Non-Colorectal Liver Metastases Undergoing Liver Resection: The NONCOLMET Study Group

Liver metastases (LM) occur in up to 90% either simultaneously with the diagnosis of the primary tumor or at a later time-point. While resection of colorectal LM and resection or transplantation of neuroendocrine LM is part of a standard therapy with a 5-year patient survival of up to 80%, resection of non-colorectal and non-neuroendocrine LM is still discussed controversially. The reason for it is the significantly lower survival benefit of all different tumor entities depending on the biological aggressiveness of the tumor. Randomized controlled trials are lacking. However, reviews of case series with ≥100 liver resections are available. They show a 5-year patient survival of up to 42% compared to only <5% in patients without treatment. Risk factors for poor survival include the type of primary tumor, a short interval between resection of the primary tumor and liver resection, extrahepatic manifestation of the tumor, number and size of the LM, and extent of liver resection. Overall, it has recently been shown that a good patient selection, the technical advances in surgical therapy and the use of a risk score to predict the prognosis lead to a significantly better outcome so that it is no longer justified not to offer liver resection to patients with non-colorectal, non- endocrine LM. Since modern therapy of LM is multimodal, the optimal therapeutic approach is decided individually by a multidisciplinary team consisting of visceral surgeons, oncologists, interventional radiologists and radiologists as part of a tumor board.

Background: Due to the uncertain benefit of liver resection for non-colorectal liver metastases (NCLM), patient selection for surgery is generally difficult. Therefore, the aim of this article was to propose standard and extended indications for liver resection in this heterogeneous disease collective. Methods: Review of the literature. Results: The myriad of biologically different primary tumor entities as well as the mostly small and retrospective studies investigating the benefit of surgery for NCLM limits the proposal of general recommendations. Only resection of neuroendocrine liver metastases (NELM) appears to offer a clear benefit with a 5- and 10-year overall survival (OS) of 74 and 51%, respectively, in the largest series. Resection of liver metastases from genitourinary primaries might offer reasonable benefit in selected cases - with a 5-year OS of up to 61% for breast cancer and of 38% for renal cell cancer. The long-term outcome following surgery for other entities was remarkably poorer, e.g., gastric cancer, pancreatic cancer, and melanoma reached a 5-year OS of 20-42, 17-25, and about 20%, respectively. Conclusion: Liver resection for NELM can be defined as a standard indication for the resection of NCLM while lesions of genitourinary origin might be defined as an extended indication.

Liver is a common metastatic site not only of colorectal but of non-colorectal neoplasms, as well. However, resection of non-colorectal liver metastases (NCRLMs) remains controversial. The aim of this retrospective study was to analyze the short- and long-term outcomes of patients undergoing laparoscopic liver resection (LLR) for NCRLMs. From a prospectively maintained database between 2000 and 2018, patients undergoing LLR for colorectal liver metastases (CRLMs) and NCRLMs were selected. Clinicopathologic, operative, short- and long-term outcome data were collected, analyzed, and compared among patients with CRLMs and NCRLMs. The primary tumor was colorectal in 354 (82.1%), neuroendocrine in 21 (4.9%), and non-colorectal, non-neuroendocrine in the remaining 56 (13%) patients. Major postoperative morbidities were 12.7%, 19%, and 3.6%, respectively (p = 0.001), whereas the mortality was 0.6% for patients with CRLMs and zero for patients with NCRLMs. The rate of R1 surgical margin was comparable (p = 0.432) among groups. According to the survival analysis, 3- and 5-year recurrence-free survival (RFS) rates were 76.1% and 64.3% in the CRLM group, 57.1% and 42.3% in the neuroendocrine liver metastase (NELM) group, 33% and 20.8% in the non-colorectal, non-neuroendocrine liver metastase (NCRNNELM) group (p = 0.001), respectively. Three- and 5-year overall survival (OS) rates were 88.3% and 82.7% in the CRLM group, 85.7% and 70.6% in the NELM group, 71.4% and 52.9% in the NCRNNELM group (p = 0.001), respectively. In total, 113 out of 354 (31.9%) patients with CRLMs, 2 out of 21(9.5%) with NELMs, and 8 out of 56 (14.3%) patients with NCRNNELMs underwent repeat LLR for recurrent metastatic tumors. LLR is safe and feasible in the context of a multimodal management where an aggressive surgical approach, necessitating even complex procedures for bilobar multifocal metastases and repeat hepatectomy for recurrences, is the mainstay and may be of benefit in the long-term survival, in selected patients with NCRNNELMs.

