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10.1245/ASO.2004.01.007
Annals of Surgical Oncology 11:869-874 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Long-term Survival After An Aggressive Surgical Approach in Patients With Breast Cancer Hepatic Metastases

Georges Vlastos, MD, David L. Smith, MD, S. Eva Singletary, MD, Nadeem Q. Mirza, MD, MPH, Todd M. Tuttle, MD, Reena J. Popat, BS, Steven A. Curley, MD, Lee M. Ellis, MD, Mark S. Roh, MD and Jean-Nicolas Vauthey, MD

From the Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, TX 77030; Fax: 713-792-0722; E-mail: jvauthey{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Metastatic breast cancer is generally believed to be associated with a poor prognosis. Therapeutic advances over the past two decades, however, have resulted in improved outcomes for selected patients with limited metastatic disease.

Methods: Between March 1991 and October 2002, 31 patients had hepatic resection for breast cancer metastases limited to the liver. Clinical and pathologic data were collected prospectively from breast and hepatobiliary databases.

Results: Median age of patients was 46 years (range, 31 to 70). Liver metastases were solitary in 20 patients and multiple in 11 patients. Median size of the largest liver metastasis was 2.9 cm (range, 1 to 8). Major liver resections (three or more segments resected) were performed in 14 patients, whereas minor resections (fewer than three segments resected) with or without radiofrequency ablation (RFA) were performed in 17 patients. No postoperative mortality occurred. Of the 31 patients, 27 (87%) received either preoperative or postoperative systemic therapy as treatment for metastatic disease. The median survival was 63 months; a single patient died within 12 months of hepatic resection. The overall 2- and 5-year survival rates were 86% and 61%, respectively, whereas the 2- and 5-year disease-free survival rates were 39% and 31%, respectively. No treatment- or patient-specific variables were found to correlate with survival rates.

Conclusions: In selected patients with liver metastases from breast cancer, an aggressive surgical approach is associated with favorable long-term survival. Hepatic resection should be considered a component of multimodality treatment of breast cancer in these patients.

Key Words: Breast cancer • Surgery • Metastasis • Radiofrequency ablation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
More than 50% of patients with breast cancer will develop liver metastases.1 Typically, this is a late finding and metastases are already present at other sites.2 These patients are not candidates for resection and can only be treated with systemic therapy. Neither regional nor systemic chemotherapy significantly improves survival in patients with breast cancer liver metastases (BCLM), and the median survival is short (1 to 4 months).3–5 Hormonal therapy is generally of limited use because most hepatic metastasis are hormone receptor negative.6

Recent studies suggest a role for surgical resection in a subset of patients with isolated metastases in the liver, brain, lung, and bone.7 Single institutional series have demonstrated 5-year survival rate of 20% to 27% following hepatic resection of BCLM.8,9 Liver resection is a safe procedure in most centers, with an operative mortality of <5% and a morbidity of 20%.10 Hepatic resections are most commonly done for colorectal liver metastasis, with 5-year survival rates of 25% to 44% being reported.11 The contemporary role of hepatic resection for metastasis from other malignancies (e.g., breast cancer) is not clearly defined.

Since the early 1990's, liver resection has been used at the University of Texas M. D. Anderson Cancer Center to treat selected patients with isolated hepatic metastases from breast cancer. This study was conducted to analyze the experience with liver resection or ablation in our institution and to assess its role in the treatment of BCLM.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We reviewed our prospective institutional breast and hepatobiliary cancer databases to identify all patients who had liver resection for BCLM at the University of Texas M. D. Anderson Cancer Center. From March 1991 to October 2002, 36 patients with isolated breast cancer metastases to the liver were referred for surgical treatment. A retrospective review of all the records of these patients was also performed. Of these 36 patients, 5 were excluded for the following reasons: no surgery performed (n = 2); extrahepatic disease noted at surgery (n = 2); and information not available (n = 1).

Clinical and pathologic parameters reviewed included the following: age at diagnosis, race, tumor size, lymph node status, stage, estrogen and progesterone receptor status, tumor margin status, chemotherapy or hormonal therapy, and locoregional and distant recurrence. Also recorded were characteristics of liver metastases, including size, number, and location of metastases; the type and the length of surgical procedures; intraoperative blood loss; and postoperative complications.

The diagnosis of metastasis was confirmed by percutaneous liver biopsy. Patients then had a staging evaluation that included history and physical examination, serum chemistries (complete blood count, transaminases [aspartate aminotransferase, alanine aminotransferase], alkaline phosphatase, bilirubin), chest radiograph, computed tomography (CT) of the abdomen and pelvis, and bone scan.

Patients were treated with preoperative, postoperative, or both chemotherapy and hormonal therapy regimens, according to institutional protocols in use at the time of diagnosis of metastases. Response was assessed by imaging studies, including liver ultrasound and abdominal CT.

