Detailed liver-specific imaging prior to pre-operative chemotherapy for colorectal liver metastases reduces intra-hepatic recurrence and the need for a repeat hepatectomy

AbstractBackgroundNeoadjuvant chemotherapy for colorectal liver metastases (CRLM) reduces the accuracy of liver imaging which may understage patients pre-operatively. Retrospective review of a prospective database to determine whether liver-specific magnetic resonance imaging (MRI) prior to pre-operative chemotherapy affects intra-hepatic recurrence and long-term outcome after hepatectomy.Patients and methodsBetween 2003 and 2009, 242 patients with CRLM underwent a hepatectomy after ≥3 cycles of oxaliplatin or irinotecan-based chemotherapy. All had a liver-specific MRI immediately pre-operatively. The outcome of patients who had a liver-specific MRI prior to chemotherapy (PCI group, n= 92) was compared with those who did not (non-PCI group, n= 150).ResultsA liver-specific MRI pre-chemotherapy changed the staging in 56% of patients. At a median (range) follow-up of 55 (6–94) months, there was a higher incidence of intra-hepatic recurrence at a new site in the non-PCI group (65% vs. 48% in the PCI group, P= 0.041) and an increased rate of recurrence in patients with the same number of lesions pre- and post-chemotherapy [hazard ratio (HR) 2.02, 1:10–3.37, P= 0.024]. The non-PCI group underwent more repeat hepatectomies than the PCI group (24.7% vs. 13%, P= 0.034), achieving similar long-term survival.ConclusionsA liver-specific MRI prior to chemotherapy reduces intra-hepatic recurrence and avoids a repeat hepatectomy

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer

The risk of poor post-operative outcome and the benefits of surgical resection as a curative therapy require careful assessment by the clinical care team for patients with primary and secondary liver cancer. Advances in surgical techniques have improved patient outcomes but identifying which individual patients are at greatest risk of poor post-operative liver performance remains a challenge. Here we report results from a multicentre observational clinical trial (ClinicalTrials.gov NCT03213314) which aimed to inform personalised pre-operative risk assessment in liver cancer surgery by evaluating liver health using quantitative multiparametric magnetic resonance imaging (MRI). We combined estimation of future liver remnant (FLR) volume with corrected T1 (cT1) of the liver parenchyma as a representation of liver health in 143 patients prior to treatment. Patients with an elevated preoperative liver cT1, indicative of fibroinflammation, had a longer post-operative hospital stay compared to those with a cT1 within the normal range (6.5 vs 5 days; p = 0.0053). A composite score combining FLR and cT1 predicted poor liver performance in the 5 days immediately following surgery (AUROC = 0.78). Furthermore, this composite score correlated with the regenerative performance of the liver in the 3 months following resection. This study highlights the utility of quantitative MRI for identifying patients at increased risk of poor post-operative liver performance and a longer stay in hospital. This approach has the potential to inform the assessment of individualised patient risk as part of the clinical decision-making process for liver cancer surgery

Study protocol: HepaT1ca - an observational clinical cohort study to quantify liver health in surgical candidates for liver malignancies.

Background Accurate assessment of liver health prior to undertaking resectional liver surgery or chemoembolisation for primary and secondary cancers is essential for patient safety and optimal outcomes. LiverMultiScan™, an MRI-based technology, non-invasively quantifies hepatic fibroinflammatory disease, steatosis and iron content. We hypothesise that LiverMultiScan™can quantify liver health prior to surgery and inform the risk assessment for patients considering liver surgery or chemoembolization and seek to evaluate this technology in an operational environment. Methods/Design HepaT1ca is an observational cohort study in two tertiary-referral liver surgery centres in the United Kingdom. The primary outcome is correlation between the pre-operative liver health assessment score (Hepatica score - calculated by weighting future remnant liver volume by liver inflammation and fibrosis (LIF) score) and the post-operative liver function composite integer-based risk (Hyder-Pawlik) score. With ethical approval and fully-informed consent, individuals considering liver surgery for primary or secondary cancer will undergo clinical assessment, blood sampling, and LiverMultiScan™multiparametric MRI before and after surgical liver resection or TACE. In nested cohorts of individuals undergoing chemotherapy prior to surgery, or those undergoing portal vein embolization (PVE) as an adjunct to surgery, an additional testing session prior to commencement of treatment will occur. Tissue will be examined histologically and by immunohistochemistry. Pre-operative liver health assessment scores and the post-operative risk scores will be correlated to define the ability of LiverMultiScan™to predict the risk of post-operative morbidity and mortality. Because technology performance in this setting is unknown, a pragmatic sample size will be used. For the primary outcome, n = 200 for the main cohort will allow detection of a minimum correlation coefficient of 0.2 with 5% significance and power of 80%. Discussion This study will refine the technology and clinical application of multiparametric MRI (including LiverMultiScan™), to quantify pre-existing liver health and predict post-intervention outcomes following liver resection. If successful, this study will advance the technology and support the use of multiparametric MRI as part of an enhanced pre-operative assessment to improve patient safety and to personalise operative risk assessment of liver surgery/non-surgical intervention

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK

The impact of pre-operative serum creatinine on short-term outcomes after liver resection

