For almost 3 decades, the major focus of radiation oncologists specializing in the management of breast cancer has been on performing both randomized and nonrandomized trials comparing breast-conserving therapy (BCT), using surgery and radiation, with the more traditionally modified radical mastectomy. With the acceptance of these 2 local-regional therapies as equivalent in the management of early-stage invasive breast cancer, attention was then refocused on identifying factors (pathologic, patient, or therapy-oriented) that predicted the success or failure of the treatment locally.
Accompanying these very real clinical goals was a philosophical discussion on the relationship of a local recurrence to the development of distant failure and eventually death from the disease. Early on, it was noted that the survival rate from salvage surgery for failures in the conserved breast was 50% or higher at 5 years.1,2 Local failures after BCT were somehow classified as “different” from local-regional failures after mastectomy, which were readily linked with the development of distant disease and thought incurable.2
Today, the success of systemic chemotherapy and hormonal therapy in the management of breast cancer has changed the natural history of locoregional failure. Analysis of 2 prospective randomized trials from the European Organization for Research and Treatment of Cancer group and the Danish Breast Cancer Group comparing mastectomy with breast-conserving surgery (BCS) and radiation in patients of similar stages with similar systemic therapy surprisingly showed almost identical 5-year actuarial local-regional and survival rates after salvage procedures for early local-only failures in both the breast-conserved arm and the mastectomy arm.3
The relationship between local failure and distant failure must be reassessed in both groups of patients, that is, those treated with mastectomy and those treated with BCT. Nevertheless, the importance of obtaining local control with initial treatment remains important, not only for the goal of preventing either the loss of the breast in the conserved patients or painful and difficult-to-control local failure in the mastectomy patients, but also to potentially decrease subsequent distant metastases that may be associated with these local failures. As chemotherapeutic regimens for the risk of distant disease become more effective, this goal of ensuring local control takes on a potentially greater importance.
Data from the Early Breast Cancer Trialists Collaborative Group demonstrate that treatments resulting in improved local control may lead to decrease in breast cancer mortality.4 The overview analysis also suggests that avoidance of local recurrence after BCT and avoidance of a local recurrence elsewhere after mastectomy, such as in the chest wall or regional nodes, are of comparable relevance to 15-year breast cancer mortality. Also, recent randomized trial updates demonstrated the value of postmastectomy radiation in stage II disease with 1 to 3 positive lymph nodes. The Danish Cooperative Breast Cancer Group 82b and 82c trials and the Vancouver British Columbia trial evaluated the local control and survival in mastectomy patients with 1 to 3 positive lymph nodes treated with systemic chemotherapy with or without postmastectomy radiation.5,6 Radiation led to both decreased local-regional recurrence (LR) and improved survival. Additional analysis of patients in the Danish trial who had a more complete axillary dissection of 8 or more lymph nodes removed also revealed both a significantly lower risk of 15-year LR and improvement in survival in patients receiving radiation.7
RECURRENCE AFTER BCS AND RADIATION
Predictors for local-regional failure after BCT can be divided into 3 broad categories. The first involves factors related to the patient. Young age at the time of diagnosis, defined as patients being in their 30s and 40s, seems to be a strong predictor.8–13
The second category consists of tumor factors that have been analyzed after BCT. Most studies have found that positive microscopic margins, gross multifocality, and an extensive intraductal component are associated with a higher risk of recurrence in the conserved breast. Some series have noted larger tumor size and lymphatic vessel invasion as risk factors.9,12,14,15 Newer studies suggest that the molecular subtype may also impact local recurrence, with both triple negative [ER− (estrogen receptor), PR− (progesterone receptor), and HER-2-neu−] and HER-2-enriched (HER-2+) subtypes associated with a higher rate of local and regional relapse.16
The third category consists of therapeutic factors, the most important of which is the omission of breast radiation. Numerous studies have demonstrated that radiation therapy (RT) dramatically reduces the risk of recurrence in the breast.17–19 Patients receiving systemic chemotherapy or hormone therapy seem to have higher local control rates, all else being equal, than those who do not.14,18,20 The addition of a radiation boost to the lumpectomy cavity may decrease the incidence of a recurrence in the conserved breast, particularly in women younger than age 40.10
