Critical Reviews in Oncology/Hematology 94 (2015) 122–135
Pooled analysis of the surgical treatment for colorectal cancer liver metastases G. Veereman a , J. Robays a , L. Verleye a , R. Leroy a , C. Rolfo b,∗ , E. Van Cutsem c , D. Bielen d , W. Ceelen e , E. Danse f , M. De Man g , P. Demetter h , P. Flamen i , A. Hendlisz j , I. Sinapi k , D. Vanbeckevoort d , D. Ysebaert l , M. Peeters b a
Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium Department of Digestive Oncology, University Hospital Antwerp (UZA), Edegem, Belgium c Department of Digestive Oncology, University Hospitals Leuven (UZLeuven), Leuven, Belgium d Department of Radiology, University Hospitals Leuven (UZLeuven), Leuven, Belgium e Department of Digestive Surgery, University Hospital Gent (UZ Gent), Gent, Belgium f Department of Radiology, Catholic University Leuven (UCL), Woluwe, Belgium g Department of Digestive Oncology, OLV Ziekenhuis, Aalst, Belgium h Department of Pathology, Free University Brussels (ULB), Brussels, Belgium i Department of Nuclear Medicine, Jules Bordet Institute, Brussels, Belgium j Department of Digestive Oncology, Jules Bordet Institute, Brussels, Belgium k Department of Oncology, Grand Hôpital de Charleroi, Charleroi, Belgium l Department of Hepatobiliary Surgery, University Hospital Antwerp (UZA), Edegem, Belgium b
Accepted 10 December 2014
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Scoping, literature search, study selection and critical appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Scoping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Search for guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Search for systematic reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Search for primary studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Critical appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data extraction and statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Grading evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Timing of surgical resection of primary tumour and synchronous liver metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Neoadjuvant, peri-operative and adjuvant chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Neoadjuvant chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Adjuvant chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions based on grade profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123 125 125 125 125 125 125 127 127 127 127 127 127 128 128 133
Abbreviations: CCO, Cancer Care Ontario; CRC, colorectal cancer; CT, chemotherapy; DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; FU, fluorouracil; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HAI, hepatic artery infusion; HR, hazard ratio; IKNL, Integraal Kankercentrum Nederland; MDT, multidisciplinary team; NICE, National Institute for Health and Care Excellence, UK; OR, odds ratio; OS, overall survival; PFS, progression-free survival; PICO, Population-Intervention-Comparator-Outcome; QoL, quality of life; RFS, recurrence free survival; RCT, randomized controlled trial; RFA, radio-frequency ablation; SIGN, Scottish Intercollegiate Guidelines Network; SR, systematic review; WMD, weighted mean difference; yrs, years. ∗ Corresponding author at: Head of Phase I – Early Clinical Trials Unit, Oncology Department, University Hospital Antwerp UZA, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3 821 36 46; fax: +32 3 825 15 92. E-mail address: [email protected] (C. Rolfo). http://dx.doi.org/10.1016/j.critrevonc.2014.12.004 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
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5.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123
133 134 134 134 134 134
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. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colorectal cancer; Liver metastasis; Hepatic metastasis; Synchronous metastasis; Metachronous metastasis
1. 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) [4–6]. 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. Table 1 P.I.C.O. What is the best therapeutic sequence for patients with resectable CRC metastases to the liver? P (patient) I (intervention)
C (comparison)
O (outcome)
Patients with resectable colorectal liver metastases Simultaneous resection followed by systemic therapy (adjuvant chemotherapy) Simultaneous resection without systemic therapy or staged resection with or without chemotherapy PFS, OS, QoL
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Table 2 Search strategy: surgery and adjuvant treatment for liver-restricted metastatic colorectal cancer. Date Database Search strategy
Date Database Search strategy
November 2012 Medline via OVID 1. exp colorectal neoplasm/(136562) 2. (colo$ adj5 cancer$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (80489) 3. (colo$ adj5 neoplasm$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (108715) 4. (colo$ adj5 carcin$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (35295) 5. (colo$ adj5 tumo$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (25817) 6. (colo$ adj5 malign$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (4670) 7. (colo$ adj5 metast$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (15760) 8. exp neoplasm metastasis/(146094) 9. (metasta$ adj3 liver$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (19042) 10. (metasta$ adj3 hepa$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (9391) 11. *Liver Neoplasm/sc (9071) 12. 1 or 2 or 3 or 4 or 5 or 6 or 7 (171426) 13. 8 or 9 or 10 or 11 (167564) 14. 12 and 13 (22488) 15. exp antineoplastic agents/(764651) 16. exp Antineoplastic Combined Chemotherapy Protocols/(96569) 17. Chemotherap$.mp. (286438) 18. Colorectal neopl$/dt, th, su (0) 19. Systemic therap$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (6518) 20. systemic treatment.