Non-resectable Colorectal Liver Metastases Research Articles

Surgical approach to achieve R0 resections in primary and metastatic liver tumors: a literature review.

Primary and metastatic liver tumors are a significant cause of mortality worldwide. Regardless of the etiology of the tumor, macro- and microscopically clear margins (R0) while preserving adequate function of the remaining organ are the main goals after liver resections. However, technically challenging procedures are required to achieve R0 resection. Currently, there is no consensus of which should be the ideal minimal safety margin for liver tumor resections, with contrasting reports in regards of safety, tumor recurrence and overall outcomes following R0. Therefore, we aim to review current worldwide surgical practices to achieve R0 resections for primary and metastatic liver tumors in challenging surgical techniques and their reported outcomes. PubMed database, Google Scholar, and OVID Medline were searched for peer-reviewed original articles related to surgical techniques performed to achieve R0 resections in the setting of primary and/or metastatic liver tumors. An up-to-date review of English-language articles published between 2015 to July 2022 was performed. Primary and metastatic liver tumors can be effectively treated using hepatic resection. Current literature highlights that tumors involving major vascular structures are not uncommon. Surgical advances have allowed for vascular control techniques, as well as vascular resections to be performed in a feasible and safe manner to achieve R0 resections. Complex resections combining surgical techniques can be performed in certain population after a detailed evaluation. Liver transplantation (LT) have been used with varying degrees of success for treatment of patients with hepatocellular carcinoma, cholangiocarcinoma (CCA), colorectal liver metastases (CRLM), non-resectable CRLM and metastatic neuroendocrine tumors. Safety and feasibility of R0 resections have been reported for multiple techniques. Technical complexity should not be a limitation to achieve or pursue R0 tumor resection. However, there has to be a balance between patient risk/benefit in attempting R0 resections. Adequate training of surgeons on implementation of complex techniques, as well as transplant oncology techniques applied to hepato-pancreato-biliary (HPB) surgery represents as a promising path to improve short and long-term outcomes for liver-related oncology patients.

Long-Term Survival, Prognostic Factors, and Selection of Patients With Colorectal Cancer for Liver Transplant

Liver transplant for colorectal cancer with liver metastases was abandoned in the 1990s due to poor overall survival. From 2006, liver transplant for in nonresectable colorectal liver metastases has been reexamined through different prospective trials. To determine predictive factors for transplant long-term survival and cure after liver transplant. This was a prospective, nonrandomized controlled cohort study derived from different clinical trials on liver transplant for colorectal liver metastases from 2006 to 2020 at Oslo University Hospital. The trials differed in prognostic inclusion criteria, but the design was otherwise identical regarding follow-up scheme to determine disease recurrence, overall survival, and survival after relapse. Final data analysis was performed on December 31, 2021. All patients with colorectal liver metastases from comparable prospective liver transplant studies were included. Liver transplant. Disease-free survival, overall survival, and survival time after recurrence were determined in all participants. A total of 61 patients (median [range] age, 57.8 [28.7-71.1] years; 35 male [57.4%]) underwent liver transplant at Oslo University Hospital. Posttransplant observation time ranged from 16 to 165 months, and no patient was lost to follow-up. Median disease-free period, overall survival, and survival after relapse were 11.8 (95% CI, 9.3-14.2) months, 60.3 (95% CI, 44.3-76.4) months, and 37.1 (95% CI, 4.6-69.5) months, respectively. Negative predictive factors for overall survival included the following: largest tumor size greater than 5.5 cm (median OS, 25.3 months; 95% CI, 15.8-34.8 months; P <.001), progressive disease while receiving chemotherapy (median OS, 39.8 months; 95% CI, 28.8-50.7 months; P = .02), plasma carcinoembryonic antigen values greater than 80 μg/L (median OS, 26.6 months; 95% CI, 22.7-30.6 months; P <.001), liver metabolic tumor volume on positron emission tomography of greater than 70 cm3 (26.6 months; 95% CI, 11.8-41.5 months; P <.001), primary tumor in the ascending colon (17.9 months; 95% CI, 0-37.5 months; P <.001), tumor burden score of 9 or higher (23.3 months; 95% CI, 19.2-27.4 months; P = .02), and 9 or more liver lesions (42.5 months; 95% CI, 17.2-67.8 months; P = .02). An Oslo score of 0 or Fong Clinical Risk Score of 1 yielded 10-year survival of 88.9% and 80.0%, respectively. Results of this nonrandomized controlled trial suggest that selected patients with liver-only metastases and favorable pretransplant prognostic scoring had long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care.

