Darius F. Mirza

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trials final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% [95·66% CI 21·3–35·5] to 35·4% [28·1–42·7]; HR 0·79 [0·62–1·02]; p=0·058) in randomised patients; 8·1% (from 28·1% [21·2–36·6] to 36·2% [28·7–43·8]; HR 0·77 [0·60–1·00]; p=0·041) in eligible patients; and 9·2% (from 33·2% [25·3–41·2] to 42·4% [34·0–50·5]; HR 0·73 [0·55–0·97]; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.

Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases?

Background:Chemotherapy is increasingly used in colorectal liver metastases (CRLMs) even when they are initially resectable. The aim of our study was to address the still pending question of whether perioperative chemotherapy is really beneficial in patients developing solitary metastases at a distance from surgery of the primary. Methods:We analyzed a multicentric cohort of 1471 patients resected for solitary, metachronous, primarily resectable CRLMs without extrahepatic disease in the LiverMetSurvey International Registry over a 15-year period. Patients who received at least 3 cycles of oxaliplatin- or irinotecan-based chemotherapy before liver surgery (group CS, n = 169) were compared with those who were resected upfront (group S, n = 1302). Results:Patients of group CS were more frequently females (49% vs 36%, P = 0.001) and had larger metastases (≥5 cm, 33% vs 23%, P = 0.007); no difference was observed with regard to age, site of the primary tumour, time delay to occurrence of metastases, and carcinoembryonic antigen (CEA) levels at the time of diagnosis in the 2 groups. The rate of postoperative complications was significantly higher in group CS (37.2% vs 24% in group S, P = 0.006). At univariate analysis, preoperative chemotherapy did not impact the overall survival (OS) (60% at 5 years in both groups); however, postoperative chemotherapy was associated with better OS (65% vs 55% at 5 years, P < 0.01). At multivariate analysis, age 70 years or older (P = 0.05), lymph node positivity in the primary tumor (P = 0.02), a primary-to-metastases time delay of less than 12 months (P = 0.04), raised CEA levels of more than 5 ng/mL at diagnosis (P < 0.01), a tumor diameter of 5 cm or more (P < 0.01), noncurative liver resection (P < 0.01), and the absence of postoperative chemotherapy (P < 0.01) were independent prognostic factors of survival. The disease-free survival (DFS) was negatively influenced by CEA level of more than 5 ng/mL (P < 0.01), size of the metastases 5 cm or more (P = 0.05), and the absence of postoperative chemotherapy (P < 0.01). When patients with metastases of less than 5 cm in size were compared to those with metastases of size 5 cm or more, preoperative chemotherapy did not influence the OS or DFS in either group. Postoperative chemotherapy, on the other hand, improved OS and DFS in patients with metastases of size 5 cm or more but not in patients with metastases of less than 5 cm in size. Conclusions:Although preoperative chemotherapy does not seem to benefit the outcome of patients with solitary, metachronous CRLM, postoperative chemotherapy is associated with better OS and DFS, mainly when the tumor diameter exceeds 5 cm.

Progression while Receiving Preoperative Chemotherapy Should Not Be an Absolute Contraindication to Liver Resection for Colorectal Metastases

PurposeTumor progression while receiving neoadjuvant chemotherapy (PD) has been associated with poor outcome and is commonly considered a contraindication to liver resection (LR). This study aims to clarify in a large multicenter setting whether PD is always a contraindication to LR.MethodsData from the LiverMetSurvey international registry were analyzed. Patients undergoing LR for colorectal metastases without extrahepatic disease after neoadjuvant chemotherapy between 1990 and 2009 were reviewed.ResultsAmong 2143 patients, PD occurred in 176 (8.2xa0%). Risk of progression was increased after 5-FU or irinotecan (22.7xa0% vs. 6.8xa0% after other regimens, pxa0<xa00.0001; 14.9xa0% vs. 7.2xa0%, pxa0<xa00.0001), while it was reduced after oxaliplatin (5.6xa0% vs. 12.0xa0%, pxa0<xa00.0001) and still diminished among patients receiving targeted therapies (2.6xa0%). PD was an independent prognostic factor of survival at multivariate analysis (35xa0% vs. 49xa0%, pxa0=xa00.0006). In the PD group, 3 independent prognostic factors were identified: carcinoembryonic antigen (CEA) ≥200xa0ng/mL (pxa0=xa00.003), >3 metastases (pxa0=xa00.028), and tumor diameter ≥50xa0mm (pxa0=xa00.002). A survival predictive model showed that patients without any risk factors had 5-year survival rates of 53.3xa0%; good survival results were still observed if metastases were >3 or ≥50xa0mm (29.9 and 19.1xa0%, respectively). On the contrary, survival was less than 10xa0% at 3xa0years in the presence of >1 prognostic factor or CEA of ≥200xa0ng/mL.ConclusionsPD is a negative prognostic factor, but it is not an absolute contraindication to LR. Patients with PD could be scheduled for LR except for those with >3 metastases and ≥50xa0mm, or CEA ≥200xa0ng/mL in whom further chemotherapy is recommended.

Role of neoadjuvant chemotherapy in resectable synchronous colorectal liver metastasis; An international multi-center data analysis using LiverMetSurvey.

The use of neo‐adjuvant chemotherapy in resectable synchronous liver metastasis is ill defined. The aim of this study was to evaluate neo‐adjuvant chemotherapy on outcomes following liver resection for synchronous CLM.

Maintaining surgical skills for military general surgery: the potential role for multivisceral organ retrieval in military general surgery training and practice.

