Rationale for local treatment of breast cancer
Local treatment for early breast cancer consists of surgery and radiotherapy, which aim to remove the cancer and achieve cure by preventing the spread of the cancer and reducing the likelihood of local recurrence within the breast, chest wall or axillary nodes.
is curative in a large marjoity of patients with early breast cancer. Large clinical trials have proven that more extensive local treatment does not improve survival unless the difference in local control rate is more than 10%. If the difference in local control between two local treatments is more than 10% at 5 years then it leads to an improvement in survival by 15 years. For example, a 20% improvement local control at 5 years, there is a 5% improvement in survival at 15 years. In general it is unsusual in modern times for a difference in local treatments to be more than 10% at 5 years, because the even the chance of a local recurrence with most treatments is now much below 10%.
Modern local treatment should therefore be tailored to give the best local control and the least harm.
Surgical treatment of the cancer in the breast
Primary surgery has long been the first treatment step for early breast cancer. The benefit of removing the primary tumor has been difficult to test in a randomized fashion for obvious ethical reasons. However, in randomized trials in women over 70 years old, it was found that primary surgery had a superior outcome compared with primary endocrine therapy with tamoxifen.
Based on a mechanistic model of spread, the aims of surgical treatment for primary breast cancer are to:
Surgery may consist of either mastectomy or breast-conserving procedures, so-called ‘lumpectomy’ in the USA and wide local excision (WLE) in the UK.
Wide local excision (lumpectomy) involves removal of the lump with a margin of normal tissue, which is typically intended to be 1 cm, but on histological examination a 1 mm margin is usually considered adequate. There is increasing consensus (including 89.8% of the expert panel at the 2013 St Gallen meeting and the Society of Surgical Oncology/American Society of Radiation Oncology [SSO–ASTRO] consensus) that as long as there is no ‘ink on margin’ or ‘tumor at the margin’, no further excision is necessary.
The latest Oxford overview has shown that breast conservation with adjuvant radiotherapy has a slightly higher risk of local recurrence than mastectomy, but does not jeopardize overall survival.
Indications. Conservative surgery is not suitable for all patients, and not all patients will desire it. However, older age should not lead to the assumption that a mastectomy would be preferred; most often, patients prefer to preserve the breast.
There is no evidence that proximity to the nipple, extensive intraductal component, vascular invasion or lobular pathology are contraindications for breast conservation. Even when there are two tumors in the breast, if they can both be well excised with good cosmesis, and followed by radiotherapy, there is no reason to automatically recommend a mastectomy, particularly in a patient who wishes to conserve her breast. In such cases, MRI to check the normality of intervening tissues could be considered. Patients with more than one tumor should be made aware that conversion to mastectomy will depend on the final pathology. Individual patients should be encouraged to make informed decisions.
Targeted intraoperative radiotherapy. In women over 45 years of age, targeted intraoperative radiotherapy (TARGIT IORT) offers a possible means of avoiding an arduous course of whole-breast radiotherapy. The 5-year results of the randomized TARGIT-A trial have shown that TARGIT IORT during lumpectomy within a risk-adapted strategy results in local recurrence no worse than several weeks of whole-breast radiotherapy, significantly reduces journeys for treatment and has environmental benefits. Furthermore, it resulted in less local toxicity and significantly fewer deaths from causes other than breast cancer such as cardiovascular causes and other cancers, perhaps because TARGIT avoids radiation to healthy organs such as the heart and lungs. Therefore, TARGIT IORT should be offered to suitable patients before they have a lumpectomy, particularly patients with a good prognosis (e.g. 45 years and older, ≤ 3.5 cm hormone sensitive infiltrating duct carcinoma ). For patients younger than 45 or those with high risk factors for recurrence, the TARGIT-B trial is testing whether a tumor bed boost using TARGIT IORT during lumpectomy is superior to the standard tumor bed boost delivered postoperatively. In this trial, all patients will receive whole-breast radiotherapy.
