph node-negative patients were randomly allocated to one of three treatment arms:
1 No axillary treatment
2 Axillary radiotherapy alone
3 Full axillary dissection
For those in the no-axillary-treatment arm, surgical treatment was offered at relapse. Forty per cent of those undergoing surgical dissection were found to have clinically occult micrometastatic disease on histological assessment. In this case, axillary failure occurred in 8% (22/292) of patients undergoing axillary node clearance, compared with 11 % (33/294) in whom radiotherapy alone was delivered to the axilla. The investigators concluded that deferring axillary treatment until nodal relapse did not affect survival and that both radiotherapy and surgery were equivalent in local control at 10 and 25 years [7,8]. Critics of this study argue it was underpowered to detect a survival advantage although other trials performed at the time returned similar results [9-12]. However, NSABP-B04 was the only one to include clinically node-negative patients. Most reported local recurrence rates for axillary relapse at between 3% and 12% for modern radiotherapy techniques in published studies [13-16].
Axillary radiotherapy (ART)
The traditional premise has been that ART may be a less invasive option than axillary lymph node dissection (ALND) for the treatment of early breast cancer. Recent advances in the technical aspects of radiotherapy planning and treatment delivery have yet to be tested in the context of ART.
The morbidity of ART includes lymphoedema, shoulder stiffness and radiation-induced brachial plexopathy (RIBP). The risk of morbidity is related to absorbed total dose to the axilla, and the dose per fraction. The standard of care is a dose of 50 Gray (Gy) in 25 daily fractions over 5 weeks.
Lymphoedema
The risk of significant lymphoedema varies according to treatment modality, being greater when ART is given after ALND [17], as follows: ART, 8.3%; ALND, 7.4%; and ALND plus ART, 38.3%.
Radiation-induced brachial plexopathy (RIBP)
RIBP is rare. It is defined as radiation damage of the nerves or compression of the nerves by fibrosis in the axilla or lower neck. It needs to be distinguished from neuropathy due to injury, surgery or tumour recurrence in the axilla or lower neck on imaging. It typically causes pain and disuse of the affected arm and hand. The mechanism is thought to be a consequence of localised ischaemia and failure of cellular proliferation. The result is fibrosis of the vasa nervorum secondary to microvascular insufficiency. Treatment of this condition is largely ineffective. Techniques used include analgesics, physiotherapy, acupuncture, TENS and surgical brachial plexus decompression. In recent times a trial utilised hyperbaric oxygen therapy for chronic side effects of radiotherapy treatment but no additional improvements were seen with this technique [18].
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
In the 1980s and 1990s, inappropriate placement of the junction between the breast and nodal radiation fields was problematic, leading to some individuals attaining higher radiation doses at the match line-overlying part of the brachial plexus. This in turn led to a cohort of women sustaining significant chronic morbidity which, in turn, altered the perception of the utility of ART. RAGE (Radiation Action Group Exposure) was set up following the experiences of a patient severely affected by RIBP and currently has a membership of around 2000 similarly affected women. Subsequently, a Parliamentary select committee was formed and an independent review was undertaken. The Royal College of Radiologists (RCR) commissioned a report on adverse effects following breast radiotherapy. This led to the commissioning of more uniform standards of breast radiotherapy throughout the country [19-22]. Modern field-matching techniques are now used for the safe administration of combined breast and lymphatic radiotherapy [23-25].
Current practice
SLNB is now routine in current practice, with a sensitivity of around 95% and a specificity of 5-10%. [3-6,26], Studies have confirmed the non-inferiority of more conservative surgical approaches with a consequent decrease in morbidity [3-6,26], The probability of skip metastases is low if ALNDs are performed at least to level 2. After a positive SLNB, most patients will undergo an axillary clearance. This will be used to complete staging and can give useful prognostic information that can dictate adjuvant treatment.
After a full axillary clearance, radiotherapy to the axilla is not routinely indicated. Radiotherapy is recommended to the supraclavicular fossa alone if more than four axillary nodes are involved following an axillary clearance (Figures 1 and 2). Meta-analysis of published trials confirms that avoidance of local recurrence translates to a survival advantage [27]. Radiotherapy confers a reduction in local recurrence risk by > 10%, which translates to avoiding one cancer death at 10 years for every four local recurrences prevented. There is a similar reduction for heavily (more than four) node-positive patients but a recent survival advantage has been reported for one to three nodes.
Systemic therapy
Recent overviews have also confirmed the increasing survival advantage with systemic, endocrine and oiological therapies [27-29]. Polychemotherapy reduces the risk of local relapse by > 30%. This benefit is age dependent, being statistically greater in women under 50 years of age [response rate (RR) 0.63 versus 0.70 for patients aged 50-691. This reduction appears to be independent of endocrine treatment. Anthracycline [+ or -] taxane-containing regimens are now routinely prescribed and appear to have a positive effect on local control.
However, ALND can also provide additional prognostic staging information which can alter or influence adjuvant treatment options. This is part of the parameters used in the Adjuvant! Online [30,31[ algorithm, which can generate mortality and relapse data for specific tumour characteristics and patient scenarios.
