Review
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 18, 2017; 9(5): 242-251
Published online Feb 18, 2017. doi: 10.4254/wjh.v9.i5.242
Role of surgical resection for non-colorectal non-neuroendocrine liver metastases
Nobuyuki Takemura, Akio Saiura
Nobuyuki Takemura, Department of Gastroenterological Surgery, JR Tokyo General Hospital, Tokyo 151-8528, Japan
Nobuyuki Takemura, Akio Saiura, Department of Gastroenterological Surgery, Cancer Institute Ariake Hospital, Japanese Foundation for Cancer Research, Tokyo 151-8528, Japan
Author contributions: Takemura N analyzed the literatures and wrote the manuscript; Saiura A reviewed and edited the manuscript.
Conflict-of-interest statement: The authors have no conflicts of interest to declare in relation to the contents of this review.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nobuyuki Takemura, MD, Department of Gastroenterological Surgery, JR Tokyo General Hospital, 2-1-3, Yoyogi, Shibuya-ku, Tokyo 151-8528, Japan. takemuranobu-tky@umin.ac.jp
Telephone: +81-3-33202200 Fax: +81-3-33707477
Received: August 30, 2016
Peer-review started: September 1, 2016
First decision: September 29, 2016
Revised: October 29, 2016
Accepted: December 7, 2016
Article in press: December 9, 2016
Published online: February 18, 2017

Abstract

It is widely accepted that the indications for hepatectomy in colorectal cancer liver metastases and liver metastases of neuro-endocrine tumors result in relatively better prognoses, whereas, the indications and prognoses of hepatectomy for non-colorectal non-neuroendocrine liver metastases (NCNNLM) remain controversial owing to the limited number of cases and the heterogeneity of the primary diseases. There have been many publications on NCNNLM; however, its background heterogeneity makes it difficult to reach a specific conclusion. This heterogeneous disease group should be discussed in the order from its general to specific aspect. The present review paper describes the general prognosis and risk factors associated with NCNNLM while specifically focusing on the liver metastases of each primary disease. A multidisciplinary approach that takes into consideration appropriate timing for hepatectomy combined with chemotherapy may prolong survival and/or contribute to the improvement of the quality of life while giving respite from systemic chemotherapy.

Key Words: Non-colorectal non-neuroendocrine liver metastasis, Metastatic liver tumor, Hepatectomy, Gastric cancer liver metastasis, Gastrointestinal stromal tumor liver metastasis, Breast cancer liver metastasis, Melanoma liver metastasis, Sarcoma liver metastasis, Renal cell carcinoma liver metastasis, Ovarian cancer liver metastasis

Core tip: Previous studies reported that the results of hepatectomy for non-colorectal, non-neuroendocrine liver metastasis (NCNNLM) showed an acceptable prognosis in the heterogeneous disease group. However, considering the indication of hepatectomy for NCNNLM, it is important to define the features of each primary disease. The present review paper describes the general prognosis and risk factors associated with NCNNLM, specifically focuses on liver metastasis associated with each primary disease. A multidisciplinary approach that takes appropriate timing for hepatectomy combined with chemotherapy into consideration may prolong survival and/or contribute to the improvement of the quality of life, while taking time off from systemic chemotherapy.



INTRODUCTION

Metastatic disease from solid organ tumors occurs frequently in the liver. Presently, surgical resection has been widely accepted as a treatment for colorectal cancer liver metastases[1,2] and liver metastases of neuro-endocrine tumors[3,4], providing a relatively better prognosis, whereas, the indications and prognosis of hepatectomy for non-colorectal non-neuroendocrine liver metastases (NCNNLM) remain controversial owing to the rarity of the disease. The biological behavior of NCNNLM varies depending on its primary origin. Discussion of this heterogeneous disease group should be performed in the order from its general to specific aspects. To date, no prospective randomized study has been conducted in this limited field; therefore, in this report we provide a general review of large cohort retrospective studies on hepatectomy for NCNNLM and a more specific review on hepatectomy for liver metastases from different primaries.