Health-Related Quality of Life in Colorectal Cancer Patients Treated With Liver Transplantation Compared to Chemotherapy.

Liver transplantation (LT) for patients with non-resectable colorectal liver metastases (CRLM) offers improved survival and has gained increased interest internationally the last years. The aim of this study was to describe the health-related quality of life (HRQoL) in patients with non-resectable CRLM receiving LT and how baseline HRQoL factors affect overall survival (OS). HRQoL data in the SECA (SEcondary CAncer) LT cohort was compared to data obtained from colorectal cancer patients starting first-line chemotherapy for metastatic disease in a clinical trial and data from a Norwegian normal population. HRQoL data from the QLQ-C30 questionnaire used in the SECA LT study and the NORDIC- VII study were reported. The relationship between patient-reported symptom burden at baseline and OS was investigated. In the SECA study longitudinal HRQoL assessment was used to describe the time until definitive deterioration as well as mean values at different time points. Patients in the SECA and NORDIC-VII studies reported similar baseline HRQoL. The median time until definitive deterioration in the transplanted patients was estimated to 36 months. In the SECA study appetite loss and pain at baseline had negative impact on OS (25.3 versus 71.7 months, p = 0.002 and 39.7 versus 71.7 months, p = 0.038, respectively). Despite a relapse in most of the LT patients the Global Health Score (GHS) remained good. Pain, and especially appetite loss at time of transplantation is associated with poor outcome after LT.

Liver Transplantation as a Curative Approach for Patients With Nonresectable Colorectal Liver Metastases.

Liver transplant is emerging as a potential treatment option for patients with isolated colorectal liver metastasis. In this review article, we analyzed the published literature on liver transplant outcomes in such patients. Four prospective studies documenting the clinical outcomes in patients with colorectal liver metastasis who underwent liver transplant were analyzed to study the feasibility of liver transplant in such patients. The SECA-II trial demonstrated the highest overall survival of 100%, 83%, and 83% at 1, 3, and 5 years, respectively, and disease-free survival of 53%, 44%, and 35%, respectively, with a narrow inclusion criterion. Conversely, extended criteria for selection and donors in arm D of the same trial resulted in median overall survival and disease-free survival of 18 and 4 months, respectively. Liver transplant provided more prolonged overall survival compared with other therapeutic modalities. Patients with isolated colorectal liver metastasis of less aggressive biology, good performance status, at least 6 weeks of chemotherapy, low clinical risk scores, and negative nodal disease should be considered for patient selection. Moreover, exclusion criteria consisting of patients with the right-sided primary tumor, less than 3 years to liver transplant after diagnosis, and elevation of carbohydrate antigen (CA19-9) in the presence of BRAF mutation should be explored.

Liver Transplantation for Non-Resectable Colorectal Liver Metastases: The International Hepato-Pancreato-Biliary Association Consensus Guidelines

Introduction: Colorectal cancer remains a prevalent disease worldwide, with over 50% of patients developing liver metastases. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases (NRCLM) only amenable to palliative systemic therapy. There is a growing interest in using liver transplantation (LT) to treat NRCLM in well-selected patients. To address the urgent need for a consensus approach, the International Hepato-pancreato-biliary Association (IHPBA) commissioned the Liver Transplantation for Colorectal Liver Metastases 2021 (LT-CoMet) working group. The aim was to standardise nomenclature and define management principles in five key domains: patient selection, evaluation of biological behaviour, graft selection, recipient considerations and outcomes. Method: A systematic review was performed and a three-step modified Delphi consensus process was undertaken between November 2020 and January 2021. Results: A final consensus of 44 statements, standardised nomenclature and a management algorithm are presented. Specific criteria for clinico-patho-radiological assessment and molecular profiling followed by an evaluation of biological behaviour via bridging therapy to transplantation is required. Sequencing of treatment in synchronous metastatic disease requires special consideration. Certain ethical dilemmas regarding organ allocation for malignant indications are discussed and the role for extended criteria grafts, living donor transplantation and machine perfusion technologies in NRCLM is reviewed. Immunosuppressive regimens and management of recurrent disease are proposed. Conclusions: This consensus guideline provides a framework by which LT for NRCLM may be safely instituted and is a meaningful step towards future evidenced-based practice for better patient selection and organ allocation to improve survival for patients with this disease.

