Robert P. Jones

Ablative therapies for colorectal liver metastases: a systematic review

Aim  The standard treatment for colorectal liver metastases (CRLM) is surgical resection. Only 20–30% of patients are deemed suitable for surgery. Recently, much attention has focused on ablative therapies either to treat unresectable CRLM or to extend the margins of resectability. This review aims to assess the long‐term outcome and complication rates of various ablative therapies used in the management of CRLM.

Effect of specialist decision‐making on treatment strategies for colorectal liver metastases

One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver‐only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess. Improved surgical technique and better chemotherapeutic manipulation of metastatic disease has increased the number of patients eligible for potentially curative resection of colorectal liver metastases. The rapid evolution in this field suggests that non‐specialist decision‐making may lead to inappropriate management. This study aimed to assess the management of colorectal liver metastases by non‐liver surgeons.

Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases†

The evidence surrounding optimal follow‐up after liver resection for colorectal metastases remains unclear. A significant proportion of recurrences occur in the early postoperative period, and some groups advocate more intensive review at this time.

Randomized clinical trial of prehabilitation before planned liver resection

Patients with low fitness as assessed by cardiopulmonary exercise testing (CPET) have higher mortality and morbidity after surgery. Preoperative exercise intervention, or prehabilitation, has been suggested as a method to improve CPET values and outcomes. This trial sought to assess the capacity of a 4‐week supervised exercise programme to improve fitness before liver resection for colorectal liver metastasis.

Microwave ablation with or without resection for colorectal liver metastases

BACKGROUND Ablation with or without resection for colorectal liver metastases has been suggested as a potential method of improving survival if complete surgical resection is not possible. This study assessed the safety and efficacy of surgical microwave ablation (MWA) with or without resection for colorectal liver metastases. METHODS A retrospective case series was reviewed. Data was extracted for all patients treated with open MWA with or without resection for colorectal liver metastases. Endpoints included postoperative 30-day morbidity and mortality, local treatment failure, disease free survival and overall survival. RESULTS A total of 43 patients with technically irresectable disease were treated with MWA; 28 underwent combined MWA and resection, whilst 15 underwent MWA as the sole treatment modality. Overall post-operative morbidity was 35%, 30-day postoperative mortality 2%. At a median follow-up of 15 months, local treatment failure was observed in 4% of ablated lesions. 3-year OS was 36% for MWA group, compared to 45% for the combined ablate/resect group with 3-year DFS of 32% and 8% respectively. CONCLUSION Microwave ablation with or without resection is a safe and effective method of achieving local disease control. Ablation with or without resection is associated with good long-term outcomes, and may be a suitable treatment option for small non-resectable colorectal liver metastases.

Comparative Proteomic Characterization of 4 Human Liver-Derived Single Cell Culture Models Reveals Significant Variation in the Capacity for Drug Disposition, Bioactivation, and Detoxication

In vitro preclinical models for the assessment of drug-induced liver injury (DILI) are usually based on cryopreserved primary human hepatocytes (cPHH) or human hepatic tumor-derived cell lines; however, it is unclear how well such cell models reflect the normal function of liver cells. The physiological, pharmacological, and toxicological phenotyping of available cell-based systems is necessary in order to decide the testing purpose for which they are fit. We have therefore undertaken a global proteomic analysis of 3 human-derived hepatic cell lines (HepG2, Upcyte, and HepaRG) in comparison with cPHH with a focus on drug metabolizing enzymes and transport proteins (DMETs), as well as Nrf2-regulated proteins. In total, 4946 proteins were identified, of which 2722 proteins were common across all cell models, including 128 DMETs. Approximately 90% reduction in expression of cytochromes P450 was observed in HepG2 and Upcyte cells, and approximately 60% in HepaRG cells relative to cPHH. Drug transporter expression was also lower compared with cPHH with the exception of MRP3 and P-gp (MDR1) which appeared to be significantly expressed in HepaRG cells. In contrast, a high proportion of Nrf2-regulated proteins were more highly expressed in the cell lines compared with cPHH. The proteomic database derived here will provide a rational basis for the context-specific selection of the most appropriate ‘hepatocyte-like’ cell for the evaluation of particular cellular functions associated with DILI and, at the same time, assist in the construction of a testing paradigm which takes into account the in vivo disposition of a new drug.