LITERATURE AND RESEARCH

In this report, we reviewed the literature reporting NCNNLM in a large number of patients and their specific primaries. More precisely, we reviewed articles in the English literature that included ≥ 100 cases with NCNNLM and relatively large case series for the specific primary (for liver metastases from gastric cancer, breast cancer, and melanoma, reports that included ≥ 40 cases were reviewed because of the limited availability of cases in many studies). Using the results reported in the selected literature, the survival outcomes and statistically significant risk factors that impacted survival by multivariate analysis (univariate analysis for some report) were evaluated.

Prognosis and risk factors after hepatectomy for NCNNLM

Along with increased evidence of prolonged survival by hepatectomy in patients with colorectal and neuroendocrine liver metastases, Schwartz et al[5] initially categorized NCNNLM and reviewed the literatures in 1995, followed by the analysis of prognosis in a large cohort study by Harrison et al[6] in 1997. Many validation studies were performed in other patient cohorts that are summarized in Table 1[7-16]. In the present report, we reviewed the 10 largest studies, each with ≥ 100 patients who underwent hepatectomy for NCNNLM. In this cohort, the 3- and 5-year overall survival rates were reported as 34%-57% and 19%-42%, respectively, with median survival times of 23-49 mo. The 3- and 5-year disease-free survival rates were 21%-37% and 18%-29%, respectively, with median disease-free survival times of 10-21 mo. The postoperative mortality and morbidity rates were reported 0%-5% and 18%-33%, respectively. In these cohort studies, the reported negative risk factors for survival were the margin status in six studies[8-11,15,16]; primary tumor type in four[8,10,11,15]; shorter disease-free interval between primary tumor resection and hepatectomy[8,10,15] and extrahepatic disease[10,12,16] in three; postoperative complications[14,16], larger hepatic metastasis in diameter[12,13], and squamous cell histology[10,15] in two; and age[10], major hepatectomy[10], minor hepatectomy[15], synchronous metastasis[11], lymphovascular invasion[13], stromal tumor histology[15] and > 3 liver metastases[16] in one (Table 1). Negative risk factors for recurrence were extrahepatic disease[12,16] in two studies; and primary tumor[8], disease-free interval[8], larger hepatic metastasis in diameter[12], blood transfusion[14], preoperative chemotherapy[14], > 3 liver metastases[16], and residual tumor[16] in one. Patients with liver metastases from breast cancer showed significantly better survival in three studies[10,11,15], whereas those with liver metastases from genitourinary tumor liver showed better survival in one[11], and patients with liver metastases from melanoma showed poorer survival compared to other primaries in two studies[10,15] (Table 2).

Table 1 Summary of studies each of which included ≥ 100 patients who underwent hepatectomy for non-colorectal non-neuroendocrine liver metastases (overall survival).
Ref.YearPeriodNo. of patientsPrimary tumor (GI/breast/GU/melanoma/sarcoma/others)MST (mo)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Elias et al[7]19981984-19961201(22/35/31/10/13/9)NRNR362NR
Yedibela et al[9]20051978-20011501(50/24/11/5/15/45)232NR262Margin status (R1,2)
Weitz et al[8]20051981-2002141(12/29/50/17/0/33)4257NRPrimary tumor type, disease-free interval ≤ 24 mo, margin status (R1,2)
Adam et al[10]20061983-20041452(314/460/332/148/0/198)354936Age, primary tumor (ocular melanoma, non-breast), squamous tumor, disease-free interval, extrahepatic disease, major hepatectomy, margin status (R1,2)
Lendoire et al[11]20071989-2006106(7/19/40/6/23/11)273419Primary tumor (non-breast, non-GU), synchronous metastasis, margin status (R1,2)
O'Rourke et al[12]20081986-2006102(27/11/31/20/3/10)425639Diameter of liver metastasis > 5 cm, extrahepatic nodal disease
Groeschl et al[13]20121990-2009420(13/15/92/31/98/71)495031Diameter of liver metastasis ≥ 5 cm, lymphovascular invasion
Takemura et al[14]20131993-2009145(91/30/12/1/8/3)425541Postoperative complication
Hoffmann et al[15]20152001-2012150(30/42/33/15/9/21)46NR42Primary tumor (melanoma, non-breast), interval < 24 mo, squamous tumor, non-stromal tumor, minor hepatectomy, margin (R2)
Schiergens et al[16]20162003-2013167(43/16/61/8/25/14)3549NR> 3 liver metastases, extrahepatic disease, residual tumor (R1,2), major complications
Table 2 Summary of studies each of which included ≥ 100 patients who underwent hepatectomy for non-colorectal non-neuroendocrine liver metastases (disease-free survival).
Ref.YearNo. of patientsMDFST (mo)3-ydfsr (%)5-ydfsr (%)Factors associated with worse disease-free survival
Elias et al[7]19981201NRNR282NR
Yedibela et al[9]20051501NRNRNRNR
Weitz et al[8]20051411730NRPrimary tumor, diseas-free interval ≤ 24 mo
Adam et al[10]20061452132721NR
Lendoire et al[11]2007106NRNRNRNR
O'Rourke et al[12]2008102183727Diameter of liver metastasis > 5 cm, extrahepatic nodal disease
Groeschl et al[13]2012420NRNRNRNR
Takemura et al[14]2013145102118Blood transfusuion, preoperative chemotherapy
Hoffmann et al[15]2015150213629NR
Schiergens et al[16]201616715NRNR> 3 liver metastases, extrahepatic disease, residual tumor (R1,2)

