Protocol for the CoNoR Study: A prospective multi-step study of the potential added benefit of two novel assessment tools in colorectal liver metastases technical resectability decision-making.

INTRODUCTION: Liver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite the existence of criteria. This paper summarises a study protocol to evaluate the potential added value of two novel assessment tools in assessing CLM technical resectability: the Hepatica preoperative MR scan (MR-based volumetry, Couinaud segmentation, liver tissue characteristics and operative planning tool) and the LiMAx test (hepatic functional capacity). METHODS AND ANALYSIS: This study uses a systematic multistep approach, whereby three preparatory workstreams aid the design of the final international case-based scenario survey:Workstream 1: systematic literature review of published resectability criteria.Workstream 2: international hepatopancreatobiliary (HPB) interviews.Workstream 3: international HPB questionnaire.Workstream 4: international HPB case-based scenario survey.The primary outcome measures are change in resectability decision-making and change in planned operative strategy, resulting from the novel test results. Secondary outcome measures are variability in CLM resectability decision-making and opinions on the role for novel tools. ETHICS AND DISSEMINATION: The study protocol has been approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences. Manuscripts will be published. REGISTRATION DETAILS: The CoNoR Study is registered with ClinicalTrials.gov (registration number NCT04270851). The systematic review is registered on the PROSPERO database (registration number CRD42019136748).

Peri-operative thrombophilia in patients undergoing liver resection for colorectal metastases.

BACKGROUND: Routine chemical venous thromboembolism (VTE) prophylaxis for liver surgery remains controversial, and often delayed post-operatively due to perceived bleeding risk. This study asked whether patients undergoing hepatectomy for colorectal metastases (CRM) were at risk from VTE pre-operatively, and the impact of hepatectomy on that risk. METHODS: Single-centre prospective observational cohort study of patients undergoing open hepatectomy for CRM, comparing pre-, peri- and post-operative haemostatic variables. RESULTS: Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were recruited. There were 28 (46.7%) major resections, with median (interquartile range [IQR]) blood loss 150.0 (76.3-263.7) mls, no blood transfusions, post-operative VTE events or deaths. Patients were prothrombotic pre-operatively (high median factor VIIIC and increased thrombin generation velocity index), an effect exacerbated post-hepatectomy. Major hepatectomies had a significantly greater median drop in Protein C, rise in Factor VIIIC and von Willebrand Factor, versus minor resections (p = 0.001, 0.005, 0.001 respectively). Patients with parenchymal transection times greater than median (40 min), had significantly increased median (IQR) PMBC-TFmRNA expression [1.65(0.93-2.70)2ddCt], versus quicker transections [0.99(0.69-1.28)2ddCt, p = 0.020]. CONCLUSIONS: Patients with CRM are prothrombotic pre-operatively, an effect exacerbated by hepatectomy, particularly longer, complex resections, suggesting chemical thromboprophylaxis be considered early in the patient pathway.

Postoperative pain control using continuous i.m. bupivacaine infusion plus patient-controlled analgesia compared with epidural analgesia after major hepatectomy.