Background: Resection of non-colorectal liver metastases (NCRLM) is one of the recent fields in hepatic surgery. It was just 10-12 years ago when those procedures were totally denied as `risky` and `useless` and therefore, they were performed as an exception. Aim: The aim of this paper is to present analyses of early and late postoperative results in our series of resections of NCRLM, discussion of the indications for surgery and evaluation of the possible benefit of surgery as an element of multimodal treatment scheme. Materials and Methods: The study design was a single-center retrospective and prospective for a 9-year period (January 1, 2007-December 31, 2015). A total of 62 patients received R0 resections of metachronous and synchronous NCRLM. Metastatic pancreatic and gastric cancer cases predominated (n=49, 80.3%). The indications for aggressive surgery included age ≤ 60(65) years, absence of serious concomitant diseases, ASA ≤ III, no data of other distant organ involvement, no peritoneal lesions, no local recurrence (in metachronous cases) and resectable primary tumor (in synchronous cases). The early postoperative results were analyzed and outpatient follow-up was done every 3 months. Disease-free survival (DFS) and overall survival (OAS) rates were studied. Results: The early postoperative mortality rate was 4.2% in the whole series (2 fatal outcomes in gastric and 1 in pancreatic NCRLM). The specific morbidity rate was very high (N=33, 54.1%) and more often ascertained after multivisceral resections of synchronous NCRLM but 84.8% of them were treated by conservative or interventional methods. Reoperation was performed on 5 patients (15.2%). Fifty-six patients (91.8%) were followed for ≥12 months or until the patient`s death was registered. DFS (8.9-22.4 months) and OAS rates (10.7-57.3 months) varied in broad range and demonstrated statistical dependence on the primary tumor location, time of detection and „N`, „G` and `R` categories. Conclusion: Indicated and reasonable resections of synchronous and metachronous NCRLM had morbidity and mortality rates comparable to that of other multivisceral resections and they lead to a positive impact on the survival rates and the quality of life.

Surgical resection is indicated for resectable colorectal liver metastases (CLM), but it is controversial for non-colorectal liver metastases (NCLM). This study aimed to compare survival outcomes of patients with resection of NCLM versus CLM and to identify prognostic factors for resection of NCLM. Consecutive patients who underwent surgical resection of liver metastases at Queen Mary Hospital, Hong Kong from January 1989 to December 2019 were retrospectively reviewed. Patients with resected NCLM were compared to those with CLM. Overall and recurrence-free survival were determined. Subgroup analyses with patients grouped according to the year of liver resection, from 1989 to 2004 and from 2005 to 2019, were conducted. Univariate and multivariate analyses were performed to identify prognostic factors. Among 674 patients included, 151 (22.4%) had NCLM while 523 (77.6%) had CLM. There were no statistically significant differences in median overall survival (65.2 vs 43.6months, p = 0.555) and recurrence-free survival (12.5 vs 11.7months, p = 0.425). The 1-year, 3-year, 5-year and 10-year overall survival rates were 89.8% vs 91.5%, 59.4% vs 58.8%, 50.6% vs 38.7% and 34.1% vs 26.3% in NCLM and CLM groups, respectively. Subgroup analyses demonstrated no statistically significant difference in overall survival between resection of NCLM versus CLM in both time intervals. In the NCLM group, better overall survival was found in liver metastasis of gastrointestinal stromal tumour (GIST) origin (hazard ratio (HR) 0.138, p = 0.003) and with a longer time interval from resection of primary tumour to resection of NCLM (HR 0.982, p = 0.042). Poor prognostic factors were presence of blood transfusion (HR 5.588, p = 0.013) and post-operative complications of Clavien-Dindo Grade IIIa or above (HR 74.853, p = 0.003). Surgical resection of NCLM had comparable survival outcomes with CLM. With appropriate patient selection, the indication of liver resection could be expanded to NCLM.

