Sri Lanka guidelines for the management of hepatic metastases from colorectal cancer

Guidelines to manage liver metastases were developed at a meeting jointly organized by the Sri Lanka Hepato Pancreato Biliary Association (SLHPBA) and the International Hepato Pancreato Biliary Association (IHPBA). Existing evidence was used in the development of guidelines, as recommended by the AGREE II consortium. Guidelines are provided for diagnosis, pre-operative workup, multi-disciplinary team review, surgery, anaesthesia, post-operative care and follow up. Consideration was given to the limitations of facilities available in the country.


Introduction
Liver resection is indicated in carefully selected patients with hepatic metastases from colorectal cancer [1]. As hepatic surgery has developed as a subspecialty, the skills and expertise required to undertake liver resection and to provide peri-operative care for these patients, have become more widely available. There is good evidence that this type of complex surgery should be concentrated in specialist units . In the current era, clinical decision making should be formulated in a multidisciplinary team.
The collaboration between the Sri Lanka National Chapter of the International Hepato-Pancreato-Biliary Association (SLHPBA) and the International Hepato-Pancreato-Biliary Association (IHPBA) started in 2015 and at the last meeting held in Colombo in August 2017, a full day was dedicated to the production of multidisciplinary, disease-specific guidelines. This process led to the publication of the Sri Lanka guidelines for the diagnosis and management of acute pancreatitis [3] and management of hepatocellular carcinoma [4]. As the 2012 revision of the Atlanta consensus document [5] on which the Sri Lanka pancreatitis guidelines were based provides an international reference standard, the process of adapting guidelines was relatively straightforward. There are no similar, universally accepted international guidelines for the management of liver metastases from colorectal cancer. Thus, the aim of this document is to utilise the approach recommended by the AGREE (Appraisal of Guidelines for Research and Evaluation) consortium [6] to adapt international guidelines to Sri Lanka.
The objectives of this guideline are to provide contemporary and practical advice for the management of patients with liver metastases from colorectal cancer within the healthcare system of Sri Lanka.

Adapting existing evidence.
Aspects of the approach recommended by the AGREE II consortium was adopted [6].
The AGREE II consortium describes a practical method for clinicians to adopt existing evidence and to synthesise guidelines. Subsequently, international guidelines from the United States of America [7], the United Kingdom [8], Europe [9] and Japan [10] were reviewed in detail and a draft discussion document was synthesised by Professor Ajith Siriwardena and has been modified over a series of discussions with all stakeholders and co-authors.
The final guidance is given below.
SRI LANKA GUIDELINES 1. Diagnosis of hepatic metastases 1.1 Imaging Ÿ Imaging for staging of patients with liver metastases from colorectal cancer should include contrast-enhanced triple-phase computed tomography (CT) of the thorax, abdomen and pelvis.
Ÿ Contrast-enhanced magnetic resonance (MR) scanning of the liver provides additional information and is also recommended [11].
Ÿ MR imaging should be undertaken at baseline and before chemotherapy, when available.
Ÿ 18Fluorodeoxyglucose positron emission scanning (FDG-PET) is not routinely available in Sri Lanka at the time of production of this guideline. A large randomised trial has demonstrated no additional survival benefit from the use of FDG-PET as an additional test and thus FDG-PET is NOT recomm-ended [12].

Blood Tests
Ÿ Baseline blood tests should include full blood count, coagulation profile, urea and electrolytes and enzymatic liver function tests.
Ÿ CEA (carcino embryonic antigen) level is useful in follow-up and in assessing response to treatment and should be considered if available [13].

Genetic Testing
Ÿ Genetic testing for mutations of the K-ras (Kirsten Rat Sarcoma virus) gene is not widely available. If available, K-ras mutation testing is useful in assessing whether to prescribe biologic chemotherapy agents aimed at inhibiting the EGFR (Epidermal Growth Factor Receptor) pathway [14]. Patients who carry mutations of K-ras are resistant to EGFR-inhibitor therapy [15].

SCIENTIFIC ARTICLE
Ÿ It should be remembered that the evidence-base for surgical resection of lung metastases from colorectal cancer is very limited.

Modern terminology of liver resections
Ÿ Modern terminology for liver resection uses the terminology outlined in the Brisbane consensus conference and illustrated in a subsequent review article [1].