871 Liver Transplant for Colorectal Liver Metastases: A Systematic Review and Meta-Analysis of Proportions

Abstract Introduction Colorectal liver metastases were historically considered a contraindication to liver transplantation, but dismal outcomes for those with metastatic colorectal cancer and advancements in liver transplantation (LT) have led to a renewed interest in the topic. We aim to compare the current evidence for liver transplantation for non-resectable colorectal liver metastases (NRCLM) with the current standard treatment of palliative chemotherapy reported in literature – 5-year survival rate &amp;lt;10%. Method A systematic review and meta-analysis of proportions was conducted following screening of MEDLINE, EMBASE, SCOPUS and CENTRAL for studies reporting liver transplantation for colorectal liver metastases. Post-operative outcomes measured included 1-, 3- and 5-year survival, overall survival, disease-free survival, and complication rates. Results Three non-randomised studies met the inclusion criteria, reporting a total of 48 patients receiving LT for NRCLM. Survival at 1-, 3- and 5-years was 83.3-100%, 58.3-80% and 50-80% respectively with no significant difference detected (p = 0.22, p = 0.48, p = 0.26). Disease free survival was 35-56% with the most common site of recurrence being lung. Thirteen out of fourteen deaths were due to disease recurrence. Conclusions Although current evidence suggests a survival benefit conferred by LT in NRCLM compared to palliative chemotherapy, the ethical implications of organ availability and allocation demand rigorous justification. Eight registered clinical trials will report on 300 more patients undergoing LT for NRCLM over the next 10 years: concomitant improvements in the management of patients following liver resection and of palliative chemotherapy regimens is paramount.

Lebertransplantation beim hepatisch metastasierten kolorektalen Karzinom: aktuelle Datenlage und mögliche Zukunftsszenarien

Colorectal cancer (CRC) is the third most common cancer worldwide. The majority of CRC patients will develop distant metastases during the course of their disease, most of them occurring in the liver. To date, liver resection represents the only curative option. However, due to insufficient liver remnant volume, only a minority of patients with hepatic CRC metastasis are candidates for liver resection. In recent years, various surgical and minimally invasive procedures have been developed for the treatment of non-resectable colorectal liver metastases (NRCRM). Whereas initial reports yielded 5‑year overall survival (OS) rates of less than 20%, results have now significantly improved owing to the ameliorated chemotherapy and refined surgical techniques. Furthermore, liver transplantation (LTX) has surfaced as a promising option for patients with NRCLM. Recent studies report 5‑year OS rates exceeding 50%. Despite this success, wider application of LTX for the treatment of NCRLM is currently hampered by the persisting organ shortage. This ethical dilemma may now be overcome through innovative protocols which allow the use of only a small part of the donor liver for NRCLM patients while the remaining part of the graft is transplanted to a second recipient. This review illustrates the underlying factors which have so far hindered a curative approach for NRCRM patients and highlights recent promising achievements in oncology and transplant medicine.

Portal vein embolization with stem cells application for increasing future liver remnant volume in primary non-resectable colorectal liver metastases

Background: Insufficient future liver remnant volume (FLRV) is the main cause of non-resectability of colorectal liver metastases (CLM). Portal vein embolization with application of autologous hematopoietic stem cells (PVEHSC) are possible methods for stimulation of FLRV growth. Methods: PVEHSC was used in 24 patients with primary non-resectable CLM due to insufficient FLRV.PVE was performed on the site of CLMs.HSC were received in the first eleven patients via apheresis after a four-day stimulation by granulocyte-colony stimulating factor and in the following 13 patients from bone marrow and prepared by centrifugation at the same time. The product was applied via vena ileocolica to the contralateral liver lobe,which was free of CLM. .Liver resection was performed as soon as after sufficient growth of FRLV. Results: Procedure morbidity and mortality was zero. Sufficient FLRV developed in all patients in the interval of three weeks. The median of FLRV enlargement was 181 ml and average FLRV growth was 3.4 ml/day. The average growth of CLM volume was 41.5 ml, resp. 0.9 ml/ day.R0 right hepatectomy was performed in 20 patients (83.3 %), exploratory laparotomy in four patients (3x tumor progression, 1x severe adhesions). One and three years OS was 76.6, resp. 50.3%, DFI 67.2, resp.32.1% in patients after liver resection. More than three CLM were the only significant factor for DFI (p<0.04). Conclusion: PVEHSC is a safe and promising method for increasing FLRV in patients with primary non-resectable CLM.

