Abstract
The aim of the present study was to evaluate the effectiveness and safety of hepatic re-resection for breast cancer liver metastases. Patients and Methods: Between January 2004 and December 2014 seven patients were submitted to liver re-resection for breast cancer liver metastases at our Center. The main inclusion criteria were presence of isolated liver metastases and absence of systemic recurrent disease Results: The median age at the time of breast surgery was 51 years (range=39-69 years). The first liver resection was performed after a median period of 34.7 months and consisted of minor hepatectomies in six and major hepatectomy in one patient. The second liver resection was performed after a median interval of 22 months from the first liver resection and consisted of major resection in one case and minor resection in the other six cases. Postoperative complications occurred in a single case after the first liver surgery and in two cases after the second hepatic resection, all cases being successfully managed conservatively. Overall postoperative mortality was 0. The median overall survival after the second liver resection was 28 months. Conclusion: Re-resection for breast cancer liver metastases can be safely performed and may bring survival benefit.
Breast cancer remains an important health problem worldwide with an estimated incidence of 207,090 cases in the United States in 2010 and a mortality rate related to metastatic disease of 39,840 cases in the same year (1). However, during the last few decades the overall survival rates significantly increased even in cases presenting recurrent disease: in a cohort study conducted at the MD Anderson Cancer Center between 1974 and 2000 involving patients with recurrent breast cancer, the median survival rate improved from 15 months to 58 months over the last decades (2). Therefore, if we accept the idea that tumor biology has not suffered significant modifications over the last few decades it seems that the improved rates of survival recently obtained rather correlate with an improved therapeutic armamentarium (3). However it seems that in the progression of breast cancer up to 60% of patients will develop liver metastases, 20% of them being estimated to be diagnosed within five years from breast surgery. Among patients with liver-confined metastatic disease only 10% of them will be eligible for liver resection (4). The 5-year survival rates after liver resection for hepatic metastases in breast cancer widely vary between 23% and 61% (5-7); the largest reported group of patients submitted to hepatectomy for breast cancer liver metastases was conducted by Groeschl et al. and included 115 cases, with a five-year survival rate after liver surgery of 31% (7). Even in cases in which surgical treatment can provide a complete resection, liver recurrence is not a rare event, being reported in up to half of patients initially submitted to liver resection (8). In selected cases presenting isolated hepatic recurrence and a good biological status re-resection might be tempted.
Patients and Methods
All patients with breast cancer liver metastases surgically treated in the “Dan Setlacec” Center of Gastrointestinal Disease and Liver Transplantation, the Fundeni Clinical Institute between January 2004 and December 2014 were retrospectively reviewed. In order to be considered eligible for the study, the patients had to meet the following criteria: histopathological confirmation of breast cancer liver metastases diagnosis at the moment of primary liver resection and re-submission to surgery for preoperative diagnosis of hepatic recurrence. Exclusion criteria were the presence of any evidence of systemic disease. Individual data were reviewed and the following data were collected; age at initial diagnosis of breast cancer, histopathological result, age at diagnosis of the first and second liver resection, type of resection, number and diameter of the lesions, type of resection at both primary and secondary liver surgery, association of neo-adjuvant and adjuvant oncologic treatment at each moment including breast surgery, first and second liver resection. Postoperative data such as hospitalization, postoperative morbidity and mortality (according to Clavien-Dindo scale) were also reviewed. In all cases an R0 resection confirmed by the absence of tumor invasion on the resected margins was performed. Major hepatectomy was defined as a hepatic resection of at least three segments, while minor hepatectomies consisted of less than three liver segments resection. The study protocol was approved by the Ethics Committee of Fundeni Clinical Institute. The protocol was implemented in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.
Results
Seven patients were eligible for the study. All patients had been initially submitted to breast surgery followed by adjuvant chemotherapy. The median age at the moment of surgery for breast cancer was 51 years (range=39-69 years). The initial characteristics of patients submitted to breast cancer surgery are shown in Table I.
Postoperatively all patients but one were submitted to adjuvant chemotherapy, while radiotherapy was administrated in four cases. In all cases taxanes-based chemotherapy was administrated. Adjuvant hormone therapy was administrated in six cases, while HER2-specific therapy (trastuzumab) was also administrated in three cases. In all cases liver was the only site of recurrence. The median interval between breast surgery and the first hepatic resection for liver metastases was 34.7 months (range=12-49 months). In all cases surgery was performed as a first therapeutic option.
At the time of first liver resection a major hepatectomy (involving more than 3 hepatic segments) was performed in one case while in the other six cases minor resections (involving less than 3 liver segments) were performed. The main characteristics of patients at the time of the first liver resection are shown in Table II.
The overall morbidity rate was 14%. Postoperatively a single patient developed a biliary leak which was successfully treated in a conservative manner, while the overall mortality rate was 0. The median interval between the first liver resection and the second liver resection was 22 months (range=11-28 months). The median age at the time of second liver resection was 55 years (range=41-74 years). In one case neo-adjuvant chemotherapy was administrated before the second liver resection, while the other six patients were submitted directly to re-resection. In one case a right hepatectomy was performed while in the other six cases minor hepatectomies were required. The main characteristics of the patients at the time of the second liver resection are shown in Table III.