Extent of safe liver resection
Ÿ The principle of safe liver surgery is to ensure adequate inflow, outflow and biliary drainage of the future remnant liver. Thus, a resection of up to 70% of the liver parenchyma in the form of a right trisection-ectomy or left trisectionectomy can be undertaken.
Ÿ The extent of safe resection is reduced by patient factors such as cirrhosis, fatty liver, non-alcoholic fatty liver disease (NAFLD) and increasing age. The extent of safe resection is also reduced by prior chemotherapy. If CT volumetry is available, it should be utilised in resection planning to assess safe future remnant liver.
Ÿ If the future remnant liver (FRL) is likely to be too small, portal vein ligation or percutaneous embolization of the portal vein (PVE) -typically the right portal vein -will produce compensatory hypertrophy of the left lobe. In patients undergoing modification of the FRL, baseline CT and follow-up CT at around 4 to 6 weeks should be undertaken.

Use of prognostic scores to determine whether to offer resection
Ÿ It is accepted that the number of liver metastases does not determine resectability. However, prognostic scores such as that developed by Memorial Sloan-Kettering Hospital indicate that patients with more than 5 liver metastases with the largest being >5 cm in size, and present within 12 months of presentation of the primary, together with a node positive tumour and high CEA have a high risk of early recurrence [17].

Anaesthesia and preparation for liver surgery
Ÿ Patients should have blood cross-matched and available in theatre.
Ÿ Peri-operative analgesia can be provided by epidural catheters although there is recent evidence that wound catheters are also effective [18].
Ÿ Intra-operative monitoring requires invasive arterial display of heart rate and blood pressure.
Ÿ Central venous pressure should be monitored and should be maintained at a low level during liver transection by avoidance of excessive infusion of intravenous fluid.

Liver transection
Ÿ It is recommended practice to use intra-operative ultrasonography to confirm the distribution of liver lesions and to confirm that the future remnant liver is disease-free.
Ÿ There is a very wide range of liver transection equipment.
There is no evidence of superiority for any particular device [19].
Ÿ Current evidence suggests that the laparoscopic approach should be offered for patients requiring left lateral sectionectomy [20]. Other resections can be undertaken laparoscopically following the same principles of open liver surgery [21].

Post-operative care after liver resection.
Ÿ Patients should be nursed in a high-dependency unit after surgery with 1:1 nursing care and facilities for inotropic support and non-invasive ventilator support.
Ÿ If a surgical drain is used the drain bilirubin should be measured on the 3rd post-operative day.
Ÿ The terminology for reporting of complications recommended by the International Study Group for Liver Surgery (ISGLS) should be used [22][23][24].

Chemotherapy
Ÿ A detailed discussion of chemotherapy is beyond the scope of these guidelines.
Ÿ The EORTC 40983 study showed that in patients with up to four metachronous liver metastases, treatment with pre-and post-operative oxaliplatin produced no improvement in 5-year survival compared to surgical resection alone. However, an increase in progression free survival was noted compared with surgery alone [25].
Ÿ This study showed no additional morbidity in patients having liver resection after chemotherapy but it should be emphasised that the amount of pre-operative chemotherapy was relatively limited.
Ÿ Current evidence indicates that either an oxaliplatinbased or an irinotecan-based chemotherapy backbone can be utilised as first line care in either the neo-adjuvant or adjuvant setting.
Ÿ The New-EPOC trial showed no additional survival benefit from adding cetuximab to these chemotherapy regimens although it is now known that cetuximab is only effective in patients who do not carry mutations of K-ras or B-raf [14]. Ÿ Ablation involves destruction of liver tumours either by using thermal energy (radiofrequency ablation, microwave ablation) or by using electrical energy to cause cellular destruction (irreversible electroporation -IRE).

Follow-up
Ÿ Cryotherapy is no longer utilised for the treatment of colorectal hepatic metastases.
Ÿ There is some evidence that ablation can be effective and it may be used in conjunction with resection.
Ÿ Advantages of ablation are that it can be used percutaneously. Ablation is currently not a preferred treatment for colorectal hepatic metastases because of the relatively high risk of recurrence.

Treatments of no proven benefit for colorectal hepatic metastases 8.1 Selective Internal Radiation Therapy (SIRT)
Ÿ SIRT involves the angiographic delivery of beads or microparticles incorporating the radio-isotope Yttrium-90 to liver tumours.
Ÿ Although initially thought to be promising, the pooled analysis of three world-wide randomised trials has shown no evidence of survival benefit [27].
Ÿ A valid criticism of these studies was the high proportion of patients with extra-hepatic disease who were subjected to SIRT. Ÿ However, even in the subgroup of patients with liverlimited hepatic metastases treated by SIRT there was neither evidence of survival benefit nor a higher conversion to resection.
Ÿ SIRT is now regarded as a treatment of no benefit for patients with colorectal hepatic metastases.

Planned review of guidelines
Ÿ The SLHPBA/IHPBA will review these guidelines in 5 years.