Survival benefit of liver resection for noncolorectal liver metastases (NCRLM) remains to be defined. This multicenter, retrospective cohort analysis included consecutive patients with NCRLM whose primary tumor and all metastases were treated with curative intent between 2000 and 2013. The primary endpoint was 5-year overall survival. Clinicopathological factors that affected prognoses were identified using multivariate Cox regression analyses and were included in a predictive model. Data for 205 patients were analyzed. The three most common primary tumor sites were stomach (39%), pancreas (13%), and urinary tract (10%), with adenocarcinomas the main pathology (52%). R0 resection was achieved in 85%, and the overall survival at 5years was 41%. In the multivariate analysis, synchronous liver metastases, R1/2 resection, and adenocarcinomas and other carcinomas (with gastrointestinal stromal tumors, neuroendocrine tumors G1/G2, and sarcomas set as the reference group) were independent negative indicators of overall survival. A predictive model effectively stratified the NCRLM patients into low-, intermediate-, and high-risk groups with overall 5-year survival rates of 63%, 38%, and 21%, respectively (P<0.001). Patients who underwent curative resection for metachronous disease and favorable tumor pathology are expected to have better survival in the NCRLM cohort.

Perioperative and Long-term Outcomes of Laparoscopic Liver Resections for Non-colorectal Liver Metastases

Advances in chemotherapy have expanded the resectability of colorectal liver (CRC) metastases. We studied treatment results in CRC patients with liver metastases in the era of molecular target-based agents. Based on data collected retrospectively, we analyzed the demographics, operative and pathological outcomes, and adjuvant chemotherapy, of 91 consecutive CRC patients with liver metastases treated between January, 2008 and June, 2010. Of the 91 patients, 42 (46.2%) underwent liver resection (group 1), 41 underwent only resection of the primary tumor without hepatectomy (group 2), and 8 underwent palliative surgery (group 3). According to multivariate analysis, resection of liver metastases was significantly influenced by the number of metastases and the existence of extrahepatic metastases. Disease-free survival (DFS) differed significantly between patients who received adjuvant therapy and those treated by surgery alone (p<0.001). The regimen (p=0.01) and duration (p<0.0001) of adjuvant chemotherapy also affected DFS. Overall survival after 1 and 3 years was 97.6% and 94.0%, respectively, in group 1, 71.9% and 30.6% in group 2, and 33.3% and 0% in group 3. Although the observation period was short, our findings suggest that high resectability and effective chemotherapy will prolong the survival of patients with colorectal liver metastases.

Liver resection for colorectal liver metastases offers a 5-year survival rate of 25%-58%. This study aimed to analyze whether patients with colorectal liver metastases undergo resection to an equal extent and whether selection factors play a role in the selection process. Data were retrieved from the Swedish Colorectal Cancer Registry (2007-2011) for colorectal cancer and colorectal liver metastases. The patients identified were linked to the Swedish Registry of Liver and Bile surgery and the National Patient Registry to identify whether liver surgery or ablative treatment was performed. Analyses for age, sex, type of primary tumor and treating hospital (university, county, or district), American Society of Anesthesiologists class, and radiology for detection of metastatic disease were performed. Of 28,355 patients with colorectal cancer, 21.6% (6127/28,355) presented with liver metastases. Of the patients with liver metastases, 18.5% (1134/6127) underwent liver resection or ablation. The cumulative proportion of liver resection/ablation was 4% (1134/28,355) of all colorectal cancer. If "not bowel resected" were excluded, the proportion slightly increased to 4.7% (1134/24,262). Around 15% of the patients with metastases were registered as referrals for liver surgery. In a multivariable analysis patients treated at a university hospital for primary tumor were more frequently surgically treated for liver metastases (p < 0.0001). Patients with liver metastases from rectal cancer (p < 0.0001) and men more often underwent liver resection (p = 0.006). A difference was found between health-care regions for the frequency of liver surgery (p < 0.0001). Patients >70 years and those with American Society of Anesthesiologists class >2 underwent liver resection less frequently. Magnetic resonance imaging of the liver was more often used in diagnostic work-up in men. Patients with colorectal liver metastases are unequally treated in Sweden, as indicated by the low referral rate. The proximity to a hepatobiliary unit seems important to enhance the patient's chances of being offered liver surgery.