Therapeutic mammoplasty – remodeling of the ipsilateral, and the contralateral, breast during a lumpectomy – has gained popularity in recent years. However, patient satisfaction appears to be similar with either simple lumpectomy or mastopexy. Importantly, the margin positivity does not seem to reduce and the risks of inflicting such additional surgical trauma may be real: one large series reported a high 5-year local recurrence rate of 9.4%.Good randomized trials would help to quantify the risks and benefits of both ipsilateral mastopexy and contralateral ‘symmetrization’ procedures.
The use of implants is associated with reduced survival from subsequent breast cancer, so using implants in the contralateral breast in women who are at high risk of developing breast cancer should be regarded with caution.
Mastectomy aims to remove all breast tissue from the clavicle to the intramammary fold and from the anterior border of the latissimus dorsi to the midline. Even in the best hands, however, not all breast tissue can be completely removed.
When an immediate reconstruction is planned, a skin-sparing mastectomy can be performed using various oncoplastic techniques, which provide sufficient access to carry out full axillary clearance if required. Despite a lack of randomized evidence to support it, the popularity of this type of skin-sparing mastectomy, which in some cases may also spare the nipple, has increased because of its cosmetic attraction; however, the risk of residual disease is higher. Several series have demonstrated a very low risk of a recurrence when the operation preserves the nipple but removes most of the subareolar tissue, although this does increase the risk of ischemic necrosis of the nipple.13 The skin envelope can be immediately filled with the newly harvested tissue, or with a prosthesis that can be later replaced during a more definitive operation. Radiotherapy is not considered essential after such surgery unless there are other indications.
Complications. Mastectomy is safe and most patients recover well. The most common complication after surgery is wound infection, but its rate should be less than 5%. In general, hematoma can be almost completely avoided by careful attention to surgical hemostasis. Acetylsalicylic acid (ASA; aspirin) does not need to be stopped before breast surgery but it may be prudent to stop clopidogrel if that is safe from the cardiologist’s point of view. Arm numbness, shoulder stiffness or weakness and lymphedema resulting from damage to the nerves and lymph nodes are becoming rarer as radical procedures are performed less often.
Choice of operation. Ideally, there should be more than one consultation with the surgeon and a consultation with the radiation oncologist. The patient’s short- and long-term satisfaction with the overall treatment, as well as the objective cancer control outcome, should be the measure of quality of care. Preserving or assessing the remaining breast should not be a concern, as the outcomes after breast-conserving therapy are the same as for invasive ductal carcinoma in large series of patients who were predominantly treated before the advent of MRI. Furthermore, in a large study, contralateral mastectomy was not associated with an improved outcome.
Achieve a cure in those patients the disease is confined to the breast or in whom microscopic systemic disease can be effectively treated with adjuvant systemic therapy
Achieve local control of the disease in order to prevent complications, such as skin ulceration
Try to stop any (further) metastatic spread from the primary tumor
Determine the pathological stage of lymph-node involvement
Sentinel lymph node biopsy and axillary clearance
Axillary surgery. The indications for axillary surgery and the extent to which it should be carried out in women with operable breast cancer remain controversial.
Full axillary clearance (levels I and II) may not be necessary if one or more nodes on the sentinel node biopsy show evidence of micrometastasis alone. If axillary dissection is necessary, the technique used must aim to minimize the morbidity of the procedure. A standard axillary clearance should involve excision of only those tissues anterior and inferior to the axillary vein, leaving behind the lymphatics that drain the arm, which are usually thought to be situated above the vein; reverse lymphatic mapping may help to identify and preserve these.
With increasing use of sentinel node biopsy (see below), lymphedema of the arm is now relatively uncommon. Radiotherapy is usually not given after full axillary clearance; although it is often used in the presence of extranodal spread, its value is not well established.
