Question

What is the best therapeutic sequence for patients with resectable metachronous or synchronous liver metastases?

Recommendation

There is no clear preference for perioperative or post-operative chemotherapy.

 

Perioperative adjuvant chemotherapy isn’t considered the standard treatment of primary resectable metastases

 

Especially in patients who have been previously treated with adjuvant therapy for stage II / III colon cancer a conservative policy seems justified.

 

Introduction

This question aims at providing the answer as to which is the best therapeutic sequence in regards to chemotherapy and excision of resectable liver metastases. The distinction was proposed for synchronous and metachronous metastases. In the literature addressing the use of chemotherapy before (neoadjuvant), before and after (peri) or after (adjuvant) surgery, the distinction is rarely made between synchronous metastases, that may be resected in a second stage, and metachronous metastases. The question of using and timing chemotherapy for resectable liver metastases has therefore been considered as one entity. The use of chemotherapy to enhance resectablility in case of initially unresectable liver metastases was excluded from this chapter.

The sequence of surgical resection of the primary tumor and synchronous liver metastases has been addressed separately.

 

Conclusions

Metachronous liver metastases

It is plausible that systemic peri-operative or adjuvant chemotherapy improves PFS compared to surgery alone in patients with resectable CRC liver metastases.
Wieser 2010, Ciliberto 2012, Quan 2012, moderate level of evidence

 

It is plausible that systemic peri-operative or adjuvant chemotherapy has no significant effect on OS compared to surgery alone in patients with resectable CRC liver metastases.
Wieser 2010, Ciliberto 2012, Quan 2012, Norlinger 2012 moderate level of evidence

 

There are indications that adjuvant HAI CT does not provide a survival advantage compared to surgery alone in patients with resectable CRC liver metastases.
Wieser 2010, Nelson 2009, very low level of evidence

 

An effect of adjuvant HAI CT on PFS could neither be demonstrated nor refuted compared to surgery alone in patients with resectable CRC liver metastases.
Wieser 2010, Nelson 2009, very low level of evidence

 

There is no evidence to inform on the effect of neoadjuvant CT compared to surgery alone on PFS or OS in patients with resectable CRC liver metastases.
Chua 2010, Lehman 2012, Quan 2012

 

Synchronous liver metastases
It is plausible that there is no difference in OS after simultaneous resection compared to staged resection of the primary tumour and resectable synchronous liver metastases.
Chen 2011, moderate level of evidence

It is plausible that simultaneous resection of the primary tumour and synchronous liver metastases results in lower postoperative morbidity compared to staged resection.
Chen 2011, Goyer 2012, moderate level of evidence

Literature summary

Metachronous liver metastases
Since RCT’s comparing neoadjuvant to adjuvant chemotherapy combined with resection of CRC liver metastases are lacking, the PICO can only be addressed indirectly. Outcomes are overall survival (OS) and depending on the study progression free survival (PFS), recurrence free survival (RFS) or disease free survival (DFS). QoL could only be appreciated from surrogate outcomes such as morbidity, adverse events, hospital stay etc. RCT’s have compared adjuvant chemotherapy to none (n=7) and peri-operative chemotherapy to none (n=1). Adjuvant chemotherapy can be systemic or loco regional i.e. administered by hepatic artery infusion (HAI). Wieser et al. performed a meta-analysis on 8 RCT’s (Wieser M, 2010), including different regimens (systemic and loco regional) of peri-operative and adjuvant chemotherapy. Ciliberto et al published a meta-analysis focusing on the 3 RCT’s involving systemic adjuvant chemotherapy(Ciliberto D, 2012) whereas Nelson’s meta-analysis reports on adjuvant hepatic artery infusion. These same RCT’s were included in the systematic review by Quan (Quan D, 2012).

The effect of neoadjuvant chemotherapy has been solely reported in observational studies. The single available RCT on peri-operative chemotherapy(Nordlinger B, 2008) was included in the systematic reviews of neoadjuvant as well as adjuvant chemotherapy. A recent analysis of this RCT is available in abstract form (Nordlinger B, 2012).