Portal vein embolization with stem cells application for increasing future liver remnant volume in primary non-resectable colorectal liver metastases

Background: Insufficient future liver remnant volume (FLRV) is the main cause of non-resectability of colorectal liver metastases (CLM). Portal vein embolization with application of autologous hematopoietic stem cells (PVEHSC) are possible methods for stimulation of FLRV growth. Methods: PVEHSC was used in 24 patients with primary non-resectable CLM due to insufficient FLRV.PVE was performed on the site of CLMs.HSC were received in the first eleven patients via apheresis after a four-day stimulation by granulocyte-colony stimulating factor and in the following 13 patients from bone marrow and prepared by centrifugation at the same time. The product was applied via vena ileocolica to the contralateral liver lobe,which was free of CLM. Liver resection was performed as soon as after sufficient growth of FRLV. Results: Procedure morbidity and mortality was zero. Sufficient FLRV developed in all patients in the interval of three weeks. The median of FLRV enlargement was 181 ml and average FLRV growth was 3.4 ml/day. The average growth of CLM volume was 41.5 ml, resp. 0.9 ml/ day.R0 right hepatectomy was performed in 20 patients (83.3 %), exploratory laparotomy in four patients (3x tumor progression, 1x severe adhesions). One and three years OS was 76.6, resp. 50.3%, DFI 67.2, resp.32.1% in patients after liver resection. More than three CLM were the only significant factor for DFI (p<0.04). Conclusion: PVEHSC is a safe and promising method for increasing FLRV in patients with primary non-resectable CLM.

Long-term survival after percutaneous irreversible electroporation of inoperable colorectal liver metastases.

BackgroundFor colorectal liver metastases (CRLM) that are not amenable to surgery or thermal ablation, irreversible electroporation (IRE) is a novel local treatment modality and additional option.MethodsThis study is a retrospective long-term follow-up of patients with CRLM who underwent IRE as salvage treatment.ResultsOf the 24 included patients, 18 (75.0%) were male, and the median age was 57 (range: 28–75) years. The mean time elapsed from diagnosis to IRE was 37.9±37.3 months. Mean overall survival was 26.5 months after IRE (range: 2.5–69.2 months) and 58.1 months after diagnosis (range: 14.8–180.1 months). One-, three-, and five-year survival rates after initial diagnosis were 100.0%, 79.2%, and 41.2%; after IRE, the respective survival rates were 79.1%, 25.0%, and 8.3%. There were no statistically significant differences detected in survival after IRE with respect to gender, age, T- or N-stage at the time of diagnosis, size of metastases subject to IRE, number of hepatic lesions, or time elapsed between IRE and diagnosis.ConclusionFor nonresectable CRLM, long-term survival data emphasize the value of IRE as a new minimally invasive local therapeutic approach in multimodal palliative treatment, which is currently limited to systemic or regional therapies in this setting.

Cost-effectiveness of liver transplantation in patients with colorectal metastases confined to the liver.

Patients with non-resectable colorectal metastases are currently treated with chemotherapy. However, liver transplantation can increase the 5-year survival rate from 9 to 56 per cent if the cancer is confined to the liver. The aim of this study was to estimate the cost-effectiveness of liver transplantation for colorectal liver metastases. A Markov model with a lifetime perspective was developed to estimate the life-years, quality-adjusted life-years (QALYs), direct healthcare costs and cost-effectiveness for patients with non-resectable colorectal liver metastases who received liver transplantation or chemotherapy alone. In non-selected cohorts, liver transplantation increased patients' life expectancy by 3·12 life-years (2·47 QALYs), at an additional cost of €209 143, giving an incremental cost-effectiveness ratio (ICER) of €67 140 per life-year (€84 667 per QALY) gained. In selected cohorts (selection based on tumour diameter, time since primary cancer, carcinoembryonic antigen levels and response to chemotherapy), the effect of liver transplantation increased to 4·23 life-years (3·41 QALYs), at a higher additional cost (€230 282), and the ICER decreased to €54 467 per life-year (€67 509 per QALY) gained. Given a willingness to pay of €70 500, the likelihood of transplantation being cost-effective was 0·66 and 0·94 (0·23 and 0·67 QALYs) for non-selected and selected cohorts respectively. Liver transplantation was cost-effective but only for highly selected patients. This might be possible in countries with good access to grafts and low waiting list mortality.