Is axillary clearance necessary if only one or two sentinel nodes are positive? The Z-11 trial randomly allocated patients to receive either complete axillary clearance or no further surgery. Although over 20% of cases of axillary clearance had further positive nodes, the recurrence in the axilla in those who received no further surgery was less than 1% at 6 years.21 Many centers around the world are therefore adopting a ‘no further surgery’ approach in patients similar to the Z-11 trial cohort (clinical [c]T1–2, cN0 disease, ≤ 2 positive sentinel lymph nodes, treated by breast conservation with whole-breast radiation therapy). The POSNAC trial, currently recruiting in the UK, will address this question further.
Radiotherapy to intramammary nodes. Although it has not been customary to irradiate the intramammary lymphatic basin, a recent large study suggests that in patients with high-risk disease such irradiation can improve overall survival.
Sentinel node biopsy is the ‘standard of care’ in many parts of the world; it can be used to establish the prognosis and select appropriate systemic therapy. Most breast cancers spread in a predictable path along the axillary lymphatics with the lowermost node in the chain (the sentinel node) being the first to be affected. Radiolabeled colloid, alone or in combination with a patent blue dye, is injected subdermally under the areola. A path can then be traced to the first draining lymph node in the axilla (the sentinel node), which is independent of the location of the tumor in the breast. If intraoperative assessment of the lymph node is negative, further axillary surgery can be avoided.
These intraoperative tests have a false negative rate of up to 30%, but the remainder avoid the need for a second operation. However, the Z-11 trial, which casts doubt on the need for further axillary surgery when 1–2 nodes are involved21 has reduced the utility of sentinel node intraoperative assessment; it has already been abandoned in some centers.
A sentinel node biopsy false negative rate as low as 3% can be achieved by meticulous technique and by not ignoring suspicious enlarged nodes found by deliberate digital palpation of axillary contents intraoperatively. Studies have reported a significant reduction in morbidity, and an improvement in quality of life and patient satisfaction, after sentinel node biopsy. However, long-term local recurrence results have yet to be reported.
It should be remembered that the technique has been tested mainly in patients with clinically negative axilla. The temptation to use the technique in every case should be avoided.
In patients receiving neoadjuvant chemotherapy, sentinel node biopsy performed initially has an acceptable level of accuracy, but this drops significantly (identification rate < 85% and false negative rate > 10%) if it is performed after chemotherapy is given.
Level I axillary nodes are below and lateral to the pectoralis minor muscle.
Level II axillary nodes are underneath or posterior to the pectoralis minor muscle.
Level III axillary nodes are above or medial to the pectoralis minor muscle.
Breast reconstruction following mastectomy to restore the natural look and feel of the breast is becoming increasingly popular, though only about 5% of patients undergo such surgery.
Immediate versus delayed reconstruction. In theory, breast reconstruction performed at the same time as the initial mastectomy should reduce the psychological impact of losing a breast and avoids the need for further surgery. While some observational studies support this theory, other studies have found it makes no difference at all whether reconstruction is immediate or delayed, and randomized evidence is poor (two trials of fewer than 200 patients with conflicting results).
Many units have a policy of not recommending immediate breast reconstruction when post-mastectomy radiotherapy is anticipated (e.g. positive nodes), as irradiating a reconstructed breast has been shown to significantly worsen the cosmetic outcome, although the risk of complications is slightly higher when reconstructing an already-irradiated breast. A non-randomized study of 229 patients undergoing immediate breast reconstruction between 2004 and 2009 found that 23% had a wound complication and those with complications had a lower recurrence-free survival (64% versus 89% in those without complications). The obvious benefit of waking up after a mastectomy with a new breast should be weighed against the need for a much larger operation with a higher risk of complications, longer convalescence, a potential delay in chemotherapy/ radiotherapy and the need for several further operations. While it is appropriate to discuss breast reconstruction with patients during discussions about mastectomy, it should not be pushed as the ‘standard’ treatment.
Reconstruction options. A number of options for breast reconstruction are available, including silicone gel implants, tissue expanders and prostheses, myocutaneous flaps, and the most commonly used deep inferior epigastric artery perforator (DIEP) free tissue transfer flap. The DIEP flap procedure can take several hours and can achieve a nearly symmetrical breast.