AbstractBackgroundThe aim of the present study was to determine whether raised pre-operative serum creatinine increased the risk of renal failure after liver resection.MethodData were studied from 1535 consecutive liver resections. Outcomes in patients with pre-operative creatinine ≤124µmol/l (Group 1) were compared with those with pre-operative creatinine ≥125µmol/l (Group 2).ResultsThe median age of the 1446 (94.3%) patients resected in Group 1 was 62 years compared with 67 years in the 88 (5.7%) patients in Group 2 (P < 0.0001). Similarly this latter group had double the number of patients who were American Society of Anesthesiologists (ASA) III or IV (34.1% vs. 15.2%, P= 0.00004). Overall, the incidence of post-operative renal failure requiring haemofiltration was low (0.9%) but significantly more in Group 2 patients (5.7% vs. 0.6, P= 0.0007). In addition, patients in Group 2 were more likely to suffer acute kidney injury post-operatively (18.2% vs. 4.3%, P < 0.0001). Patients with acute kidney injury had significantly higher blood loss. Although there was no difference in mortality, patients in Group 2 had higher post-operative morbidity (37.5%) than Group 1 (21.7%, P= 0.0006), with the incidence of cardiorespiratory complications being higher in Group 2 (25.9% vs. 8.9%, P= 0.0025).ConclusionsAfter liver resection, renal failure is rare but patients with an elevated creatinine pre-operatively are at an increased risk of both renal and non-renal complications

Patient-reported outcomes after hepatic resection of colorectal cancer metastases

Purpose Hepatic resection of colorectal carcinoma (CRC) liver metastases is increasing, but evidence for the impact of surgery on patient-reported outcomes (PROs) is limited. This study aimed to describe comprehensively the impact of liver surgery for CRC hepatic metastases on PROs. Patients and Methods Consecutive patients selected for hepatic resection completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–C30 and Quality of Life Questionnaire–Liver Metastases C21 before and 3, 6, and 12 months after surgery. For functional scales, mean scores with 95% CIs were calculated at each time point, with differences in scores of at least 10 points considered clinically significant. Responses to symptom scales and items were categorized as minimal or severe. Proportions and 95% CIs for each symptom category were calculated. Results Hepatic surgery was planned in 241 patients but abandoned in nine because of unresectable disease. There were two postoperative deaths, 58 complications (25.2%), and 32 patients (14.9%) with disease recurrence. Questionnaire compliance was excellent (&gt; 95% at all time points). After surgery, most functional aspects of health decreased, and the proportions of patients with severe symptoms increased; role function deteriorated significantly, and 30% of patients reported severe activity/vigor problems. Functional scales recovered by 6 months and were maintained at 1 year. Postoperative symptoms returned to baseline levels at 12 months, but 32.1% of patients reported severe problems with sexual dysfunction and 11.9% with abdominal pain. Conclusion These findings provide new evidence regarding outcomes of liver resection for CRC metastases. It is recommended that patients be reassured that surgery has a minimal and short-lived detrimental impact on health. </jats:sec

One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score case-match approach

OBJECTIVE: To investigate the influence of clear surgical resection margin width on disease recurrence rate after intentionally curative resection of colorectal liver metastases.BACKGROUND: There is consensus that a histological positive resection margin is a predictor of disease recurrence after resection of colorectal liver metastases. The dispute, however, over the width of cancer-free resection margin required is ongoing.METHODS: Analysis of observational prospectively collected data for 2715 patients who underwent primary resection of colorectal liver metastases from 2 major hepatobiliary units in the United Kingdom. Histological cancer-free resection margin was classified as positive (if cancer cells present at less than 1 mm from the resection margin) or negative (if the distance between the cancer and the margin is 1 mm or more). The negative margin was further classified according to the distance from the tumor in millimeters. Predictors of disease-free survival were analyzed in univariate and multivariate analyses. A case-match analysis by a propensity score method was undertaken to reduce bias.RESULTS: A 1-mm cancer-free resection margin was sufficient to achieve 33% 5-year overall disease-free survival. Extra margin width did not add disease-free survival advantage (P &gt; 0.05). After the propensity case-match analysis, there is no statistical difference in disease-free survival between patients with negative narrow and wider margin clearance [hazard ratio (HR) 1.0; 95% (confidence interval) CI: 0.9-1.2; P = 0.579 at 5-mm cutoff and HR 1.1; 95% CI: 0.96-1.3; P = 0.149 at 10-mm cutoff]. Patients with extrahepatic disease and positive lymph node primary tumor did not have disease-free survival advantage despite surgical margin clearance (9 months for &lt;1-mm vs 12 months for ≥1-mm margin clearance; P = 0.062).CONCLUSION: One-mm cancer-free resection margin achieved in patients with colorectal liver metastases should now be considered the standard of care.</p

Laparoscopic staging in selected patients with colorectal liver metastases as a prelude to liver resection

Background: Careful selection of patients with colorectal liver metastases for liver resection should minimize the risk of unnecessary laparotomy due to unresectable disease. The impact of staging laparoscopy with laparoscopic ultrasonography (LapUS) on clinical decision making in selected patients with potentially resectable colorectal liver metastases was evaluated. Patients and methods: Staging laparoscopy with or without LapUS was performed in 77 of 415 consecutive patients (19%) with colorectal liver metastases deemed potentially resectable following liver-specific CT and/or MRI scanning. Retrospective analysis of prospectively collected data compared clinical outcomes with those in whom laparoscopy had been deferred in favour of laparotomy. Results: Staging laparoscopy was successful in 76 of 77 patients (99%). Adverse events occurred in three patients (4%): bowel injury n=2; late port site metastasis, n=1. Laparoscopic staging identified factors precluding curative resection in 16 patients (21%), thus averting unnecessary laparotomy. Of the 57 patients (74%) staged laparoscopically who underwent surgical exploration, 7 patients (12%) were unresectable and liver resection was achieved in 50 (88%). Discussion: Laparoscopic staging remains useful in detecting occult intra- and extra-hepatic tumour in selected patients with potentially operable colorectal liver metastases