The relevance of micrometastatic disease to patient outcome has recently been assessed in the MIRROR Study [Micrometastases and Isolated tumour cells: Relevant and Robust or Rubbish? (32,33)]. This was a retrospective Dutch study reviewing a database of all patients with a positive sentinel node, whether that be isolated tumour cells (< 0.2 mm) or micrometastases (0.2-2 mm) and looking at outcome. In this study, at 5 years both micrometastases and isolated tumour cells were associated with a 9% absolute reduction in disease-free survival compared with negative nodes. Adjuvant chemotherapy eliminated the recurrence hazard, and disease-free survival was equivalent to those with negative nodes (86.3%). The researchers concluded that residual microscopic disease required systemic therapy, with a reduction in the hazard ratio of 50% for micrometastases and 33% in isolated tumour cells.
The relevance to the current debate is that these data suggest that, although the number of involved lymph nodes is of prognostic relevance, the decision to administer chemotherapy can sometimes be taken without a full ALND. Patients with micrometastatic disease in lymph nodes or isolated tumour cells might be better candidates for a less aggressive approach to treating the axilla.
Current research questions
Further evaluation is needed, however, to compare morbidity rates in patients receiving SLNB with ALND or SLNB with ART Avoidance of ALND following SLNB has confirmed statistical improvements in quality of life and reductions in arm morbidity. Consequently, there is a drive for less aggressive surgery due to the documented side effects of ALND, including limitation of movement (8-32%), and longer-term issues including lymphoedema (20-38%), pain (30-55%) and numbness (35-58%) [34-36], However, ART confers its own risk of arm morbidity in the form of lymphoedema and the potential for pulmonary injury.
[FIGURE 3 OMITTED]
This issue of ALND versus ART is currently being evaluated within the EORTC AMAROS Trial [37] which dosed to accrual earlier this year. This is a randomly allocated Phase III study comparing ALND with ART in sentinel node-positive patients. The aim is to prove equivalent locoregional control for patients with proven axillary lymph node metastasis as detected by sentinel node biopsy, potentially with reduced morbidity by avoiding ALND.
AMAROS: eligibility criteria and study design
Patients with T1/T2 breast cancers, where clinically node negative, receive a sentinel node biopsy. In the event that this is positive, they either receive surgery or radiotherapy to the axilla. The overall trial aim is to prove equivalence in terms of local recurrence rates. Multicentric disease and clinical pathological nodes were ineligible. In the case of adjuvant chemotherapy, these decisions were made in line with the St Gallen recommendations, according to T not N stage. According to trial protocol, axillary relapse is treated surgically (see Figure 3) [38].
Within the study, in order to maintain sequencing and standardisation with ALND, ART was given prior to chemotherapy within 12 weeks of SLNB. The radiotherapy target volume was all three axillary levels and the medial part of the supraclavicular fossa. This was treated with an anterior field covering this volume and a smaller posterior field with the medial border at the coracoid process. The prescribed dose was 50 Gy in 25 fractions, treating daily. Quality assurance was performed in all recruiting centres, assuring standardisation of treatment protocols [39],
An early report [40] from the first 2000 patients entered into this study with operable unifocal clinically node-negative breast cancer has observed no statistical difference between the two treatment arms in the decision to treat with adjuvant systemic therapy (both 58%) or adjuvant endocrine treatment (76% versos 71 %, respectively). In the ALND, however, heavy nodal involvement (> four nodes) was seen in 17% of participants. This knowledge did impact upon further ART in a small number of patients in the ALND arm.
Discussion
Within recent studies, following a positive SLNB, the additional benefit of ALND on local control and overall survival in the presence of the best possible systemic management is likely to be smaller than anticipated. It is possible that this advantage may potentially be balanced by improvements in systemic hormone therapy, chemotherapy and biological therapies.
Prognostic information in terms of the degree of axillary lymph node involvement has been important to guide adjuvant therapy. However, improvements in translational characterisation of individual tumours might allow optimisation of the selection and sequencing of these treatments.
Conclusion
Survival rates in breast cancer are rising and, in turn, survivorship is an increasingly relevant consideration. Reductions in local recurrence rates with radiotherapy have been translated into improved survival rates. However, the equivalence of ART and ALND remain un proven.
Studies addressing the long-term effects of ART are lacking with regard to modern treatment planning and delivery. There is a need for a large, randomly allocated, adequately powered clinical trial to compare surgical versus non-surgical management of the axilla. It is hoped that the planned POWER (Positive sentinel node Wait Excision Radiotherapy) study will to some extent test this hypothesis.
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Clare Crowley
Department of Clinical Oncology, Cancer Care, Southampton University Hospitals NHS Trust, Southampton, UK
Correspondence to: Clare Crowley
Department of Clinical Oncology, Cancer Care
Southampton University Hospitals NHS Trust
Tremona Road, Southampton
Hampshire S016 6YD, UK
(email: clare.crowley@suht.swest.nhs.uk)
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| Title Annotation: | Feature Article |
|---|---|
| Author: | Crowley, Clare |
| Publication: | Advances in Breast Cancer |
| Date: | Dec 1, 2010 |
| Words: | 3199 |
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