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (4377) 21. neo$adjuvant.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (16191) 22. exp Colorectal Surgery/(1767) 23. colorectal surgery.mp. (3969) 24. exp laparotomy/(14832) 25. resect$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (207462) 26. excis$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (135326) 27. metastatec$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (71) 28. 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 (1206077) 29. 14 and 28 (12143) 30. Animals/(5091368) 31. Humans/(12693665) 32. 30 not (30 and 31) (3717557) 33. 29 not 32 (11614) 34. Meta-analysis.mp,pt. or review.pt. or search:.tw. (1902527) 35. 33 and 34 (1899) 36. limit 35 to yr=“2009-Current” (469) November 2012 Embase via embase.com ‘colorectal cancer’/exp OR (colo* NEAR/3 cancer* AND [2009–2013]/py) OR (colo* NEAR/3 neoplas* AND [2009–2013]/py) OR (colo* NEAR/3 carcin* AND [2009–2013]/py) OR (colo* NEAR/3 tumo* AND [2009–2013]/py) OR (colo* NEAR/3 malign* AND [2009–2013]/py) OR (colo* NEAR/3 metast* AND [2009–2013]/py) AND ‘liver metastasis’/exp AND (‘liver metastasis’/exp AND [2009–2013]/py OR (‘cancer chemotherapy’/exp AND [2009–2013]/py) OR (‘cancer combination chemotherapy’/exp AND
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125
Table 2 (Continued) Date
Date Database Search Strategy
November 2012 [2009–2013]/py) OR (‘molecularly targeted therapy’/exp AND [2009–2013]/py) OR (‘cancer palliative therapy’/exp AND [2009–2013]/py) OR (‘surgery’/exp AND [2009–2013]/py) OR (resect* AND [2009–2013]/py) OR (metastatec* AND [[2009–2013]/py)) NOT (‘animal experiment’/exp AND [2009–2013]/py) AND [2009–2013]/py AND ‘systematic review’/de November 2012 Cochrane library #1 MeSH descriptor: [Colorectal Neoplasms] explode all trees #2 MeSH descriptor: [Neoplasm Metastasis] explode all trees #3 #1 and #2 #4 MeSH descriptor: [Drug Therapy] explode all trees #5 MeSH descriptor: [General Surgery] explode all trees #6 MeSH descriptor: [Colorectal Surgery] explode all trees #7 #4 or #5 or #6 #8 #3 and #7 from 2009 to 2012, in Cochrane Reviews (Reviews only), Other Reviews and Cochrane Groups (Word variations have been searched)
2. Methods 2.1. Scoping, literature search, study selection and critical appraisal 2.1.1. 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 liver metastases has therefore been considered as one entity despite the overall better prognosis for metachronous liver metastases [11]. The use of CT to enhance resectability in case of initially unresectable liver metastases was out of scope for this review. The sequence of surgical resection of the primary tumour and synchronous liver metastases has been addressed separately. The term ‘simultaneous’ resection is commonly used but the term ‘concomitant’ may be more appropriate. Staged resection involves the classical approach with initial resection of the primary tumour.
2.1.2. Search for guidelines An initial search and critical appraisal of guidelines on CRC performed in September 2012 yielded 5 guidelines: a 2006 guideline by IKNL on liver metastases [8], a 2008 guideline by IKNL that did not address treatment of liver metastases [12], a 2011 guideline by the Scottish Intercollegiate Guidelines Network (SIGN), a 2011 guideline by the National Institute for Health and Care Excellence, UK (NICE) [5] and a 2012 guideline by Cancer Care Ontario,
Canada (CCO) [4]. We decided to update the literature from the search date of the IKNL 2006 guideline. 2.1.3. Search for systematic reviews We first searched for SR published since February 2009 until January 14th, 2013. SRss and meta-analyses were searched in the following databases: OVID Medline and PreMedline, EMBASE, Cochrane Database of Systematic Reviews. RCT’s and clinical trials were searched in: OVID Medline, Pubmed and OVID PreMedline. Hand search was performed based on reference lists of retrieved manuscripts. There were no other sources. Languages were limited to English, German, French and Dutch. The search strategy can be found in Table 2. All citations retrieved from the systematic literature search were screened on title and abstracts by one researcher (GV). Possible citations of interest were further selected based on the full text article by two researchers (GV and LV). Study selection criteria are summarised in Table 3. Search for SRs and meta-analyses published between 2009 and 2012 retrieved 516 citations after removal of duplicates. The further selection process, summarised in Fig. 1, yielded 7 SRs and/or meta-analyses. All reviews on surgery with or without CT included synchronous and metachronous liver metastases. Adjuvant CT was the exclusive subject of 3 reviews [13–15], neoadjuvant CT the exclusive subject of 2 reviews [16,17] and all types of CT the subject of one review [18]. The treatment of synchronous CRC liver metastases was addressed in one review [19]. 2.1.4. Search for primary studies A search for RCT’s and all types of clinical trials between January1, 2010 (last search date of the SRs) and January 14, 2013 yielded 22 citations and an additional hand search for primary studies yielded 6 citations after removal of duplicates. The further selection process (Table 4) based
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Potentially relevant citations identified:
Additional potentially relevant citations (hand searching):
516
Based on title and abstract evaluation, citations excluded:
3
Studies retrieved for more detailed evaluation:
320
199
Based on full text evaluation, studies excluded: Reasons: Population Intervention Outcome Design Language other (duplicate information)
192 61 28 3 92 0 6
Relevant studies: 7 Fig. 1. Flow chart of the selection of retrieved literature for systematic reviews. Table 3 Selection criteria systematic reviews and meta-analysis.