An increasing number of women are being treated with accelerated partial-breast irradiation with either interstitial or balloon brachytherapy or external beam treatment. Long-term follow-up regarding patterns of locoregional failure is generally lacking. However, existing data do suggest that the rate of ipsilateral breast tumor recurrence (IBTR) is comparable with whole-breast irradiation, with 10-year recurrence rates reported to be up to 5%.21–24 With a median follow-up of 36 months, the update of the American Society of Breast Surgeons MammoSite brachytherapy trial yielded a 3-year IBTR rate of 2.1% and an axillary recurrence rate of 0.36%. One third of the recurrences were felt to be a true recurrence of the original primary, whereas two thirds were believed to be a new primary. Factors associated with the development of an IBTR include presence of an extensive intraductal component, receptor-negative disease, decreasing age, and absence of adjuvant tamoxifen therapy.21,23
Neoadjuvant therapy is increasingly being used in breast cancer patients. Data on its use related to local and regional control are sparse. Limited data suggest that BCT can be used after neoadjuvant therapy.25,26
The generally recommended treatment for locally recurrent breast cancer after BCT is salvage mastectomy, although a repeat attempt at breast conservation may also be possible in selected cases (Table 1).27
After an IBTR in patients undergoing BCT, the 5-year survival rate for node-negative patients is 76.6% and for node-positive patients is 59.9%.1,8,13 Limited data exist on salvage of patients who develop IBTR after accelerated partial-breast irradiation. Repeat BCS or mastectomy has been shown to produce excellent salvage rates comparable with the low rate of failures after whole-breast irradiation, but patient numbers are small.22,24
In patients who are operable after local recurrence only, the incidence of nodal recurrence in breast-conserving series is low.28 However, involvement of the nodes would have significant impact on outcome; therefore, assessment of the axillary status for an invasive local recurrence of the breast should be considered. The role of sentinel lymph node biopsy (SLNB) in this scenario remains to be defined. Preliminary data indicate that SLNB may be performed at the time of salvage surgery, as previous breast conservation or axillary surgery may not be a contraindication to SLNB.29
Because of the relationship between local recurrence and distant failure, systemic therapy must also be considered in the treatment program for this patient group (Table 2).
To date, no published series has shown a statistically significant improvement in subsequent outcome with the administration of salvage chemotherapy or hormonal intervention at the time of local recurrence. Factors to be considered in this clinical decision include (1) prior systemic therapy, if any; (2) extent of recurrence; (3) time interval from initial treatment to recurrence; (4) tumor hormone receptor status; (5) patient age; (6) tumor size; (7) margin status; and (8) general medical condition.1,8,13 The National Surgical Adjuvant Breast and Bowel Project is evaluating the benefit of adjuvant chemotherapy after radical resection of recurrent breast cancer. This prospective randomized trial is currently open to accrual.30
Some patients who present with an IBTR after conservative surgery with or without RT may have a new primary tumor as opposed to a true local recurrence.31,32 The second breast tumor is defined as a new primary if it is distinctly different from the original tumor with respect to histologic subtype, if it presents in a different location in the breast, or if it is of different clonality. The time interval between the original primary and the second tumor is generally considerably greater for new primaries compared with true recurrences (average, 55 vs. 33 mo).31 In patients receiving RT as part of BCT, 10-year overall survival rates (75% vs. 55%) and distant disease-free survival rates (85% vs. 41%) tend to be much better for patients with new primaries compared with those with true recurrences.32 Thus, the diagnosis of a new primary as opposed to a true recurrence implies a different natural history and prognosis and has implications for therapeutic management. Unfortunately, most series addressing breast tumor recurrences do not adequately distinguish between the 2 entities. This may be of particular importance to breast cancer management in young women with BRCA 1/2 gene mutations, who are at increased risk for new primaries.33
Patients with ductal carcinoma in situ who undergo BCT and subsequently sustain a recurrence in the treated breast seem to have an excellent outcome after salvage therapy (Table 3).34
RECURRENCE AFTER MASTECTOMY
Risk factors for local-regional failure after mastectomy can also be divided into clinical, pathologic, and treatment-related categories. Young age (<35 y), nodal status, tumor size, lymphovascular invasion, multicentricity, and adequacy of nodal dissection as measured by the number of lymph nodes removed are all risk factors for postmastectomy recurrence.35,36 Elective postmastectomy irradiation reduces this risk.37 There is controversy regarding the risk of chest wall recurrence in the subgroup of patients with 1 to 3 positive nodes and their need for postmastectomy RT (See the Appropriateness Criteria topic on “Postmastectomy Radiotherapy”).