Importance of 18F-FDG PET/CT to select patients with nonresectable colorectal liver metastases for liver transplantation.

The aim of this study was to evaluate fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT for the selection of patients with nonresectable colorectal liver metastases (NCLM) for liver transplantation (LT). In the secondary cancer study, we reported an improved 5-year overall survival in patients treated with LT for NCLM (56%) compared with chemotherapy (9%). However, many patients were rejected for LT owing to the detection of extrahepatic disease at preoperative imaging. F-FDG PET/CT and contrast-enhanced computed tomography (ceCT) examinations before tentative LT for NCLM were assessed, and findings contraindicating LT were registered. Maximum, mean and peak standardized uptake values; tumor-to-background ratio; metabolic tumor volume; and total lesion glycolysis were measured and calculated for all liver metastases. Overall survival was calculated by the Kaplan-Meier method. Thirty-two patients excluded by F-FDG PET/CT and/or ceCT before tentative LT for NCLM were identified. F-FDG PET/CT from 20 of the 32 excluded patients revealed extrahepatic disease. Eight of the other 12 patients had a negative F-FDG PET/CT finding but were excluded by ceCT. Ten patients were excluded by F-FDG PET/CT only. Four patients were excluded owing to detected malignancy from frozen sections at the start of the intended transplant operation. Tumor-to-background ratio of the liver metastases was significantly higher in patients where F-FDG PET/CT detected extrahepatic disease (P=0.03). The median (range) survival after exclusion was 16 (0-52) months. The ability of F-FDG PET/CT to detect extrahepatic disease before LT for NCLM is vital to establish LT as a treatment option.

The prognostic value of 18F–FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases

The main objective of this study was to evaluate the prognostic value of volumetric and metabolic information derivied from F-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) in combination with computed tomography (CT) prior to liver transplantation (LT) in patients with nonresectable colorectal liver metastases (CLM). Due to scarcity of liver grafts, prognostic information enabling selection of candidates who will gain the highest survival after LT is of vital importance. 18F-FDG PET/CT was a part of the preoperative study protocol. Patients without evidence of extrahepatic malignant disease on 18F-FDG PET/CT who also fulfilled all the other inclusion criteria underwent LT. The preoperative 18F-FDG PET/CT examinations of all patients included in the SECA (secondary cancer) study were retrospectively assessed. Maximum, mean and peak standardized uptake values (SUVmax, SUVmean and SUVpeak), tumor to background (T/B) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured and calculated for all liver metastases. Total MTV and TLG were calculated for each patient. Cut-off values were determined for each of these parameters by using receiver operating characteristic (ROC) analysis dividing the patients into two groups. One, three and five-year overall survival (OS) and disease free survival (DFS) for patients over and under the cut-off value were compared by using the Kaplan-Meier method and log rank test. Twenty-three patients underwent LT in the SECA study. Total MTV and TLG under the cut-off values were significantly correlated to improved OS at three and five years (p=0.027 and 0.026) and DFS (p=0.01). One, three and five-year OS and DFS were not significantly related to SUVmax, SUVmean, SUVpeak or T/B-ratio. Total MTV and TLG from 18F FDG PET/CT prior to LT for nonresectable CLM were significantly correlated to improved three and five-year OS and DFS and can potentially improve the patient selection for LT.

Liver transplantation in treatment of colorectal liver metastases.

Surgical resection is the only curative modality for colorectal liver metastases (CLM) and 5-year overall survival after resection is about 40%. Nonresectable CLM is not curable and 5-year overall survival is currently about 10%. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%). Liver transplantation for CLMs was abandoned and CLMs were even considered a contraindication to the procedure. Since then, the survival rate after liver transplantation in general has improved by almost 30%. In a prospective pilot study of liver transplantation for nonresectable CLM, a 5-year overall survival rate of 60% was demonstrated, however 19 of 21 patients experienced recurrence of disease. Here, current knowledge and ongoing research in this field is reviewed, and the potential role for liver transplantation as one of several treatment modalities for CLM discussed.