Long-term outcome after sequential resections of liver and lung metastases from colorectal carcinoma

Management of liver metastases in colorectal cancer patients: A retrospective case-control study of systemic therapy versus liver resection

Hepatocellular Carcinoma (HCC) is the most frequent malignant primary liver tumour in a cirrhotic liver. Liver transplantation and resection are the only curative treatment options in compensated liver cirrhosis, but liver resections are associated with increased perioperative morbidity and mortality. We identified 108 cirrhotic patients, who underwent liver resections at the University Hospital of Mainz between January 2008 and December 2019. During the same period, 185 liver resections were performed for HCC in non-cirrhotic livers. Furthermore, 167 liver resections served as control group, which were performed for colorectal liver metastases (CRLM) with comparable extent of resection to HCC in cirrhotic livers. Preoperatively, we assessed the Charlson Comorbidity Index (CCI), MELD and Child scores in addition to the general patient characteristics. Perioperative morbidity was graded according to the Clavien-Dindo classification. Resections of HCC in cirrhosis and liver metastases were additionally compared by a matched-pair analysis. The three groups were comparable in age. Preoperative liver function was best in patients with CRLM (p < 0.001). Resections for HCC in non-cirrhotic livers were more extended than in cirrhotic livers (p < 0.001). The overall morbidity (Clavien/Dindo stage III - IV) was higher after resections in cirrhotic livers than in CRLM resections (p = 0.026). Postoperative mortality was comparably low in all three groups (2.2%). Neither MELD nor Child score was predictive for postoperative morbidity or mortality (area under the curve: AUC < 0.6, each). Preoperative CCI was predictive for postoperative mortality (AUC = 0.78). Liver resections in cirrhotic livers are feasible after adequate patient selection and limitation of the extent of surgery. Comorbidities additionally increase the postoperative mortality in addition to impaired liver function and should therefore always be included into the preoperative assessment of patients undergoing liver surgery.

To determine the risk, the benefit, and the main factors of prognosis of third liver resections for recurrent colorectal metastases. Recurrence following liver resection is frequent after a first as after a second hepatectomy. Second liver resections yield a similar survival to that obtained with first liver resection, but little is known about third hepatectomy. This study reports a retrospective analysis of 60 patients who underwent a third liver resection for colorectal metastases in a 16-year experience (1984-2000). Patients were identified from a prospective database that collected 615 consecutive patients who cumulated 883 hepatectomies (615 first, 199 second, 60 thirds, and 9 fourths). Third hepatic resections were compared with first and second procedures, in terms of risk and benefit for the patient. Prognostic factors of survival after third hepatic resection were determined by univariate and multivariate analysis. A third hepatic resection was attempted in 68 of 115 of liver recurrences following a second hepatectomy (59%) and achieved in 88% of the cases (60 of 68). There was no intraoperative mortality or postoperative deaths within the 2 months. Fifteen patients developed postoperative complications (25%), a rate similar to that of first and second hepatectomies. Overall 5-year survival was 32% and disease-free survival was 17% after the third resection. Survival compared favorably to that of patients with recurrence following a second hepatectomy who could not be operated (5% at 3 years) or who failed to be resected (15% at 2 years, P = 0.0001). It also compared favorably to that of patients who underwent only two hepatectomies (5-year survival, 27%). When estimated from the time of first hepatectomy, survival was 65% at 5 years for the 60 patients who underwent three hepatic resections. Concomitant extrahepatic tumor was treated in 16 patients (27%) by 11 abdominal procedures and 5 pulmonary resections. By multivariate analysis, tumor size > 30 mm for first liver metastases, presence of extrahepatic tumor at second hepatectomy, and noncurative pattern of third liver resection were independent prognostic factors of reduced survival. Third hepatectomy is safe and provides an additional benefit of survival similar to that of first and second liver resections. It is worthwhile when curative and integrated into an intended multimodal strategy of tumoral eradication.