Systemic therapy seems to have an impact on local-regional control. In the most recent meta-analysis of systemic therapy from the Early Breast Cancer Trialists Collaborative Group, 5 years of tamoxifen therapy reduced the local recurrence rate by about one half in women with hormone receptor-positive disease (local recurrence ratio of 0.47), whereas, irrespective of hormone receptor status, polychemotherapy reduced it by about one third (ratios 0.63 to 0.70 depending on patient age).38
Five-year survival rates range from 35% to 75% and 10-year survival rates range from 25% to 55% after LR after mastectomy. Long-term control of the local-regional disease is achieved in only 45% to 70% of patients with most patients developing distant metastases.39–41 Prognostic factors include the extent of disease initially and at recurrence, the disease-free interval, grade, and the ER status as well as the use of surgical excision, radiation, and hormonal therapy. Patients with uncontrolled local-regional disease are usually symptomatic, are more likely to develop distant metastases, and die sooner than patients whose LR are controlled. Consequently, aggressive attempts at controlling the LR are warranted.
A multidisciplinary approach is required for the management of a chest wall recurrence after mastectomy (Table 4).
Surgical resection should be performed if the size and location of the recurrence permit. In patients who have not received prior RT, LRs are managed with irradiation.35 LR after mastectomy is a harbinger of distant metastases; therefore, systemic treatment should also be considered. If the patient is ER positive, tamoxifen, an aromatase inhibitor (depending on menopausal status) or ovarian ablation, may be used. If the patient is ER negative, then chemotherapy may be given.30
TREATMENT GUIDELINES AFTER BCT
For patients failing BCT that included standard whole-breast radiation and an axillary node dissection, simple mastectomy is recommended as the local treatment of choice when the failure is confined to the breast parenchyma and is operable.27 The role of partial-breast irradiation in this setting is currently under investigation, and consideration should be given to placing the patient on an available clinical trial. The Radiation Therapy Oncology Group phase II trial 1014 is currently open for accrual. It uses 3D conformal partial-breast irradiation for patients with an in-breast local recurrence ≤3 cm and 3 or more positive lymph nodes without extranodal extension.
In the clinical situation involving recurrence in the treated breast, along with a supraclavicular nodal failure, the recommendation is for radiation to the untreated supraclavicular area plus chemotherapy. Although this pattern of recurrence is not common, it is viewed as systemic failure based on existing evidence. Similarly, for patients with clear distant metastases and local failure, primary systemic management is recommended rather than mastectomy.
In the rare clinical situation of a local recurrence for a patient whose initial treatment consisted only of a wide local excision without radiation or axillary dissection, treatment options include simple excision or lumpectomy, axillary nodal evaluation, and RT in the absence of distant metastasis.
Given the situation of a patient with recurrent ductal carcinoma in situ treated initially with lumpectomy plus RT only, simple excision is recommended.
TREATMENT GUIDELINES FOR LOCAL RECURRENCE AFTER MASTECTOMY
Options for treatment of LR after mastectomy include: surgery, RT, chemotherapy, hormonal therapy, or a combination of modalities. Patients experiencing LR after mastectomy should undergo a workup for metastatic disease. In the absence of distant metastases, aggressive attempts at salvage should be entertained. When possible, surgical excision followed by RT to the involved chest wall and regional lymphatics is the standard treatment approach. Haffty et al42 reported an overall survival after chest wall recurrence of 46% at 5 years and 28% at 10 years for patients treated with full-course external beam irradiation. Ten-year local-regional control of disease was achieved in 79% of patients, with a distant metastasis-free survival rate of 49% at 5 years and 40% at 10 years. In this series, HER-2 status was the only significant factor affecting local-regional progression. Patients with HER-2–positive disease had a local-regional progression-free rate of 59%, compared with 92% for patients with HER-2–negative disease. Both PR-positive status and time longer than 2 years from the original diagnosis to chest wall recurrence were associated with favorable distant metastasis-free and long-term survival. Along with disease-free interval, the adequacy of local control for LR has also been shown to have a favorable impact on long-term survival.43
* Five-year actuarial LR and survival rates after salvage procedures for early local-only failures are similar in patients undergoing mastectomy versus BCT.
* Salvage mastectomy is generally recommended for locally recurrent breast cancer after BCT. Repeat attempts at breast conservation may be considered, preferably through participation in a clinical trial.
* To date, no published series has shown statistically significant improvement in outcome with salvage chemotherapy or hormonal therapy at the time of local recurrence after BCT.
* Multidisciplinary management of chest wall recurrence after mastectomy is warranted, including surgery, RT, and systemic therapy. In the absence of distant metastasis, aggressive attempts at salvage should be entertained.
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