Enhanced recovery in the resection of colorectal liver metastases.

There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM).

Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer

AIMS Long-term survival has been demonstrated for patients with irresectable colorectal liver metastases who are brought to resection by chemotherapy. However, it remains unclear whether improved long-term outcome seen with modern therapies translates to increased rates of secondary resection and whether response rates correlate with rates of secondary liver resection. METHODS A systematic review of literature published between January 1998 and September 2013 was performed. Phase II/III trials were included if they reported the rate of objective response and the rate of secondary resection of initially irresectable metastases. For the phase III trials, the ratio between response and resection rates within the trials was investigated as well as the correlation for both parameters in all trials. RESULTS Twenty-five studies were identified. Response rate demonstrated a strong correlation with rates of secondary resection (R(2)=0.44, p=0.008). Ratios of response/resection between both arms of 10 randomised control trials (RCTs) were calculated to control for selection bias, and showed that in a randomised setting response rates correlate with increased rates of secondary resection in an intra-trial comparison (R(2)=0.87, p=0.002). Linear regression analysis demonstrated a significant difference between studies where criteria for resectability were defined (median 39.5%), and those where it was not (median 11%) (p=0.006). CONCLUSION There is a clear correlation between radiological response and rates of secondary resection, with studies that define resectability achieving much higher rates. All trials investigating first line treatment in patients with metastatic colorectal cancer should have criteria for resection, with conversion to secondary resection as a defined study end-point.

The history of adoption of hepatic resection for metastatic colorectal cancer: 1984–95

BACKGROUND Liver resection for metastatic colorectal cancer became established without randomized trials. Proponents of surgical resection point out 5-year survival approaching 50% whilst critics question how much of the apparent effect is due to patient selection. METHOD A 2006 systematic review of reported outcomes provided the starting point for citation analysis followed by thematic analysis of the texts of the most cited papers. RESULTS 54 reports from 1988 to 2002 cited 709 unique publications a total of 1714 times. The 15 most cited papers were explored in detail, and showed clear examples of duplicate reporting and overlapping data sets. Textual analysis revealed proposals for a randomized controlled trial, but this was argued to be unethical by others, and no trial was undertaken. CONCLUSIONS This critical review reveals how the case for this surgery was made, and examines the arguments that influenced acceptance and adoption of this surgery.

Microwave ablation of ex vivo human liver and colorectal liver metastases with a novel 14.5 GHz generator

Purpose: This study assessed the relationship between time, power and ablation size using a novel high-frequency 14.5 GHz microwave applicator in ex vivo human hepatic parenchyma and colorectal liver metastases. Previous examination has demonstrated structurally normal but non-viable cells within the ablation zone. This study aimed to further investigate how ablation affects these cells, and to confirm non-viability. Materials and methods: Ablations were performed in ex vivo human hepatic parenchyma and tumour for a variety of time (10–180 s) and power (10–50 W) settings. Histological examination was performed to assess cellular anatomy, whilst enzyme histochemistry was used to confirm cellular non-viability. Transmission electron microscopy was used to investigate the subcellular structural effects of ablation within these fixed cells. Preliminary proteomic analysis was also performed to explore the mechanism of microwave cell death. Results: Increasing time and power settings led to a predictable and reproducible increase in size of ablation. At 50 W and 180 s application, a maximum ablation diameter of 38.8 mm (±1.3) was produced. Ablations were produced rapidly, and at all time and power settings ablations remained spherical (longest:shortest diameter <1.2). Routine histological analysis using haematoxylin-eosin (H&E) confirmed well preserved cellular anatomy despite ablation. Transmission electron microscopy demonstrated marked subcellular damage. Enzyme histochemistry showed complete absence of viability in ablated tissue. Conclusions: Large spherical ablation zones can be rapidly and reproducibly achieved in ex vivo human hepatic parenchyma and colorectal liver metastases using a 14.5 GHz microwave generator. Despite well preserved cellular appearance, ablated tissue is non-viable.