As previously mentioned, the type of primary origin was one of the greatest predictors of survival in patients with this heterogeneous disease. Among the 10 largest studies, the most dominant primary origin was the breast[7,10,13,15] and genitourinary[8,11,12,16] in four studies and gastrointestinal tract in two[9,14]. Elias et al[7] and Yedibela et al[9] commented that the resection of liver metastases from gastrointestinal adenocarcinoma correlated with a poor prognosis; however, a more recent report by Takemura et al[14] showed acceptable prognosis after resection of liver metastases from gastrointestinal carcinoma in their largest cohort with a median survival time of 33.5 mo after hepatectomy. As Yedibela et al[9] and Groeschl et al[13] reported that in the more recent years, patients undergoing hepatectomy for NCNNLM appeared to have longer survival compared to previous years, advances in chemotherapy regimens might contribute to prolong survival after the resection of NCNNLM. Adam et al[10] developed a risk model based on their results of multivariate prognostic factor analysis, which was validated by Lendoire et al[11]. Their risk model can efficiently stratify the patients into groups; however, the prognosis of each group differed between the two studies depending on the heterogeneous backgrounds of the patient. To facilitate discussion, the prognosis of each primary disease after hepatectomy for NCNNLM has been discussed separately in following section.

LIVER METASTASES FROM GASTROINTESTINAL PRIMARY TUMORS
Gastric cancer liver metastases

In the present report, we reviewed the largest 8 studies, each with ≥ 40 patients who underwent hepatectomy for liver metastases from gastric cancer. In this series, the 3- and 5-year overall survival rates were reported as 14%-51% and 9%-42%, respectively, with median survival times of 12-41 mo (Table 3)[10,17-23]. Among these studies, the negative risk factors for survival were multiple liver metastases in three studies[18,20,23]; larger hepatic metastasis in diameter[19,21] and serosal invasion of primary gastric cancer[19,21] in two; and synchronous hepatic metastases[17], > 3 liver metastases[21] and > 2 positive regional lymph node metastases of primary gastric cancer[23] in one (Table 3). The results of hepatectomy for liver metastasis from gastric cancer are influenced by the statuses of both the primary cancer and liver metastasis. The recent meta-analysis of gastric cancer liver metastases revealed that the surgical resection of liver metastases from gastric cancer was associated with a significantly improved survival and among the patients who underwent surgical resection, patients with solitary hepatic metastasis demonstrated a significantly prolonged survival compared to patients with multiple hepatic metastases[24]. Compared to colorectal liver metastasis, reports on aggressive repeat hepatectomy have been highly limited[25], which might be owing to the frequent occurrence of extrahepatic recurrence such as peritoneal seeding and lymph node recurrence. However, advancements in effective chemotherapy regimens can expand not only the prognosis but also the surgical indications for hepatectomy in patients with liver metastasis from gastric cancer and colorectal live metastases alike.