Initial characteristics at the moment of breast surgery.
Postoperative complications occurred in 2 cases (28%): one patient developed a wound infection while the second one developed a biliary fistula, both cases being treated conservatively; the overall mortality rate was 0. The overall survival after the second liver resection was 28 months (range=10-44 months), four cases being alive and free of recurrent disease at the moment of ending the study.
Discussion
More than half of patients diagnosed with breast cancer will develop distant metastases while up to one third of these cases present liver involvement. Traditionally patients diagnosed with metastatic breast cancer were considered as candidates solely for palliative chemotherapy (9-12); however, the benefits in terms of survival provided by liver resection for colorectal and neuroendocrine hepatic metastases (13-18) encouraged surgeons worldwide to explore the possibility of association of liver resection as part of the standard therapeutic protocol for selected cases with metastatic breast cancer (3, 5, 6, 8, 20-23). In the last few decades since the surgical techniques of liver resection improved and postoperative complications significantly decreased, liver resection has been successfully associated as part of the standard treatment of isolated breast cancer hepatic metastases. However there is an important difference consisting of the patho-physiological mechanism of liver involvement between colorectal and breast cancer. While in patients with colorectal cancer liver involvement occurs via portal flow (thus a systemic spread being excluded), in patients with breast cancer hepatic metastases develop in the context of a presumed systemic spread (24). In patients with breast cancer liver metastases the overall survival remains poor even if a standard chemotherapeutic protocol is applied; this aspect is explained by the fact that finally most patients will develop liver failure related to disease progression associated with the hepato-toxic action of some chemotherapeutic agents and exitus will occur. In the last few decades attention was focused on determining which are the most suitable cases for liver resection; however a standard therapeutic protocol has not been yet established.
Patients' characteristics at the time of first liver resection.
Walsum et al. included in their study 32 patients with breast cancer liver metastases submitted to hepatectomy. Major resections (involving more than 3 segments) were performed in 13 patients, while minor resections (less than 3 segments) were needed in 19 cases. Radiofrequency ablation was was combined with liver resection in two patients. Nineteen patients developed recurrence after liver resection, in nine cases the recurrent disease being limited to the liver. The reported median time to recurrence was 11 months while 5-year disease-free survival was 19%. When studying the long-term outcomes a 5-year overall survival from the date of hepatic resection of 37% was reported, with a median overall survival of 55 months (19).
However, when it comes to second hepatectomy for metastatic breast cancer literature data is even scarcer. One of the largest studies focused on this issue is Rene Adam's article published in 2006. In this study were 85 consecutive patients submitted to hepatic resections for breast cancer liver metastases in Paul Brousse Hospital, Paris, between 1984 and 2004 included. The first hepatic resection was performed for synchronous liver metastases in six cases and metachronous lesions in the other 76 patients. The median time between breast surgery and diagnosis of breast cancer liver involvement was 34 months. Preoperatively, 84% of cases were submitted to neo-adjuvant chemotherapy between breast cancer liver metastases involvement and hepatic resection; as type of surgery, major hepatectomies were performed in 64% of cases. Other associated procedures consisted of radiofrequency ablation in 4% of cases and cryoablation in 5% of cases. Following hepatic resection, the authors reported a global recurrence rate of 69%, 48% of them presenting limited to liver recurrent disease after a median time of 10 months. Liver re-resection was performed in 12 cases, 4 of these being submitted even to the third hepatectomy. At follow-up intervals ranging from 14 to 66 months six of the 12 patients submitted to re-resection were free of recurrent disease (8).
Patients' characteristics at the time of second liver resection.
Regarding safety, in our study the overall mortality rate was 0 while the morbidity rate was 14% at the time of first liver resection and 28% at the time of second liver resection, all complications being classified as grade 1-2 according to that Clavien-Dindo scale and being successfully managed in a conservative manner. In the large majority of the studies conducted on the subject of breast cancer liver metastases resection the overall morbidity rate ranged between 0 and 36%; however these studies did not evaluate the postoperative complications at the moment of the second liver resection, most of them being addressed to a single hepatic resection (5, 19-23).
Conclusion
Re-resection for isolated breast cancer liver metastases is an efficient method increasing disease-free and overall survival with acceptable rates of postoperative complications and almost null postoperative mortality. However more prospective studies are still required in order to determine which are the most important prognostic factors associated with an improved outcome after re-resection.
Acknowledgments
This study was co-financed from the European Social Fund, through POSDRU 2007-2013, Prioritary axis no. 1, Education and formation supporting economical development and aknowledgment based society development– major domain of intervention 1.5 “Doctoral and post-doctoral programs supporting research” CERO-carrier profile: -Romanian researcher. Financial contract: POSDRU/159/1.5/S/135760
Footnotes
This article is freely accessible online.
- Received August 19, 2015.
- Revision received September 19, 2015.
- Accepted September 23, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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