Pooled analysis of the surgical treatment for colorectal cancer liver metastases

https://doi.org/10.1016/j.critrevonc.2014.12.004Get rights and content

Highlights

  • In colorectal cancer patients with liver metastases resection should always be attempted.

  • In case of synchronous metastases overall survival is not affected by timing of surgery (concomitant vs. staged).

  • In case of synchronous metastases in a fit patient, concomitant resection may result in lower postoperative morbidity.

  • Systemic peri-operative or adjuvant chemotherapy may improve progression free survival.

  • Overall survival is not affected by the use of adjuvant chemotherapy.

Abstract

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone.

Introduction

Colorectal cancer (CRC) is one of the most common cancers in the Western world. In the United States it is the second leading cause of cancer-related deaths and the third most common cancer in men and in women with an incidence of 46.4 per 100,000 in 2010 [1]. According to the Belgian Cancer Registry, CRC is the second and third most common cancer in women and men. Stage at diagnosis determines survival: the 5-years (yrs) relative survival rates range from 91.8% to 91.3% for stage I but only from 11.9% to 12.9% for stage IV in men and women respectively [2].

However, case series have shown that patients with liver metastases can achieve long-term survival when liver metastases are resected [3]. Based on these observations, recent guidelines recommend attempting curative resection of CRC liver metastases, sometimes in combination with other local treatment modalities such as radiofrequency ablation (RFA) despite lack of evidence from randomised controlled trials (RCT) [4], [5], [6]. A recent review reports that 15–30% of patients with liver metastases may be appropriate for curative resection. Five years survival then varies between 30% and 60% [7].

The criteria for resectability are discussed in the 2006 guideline of the Comprehensive Cancer Centre from the Netherlands (Integraal Kankercentrum Nederland) [8]. Important elements are the estimated residual liver volume, the number and location of lesions and the resection margins. Co-existing medical conditions need to be taken into account, but age per se is not a limiting factor. Portal vein embolization may optimise residual volume in the contra-lateral side. In a recent review [9] a 37.9% gain in liver volume occurred 2–4 weeks after embolisation in patients with preserved liver function and 6–8 weeks after embolisation in patients with cirrhosis or diabetes.

When patients are considered for resection of metastases, questions arise about the best timing for liver surgery (sequential or simultaneous with surgery of the primary tumour) and the timing of chemotherapy (CT). Current guidelines recommend multidisciplinary team (MDT) discussion [6] and staged surgery [8], [10]. The importance of a centre's expertise is stressed [8]. Expert opinion was the sole basis to recommend peri-operative chemotherapy with a combination of oxaliplatin and 5-fluorouracil (FU)/leucovorin for a total period of 6 months [6] and similar modalities of neoadjuvant chemotherapy, whether or not combined with biological therapy both for synchronous and metachronous liver metastases [10]. We therefore undertook a systematic review (SR) to address the research question as to what is the best therapeutic sequence for CRC patients with resectable synchronous or metachronous liver metastases.

Section snippets

Scoping

The research question was described in terms of Population-Intervention-Comparator-Outcome (PICO) as illustrated in Table 1. Note that the PICO addresses all treatment options for both synchronous and metachronous liver metastases. In the literature on the use of CT before (neoadjuvant), before and after (perioperative) or after (adjuvant) surgery, no distinction is usually made between synchronous metastases and metachronous metastases. The question about use and timing of CT for resectable

Timing of surgical resection of primary tumour and synchronous liver metastasis

Chen et al. [27] performed a meta-analysis on 14 studies that retrospectively compared concomitant resection to staged resection in patients with resectable synchronous hepatic metastases. The analysis was performed on a total of 2204 patients of whom 1384 (ages 56–64.9 yrs) had received simultaneous resection and 817 (ages 58–61 yrs) staged resection. The median follow up was 2.5 yrs, maximal follow-up 5 yrs. The outcomes of interest are PFS, OS and quality of life (QoL). There are no data on

Conclusions based on grade profiles

The level of evidence for treatment of patients with resectable CRC liver metastases, assessed according to GRADE is summarised in Table 10, Table 11. The level of evidence for OS and postoperative morbidity in case of simultaneous vs. staged resection of the primary tumour and hepatic metastases was downgraded to moderate (Table 10). It is therefore plausible that there is no difference in OS after simultaneous resection compared to staged resection of the primary tumour and resectable

Discussion

This SR of the evidence related to the optimal treatment of resectable CRC liver metastases is in favour of concomitant resection of synchronous metastases with regards to postoperative morbidity and in favour of systemic peri-operative or adjuvant CT with regards to PFS. No clinically relevant effects could be demonstrated on OS.

The assessment and treatment of liver metastases requires expert skill, experience, high level technical support and MDT discussion. In the clinical setting the choice

Funding

The Belgian Health Care Knowledge Centre is an independent institute, funded by the Belgian government. There was no other type of financial support for the work presented.

Conflict of interest statement

A grant, fees or funds for a member of staff or another form of compensation for the execution of research: Patrick Flamen (Sirtex, Bayer Roche), Marc Peeters (Amgen, Roche), Dirk Ysebaert. Consultancy or employment for a company, an association or an organisation that may gain or lose financially due to the results of this report: Patrick Flamen, Marc Peeters (Amgen, Merck Serono, Roche, Sanofi). Payments to speak, training remuneration, subsidised travel or payment for participation at a

Reviewers

Riccardo A. Audisio, MD, FRCS, Professor, University of Liverpool, St Helens Hospital, Marshalls Cross Road, St Helens, Merseyside WA9 3DA, United Kingdom.

Antonio Russo, MD, University of Palermo, Section of Medical Oncology, Department of Oncology, Vai del Vespro 127, Palermo, I-90127, Italy.

Alberto Sobrero, MD, Head, Medical Oncology Unit, University Hospital San Martino, Medical Oncology Department, Largo Benzi 10, Genova, I-16132, Italy.

Ignacio Gil-Bazo, M.D., Ph.D., Clínica Universidad de

Acknowledgments

This work was part of a larger project by the Belgian Health Care Knowledge Centre (KCE) entitled: ‘Colon Cancer: Diagnosis, Treatment and Follow-up’ and published as Good Clinical Practice Guideline in January 2014 [30]. All authors participated to the elaboration of the full guideline, Leen Verleye was principal investigator, Marc Peeters was chair of the guideline development group.

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