Table 3 Summary of studies each of which included ≥ 40 patients who underwent hepatectomy for liver metastasis from gastric cancer.
Ref.YearPeriodNo. of patientsMST (mo)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Ambiru et al[17]20011975-19994012NR18Synchronous metastasis
Adam et al[10]120061983-20046415NR27NR
Cheon et al[18]20081995-200541183221Multiple liver metastases
Takemura et al[19]20121993-201164345037Serosal invasion of primary gastric cancer, maximum hepatic metastasis diameter > 5 cm
Aizawa et al[20]20141997-20105327NR18Multiple liver metastases
Kinoshita et al[21]20141990-2010256314231Serosal invasion of primary gastric cancer, > 3 liver metastases, maximum hepatic metastasis diameter > 5 cm
Tiberio et al[22]20151997-20115313149NR2
Oki et al[23]20152000-201069415142Multiple liver metastases, > 2 positive regional lymph node metastases of primary gastric cancer
Gastrointestinal stromal tumors liver metastases

The 7 largest studies on the hepatectomy for liver metastases from gastrointestinal stromal tumors (GIST) reported 50%-90% and 30%-76% overall 3- and 5-year survival rates, respectively, with median survival times of 33-96 mo (Table 4)[26-32]. Non-surgical therapy[28,31], positive resection margin[30,32], and extrahepatic disease[29,30] in two studies each and a disease free interval ≤ 24 mo[26], absence of tyrosine kinase inhibitor (TKI) therapy[29], male patients[30] and progression disease to TKI therapy at the time of surgery[30] were the factors associated with worse survival (Table 4). Different from other NCNNLMs, the emergence of TKI dramatically changed the treatment and prognoses of patients with advanced GIST. The role of surgical resection in the treatment of metastatic GIST had remained unclear in the initial era of treatment with TKI[33]; however, recent reports showed evidence that surgical resection combined with TKI offered better prognosis than TKI monotherapy[29,31,32]. As Bauer et al[30] reported progression disease to TKI therapy at the time of surgery, an urgent issue to debate is the appropriate duration of preoperative therapy to minimize the risk of acquiring secondary mutations responsible for TKI resistance[26,29].

Table 4 Summary of studies with relatively large cohort of patients who underwent hepatectomy for liver metastasis from gastrointestinal stromal tumors.
Ref.YearPeriodNo. of patients underwent hepatectomyMST (mo)3-ysr (%)5-ysr (%)3-yPFS (%)No. of patients with TKIFactors associated with worse overall survival
DeMatteo et al[26]20011982-2000341391501301451NRInterval from primary tumor diagnosis ≤ 24 mo2
Nunobe et al[27]20051984-200318366434NR3 (17%)NR
Xia et al[28]201020051933 (mean)90NRNR19 (100%)Non-surgical therapy2
Turley et al[29]20121995-201039Not reached at 5 yr68NRNR27 (73%)3Non-TKI therapy, extrahepatic disease
Bauer et al[30]2014Until 201110496NRNRNR> 84%Male4, R2 resection4, progression disease to TKI at the time of surgery4, extrahepatic disease4
Du et al[31]2014NR19Not reachedNRNR88 (2-yr)19 (100%)Non-surgical therapy2
Seesing et al[32]20161999-2014489080766742 (88%)Margin status (R1,2)
Other gastro-intestinal primary tumor liver metastases

Pertaining to reports of liver resection for other gastro-intestinal primary liver metastases that rarely indicated hepatectomy, esophagus and pancreas cancer liver metastasis showed dismal prognosis with a median overall survival time of 7-20 mo[10,16,34,35]. In the meanwhile, intestinal type primary tumors such as duodenal, ampullary and small intestinal cancer showed relatively better prognosis with median survival times of 23-58 mo[10,34] (Table 5).