OBJECTIVES: There is debate concerning the best mode of delivery of analgesia following liver resection, with continuous i.m. infusion of bupivacaine (CIB) plus patient-controlled i.v. analgesia (PCA) suggested as an alternative to continuous epidural analgesia (CEA). This study compares these two modalities. METHODS: A total of 498 patients undergoing major hepatectomy between July 2004 and July 2011 were included. Group 1 received CIB + PCA (n = 429) and Group 2 received CEA (n = 69). Groups were analysed on baseline patient and surgical characteristics. Primary endpoints were pain severity scores and total opioid consumption. Secondary endpoints were pain management failures, need for rescue medication, postoperative (opioid-related) morbidity and hospital length of stay (LoS). RESULTS: In both groups pain was well controlled and >70% of patients had no or minimal pain on PoDs 1 and 2. The numbers of patients experiencing severe pain were similar in both groups: PoD 1 at rest: 0.3% in Group 1 and 0% in Group 2 (P = 1.000); PoD 1 on movement: 8% in Group 1 and 2% in Group 2 (P = 0.338); PoD 2 at rest: 0% in Group 1 and 2% in Group 2 (P = 0.126), and PoD 2 on movement: 5% in Group 1 and 5% in Group 2 (P = 1.000). Although the CIB + PCA group required more opioid rescue medication on PoD 0 (53% versus 22%; P < 0.001), they used less opioids on PoDs 0-3 (P ≤ 0.001), had lower morbidity (26% versus 39%; P = 0.018), and a shorter LoS (7 days versus 8 days; P = 0.005). CONCLUSIONS: The combination of CIB + PCA provides pain control similar to that provided by CEA, but facilitates lower opioid consumption after major hepatectomy. It has the potential to replace epidural analgesia, thereby avoiding the occurrence of rare but serious complications.

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

BACKGROUND: Neoadjuvant 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 METHODS: Between 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). RESULTS: A 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. CONCLUSIONS: A liver-specific MRI prior to chemotherapy reduces intra-hepatic recurrence and avoids a repeat hepatectomy.

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 (> 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.

Extrahepatic versus intrahepatic hilar control for right hepatectomy: an updated experience.

BACKGROUND: Inflow control prior to transection for right hepatectomy may be achieved either by dissection and ligation of the individual hilar structures outside of the liver (EHD) or by mass stapling of the inflow structures within the hepatic parenchyma. Our preference is for the anterior intrahepatic approach (AIA) with mass stapling, in order to minimise the risk of inadvertent injury of the left-sided inflow and to preserve as much parenchyma as possible. In this paper, we present our experience over the last 10 years and compare it with results from the EHD technique. METHODS: Data for a 10-year period from 2000 to 2010 were extracted retrospectively from a prospectively collected database. Results in each group were measured by a combination of technical and oncological outcomes. Groups were compared by way of descriptive statistics and differences tested for significance by appropriate statistical means. RESULTS: 411 right hepatectomies were performed for colorectal metastases. Of these, 242 were by AIA and 169 by EHD. Both groups were well matched in demographic terms and according to disease burden, although more extended resections were performed in the EHD group. Operative duration (433 vs. 350 min), blood loss (420 vs. 348 ml) and incidence of bile leaks (4 vs. 2) were all lower in the AIA group. All other technical and oncological outcomes were equivalent. CONCLUSION: The AIA approach provides equivalent morbidity, mortality and oncological outcome to the EHD dissection technique and may confer the benefits of being safer and providing greater scope to preserve hepatic parenchyma.

Open liver resection for colorectal metastases: better short- and long-term outcomes in patients potentially suitable for laparoscopic liver resection.

BACKGROUND: There is no prospective randomized data comparing laparoscopic to open hepatectomy. This study compared short- and long-term outcomes in patients undergoing hepatectomy for colorectal metastases (CRM), who were suitable for either laparoscopic or open surgery. METHODS: Data were prospectively collected from consecutive patients undergoing hepatic resection of CRM at a single centre (1987-2007). Patients who were suitable for laparoscopic resection (Group 1) were compared with patients whose tumour characteristics would best be considered for open resection (Group 2). RESULTS: Out of 1152 hepatectomies, 266 (23.1%) were deemed suitable for a laparoscopic approach. The median (IQR) number of metastases was greater in Group 2 [2(1-20) vs. 1(1-10), P < 0.001], as was the mean (SD) tumour size [5.3(3.6) cm vs. 3.3(1.2) cm, P < 0.001]. The median (IQR) operation time [210 (70) min vs. 240 (90) min, P < 0.001] and blood loss [270 (265) ml vs. 355 (320) ml, P < 0.001] were less in Group 1. There was no difference in length of stay, morbidity or mortality. Patients in Group 2 had a higher R1 resection rate (14.9%) compared with Group 1 (4.5%, P < 0.001) and lower 5-year survival (37.8% vs. 44.2%, P= 0.005). DISCUSSION: Current criteria for laparoscopic hepatectomy selects patients who have more straight-forward surgery, with less risk of an involved resection margin and better long-term survival, compared with patients unsuited to a laparoscopic approach. Clearly defined criteria for laparoscopic hepatectomy are essential to allow meaningful analysis of outcomes and the results of unrandomized series of laparoscopic hepatectomies must be interpreted with caution.