Patients with extrahepatic disease were considered ineligible for resection. A standardized approach was used for intraoperative staging, which included a thorough exploration of the peritoneal cavity and biopsy of any suspicious lesions. Periportal nodes were also examined, with any suspicious nodes or those >1 cm in size sent for frozen section evaluation. If no extrahepatic disease was detected, patients were evaluated by intraoperative ultrasound (IOUS). An IOUS with a 5- to 7.5-MHz probe (Aloka, Co. Ltd., Tokyo, Japan) was used to assess the extent of the known metastases and to search for additional lesions. The liver was fully mobilized by dividing the triangular ligaments, round ligament, and falciform ligament.

Surgical procedures for hepatic lesions were determined on the basis of disease extent and location. If IOUS demonstrated that each lesion could be treated, patients had resection aimed at a surgical clearance margin of at least 1 cm or combined resection plus radiofrequency ablation (RFA) with a 1-cm margin. Hepatic resection consisted of major hepatectomy (three or more segments resected) or minor hepatectomy (fewer than three segments resected). Surgical margins were evaluated intraoperatively. RFA was performed through an open technique if the tumor to be ablated was unresectable because of location or distribution. Ablation was performed using the RF 2000 or 3000 generator system (Boston Scientific Corp., Natick, MA) and a 15-gauge insulated LeVeen monopolar needle electrode (4.0 cm maximal array was used), placed under IOUS guidance, and ablation performed using a previously described technique.12

The Statistical Package for the Social Sciences, version 10.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. Statistical analysis was performed only on patients having hepatic resection of BCLM. Differences in the distribution of characteristics were analyzed by the {chi}2 test. Disease-specific and disease-free interval probabilities were calculated by the Kaplan-Meier product limit method from the dates of liver surgery to the date of death or last follow-up. Possible prognostic factors in term of survival after liver surgery were assessed, including age at diagnosis of breast cancer, characteristics of the primary breast cancer, type of treatment, disease-free interval, number of liver metastases, the size of liver metastases, response to systemic treatment, type of surgery performed using log-rank test. P values ≤ .05 were considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 31 female patients had surgical treatment for isolated BCLM. Demographic and treatment characteristics of these patients are summarized in Table 1. The median breast tumor size was 2.5 cm (range, 1 to 8). Most patients received a diagnosis of either stage II or stage IV disease. Histology was 80.6% invasive ductal carcinoma ± in situ component. Black’s nuclear grade status in patients was I in 19%, II in 28%, and III in 28%, respectively. Estrogen receptors were positive in 58% of patients and progesterone receptors positive in 35%. Surgical treatment of the primary tumor was a modified radical mastectomy in 25 patients (81%) or wide local excision and axillary lymph node dissection in 6 patients (19%). The median number of positive lymph nodes removed was 4 (range, 0 to 16). Of patients, 87% received chemotherapy, and 45% received hormonal therapy; 43% received adjuvant radiation therapy to the breast and nodal areas. The patient characteristics are described in Table 2. A total of 20 patients had solitary liver metastases and 11 had two or more lesions. One patient was noted to have seven left lobe lesions at the time of surgery, all of which were felt to be resectable. This patient had an extended left hepatectomy. The median size of the largest liver metastasis was 2.9 cm (range 1 to 8). Liver metastases developed after a median of 22 months (range, 0 to 144) from initial diagnosis. Nine patients had synchronous liver metastases at time of diagnosis of breast cancer.


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  		TABLE 1. Characteristics and treatment of primary tumor
 

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  		TABLE 2. Characteristics and treatment of patients with liver metastases
 
A major hepatectomy was performed in 14 patients, whereas 17 patients had minor hepatectomy, with or without RFA. The median operative time was 148 minute (range 65 to 237). Median intraoperative blood loss was 100 mL (range, 0 to 600). No perioperative mortality occurred. Chemoendocrine regimens used for the treatment of liver metastases are detailed in Table 2. The median follow-up time was 25 months (range 3 to 140). In those patients who developed recurrent disease, the median time to recurrence after liver surgery was 13 months (range, 2 to 140). At the time of analysis, 22 patients (71%) were alive, 9 (29%) had died; 16 patients had recurrence after hepatectomy, with systemic recurrence in 12 and hepatic recurrence in 4 patients. The median overall survival after liver resection was 25 months (range, 3 to 140). The 2- and 5-year actuarial survivals were 86% and 61%, respectively. Survival curves are presented in Figure 1. Prognostic factors for survival are summarized in Table 3. No specific factor predicted survival.



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  		FIG. 1. (A) Overall survival following hepatic resection. (B) Disease-free survival following hepatic resection.