Table 5 Summary of studies with relatively large cohort of patients who underwent hepatectomy for liver metastases from gastrointestinal primaries other than gastric cancer and gastrointestinal stromal tumors.
DiseaseRef.YearPeriodNo. of patientsMST (mo)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Peri-ampullaryDe Jong et al[34]20101993-20094017 [23 (intestinal), 13 (pancreaticobiliary)]18NRIntestinal type (ampullary or duodenal) tumors
AmpullaryAdam et al[10]120061983-20041538NR46NR
Small bowelAdam et al[10]120061983-20042858NR49NR
PancreasAdam et al[10]120061983-20044020NR25NR
Schiergens et al[16]120162003-201319717NRNR
EsophagousAdam et al[10]120061983-2004201632NRNR
Ichida et al[35]20132003-2005513NRNRNR
LIVER METASTASES FROM BREAST CANCER

The largest 10 studies, each with ≥ 40 patients who underwent hepatectomy for liver metastases from breast cancer were reviewed. In this series, the 3- and 5-year overall survivals rates were 49%-68% and 27%-53%, respectively, with median survival times of 41-115 mo (Table 6)[10,13,15,36-42]. The negative prognostic predictive factors were short disease-free interval[36,39], negative expression of hormone receptors[37,40], poor response to systemic chemotherapy before surgery[38,40], and positive hepatic resection margin[38,39] in two studies; and the absence of repeat hepatectomy[38], non-hepatectomy[41], bone metastasis[41], lymph node metastasis in the primary tumor[42], absence of trastuzumab therapy[42], and multiple liver metastases[42] in one (Table 6). Some prognostic factors of liver metastases from breast cancer are unique and different from other NCNNLMs, which could indicate that the presence of hormone receptors and HER2 overexpression requires the use of chemotherapy and/or hormone therapy and influences patient survival. Neuman et al[43] suggested that the impact of local control for liver metastases from breast cancer was greatest in the presence of effective targeted therapy. Similar to other NCNNLMs, surgical resection before progression of disease even with chemotherapy might result in better outcomes of selected patients with liver metastases from breast cancer[40]. As Sadot et al[42] advocated in their study, hepatic resection for liver metastases from breast cancer might not confer a survival advantages; however, might allow time off from systemic chemotherapy.

Table 6 Summary of studies with ≥ 40 patients who underwent hepatectomy for liver metastasis from breast cancer.
Ref.YearPeriodNo. of patientsMST (mo)3-ysr (%)5-ysr (%)MDFS (mo)Factors associated with worse overall survival
Pocard et al[36]20001988-1997524249NRNRDisesase free interval ≤ 48 mo (univariate)
Elias et al[37]20031986-200054345034NRHormone receptor-negative
Adam et al[38]20061984-20048532NR3720Poor response to preoperative chemotherapy, R2, no repeat hepatectomy
Adam et al[10]120061983-200445445NR41NRNR
Hoffman et al[39]20101999-20084158684834Positive resection margin, disease-free interval < 24 mo
Abbott et al[40]20121997-20108657NR4414ER-negative, disease progression before hepatectomy
Groeschl et al[13]120121990-200911552522722NR
Mariani et al[41]20131988-20075191NRNRNRNon-hepatectomy3, bone metastasis4
Hoffmann et al[15]120152001-20124263NR53NRNR
Sadot et al[42]20161991-2014692502NR38229Lymph node metastasis in the primary tumor, absence of trastuzumab therapy, multiple liver metastases
LIVER METASTASES FROM MELANOMA

The largest four studies, each with ≥ 40 patients who underwent liver resection for liver metastases from melanoma, reported an overall 5-year survival rate of approximately 7%-20% with a median survival time of 14-28 mo (Table 7)[10,44-46]. Short disease-free interval from the diagnosis of primary tumor[45], positive resection margin[45], > 4 liver metastases[45], miliary disease of the primary melanoma[45], cutaneous melanoma[46], and no preoperative chemotherapy were the risk factors predicting poor patients survival (Table 7). The metastatic pathway of ocular and cutaneous melanomas is different. Ocular melanoma often spreads hematogenously to the liver because there are no lymphatics in the uveal tract. In contrast, cutaneous melanomas potentially spread to the lung, lymph node and soft tissue, and infrequently to the liver[47]. Liver metastases from ocular melanoma often recur within the liver, whereas cutaneous melanoma is more likely to develop extrahepatic recurrence[44]. Surgical resection should be performed concomitantly with system in chemotherapy as part of a multidisciplinary approach because recurrent disease frequently develops after hepatectomy.