Lipofilling involves using harvested fat (assuming a 60% loss of volume) from the anterior abdominal wall and the flanks. One study found a high local recurrence rate after lipofilling of 1.5% per year (a 7.5% recurrence rate over 5 years). Knowing that aromatase in fat can increase the local concentration of estrogen, the novel and promising technique of fat transfer needs randomized evidence to at least prove its oncologic safety.
If desired, the nipple can be reconstructed surgically to give a reasonable cosmetic appearance.
Radiotherapy (4–6 week course of 2 Gy fractions) is considered mandatory for most patients undergoing conservative surgery. It is also appropriate for women with a large primary tumor who are at high risk of recurrence after mastectomy, particularly if the tumor is poorly differentiated and involves the skin or pectoral muscles, or if there is lymph-node involvement (e.g. four or more). The most common side effects are skin reactions and, occasionally, nausea and vomiting; pneumonitis from irradiation of the lung occurs in 2% of patients. Tangential radiotherapy fields inadvertently included the lung, heart and the anterior descending coronary artery, causing an excess of cardiac mortality that was most conspicuous in, but not limited to, those with left-sided breast cancers. Newer regimens, including techniques such as voluntary breath holding, reduce the cardiac dose and are expected to reduce morbidity, although randomized evidence of safety for these new techniques is lacking. One study found that the risk of increased cardiac mortality from radiotherapy is highest in the first 5 years (16% increase per Gy of cardiac dose) and continues for 20 years. A metaanalysis of randomized trials of partial versus whole breast irradiation has confirmed the definite, albeit small, overall survival benefit of partial breast irradiation.
Hypofractionated radiotherapy. A large trial in Canada and the Standardisation of Radiotherapy (START) trials in the UK have shown that local recurrence rates at 5-year follow-up were equivalent whether patients received a 3-week or conventional 6-week regimen. The FAST-Forward trial is now testing whether 1 week of therapy can be as good and without side effects.
Targeted intraoperative radiotherapy immediately after local excision of early breast cancer has become the standard of care in selected cases in many centers around the world. In the randomized TARGIT-A trial, the 5-year survival without local recurrence with targeted intraoperative radiation therapy (TARGIT) during lumpectomy was similar to that with external beam radiation therapy (EBRT): 93.7% (95%CI 90.9–95.9%) for TARGIT vs 92.5% (95%CI 89.7–94.6%) for EBRT, p=0.35.
Translational research has shown that postoperative wound fluid normally stimulates cancer cell growth, motility and invasiveness (commensurate with the need to heal the wound). TARGIT has been found to abrogate this effect of surgical wounding. Thus, in addition to reaching the right tissues, TARGIT is also applied at the right time. The actuarial local recurrence rates in the first series of patients to receive TARGIT as well as external radiotherapy have been very low – 1.7% at 5 years (see also pages 41–2). The ongoing TARGIT-B trial will determine if a TARGIT boost to the tumor bed is superior to a conventional externally delivered boost.
The most important benefit of TARGIT for a woman with breast cancer is that it allows her to complete her entire local treatment (lumpectomy and radiation therapy) at the time of her operation, with lower toxicity, and results in better breast-related quality of life. It is also significantly less expensive for the healthcare system. In addition, adaptation of TARGIT could reduce the harms of overdiagnosis in screen-detected cancers.
Patients who are 45 years or older who have invasive ductal breast cancer, ≤ 3.5 cm, unifocal on conventional imaging and ER and PgR positive would be considered suitable for TARGIT within an approach of risk-adapted radiotherapy, i.e. 15–20% of such patients would receive EBRT as well.
Other techniques with a similar rationale include ‘ELIOT’ (ELectron IntraOperative Therapy) and the Mobitron system. The MammoSite technique uses a balloon catheter to deliver brachytherapy. The Xoft is a hybrid between Intrabeam and MammoSite, but clinical experience in its use is very limited. All these techniques offer different advantages, and the results of randomized trials should guide clinicians’ choices.