 

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  		TABLE 3. Prognostic variables of survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Of all patients with metastatic breast cancer, approximately 5% will develop hepatic only metastasis.3,4 Only a small number of retrospective studies have examined outcomes in patients with breast cancer with isolated liver metastases treated by resection. The numbers in these studies are relatively small, with only a few series having >20 patients. Evidence, however, indicates that surgery, with or without chemotherapy, is associated with extended survival in this subset of patients. As shown in Table 4, the median survival for patients in these studies ranged from 15 to 47 months, with a 5-year survival from 22% to 61%. In patients who received medical treatment alone, survival ranged between 3 and 6 months, but rarely exceeded 2 years.13


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  		TABLE 4. Comparison of survival after hepatic resection of BCLM
 
Isolated metastasis, which may be the only sign of recurrence, is likely a favorable condition for aggressive treatment, including hepatic resection, similar to that for patients with isolated hepatic colorectal metastases.11,14 In our series, the 5-year survival rate was 61%, suggesting a benefit for selected patients. Data in the literature remain controversial, however. Elias et al.15 reported a 50% survival rate at 2 years and 9% survival rate at 5 year. Schneebaum et al.9 reported a 42-month median survival in patients after resection. Pocard et al.16 reported a 46% 4-year survival after surgery in a series of 65 patients. Other studies failed to show a survival advantage.17,18 This survival variability reflects the small number of patients in each of these series.

Because the mortality and morbidity associated with liver resection has decreased dramatically during the past decade, the indication for surgery has widened for metastatic diseases. Hepatic resection, therefore, can be offered to selected patients with isolated disease to render them disease free, or at least disease stable. A recent report of the Institute Curie in Paris19 found two factors to be predictive of outcome: the time to metastasis to the liver and the initial stage of breast cancer. Because of the small number of patients in this series, we were unable to identify specific prognostic factors that affected survival after resection. Selection criteria are still controversial; however, important criteria are likely to be fewer than four metastases, no extrahepatic disease, and demonstrated disease regression or stability with systemic therapy before resection. We had one patient who experienced recurrence very early after hepatic resection and died within 6 months. At the time of surgery, it was noted that this patient had extensive (seven separate lesions) left lobe disease. Additionally, she had 6 months of preoperative chemotherapy, during which time her hepatic disease progressed. This suggests, perhaps, that systemic disease progression in this patient on chemotherapy also likely occurred. The extent and behavior of disease can indicate a more aggressive biology and, perhaps, those patients who have not demonstrated disease stability or regression during preoperative chemotherapy should not be considered for resection.

As the treatment recommendations for breast cancer continue to evolve, so too does the goal of surgical intervention. We may be approaching the time when the goal for the treatment for metastatic breast cancer is to render it harmless as a result of prolonged remission. In our series, 52% of the patients eventually developed recurrent metastatic disease, usually not in the liver, with a mean recurrence time of 21 months after treatment. Of those patients with recurrent disease, 50% remain alive and are doing well clinically. Most of these patients remain on some type of long-term chemotherapy. The optimal treatment for selected patients with isolated metastases can include, as in our patients, a combination of chemotherapy or hormonal therapy and hepatectomy.

In light of the fact that surgical treatment can be performed with low morbidity and minimal mortality (61% 5-year survival rate), hepatic resection can be proposed in this selected group of patients. Further studies need to be conducted to define which patients best benefit from this treatment strategy. We recommend an extensive preoperative staging evaluation before considering hepatic resection for BCLM. Radiographic studies include CT of the chest, abdomen, and pelvis; bone scan and, perhaps, positron emission tomography (PET) scan. Recent studies suggest that PET imaging can identify metastases that are not seen with other types of imaging.19,20 Our preference is that chemotherapy be given before hepatic resection. After two to three cycles of chemotherapy, radiographic studies are then repeated. Hepatic resection can be considered for patients with stable or improved disease isolated to the liver who have tumors that are resectable with a tumor-free margin or amenable to RFA. Laparoscopy is recommended to prevent nontherapeutic laparotomy if extrahepatic disease based on preoperative imaging is suggested. In our study, two patients with BCLM had unsuspected extrahepatic disease found at laparotomy. Hepatic resection is preferable if metastases can be safely removed with a negative surgical margin. Because of the higher local recurrence rates seen with RFA for colorectal metastases as compared with resection,21 RFA should be reserved for those patients with tumors not amenable to safe resection.

The biology of this subset of patients with isolated liver metastases, or single organ stable metastases, requires further study. This is particularly so in light of improving chemotherapeutic strategies because the natural history of these patients can differ from patients with multiorgan, metastatic breast cancer, or large tumor burdens. By changing our focus from complete eradication of all viable tumor cells as the goal of therapy to that of rendering the disease stable, selected patients with metastatic breast cancer to the liver may have prolonged remission if their cancer is detected early and treated aggressively. Further studies are needed to answer this question.


   ACKNOWLEDGMENTS
 
We would like to thank Elaine Evers, ART, CCS, CPC (Professional Coding Services), Vickie Ellis, data manager, and Misty Woodall, RN (Department of Surgical Oncology) for their help in data collection.


   FOOTNOTES
 
Surgery for breast cancer liver metastases can be performed safely. Liver resection is associated with a favorable long-term survival. Selected patients benefit from hepatic resection.

Received for publication January 9, 2004. Accepted for publication May 14, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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