Patterns of Recurrence After Liver Transplantation for Nonresectable Liver Metastases from Colorectal Cancer

BackgroundSurgical resection is the only curative modality for colorectal liver metastases (CLM), and the pattern of recurrences after resection affects survival. In a prospective study of liver transplantation (Lt) for nonresectable CLM we have shown a 5-year overall survival rate of 60 %, but 19 of 21 experienced recurrence. This study reports the pattern of recurrences after Lt for CLM and the effect on survival.MethodsCharacterization of metastatic lesions in a prospective study for Lt for nonresectable CLM was performed (n = 21). The study included reexamination of chest computed tomographic scans taken before Lt.ResultsAt the time of first recurrence, 16 were a single site, and three were multiple sites. Thirteen of the single sites were pulmonary recurrences. The pulmonary recurrences appeared early and were slow growing, and several were accessible to surgical treatment. When chest computed tomographic scans were reexamined, seven patients had pulmonary nodules at the time of Lt without an effect on survival. There was no first single-site hepatic recurrence. Six of the seven patients who developed metastases to the transplanted liver died from metastatic disease.ConclusionsThe pulmonary recurrences after Lt for CLM were of an indolent character, even those that were present at the time of Lt. This contrasts with the finding of metastases to the transplanted liver, which was prognostically adverse. The lack of single hepatic first-site recurrences and hepatic metastases only as part of disseminated disease is different from the pattern of recurrence after liver resection. This suggests two distinct mechanisms for hepatic recurrences after resection for CLM.

ALPPS for Patients with Colorectal Liver Metastases: Effective Liver Hypertrophy, but Early Tumor Recurrence

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a promising method to increase resectability rates of liver tumors. Little has been published about oncological results so far. This report describes clinical evidence regarding a possible effect of ALPPS on tumor recurrence. Ten ALPPS procedures were performed for otherwise non-resectable colorectal liver metastases. Seven of these ten patients had a follow-up of at least 3 months and were analyzed for tumor recurrence. Six of these seven patients had tumor recurrence to the liver. Three of seven patients presented with lung metastases, occurring earlier than liver metastases in two of three cases. One patient with a follow-up of 3 months had no visible recurrent disease, but increasing carcinoembryonic antigen levels. The patient group operable only through ALPPS is at high risk for recurrence and early tumor progression. Still, this new method is the only chance for an oncological treatment strategy including a surgical approach and possibly better outcome.

Liver Transplantation for Nonresectable Liver Metastases From Colorectal Cancer

The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs). Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated. In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy. Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors. OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).

Liver Transplantation for Non-Resectable Liver Metastases from Colorectal Cancer

Introduction: Colorectal liver metastases (CLM) are currently considered an absolute contraindication for liver transplantation (Lt). Before 1995 several Lts for CLM were performed, but the outcome was poor (18% 5 year survival) and Lt for CLM was abandoned. Since then, several advances have been achieved and survival following Lt has improved by almost 30%. Based on this, a 5 year survival of 50% following Lt for CLM could be anticipated. Less than 10% of patients with non-resectable CLM will survive beyond five years. Methods: In a prospective study, Lt for non-resectable CLM was performed (n=21). The objective was to investigate safety and the potential for long term overall survival (OS). Main inclusion criteria were non-resectable CLM, excised primary tumor, good general health status and minimum 6 weeks of chemotherapy. Results: OS at 1-, 3-, and 5 year post Lt were 95%, 68% and 60%, respectively. Recurrence of disease was common and appeared in 19 of 21 patients, mainly in the lungs. However, a significant proportion of the recurrences were accessible for surgery and at follow up (median 27 months (range 8 - 60)), 7 patients (33%) had no evidence of disease. Conclusions: All patients had advanced CLM at the time of Lt. Long term OS exceeds by far previously reported outcome for this patient group and is comparable or better than survival following repeat Lt for non-malignant diagnoses. Refinement of robust selection criteria may further improve the results.[Figure 1]

Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004)

This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.

Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities.