A small but important subset of patients with metastatic breast cancer have limited systemic tumor burden and biologically indolent disease. They represent less than five percent of patients with newly diagnosed metastatic breast cancer [1-3]. However, for such patients, an intensified multidisciplinary approach combining systemic therapies with surgery, radiation, and regional chemotherapy may not only prevent local complications, but prolong survival.
Local treatment of breast cancer metastases is reviewed here. Systemic therapy and general principles of management of metastatic breast cancer, including treatment of the breast primary in the metastatic setting, treatment of brain and bone metastases, and management of locoregionally recurrent breast cancer are discussed separately.
The median survival for patients with metastatic (stage IV) breast cancer is 18 to 24 months, although the range extends from only a few months to many years [4,5]. The few patients who experience long-term survival tend to be young with an excellent performance status and limited metastatic disease. For such patients, an intensified multidisciplinary approach combining systemic therapies with local treatment (surgery, radiation, and regional chemotherapy) may not only prevent local complications, but prolong survival.
Several retrospective series, as described below, have suggested that patients with metastatic breast cancer treated with local treatment for the primary tumor or distant metastases achieve long-term survival. However, interpretation of these results is limited by bias, including selection bias and reporting bias. Patients selected for surgery are younger, with less disseminated disease and less visceral metastases . Patients with significant comorbidities are not recommended for intensive therapies, whereas patients selected for surgery are often those who have good prognostic features and indolent biologic behavior. Local treatment has not been compared to systemic therapy or supportive care in randomized trials. Furthermore, it is unknown how advances in systemic therapy [such as human epidermal growth factor receptor 2 (HER2)-directed therapies], impact upon previously reported benefits from local therapy.
Selection of patients
The selection of appropriate candidates for surgical intervention requires a thorough assessment of the patient’s medical condition, extent and clinical behavior of the breast cancer, and the feasibility of resecting the metastasis with a negative margin. The relative risks and benefits of surgery must be weighed for each individual patient.
Several factors that are predictive of outcome may help in the selection of appropriate patients for surgical consideration.
Performance status and comorbidity
Perhaps the most important issues in choosing patients for local treatment of metastatic disease are the performance status and an estimation of the relative risks of a planned operation. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or worse (table 1) or those with significant medical comorbidity should be considered carefully for local treatment, especially surgery, as they are likely to have high rates of postoperative morbidity and mortality.
Patients evaluated for lung resection should have a complete pulmonary evaluation, while those being considered for liver resection should have relatively preserved liver function.
Multivariable analysis of local treatment outcomes suggest that those patients with limited metastatic disease, ie, solitary or few detectable lesions (oligometastatic disease) and limited to a single organ are more likely to benefit from local therapy than those with multiple metastases [6-10]. One exception is solitary bone disease, as a few studies found no difference in long-term outcomes in patients undergoing hepatic resection in the presence or absence of extrahepatic disease (predominantly bone) [11-13].
Many of the studies that report successful surgery for metastatic disease (discussed below) limited enrollment to patients with single organ involvement. Patients being considered for local therapy should undergo a thorough restaging evaluation.
A long disease-free interval (DFI, the period of time between the diagnosis of breast cancer and the development of distant metastases) is associated with a better outcome with local therapy [14-16]. The specific cutoff value of DFI that best discriminates between favorable and unfavorable outcomes is unclear. However, the shorter the DFI, the less likely the patient will benefit from local therapy.
Careful preoperative evaluation is necessary to determine the likelihood that complete resection of the metastatic deposit is feasible. Positive margins are associated with worse outcomes in most but not all series [7,15,17-19].
Local treatment of specific sites
Resection or other means of local therapy, such as radiation therapy (RT), radiofrequency ablation, or cryotherapy, of isolated metastases has been shown in several small studies (discussed below) to be associated with longer progression-free survival and overall survival than might be otherwise reported for patients with metastatic breast cancer. However, it is not clear if the local therapy is responsible for long-term survival or if these highly selected patients would have done well anyway. With the exception of brain and spinal cord metastases, there are no prospective randomized clinical trials to determine if such approaches improve palliation and/or survival.
Perhaps the main indication for resection of new isolated metastases, especially pulmonary, hepatic, or abdominopelvic, in a patient with a prior history of breast cancer is diagnostic, since some patients may have a new primary malignancy or a change in tumor marker status.
Thus, the decision to approach a patient with local therapy in the absence of a local emergency, such as impending fracture, must be made on an individual basis, either because it might permit the patient to forgo or delay toxic systemic therapy or because the physician believes that the available uncontrolled data suggest a survival benefit.
Isolated lung metastases occur in 10 to 25 percent of patients with metastatic breast cancer [8,16]. Pulmonary resection or metastasectomy offers an opportunity for long-term survival in highly selected patients with metastatic breast cancer, with cases series demonstrating five-year overall survival ranging from 30 to 80 percent and median survival duration ranging from 40 to 100 months [7,16,19-21]. Patients most likely to experience long-term survival after mastectomy are those with solitary metastases and a disease-free interval greater than 36 months. Other prognostic factors may include hormone-receptor status, size of metastases, completeness of resection, and use of anatomic resection (as opposed to wedge resection) [7,9].
Pulmonary resection may be diagnostic as well as therapeutic in breast cancer patients, since a significant number of solitary pulmonary nodules in patients with a history of breast cancer are not breast cancer metastases [19,22,23].
The differential diagnosis, diagnostic evaluation, and local management of lung metastases, including surgical resection, radiofrequency ablation (RFA), and stereotactic body RT, are discussed separately.