Chua performed a systematic review including this one RCT, 3 phase 2 and 19 observational studies (Chua TC, 2010). A later review by Lehman et al. details the different systemic regimens for 14 studies, of which 11 were included by Chua. This report adds no new information related to the PICO (Lehmann K, 2012). The last systematic review discusses the 3 RCT‘s on systemic peri-operative and adjuvant chemotherapy and 28 retrospective and prospective studies on neoadjuvant and adjuvant chemotherapy (Quan D, 2012). The authors state that heterogeneity and poor quality of the evidence were incompatible with a meta-analysis comparing different sequences of chemotherapy. The Cancer Care Ontario guidelines are based on this last review(Gallinger S, 2012).

In conclusion, direct evidence needed to answer the PICO directly is currently lacking. The evidence on related aspects of the question has been reviewed hereunder.

Adjuvant chemotherapy

Systemic adjuvant chemotherapy

Wieser’s meta-analysis includes the largest number of patients: a total of 1058 patients from which 525 were randomized to surgery with peri-operative or adjuvant chemotherapy and 533 to surgery alone (Wieser M, 2010). Their median mean age was under 65 yrs and the median follow-up 81 months. The intervention included both HAI and systemic chemotherapy. OS did not differ in the intervention group (HR, 0.94; 95%CI, 0.8-1.10; p = 0.43) but RFS was clearly improved by the intervention (HR, 0.77; 95% CI, 0.67-0.88; p = 0.0001). A QoL measure in this study are the adverse events which were rated as mild and acceptable toxicities: grade 3-4 leucopoenia in 4.9%, grade 3-4 neutropenia in 13 %, grade 3 nausea and vomiting in 13.9%, diarrhoea in 7.3% and hepatic toxicity in 6.4%. Noteworthy are 12% treatment related deaths in the HAI group.

For the subgroup treated with systemic chemotherapy the benefit in OS approached statistical significance (HR, 0.74; 95% CI, 0.53-1.04; p = 0.08; I2 = 0%) and RFS was clearly improved (HR, 0.75; 95% CI, 0.62-0.91; p = 0.003).

Ciliberto published a separate meta-analysis of the 3 available RCT’s (one in abstract form) comparing peri and adjuvant systemic CT combined with surgery to surgery alone. They demonstrate improved DFS (HR 0.71; CI 0.582-0.878; P=0.001) and PFS (HR 0.75; CI 0.620-0.910; P=0.003) in 666 patients. OS based on 2 studies was unaffected by combined systemic CT (HR 0.743; CI 0.527-1.045; P=0.088) (Ciliberto D, 2012). These numbers are identical to the subgroup with systemic CT reported by Wieser (Wieser M, 2010). We updated the meta-analysis for overall survival with the recently presented results of the EORTC study (Nordlinger B, 2012). A total of 642 patients were included in this analysis. OS was not improved by the intervention (HR 0.83, 95%CI 0.67-1.02; p= 0.07).

Hepatic artery infusion adjuvant chemotherapy

In the report by Wieser, there was no treatment benefit (HR, 1.0; 95% CI, 0.84-1.21; p = 0.96; I2 = 30%) in terms of OS for the subgroup receiving HAI. RFS appears improved by the intervention (HR, 0.78; 95% CI, 0.65-0.95; P = 0.01) using a fixed model but not with a random effects model, because of high heterogeneity (I2=54%), the results loose significance (HR, 0.72; 95%CI, 0.51-1.02; p=0.07)(6).

The outcomes for hepatic artery adjuvant CT (HAI) were also reviewed in a meta-analysis by Nelson (Nelson RL, 2009). Out of a total group of 592 patients, 289 were treated with postoperative intra arterial chemotherapy and followed up for a mean of 81 months. Results for OS favoured the control group (8.9% survival advantage) but were not significant (HR 1.09, 95% CI: 0.89-1.34). The author states that other outcomes could not be calculated due to lack of a common denominator (PFS, DFS, etc). Five deaths were attributed to the HAI procedure; intra-hepatic recurrence was more frequent in the control group (43 vs. 97).


Neoadjuvant chemotherapy

Outcomes for neoadjuvant chemotherapy were reported without comparator.

Chua’s review reports DFS (reported in 12 studies) ranging from 11 to 40 months, with a median of 21 months, and OS (reported in 13 studies) ranging from 20 to 67 months with a median of 46 months (Chua TC, 2010).