Evaluation of intrahepatic, extra-Glissonian stapling of the right porta hepatis vs. classical extrahepatic dissection during right hepatectomy.

BACKGROUND: Control of hepatic inflow is a key manoeuvre during right hepatectomy and has traditionally been achieved by extrahepatic dissection of the component right portal inflow structures at the hepatic hilum. An alternative technique is the anterior intrahepatic approach (AIA), in which the Glissonian sheath is isolated within the substance of the liver during parenchymal transection and secured using an endovascular stapling device. This study evaluates the intrahepatic, extra-Glissonian technique in comparison with classical extrahepatic dissection (EHD) in right hepatectomy. METHODS: A retrospective case-controlled study referring to a 20-year period identified 342 consecutive patients who underwent right hepatectomy for colorectal liver metastases from a prospectively compiled database. The AIA to right hepatectomy was used in 182 of these patients and the extrahepatic approach in 160. The two groups were matched for age, gender, stage of primary tumour and number and size of metastases. Outcome measures included safety factors (bleeding, bile duct injury and gun failure), operative duration, oncological margin, morbidity and mortality. RESULTS: There were no significant differences between the two groups in terms of operative duration (240 min vs. 260 min) or postoperative change in haemoglobin (1.3 g/dl vs. 1.4 g/dl). The AIA was associated with lower operative blood loss (355 ml vs. 425 ml; P < or = 0.001), a reduced rate of significant morbidity (14.6% vs. 23.1%; P = 0.005), better R0 resection rates (93% vs. 89%; P = 0.014) and a lower 90-day mortality rate (3% vs. 7%; P = 0.046). There was one minor bile leak in each group, two clinically significant bile leaks requiring endoscopic retrograde cholangiopancreatography and stenting in the extrahepatic group, and a further persistent bile leak requiring biliary reconstruction in each group. In two instances the endovascular stapler misfired. Both cases were dealt with at the time of surgery with no further sequelae. The length of hospital stay was equivalent in the two groups (8 days vs. 9 days). CONCLUSIONS: In selected patients, intrahepatic, extra-Glissonian stapled right hepatectomy is feasible, safe and avoids the need for EHD. The anterior approach to right hepatectomy may achieve outcomes at least as good as those associated with the classical extrahepatic approach.

A diagnostic paradigm for resectable liver lesions: to biopsy or not to biopsy?

BACKGROUND: Despite a growing body of evidence reporting the deleterious mechanical and oncological complications of biopsy of hepatic malignancy, a small but significant number of patients undergo the procedure prior to specialist surgical referral. Biopsy has been shown to result in poorer longterm survival following resection and advances in modern imaging modalities provide equivalent, or better, diagnostic accuracy. METHODS: The literature relating to needle-tract seeding of primary and secondary liver cancers was reviewed. MEDLINE, EMBASE and the Cochrane Library were searched for case reports and series relating to the oncological complications of biopsy of liver malignancies. Current non-invasive diagnostic modalities are reviewed and their diagnostic accuracy presented. RESULTS: Biopsy of malignant liver lesions has been shown to result in poorer longterm survival following resection and does not confer any diagnostic advantage over a combination of non-invasive imaging techniques and serum tumour markers. CONCLUSIONS: Given that chemotherapeutic advances now often permit downstaging and subsequent resection of 'unresectable' disease, the time has come to abandon biopsy of solid lesions outside the setting of a specialist multi-disciplinary team meeting (MDT).