Table 7 Summary of studies with ≥ 40 patients who underwent hepatectomy for liver metastasis from melanoma.
Ref.YearPeriodNo. of patientsOcular/cutaneousMST (mo) (ocular/cutaneous)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Adam et al[10]120061983-2004148104/4419/27NR21 (ocular)/22 (cutaneous)NR
Pawlik et al[44]20061988-20044016/2428 [29 (ocular)/24 (cutaneous)]62 (ocular)/48 (cutaneous) (2-yr)11 (21 (ocular)/0 (cutaneous))Cutaneous melanoma, no preoperative chemotherapy (in cutaneous melanoma) (univariable)
Mariani et al[45]20091991-2007255 (R2 = 157)255/014 (27 mo after R0 resection)NR7Interval from primary tumor diagnosis ≤ 24 mo, R1 and R2, number of the metastases > 4, miliary disease
Mariani et al[46]20162000-201370 (inclding 13 concomitant with RFA)70/027 (hepatectomy), 28 (+RFA)NRNRNR
LIVER METASTASES FROM SARCOMA

The six largest studies on the resection of liver metastases from sarcoma reported 50%-65% and 13%-46% overall 3- and 5-year survival rates, respectively, with median survival times of 24-72 mo (Table 8)[13,26,48-51]. Negative risk factors for overall survival in this cohort were a time of < 24 mo from the diagnosis of primary tumor to the time of liver metastasis[26,51], non-GIST[49], leiomyosarcoma[50], extrahepatic disease[51], and positive resection margins[51] (Table 8). These studies included some GIST patients particularly in the early study periods because GIST had been considered as leiomyosarcoma before around 1993. Repeat hepatic resection was reported in four studies. Lang et al[48] reported 9 second and 2 third cases of hepatectomy for intrahepatic recurrent sarcoma. Less sensitivity to chemotherapy might prompt the surgeon to conduct a repeat hepatectomy with R0 resection, resulting in a favorable outcome[48].

Table 8 Summary of studies with relatively large cohort of patients who underwent hepatectomy for liver metastasis from sarcoma.
Ref.YearPeriodNo. of patientsMST (mo)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Lang et al[48]20001982-199626 (including 9 second, 2 third resection)32 (R0 first resection), 21 (R1,2 resection)NR13NR
DeMatteo et al[26]120011982-2000561391501301Time to liver metastasis from the primary tumor diagnosis ≤ 24 mo
Pawlik et al[49]20061996-200553 (35Hx, 18RF + Hx, and 13RF), (including 36 GISTs)472652272Non-GIST
Marudanayagam et al[50]20111997-2009361 (including 5 GISTs)244832Primaly leiomyosarcoma
Groeschl et al[13]320121990-200998726032NR
Zhang et al[51]20152000-200927NRNR46Interval from primary tumor diagnosis ≤ 24 mo, extrahepatic disease, positive margins
LIVER METASTASES FROM GENITOURINARY TUMORS

Genitourinary tumors mainly comprise renal cell carcinoma, gynecological carcinoma most commonly with ovarian cancer, and testicular cancer. In the present report, we have reviewed 6 studies pertaining to liver metastases from the renal cell carcinoma which reported overall 3- and 5-year survival rate of 54%-68% and 38%-62%, respectively, with median survival times of 33-142 mo (Table 9)[10,16,52-55]. The negative prognostic risk factors were the resection margin[52,54], high-grade tumor[53], poor performance status[53], lymph node metastasis[53], synchronous metastasis[54], short disease-free interval[55], and extra hepatic disease[55] (Table 9). Staehler et al[53] is the first to advocate a favorable prognosis for hepatectomy in patients who underwent resection of liver metastases from renal cell carcinoma over the prognosis of patients who refused to undergo hepatectomy for metastatic renal cell carcinoma, albeit the requirement for further systemic treatment.