Lehman report on 11 studies that were included in Chua’s review and 3 additional ones. Retrospective comparisons suggest improved outcome for neoadjuvant CT compared to surgery alone and for adjuvant compared to neoadjuvant therapy but these conclusions are not evidence based (Lehmann K, 2012).

A systematic review of all types of publications on systemic CT (Quan D, 2012) describes the outcomes of interest for the 3 RCT’s that were analyzed separately earlier on (Ciliberto D, 2012). These outcomes are lacking for the 28 observational studies, 14 of them on neoadjuvant CT, since a meta-analysis proved impossible due to heterogeneity. Mention is made of a single study reporting a significant increase in post resection complication rates with neoadjuvant CT (38% vs. 13.5 % p=0.03). Since evidence is lacking for the outcomes on neoadjuvant chemotherapy, GRADE profiles could not be provided.

Synchronous liver metastases
Chen (Chen J, 2012) performed a meta-analysis on 14 studies that retrospectively compared simultaneous 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) a staged resection. The median follow up was 2.5 yrs, maximal follow-up 5 yrs. The outcomes of interest are PFS, OS and QoL. There are no data on PFS. Overall survival did not significantly differ at 1, 3 or 5 yrs (1yr: OR, 0.77; 95% CI, 0.51–1.16, P=.21; 3 yrs: OR, 1.12; 95% CI, 0.85–1.47, P=.43, 5 yrs: OR, 1.14; 95% CI, 0.86–1.50, P=.37).

The following variable can be considered as indirect QoL indicators. Operative time (weighted mean difference [WMD], −34.19; 95% CI, −81.32–12.95, P=.16) and intra-operative blood loss (WMD, −161.33; 95% CI, −351.45–28.79, P=.10) were similar in both groups. Hospital stay (WMD, −4.77; 95% CI, −7.26–2.28, P<.01) and postoperative morbidity rate (odds ratio [OR], 0.71; 95% CI, 0.57–0.88, P=.002) were significantly lower in patients undergoing simultaneous resection of the primary tumour and the synchronous liver metastases. The authors caution the reader because of heterogeneity of the albeit high quality studies.

A 2012 single-centre retrospective study, reports higher morbidity rates in patients who were referred for a (staged) liver resection (n=32) as compared to patients diagnosed and treated in their own center. (n=47)(24). Simultaneous resection was performed in 53% of the non-referred patients. The median follow-up was 43 months Treatment with chemotherapy or not was variable, as was the number of surgical interventions. Overall PFS and OS were not significantly different between the two groups but postoperative morbidity was significantly higher in the referred group (75 vs. 47%, P = 0.023). Simultaneous resection was one of the many variables that may play a role in this improved outcome. This study was not included in the GRADEprofile.

References

  1. <span style="font-family: 'Arial','sans-serif'; font-size: 10pt; mso-fareast-font-family: Arial; mso-fareast-theme-font: minor-latin; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA; mso-no-proof: yes;">Gallinger S, Biagi JJ, Fletcher GG, Nhan C, Ruo L, McLeod RS, et al. The role of liver resection in colorectal cancer metastases. Toronto (ON): 2012, June15. Program in Evidence-based Care Evidence-based Series
  2. <span style="font-family: 'Arial','sans-serif'; font-size: 10pt; mso-fareast-font-family: Arial; mso-fareast-theme-font: minor-latin; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA; mso-no-proof: yes;">Wieser M, Sauerland S, Arnold D, Schmiegel W, Reinacher-Schick A. Peri-operative chemotherapy for the treatment of resectable liver metastases from colorectal cancer: A systematic review and meta-analysis of randomized trials. BMC Cancer. 2010;10.
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  4. <span style="font-family: 'Arial','sans-serif'; font-size: 10pt; mso-fareast-font-family: Arial; mso-fareast-theme-font: minor-latin; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA; mso-no-proof: yes;">Nelson RL, Freels S. Hepatic artery adjuvant chemotherapy for patients having resection or ablation of colorectal cancer metastatic to the liver. Cochrane Database of Systematic Reviews. 2009(4).
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  7. <span style="font-family: 'Arial','sans-serif'; font-size: 10pt; mso-fareast-font-family: Arial; mso-fareast-theme-font: minor-latin; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA; mso-no-proof: yes;">Quan D, Gallinger S, Nhan C, Auer RA, Biagi JJ, Fletcher GG, et al. The role of liver resection for colorectal cancer metastases in an era of multimodality treatment: A systematic review. Surgery (United States).2012;151(6):860-70.
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Authorization date and validity

Last review : 16-04-2014

Last authorization : 16-04-2014

The validity of this guideline and its associated modules is five years. For various reasons, it may be necessary to edit modules sooner than intended. The National Working Group on Gastrointestinal Cancers therefore annually assesses the content of the guideline and its associated modules. By 2016 it is decided whether a new multidisciplinary working group should be installed to revise the entire guideline.