Hepatic metastases occur in over half of patients with metastatic breast cancer. They are most commonly a late development, associated with disseminated disease and a poorer prognosis than bone or soft tissue metastases. Only 5 to 12 percent of patients have isolated liver involvement [24-26].
Hepatic resection for breast cancer metastases may be associated with long-term survival in appropriately selected patients. In a systematic review of 19 studies involving 535 patients who underwent hepatectomy for metastatic breast cancer, median overall survival was 40 months (range, 23 to 77 months) with five-year survival following resection of 40 percent (range, 21 to 80 percent) . Postoperative mortality ranged from zero to six percent and the complication rate ranged from 0 to 44 percent. Prognostic factors following hepatic resection were positive margins and hormone-refractory disease.
The ideal candidate has a solitary metastasis, no evidence of extrahepatic metastatic disease, normal liver function, a good performance status, and a long DFI [9,11,14]. An essential part of the diagnostic work-up in patients who are considered for hepatectomy is precise imaging of the liver (helical computed tomography scan or magnetic resonance imaging) to evaluate whether a complete resection can be achieved while retaining a sufficient volume of functional liver. It is not clear that multiple metastases are a negative prognostic feature for resection of liver metastases, as long as they can be completely resected [11,12,17]. Bilobar disease and location close to the porta hepatis are typically considered a contraindication to resection. Initial laparoscopic exploration may spare unresectable patients the morbidity of a laparotomy, since up to one-half of patients considered for resection are discovered to have diffuse liver lesions or peritoneal dissemination at the time of laparotomy .
Hepatic resection is appropriate for highly selected patients, but alternative local therapies are being increasingly used to treat liver metastases. Liver-directed therapy includes radiofrequency ablation (RFA), stereotactic body RT (SBRT), selective internal RT (SIRT), percutaneous ethanol injection, cryotherapy, hepatic arterial infusion chemotherapy, transhepatic arterial chemoembolization (TACE), and interstitial laser therapy. In general, there are fewer less data regarding the use of these techniques for metastatic breast cancer than there are for patients with colorectal cancer liver metastases or primary hepatocellular cancer. Furthermore, none of these methods has been directly compared to systemic chemotherapy in metastatic breast cancer.
- Radiofrequency ablation (RFA) can be used alone or in combination with resection [29-32]. It is most effective with solitary lesions less than 3 cm in diameter.
RFA entails the local application of radiofrequency thermal energy to a lesion, in which a high frequency alternating current moves from the tip of an electrode into the tissue surrounding that electrode. As the ions within the tissue attempt to follow the change in the direction of the alternating current, their movement results in frictional heating of the tissue. As the temperature within the tissue becomes elevated beyond 60º C, cells begin to die, resulting in a region of necrosis surrounding the electrode.
- Selective internal RT (SIRT or targeted radiotherapy with Yttrium-90 microspheres [SIR-Spheres]) uses millions of microscopic beads injected into the liver to deliver internal radiation directly to the tumor.
- Interstitial laser therapy (ILT) causes local tumor destruction by the application of laser light, delivered through quartz diffusing laser fibers that can be percutaneously placed within tumors [33-35]. This technique can be used to treat lesions that are up to 5 cm in diameter .
Transarterial chemoembolization (TACE) is able to deliver chemotherapy directly to the tumor while blocking blood flow to the liver because the majority of the blood supply to liver tumors is from the hepatic artery rather than the portal vein. Experience with these techniques in patients with breast cancer is limited [36-39].
- Stereotactic Body Radiation Therapy (SBRT or fractionated radiosurgery) is a technique that delivers external beam radiation to the tumor using high-dose, precisely focused beams of radiation.
As patients with metastatic breast cancer live longer, the incidence of brain metastases appears to be increasing. The risk factors, prognosis, and management of brain metastases in breast cancer are discussed separately.
Bone is the most common site of metastatic involvement in breast cancer and can be associated with significant morbidity and mortality. Surgery, RT, and RFA can provide effective pain relief and prevent fracture. Surgery and RT is also used for the palliative treatment of epidural spinal cord or nerve compression. Bisphosphonates and other osteoclast inhibitors have been shown to reduce the morbidity of metastatic bone disease, in particular skeletal-related events (SREs), which include fracture, need for surgery or radiation to bone, spinal cord compression, and hypercalcemia of malignancy.
Bone-confined metastatic breast cancer is usually characterized by an indolent course and good response to systemic therapy [40-42]. There is a limited role for resection as a curative option for the majority of bone metastases, except for selected patients with isolated spine or sternal involvement [43-47].
Sternal metastases may remain solitary for a long time, possibly because there is no communication with the paravertebral venous plexus through which cancer cells can spread to other bones [46,48]. In other cases, isolated sternal involvement represents locoregional recurrence (ie, direct extension from an internal mammary nodal recurrence) rather than true metastatic disease. Surgical resection of breast cancer confined to the sternum may improve quality of life and prolong survival.
Abdominal and pelvic metastases
Limited data suggest ovarian breast cancer metastases can appear many years following the initial diagnosis of breast cancer and tend to be hormone receptor-positive [49-52]. Surgical evaluation of an adnexal mass may be required to discriminate metastatic breast cancer from a primary ovarian cancer.
Systemic therapy after local treatment
Many patients in the studies described above were treated with systemic therapy, whether chemotherapy or endocrine therapy, either prior to or after local therapy. The role of systemic treatment after control of oligometastatic disease has been achieved is discussed separately.
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