Quantification of risk of a positive (R1) resection margin following hepatic resection for metastatic colorectal cancer: an aid to clinical decision-making.

BACKGROUND AND AIMS: Margin involvement following liver resection for colorectal cancer is associated with early disease recurrence and shorter long-term survival. This study aimed to develop a predictive index for quantifying the likelihood of a positive resection margin (R1) for patients undergoing hepatic resection for metastatic colorectal cancer. METHODS: Clinical, pathological and complete follow-up data were prospectively collected from 1005 consecutive liver resections performed in 929 patients for colorectal liver metastases with curative intent at a single centre between 1987 and 2005. Ninety-four resections in 81 patients with extra-hepatic disease were excluded, leaving 911 resections (844 primary and 67 repeat) in 848 patients for analysis. Multivariate logistic regression was used to identify independent predictors of margin involvement and from the beta-coefficients generated, develop a predictive model that was validated using measures of discrimination and calibration. RESULTS: There were 80 (8.8%) R1 resections, with a 5-year cancer-specific survival for R0 and R1 hepatic resections of 39.7% and 17.8%, respectively; p<0.001. On multivariate analysis, five risk factors were found to be independent predictors of an R1 resection: non-anatomical resection vs. anatomical resection (odds ratio (OR)=4.3, p=0.001), >3 hepatic metastases involving >50% of the liver vs. <3 metastases (OR=4.0, p<0.001); bilobar vs. unilobar disease (OR=2.9, p<0.001); repeat vs. primary hepatic resection (OR=3.1, p=0.006); abnormal vs. normal pre-operative liver function tests (OR=1.6, p=0.044). These five factors were used to develop a predictive model, which when tested, fitted the data well, with an area under the receiver operating characteristic curve of 78.1% (S.E.=2.7%). CONCLUSIONS: This study describes an accurate model for quantifying the risk of a positive margin following hepatic resection for liver metastases. It may be used pre-operatively by multi-disciplinary teams to identify patients who may benefit from neoadjuvant therapy prior to liver surgery, thus minimizing the risk of a positive resection margin.

Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients.

OBJECTIVE: To identify risk factors associated with cancer-specific survival and develop a predictive model for patients undergoing primary hepatic resection for metastatic colorectal cancer. BACKGROUND: No published studies investigated collectively the inter-relation of factors related to patient cancer-specific survival after hepatectomy for metastatic colorectal cancer. METHODS: Clinical, pathologic, and complete follow-up data were prospectively collected from 929 consecutive patients undergoing primary (n = 925) or repeat hepatic resection (n = 80) for colorectal liver metastases at a tertiary referral center from 1987 to 2005. Parametric survival analysis was used to identify predictors of cancer-specific survival and develop a predictive model. The model was validated using measures of discrimination and calibration. RESULTS: Postoperative mortality and morbidity were 1.5% and 25.9%, respectively. 5-year and 10-year cancer-specific survival were 36% and 23%. On multivariate analysis, 7 risk factors were found to be independent predictors of poor survival: number of hepatic metastases >3, node positive primary, poorly differentiated primary, extrahepatic disease, tumor diameter > or =5 cm, carcinoembryonic antigen level >60 ng/mL, and positive resection margin. The first 6 of these criteria were used in a preoperative scoring system and the last 6 in the postoperative setting. Patients with the worst postoperative prognostic criteria had an expected median cancer-specific survival of 0.7 years and a 5-year cancer-specific survival of 2%. Conversely, patients with the best prognostic postoperative criteria had an expected median cancer-specific survival of 7.4 years and a 5-year cancer-specific survival of 64%. When tested both predictive models fitted the data well with no significant differences between observed and predicted outcomes (P > 0.05). CONCLUSION: Resection of liver metastases provides good long-term cancer-specific survival benefit, which can be quantified pre- or postoperatively using the criteria described. The "Basingstoke Predictive Index" may be used for risk-stratifying patients who may benefit from intensive surveillance and selection for adjuvant therapy and trials.