The closure of the Medical Treatment facility in Camp BASTION and the return to contingency operations presents a new challenge in training and maintaining the skills of military surgeons. Multivisceral organ retrieval presents a unique opportunity to practice some of the more unusual techniques required in military surgery in the National Health Service. This article details the experience that organ retrieval offers and matches this to the needs of military surgeons. National Organ Retrieval Service teams need skilled surgeons, and a mutually beneficial partnership is in prospect.

Long-term outcomes of patients with 10 or more colorectal liver metastases

Background:Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients.Methods:The study population consisted of a multicentre cohort of patients with CLM (N=12u2009406) operated on, with intention to resect, from January 2005–June 2013 and whose data were prospectively collected in the LiverMetSurvey registry.Results:Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26–0.48)). Other independent favourable factors were as follows: maximal tumour size <40u2009mm (HR 0.67 (0.49–0.92)); age <60 years (HR 0.66 (0.50–0.88)); preoperative MRI (HR 0.65 (0.47–0.89)); and adjuvant chemotherapy (HR 0.73 (0.55–0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor.Conclusions:Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review.

Long‐standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies.

The rate of false-positive diagnosis of colorectal liver metastases in patients undergoing resection with the development of a novel, externally validated risk score

Background: Diagnostic error in patients undergoing resection of colorectal liver metastases (CRLM) is unusual but exposes patients to unnecessary risks associated with treatment. The primary aim of this study was to determine the rate of and risk factors for a false‐positive diagnosis of colorectal liver metastases in patients undergoing hepatic resection. The secondary aim was to develop and validate a risk score to predict a false‐positive diagnosis. Methods: Patients were identified from prospectively maintained databases. Patients who underwent a first liver resection for presumed colorectal liver metastases were divided into 2 groups: CRLMPOS (colorectal liver metastases present on histology or appearance of complete pathologic response to preoperative chemotherapy) and CRLMNEG (all others). Univariable analysis and multivariable binary logistic regression were used to identify risk factors for CRLMNEG. Risk scores were developed for CRLMNEG both with and without the use of preoperative carcinoembryonic antigen and were validated on an external cohort. Results: 3.1% of patients in both test and validation cohorts were CRLMNEG (39/1,252 and 59/1,900, respectively). CRLMNEG patients had fewer (P=.006) and smaller lesions (P < .001) with lower serum levels of carcinoembryonic antigen (P < .001), T (P=.031) and N (P < .001) and a lower Dukes’ stage of the primary (P < .001). The risk score performed well (area under the receiver operating characteristic curve 0.869; standard error=0.030; P < .001) with reasonable performance on validation (area under receiver operating characteristic curve 0.743; standard error=0.058; P < .001]). Conclusion: A false‐positive diagnosis of colorectal liver metastases affected the same proportion of patients in 2 unrelated cohorts. This study identified risk factors for false‐positive diagnosis with development of a novel risk score supported by external validation.

An effective protocol for pharmacological defatting of primary human hepatocytes which is non-toxic to cholangiocytes or intrahepatic endothelial cells

Introduction Pharmacological defatting of rat hepatocytes and hepatoma cell lines suggests that the same method could be used to ameliorate macrovesicular steatosis in moderate to severely fatty livers. However there is no data assessing the effects of those drugs on primary human liver cells. We aimed to determine the effectiveness of a pharmacological cocktail in reducing the in vitro lipid content of primary human hepatocytes (PHH). In addition we sought to determine the cytotoxicity of the cocktail towards non-parenchymal liver cells. Methods Steatosis was induced in PHH by supplementation with a combination of saturated and unsaturated free fatty acids. This was followed by addition of a defatting drug cocktail for up to 48 hours. The same experimental method was used with human intra-hepatic endothelial cells (HIEC) and human cholangiocytes. MTT assay was used to assess cell viability, triglyceride quantification and oil red O staining were used to determine intracellular lipids content whilst ketone bodies were measured in the supernatants following experimentation. Results Incubation of fat loaded PHH with the drugs over 48 hours reduced the intracellular lipid area by 54%, from 12.85% to 5.99% (p = 0.002) (percentage of total oil red O area), and intracellular triglyceride by 35%, from 28.24 to 18.30 nmol/million of cells (p<0.001). Total supernatant ketone bodies increased 1.4-fold over 48 hours in the defatted PHH compared with vehicle controls (p = 0.002). Moreover incubation with the drugs for 48 hours increased the viability of PHH by 11%, cholangiocytes by 25% whilst having no cytotoxic effects on HIEC. Conclusion These data demonstrate that pharmacological intervention can significantly decrease intracellular lipid content of PHH, increase fatty acids β-oxidation whilst being non-toxic to PHH, HIEC or cholangiocytes.

Proof of concept: liver splitting during normothermic machine perfusion

Abstract Introduction Despite utilizing extended criteria donors, there remains a shortage of livers for transplantation. No data exists on splitting donor livers with concurrent NMP-L. Methods A liver recovered from a donor after circulatory death was subjected to NMP-L using a red cell based fluid. During NMP-L, a ‘classical’ left lateral + right trisegmentectomy split was performed using an integrated bipolar/ultrasonic device. After splitting, blood flow was confirmed using Doppler ultrasound in each lobe. Results Prior to splitting, flow rates were maintained physiologically. Lactate decreased from 13.9 to 3.0 mmol/L. Lactate before and after splitting were similar in the hepatic arteries, portal veins and IVC. Doppler ultrasound demonstrated arterial and venous waveforms in both lobes after splitting. Conclusions ‘Classical’ liver splitting during NMP-L is feasible, maintaining viability of both lobes. Establishing this procedure may attenuate cold ischaemic injury, allow pre-implantation monitoring of both grafts and facilitate logistics of transplanting two grafts.