Table 9 Summary of studies with relatively large cohort of the patients who underwent hepatectomy for liver metastasis from genitourinary primary tumor.
DiseaseRef.YearPeriodNo. of patientsMST (mo)3-ysr (%)5-ysr (%)Factors associated with worse overall survival
Renal cell carcinomaAdam et al[10]120061983-20048536NR38NR
Thelen et al[52]20071988-200631485439Resection margin (R1,2)
Staehler et al[53]20101995-200668142NR62High-grade primary renal cell carcinoma, performance status ≥ 1, lymph node status
Ruys et al[54]20111990-200829334743Synchronous metastases, R1,2 resection margin (univariate)
Hatzaras et al[55]20121994-201143Not reached62NRDisease-free interval ≤ 12 mo, exrahepatic disease (univariate)
Schiergens et al[16]120162003-2013285068NRNR
Gyneclogic primaryKamel et al[56]20111990-201052535741NR
Ovarian cancerMerideth et al[57]20031976-199926226NRNRInterval from the primary diagnosis < 12 mo, residual disease > 1 cm (univariate)
Adam et al[10]120061983-20046598NR50NR
Lim et al[58]20092001-2008142Not reachedNR51Hematogeneous liver metastasis < hepatic parenchymal metastasis from peritoneal seeding5
Neumann et al[59]20121991-20074142(R0 resection)NRNRR1,2 resection, pre-operative ascites, bilobular liver metastasis
Niu et al[60]20122000-20116039NR30R1,2 resection
Kolev et al[61]20141988-201227356NRNRInterval from the primary surgery ≤ 24 mo, residual disease ≥ 1 cm
Bacalbasa et al[62]20152002-2014312416 (metastasis from seeding), 13 (hematogeneous)NRNRNo significant risk factor
Schiergens et al[16]120162003-2013243343NRNR
Testicular cancerHahn et al[63]19991974-199657NR97 (2-yr)NRNR
Adam et al[10]120061983-20047882NR51NR

The nine largest studies pertaining to gynecological primary cancers, particularly with ovarian cancer, reported 5-year overall survival rates of 30%-51% with median survival times of 26-98 mo (Table 9)[10,16,56-62]. Factors associated with worse survival were shorter interval from the diagnosis of primary disease to metastasis[56,61], residual tumor measuring > 1 cm[56,61], hematogenous liver metastasis[57], positive resection margins[59,60], pre-operative ascites[59], and bi-lobular hepatic metastasis[59] (Table 9). Owing to the unique features of ovarian cancer, hepatectomy was regarded as a part of cytoreductive surgery and concomitant chemotherapy, which has been accepted as the standard treatment for advanced ovarian cancer. In contrast to other NCNNLMs, the resection of liver metastases from the peritoneal seeding showed better prognosis than resection of hematogenous liver metastases[57].

Chemotherapy is highly effective in the treatment of testicular carcinoma; however, one-third of the patients either did not achieve complete responces or experienced relapses[63]. The limited studies involving treatment with sensitive chemotherapy and subsequent hepatectomy for testicular carcinoma have sufficiently demonstrated a favorable prognosis in patients who underwent this treatment regimen[63].

CONCLUSION

The clinical evidence accumulated with regards to NCNNLM has indicated the possibility of a chemotherapy-free period and a few studies have demonstrated a curing potential; however, almost all studies reviewed in the present report were conducted retrospectively in selected patients who underwent hepatic resection, which makes determining the absolute indications for hepatectomy in patients with NCNNLM challenging. Indications of hepatectomy for NCNNLM change according to the development of chemotherapy regimens. Strong and highly effective chemotherapy regimens might either expand the indications for hepatectomy or replace hepatectomy in this field. A multidisciplinary approach is required for the treatment of patients with diseases that are otherwise difficult to treat.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Japan

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B, B

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P- Reviewer: Arigami T, Kamiyama T, Wang GY S- Editor: Qiu S L- Editor: A E- Editor: Li D

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