The aim of the present study was to evaluate the risk factors for postoperative complications following liver resection for colorectal cancer liver metastases. Patients who underwent hepatic resection for colorectal cancer liver metastases were stratified according to chemotherapy administration and body mass index (BMI) to eliminate potential confounding factors. A univariate analysis was conducted to identify potential risk factors for postoperative complications following liver resection. Variables that exhibited a potential association were evaluated by multivariable logistic regression analysis to identify those independently associated with postoperative morbidity. Between January 2012 and March 2012, 100 patients underwent hepatic resection for liver metastases from colorectal carcinoma at the Treviso Regional Hospital (Treviso, Italy) and at the Regina Elena National Cancer Institute (Rome, Italy). Of the 100 patients, 61 received preoperative oxaliplatin- or irinotecan-based chemotherapy. A total of 25 the patients had a BMI of ≥28 kg/m2. On univariate analysis, BMI ≥28 kg/m2 was found to be positively correlated with the presence of steatosis (P<0.01) and steatohepatitis (P<0.01). The administration of preoperative chemotherapy was correlated with the development of steatosis (P<0.01), steatohepatitis (P=0.02) and postoperative complications (P=0.03). Even following stratification for the use of preoperative chemotherapy, BMI ≥28 kg/m2 maintained its positive association with steatohepatitis. On multivariate analysis, steatohepatitis (P=0.005, HR=0.118, 95% CI: 0.027–0.518) and blood transfusions (P=0.001, HR=0.131, 95% CI: 0.038–0.452) were independently associated with postoperative complications. BMI ≥28 kg/m2 (P=0.004, HR=8.30, 95% CI: 2.39–28.7) and irinotecan treatment (P=0.016, HR=0.16, 95% CI: 0.037–0.711) were independent risk factors for steatohepatitis. In conclusion, steatohepatitis and perioperative blood transfusions were found to be the main determinant of postoperative complications following liver resection for colorectal liver metastases. Overweight patients may be more prone to the cytotoxic effects of irinotecan, harboring a higher risk of developing steatohepatitis.

Liver metastases of colorectal cancer can be operated with a curative intent in selected cases. However, more than half of the patients have a recurrence. The aim of this study was to evaluate the prognostic and predictive value of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), human chorionic gonadotropin β (hCGβ) and tumour-associated trypsin-inhibitor (TATI) in colorectal cancer patients before and 3 months after resection of liver metastases. Marker concentrations were determined in blood samples from 168 colorectal cancer patients, who underwent liver resection between the years 1998 and 2007 at Helsinki University Hospital, Finland. The samples were taken before and 3 months after curative resection. Increased concentrations of CEA (>5 µg/L) and hCGβ (>1 pmol/L) 3 months after liver resection correlated with recurrence and impaired overall survival and increased CA19-9 (>26 kU/L) with impaired overall survival, but postoperative TATI was not prognostic. Preoperatively elevated CEA and CA19-9 correlated with impaired overall survival, but not with recurrence. Neither preoperative hCGβ nor TATI was prognostic. In conclusion, CEA is a useful prognostic marker, when measured 3 months after resection of colorectal liver metastases. CA19-9 also has prognostic significance and may have additional value.