Initiative and authorization

Initiative : Nederlandse Vereniging voor Radiotherapie en Oncologie

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Maag-Darm-Leverartsen
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Klinische Geriatrie
  • Nederlandse Vereniging voor Nucleaire geneeskunde
  • Nederlandse Vereniging voor Pathologie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie
  • Vereniging Klinische Genetica Nederland

General details

All members were mandated by a scientific, professional or patient association. In the composition of the working group we tried to take national distribution, input from participants from both academic and general hospitals and representatives of various disciplines into account. Patients are also represented by delegation into the working group, as well as a focus group meeting.

Scope and target group

Goal

This guideline and its associated modules are - as much as possible - based on scientific research and / or consensus. It is a document with recommendations to support the daily practice of health care professionals involved in patients with (possible) colon cancer, rectal cancer or colorectal liver or lung metastases. It provides recommendations for diagnosis, treatment, follow-up and organization of care. The guideline and its associated modules are thus seeking to improve the quality of care, to increase transparency of choice for treatment and reduce diversity.

 

Target population

Each year colorectal cancer is identified in approximately 13,000 new patients. Rectal carcinoma occurs in about 1 in 3 patients of this. In the Netherlands, the colorectal cancer in both men and women rank third place in incidence of oncological diseases. The expected number of patients diagnosed with colorectal cancer are increased in 2020 to about 17,000, reflecting a slight increase in incidence (especially in men), population growth and aging.

Colorectal cancer is slightly more common in men than in women and ninety percent of patients 55 years or older. More information about the Dutch population can be found at the Netherlands Cancer Registry: www.cijfersoverkanker.nl

This guideline is applicable to all adult patients with (suspected) a primary colorectal carcinoma and patients with metastatic disease. Particular attention is given to the elderly. A separate guideline is available for adult patients with an increased risk of hereditary colon cancer.

Target Audience

This guideline and its associated modules are intended for all professionals involved in the diagnosis, treatment and rehabilitation of patients with (metastatic) colorectal cancer, such as surgeons, general practitioners, consultants, internists, gastroenterologists, (specialist) nurses, clinical geneticists, paramedics, pathologists, radiologists and radiotherapists. The complete guideline is used to develop a patient education text from the Dutch patients Consumer Federation (NPCF).

 

Members of the guideline panel

Name

Function

Hospital

Mandated

Mw. prof. dr. C.A.M. Marijnen chair

Radiotherapist

LUMC Leiden

NVRO

Mw. prof. dr. R.G.H. Beets-Tan

Radiologist

MUMC Maastricht

NVVR

Mw. S. de Bruijn

Specialist nurse

Renier de Graaf hospital Delft

V&VN

Mw. dr. A. Cats

Gastroenterologist

NKI-AVL Amsterdam

NVMDL

Prof. dr. E.F.I. Comans

Nuclear doctor

VUMC Amsterdam

NVNG

Dr. A.R. van Erkel

Intervention radiologist

LUMC Leiden

NVVR

Mw. dr. M.A.M. Frasa

Clinical chemist

Groene Hart hospitalGouda

NVKC

Mw. C. Gielen

Specialist nurse

MUMC Maastricht

V&VN

Dr. E.J.R. de Graaf

Surgeon

IJsselland hospital Capelle a/d IJssel

NVVH

Mw. dr. M. Hamaker

Geriatrician

Diakonessenhuis Utrecht

NVKG

Mw. dr. J.E. van Hooft

Gastroenterologist

AMC Amsterdam

NVMDL

Mw. H.J.A.M.. Kunneman

Researcher

LUMC Leiden

n.v.t.

