Improving definition of the term “synchronous Iiver metastases” from coIorectaI cancer

Anthony KC Chan and Ajith K Siriwardena

Manchester， UK

Improving definition of the term “synchronous Iiver metastases” from coIorectaI cancer

Anthony KC Chan and Ajith K Siriwardena

Manchester， UK

The liver is the most frequent site of metastasis in colorectal cancer with up to a quarter of patients having liver metastases at the time of initial diagnosis and a further third subsequently developing liver lesions.［1］Patients who present with metastatic liver disease after treatment of the primary （termed metachronous disease） receive care focused on this new metastatic disease.［2］In contrast， the management of patients who present with colorectal cancer and concurrent liver metastases （termed synchronous metastasis） is more complex.［2］These patients may have less favorable cancer biology and treatment needs not only to address both the primary and the metastatic sites but also to reflect the likely systemic nature of the disease.［3］

Historically， accurate definition of synchronous disease was not a high priority； the mainstay of care was directed at surgical treatment of the primary colorectal typically followed by systemic chemotherapy with liver resection being undertaken in only a few patients and in highly specialized centers.［4］The last two decades have witnessed a profound change in the management of liver metastases from colorectal cancer.［5］The advent of synchronous resection of liver and bowel tumors， the liver-first approach and the availability of effective chemotherapy including combination （doublet or triplet treatments） and biologic agents have changed the paradigms of care.［2］This increased spectrum of available treatment options brings renewed emphasis to the need for accurate baseline staging and clinically and biologically relevant disease descriptors.

In relation to the use of the term “synchronous metastasis” there is evidence of variation in the application of the nomenclature. In the modern era， imprecision，variation or overlapping definitions of the term “synchronous metastasis” can compromise care. Evidence of this variation is seen in the Table. These papers， drawn from a recent meta-analysis of synchronous colorectal liver metastases show that worldwide， there are ongoing differences in the use of the term synchronous.［16］

Components of variation in the definition of synchronous include firstly whether the term is restricted to those diagnosed prior to surgery［7］and whether or not intra-operative diagnoses made at the time of index colorectal surgery are included （a further element of uncertainty introduced here relates to whether there is a need for histological confirmation of liver metastases found at operation--a standard not applied to those detected on imaging either prior to or after surgery）.［17］A second and important component of variation is introduced by the incorporation of metastases found after treatment targeting the primary lesion. For example， in the Table it can be seen that several authors include metastases diagnosed up to 12 months after treatment of the primary tumor in the timeline of synchronous metastases.［11，12］This broad time frame is no longer practical as patients presenting at a year after treatment of their primary with liver metastases will have treatment directed solely at this liver metastatic burden and are therefore effectively receiving care targeted at metachronous disease.

In 2015， a multidisciplinary international conference of the expert group on oncosurgery management of liver metastases （EGOSLIM） produced a consensus statement on the terminology and management of patients with colorectal cancer and synchronous liver metastases.［18］The evidence is based on reported outcome data from the multinational LiverMetSurvey liver resection registry and makes important recommendations for an updated，modern terminology. The recommendations are compatible with current knowledge of the cancer genetics of bowel cancer which indicate that there are severaldifferent genetic subtypes of colorectal cancer carrying differential risks of metastasis.［19］Further， the current terminology is compatible with a view that most （if not all） liver metastases are present at the outset of the disease and that variations in regional cell cycle control in metastatic cell clusters associated with these different cancer genotypes may contribute to the phenomenon of early and late metastasis. Although this oncological basis of early and late liver metastases is not fully resolved， it is important that updated terminology is compatible with current understanding in this area.

Table. Examples of terminology used to define colorectal cancer with synchronous liver metastases from recent literatures

Taking these factors into consideration， the EGOSLIM group proposed that the term “synchronously detected liver metastases” should be adopted. This is defined as liver metastases diagnosed at or before diagnosis of the primary tumor. Practical requirements for application of this definition include adequate crosssectional imaging typically with contrast-enhanced computed tomography of the chest， abdomen and pelvis at the time of diagnosis of the primary tumor， with options for additional sensitivity in detection of liver metastases being gained by the use of contrast-enhanced magnetic resonance scanning of the liver.18Fluoro-deoxy-glucose positron emission tomography may also be utilized for staging. The removal of a time frame associated the definition does not allow for greater laxity in staging but implies that full-body cross-sectional imaging must be undertaken as close to the time of diagnosis as is practically feasible. Although the EGOSLIM collaborators do not elaborate on settings where these standards cannot be applied， it must be accepted that comprehensive staging may not initially be possible in patients who present with emergency presentations， such as perforated bowel tumors and in a global perspective， this standard may not be applicable in healthcare systems where techniques such as computed tomography are not readily available.

Accepting these limitations， whether applied as “synchronously detected” or as the simpler term “synchronous” the restriction of the time frame for diagnosis to the time of presentation of the primary （or before） is practical and readily adopted internationally.

The question of whether biopsy-proof of metastases at operation is required is not addressed by the EGOSLIM collaborators. As contemporary clinical diagnosis and management of colorectal liver metastases is based on cross-sectional imaging without biopsy， it is suggested that intra-operative biopsy of liver metastases at operation is not mandatory. There is evidence that percutaneous liver biopsy is associated with compromise of outcome and therefore should not generally be undertaken.

The international multidisciplinary consensus conference characterizes patients with metachronous disease as either early metachronous metastasis： those diagnosed within 12 months of the primary diagnosis or late metachronous metastasis： those detected more than 12 months after diagnosis of the primary tumor. Their survival data indicate significant differential behavior of these two groups and the outcome of both groups is different from that of patients with synchronously detected liver metastases.

In conclusion， this article highlights historical inaccuracies in the use of the terms used to describe disease in patients with liver metastases presenting at the same time as their primary colon cancer. The persistence of these inaccuracies into the modern era is demonstrated（Table）. Recognition of this variance and the need for modern terminology led to the international consensus conference categorization of liver metastases into synchronously detected liver metastases， early metachronous liver metastases--detected within 12 months of the primary or late metachronous metastases--detected more than 12 months after diagnosis of the primary. This categorization was based on evidence of differential survival drawn from the large LiverMetSurvey registry data and allows for practical direction of therapy. In this article， we provide guidance for adoption of these terms，emphasize the need for timely contrast-enhanced crosssectional imaging， the removal of an arbitrary temporal definition of the term synchronous and the need （in most circumstances） to avoid lesion biopsy.

Adoption of this terminology into future editions of the American Joint Committee on Cancer cancer staging manuals， the National Comprehensive Cancer Network guidelines and national reference documents such as those advocated by the United Kingdom National Institute for Health and Care Excellence will lead to better standardization of care and allow more meaningful comparisons of the treatment given to patients with metastatic colorectal cancer.

Contributors： SAK proposed the study. CAKC searched the relevant literature. CAKC and SAK co-wrote the manuscript. SAK is the guarantor.

Funding： None.

Ethical approval： Not needed.

Competing interest： No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Accepted after revision July 4， 2016

February 4， 2016

Author Affiliations： Hepatobiliary Surgery Unit， Manchester Royal Infirmary，Oxford Road， Manchester M13 9WL， UK （Chan AKC and Siriwardena AK）Corresponding Author： Professor Ajith K Siriwardena， MD， FRCS， Hepatobiliary Surgery Unit， Manchester Royal Infirmary， Manchester M13 9WL， UK （Email： ajith.siriwardena@cmft.nhs.uk）

? 2016， Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872（16）60125-X

Published online August 9， 2016.