Predictive models in colorectal liver metastases--can we personalize treatment and outcome?

BACKGROUND/AIMS: Hepatic resection for colorectal liver metastases offers patients the best chance of long-term survival. Survival rates after resection range from 25 to 60%. Predictive models may risk-stratify patients and allow improved selection for surgery or other therapies. This review aims to achieve consensus regarding the predictors of survival after hepatic resection for colorectal metastases and evaluate current predictive models of outcome. METHODS: A comprehensive literature review of published studies with more than 500 patients describing models for predicting long-term survival in patients undergoing hepatic resection for colorectal metastases. RESULTS: Five large predictive models have been published to date. The three predictive models developed from the largest series agree over the key independent predictors of poor long-term outcome for patients undergoing liver resection for colorectal metastases. All five models have individual shortcomings, and whilst three have been internally validated, two have been externally validated with conflicting results. The Basingstoke Predictive Index appears to be accurate and internally validated. CONCLUSIONS: There is need within the international surgical oncology community for consensus regarding a predictive model to be universally adopted for risk-stratifying patients who may benefit from intensive surveillance and selection for adjuvant therapy and clinical trials.

Meta-analysis of clinical outcome after first and second liver resection for colorectal metastases.

BACKGROUND: The perioperative risk and long-term survival benefit of repeat hepatectomy for patients with liver metastases from colorectal cancer, compared with that of a first liver resection, has been reported with varying results in the literature. METHODS: The literature was searched using Medline, Embase, Ovid, and Cochrane databases for all studies published from 1992 to 2006. Two authors independently extracted data using the following outcomes: postoperative complications and mortality; disease recurrence; and long-term survival. Trials were assessed using the modified Newcastle-Ottawa Score. Random-effect meta-analytical techniques were used for analysis. RESULTS: Twenty-one studies met the inclusion criteria, comprising 3,741 patients. The use of adjuvant chemotherapy was similar in both groups (odds ratio [OR] = 0.97; 95% confidence interval [CI] = 0.54, 1.74; P = .92), as was the number of hepatic nodules present at the time of first or second resection (weighted mean difference [WMD] = 0.18; 95% CI = -0.22, 0.57; P = .380). Wedge resection was carried out less often at first hepatectomy (39% vs 46%; OR = 0.66; 95% CI = 0.44, 1.00; P = .05). There was significantly less blood loss in patients undergoing first versus second hepatectomy (WMD = 238 ml; 95% CI = 90, 385; P = .002). There was no difference in perioperative morbidity (OR = 1.01; 95% CI = 0.65, 1.55; P = .98), mortality (OR = 1.01; 95% CI = 0.18, 5.72; P = .99) or long-term survival (HR = 0.90; 95% CI = .66, 1.24; P = .530) between groups. CONCLUSIONS: Repeat hepatectomy for patients with colorectal cancer metastases is safe and provides survival benefit equal to that of a first liver resection.

Roux-en-Y Choledochojejunostomy is the method of choice for biliary reconstruction in liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Opinion is divided regarding the optimal method of biliary reconstruction after liver transplantation for primary sclerosing cholangitis (PSC). METHODS: We investigated biliary complications and graft and patient survival in all patients who underwent liver transplantation for PSC in the United Kingdom between 1994 and 2003. RESULTS: Anastomotic leak rates were similar, but a significantly higher stricture rate was observed in patients who had a duct-to-duct reconstruction compared with those who underwent a Roux-en-Y anastomosis. Graft and patient survival were also markedly worse in patients with a duct-to-duct anastomosis. CONCLUSIONS: Roux-en-Y choledochojejunostomy is the method of choice for biliary reconstruction in liver transplantation for PSC.