Mw. dr. M.E. van Leerdam

Gastroenterologist

NKI-AVL Amsterdam

NVMDL

Dr. H. Martijn

Radiotherapist

Catharina-hospital Eindhoven

NVRO

Mw. dr. A.M. Mendez

Romero

Radiotherapist

EMC Cancer Insititute Rotterdam

NVRO

Mw. prof. dr. I.D. Nagtegaal

Pathologist

UMCN St Radboud Nijmegen

NVVP

Dr. L.A. Noorduyn

Pathologist

Lab. Voor Pathologie Dordrecht e.o.

NVVP

Mw. A. Ormeling

Patient

Stomavereniging

NFK

Drs. T.A.M. van Os

Klinisch Geneticus

AMC Amsterdam

VKGN

Dr. F.T.M. Peters

Gastroenterologist

UMCG Groningen

NVMDL

Mw. J. Pon

Patient

NFK/SPKS

NFK

Mw. dr. J.E.A. Portielje

Medical oncologist

Haga hospital Den Haag

Gerionne

Prof. dr. C.J.A. Punt

Medical oncologist

AMC Amsterdam

NIV

Mw. dr. H. Rütten

Radiotherapist

UMCN Radboud Nijmegen

NVRO

Prof. dr. H.J.T. Rutten

Surgeon

Catharina-hospitalEindhoven

NVVH

Prof. dr. J. Stoker

Radiologist

AMC Amsterdam

NVVR

Dr. P.J. Tanis

Surgeon

AMC Amsterdam

NVVH

Dr. J.H. von der Thüsen

Pathologist

MC Haaglanden Den Haag

NVVP

Prof. dr. H.M.W. Verheul

Medical oncologist

VUMC Amsterdam

NIV

Prof. dr. C. Verhoef

Surgeon

EMC Cancer Insititute Rotterdam

NVVH

Dr. Tj. Wiersma

General practitioner

NHG

NHG

 

 

Name

Function

Location

Mw. drs. A.Y. Steutel

process manager

Utrecht

Drs. T. van Vegchel

process manager

Amsterdam

Mw. S. Janssen-van Dijk

secretary

Rotterdam

M.P.  van den Berg

Researcher

Bilthoven

P.F. van Gils

Researcher

Bilthoven

Mw. J. Robays

Methodologist

Brussels

Mw. drs. Y Smit

Methodologist

Germany

Mw. A. Suijkerbuijk

Researcher

Bilthoven

Mw. dr. L. Veerbeek

Methodologist

Groningen

Mw. dr. L. Verheye

Methodologist

Brussels

Mw. dr. G.A. de Wit

Researcher

Bilthoven

 

Patient involvement

Two patient experts have been part of the guideline development group. One on behalf of the Dutch Ostomy Association and on behalf of SPKS/NFK. Based on a focus group meeting experiences of patients regarding care were collected. The guideline also has been used to develop a patient education text for the Dutch patients Consumer Federation (NPCF).

Method of development

Evidence based

Implementation

Promoting the use of recommendations begins with a broad (digital) distribution of the guideline, using direct mailing and an article published in the Dutch Journal of Oncology. In other journals or training sessions, for example, the guideline is brought to the attention. An implementation plan for this guideline contains the key recommendations and an overview of barriers and facilitators for implementation.

Methods and proces

The working group met in July 2012 for the first time. Based on an initial list of problems by working group members a survey among professionals involved in patients with colorectal carcinoma was held. Through this survey, sixty professionals supplied and prioritized possible subjects for revision. Also, a focus group meeting was held, collection patients' experiences. The eleven most relevant questions were answered, and translated into English. Also, alle recommendations were translated into English.

 

Each clinical question was andwered by a subgroup within the development group. External methodologists provided the literature search, review, critical assessment, evidence tables and a draft literature review. Workgroup members suggested other considerations and recommendations.

Responsibility

The Comprehensive Cancer Organisation the Netherlands (IKNL) promotes that people with cancer and their families have access to a consistent and qualitatively adequate care as close to home as possible. IKNL was established to improve treatment, care and clinical research in oncology. It also has a role in setting up and supporting networks for palliative care. IKNL supports multidisciplinary guideline development for oncology and palliative care and facilitates the maintenance, management, implementation and evaluation of these guidelines.

AGREE was used to check the methodological quality of the guideline.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.