Table 4 Selection criteria primary studies.
Review question
Review question
Selection criteria Population
Intervention
Outcome
Best therapeutic schedule for resectable synchronous and metachronous levermetastases of CRC Inclusion criteria Patients with resectable colorectal metastasis in liver Any sequence of metastatectomy ± systemic therapy PFS, OS, QoL
Design
SR, MA, evidence based GL
Language
English, French, German, Dutch No
Duplicate
Exclusion criteria
Selection criteria
Unresectable liver metastases, other organ involvement Chemotherapy for unresectable metastases
Population
Prognostic factors, biomarkers, cost, no outcome variables Narrative reviews, editorials, letters, consensus based GL Other languages
Outcome
Yes
on exclusion of non-resectable liver metastases, studies on predictive factors and types of treatments that were not CT resulted in a single retrospective review of patients receiving adjuvant CT following hepatic resection with no comparator [3] and one RCT which is a large study by the European Organisation for Research and Treatment of Cancer
Intervention
Design Language Duplicate Full text not available
Best therapeutic schedule for resectable synchronous and metachronous levermetastases of CRC Inclusion criteria Patients with resectable colorectal metastasis in liver Any sequence of metastatectomy ± systemic therapy PFS, OS, QoL
RCT, observational studies, case series English, French, German, Dutch No No
Exclusion criteria Unresectable liver metastases, other organ involvement Chemotherapy for unresectable metastases Prognostic factors, biomarkers, cost, no outcome variables Case report, editorial Other languages Yes Yes
(EORTC) on perioperative FOLFOX4 chemotherapy and surgery vs. surgery alone. Interim results from this study were published in 2008 and 2012 [20,21] and in 2013 the final analysis became available [22].
G. Veereman et al. / Critical Reviews in Oncology/Hematology 94 (2015) 122–135
2.1.5. Critical appraisal The critical appraisal of guidelines was performed with the Agree II tool (http://www.agreetrust.org) SRs were appraised using the AMSTAR checklist (http://amstar.ca) (Table 5). To judge the possibility of publication bias we used information available in the identified SRs (e.g. funnel plots reported in the review) and other criteria suggested by Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (e.g. only small studies sponsored by industry sponsors available). 2.2. Data extraction and statistical analysis Data extraction was summarised for SRs (Tables 6 and 7 ) and for primary studies (Tables 8 and 9). A meta-analysis was performed on the data from the new RCT and the retrieved meta-analysis using Review Manager (RevMan, version 5.0; The Cochrane Collaboration, updated February 2011, Oxford, England) using a generic inverse variance method. Heterogeneity was statistically assessed using χ2 based on the Q statistic and I2 statistic as described by Higgins et al. [23]. A fixed-effect model was used as no statistical evidence for heterogeneity was found for progression-free survival (PFS) and overall survival (OS), Ahazard ratio (HR) was extracted from the reported analyses using the extraction methods following Parmar et al. [24] and I2 statistic. 2.3. Grading evidence We applied the grade methodology and terminology in evaluating the following quality elements for intervention studies: study limitations, inconsistency, indirectness, imprecision and publication bias [25]. The quality of evidence was evaluated using grade methodology by two reviewers and a level of evidence was assigned to each conclusion [26]. The assessors (gv, jr, lr, lv) decided on downgrading with −1 or −2 points and summarised the reasons in the grade profiles.
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The following variables can be considered as indirect QoL indicators. Operative time (weighted mean difference [WMD] −34.19; 95%CI −81.32–12.95, p = 0.16) and intra-operative blood loss (WMD −161.33; 95%CI −351.45–28.79, p = 0.10) were similar in both groups. Hospital stay (WMD, −4.77; 95%CI −7.26–2.28, p < 0.01) and postoperative morbidity rate (odds ratio (OR) 0.71; 95%CI 0.57–0.88, p = 0.002) 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 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 centre (n = 47) [3]. Simultaneous resection was performed in 53% of the non-referred patients. The median follow-up was 43 months treatment with CT or not was variable, as was the number of surgical interventions. OS and PFS were not significantly different between the two groups. OS at 3 and 5 yrs was 73.8% and 57.3% in the nonreferred group and 74.9% and 61.2% in the referred group respectively, P = 0.360). PFS at 3 and 5 yrs was 43.0% and 25.9% in the non-referred group and 34.8% and 23.2% in the referred group respectively (P = 0.422). Postoperative morbidity however, was significantly higher in the referred group (75 vs. 47%, P = 0.023). Multivariate analysis showed no significant confounding factor. Simultaneous resection was one of the many variables that may play a role in this improved outcome. This study was not included in the GRADE profile (Table 10). After completing the literature searches and analyses, a recent review came to our attention [28]. The conclusions of this meta-analysis of 2880 patients agree with the previous studies: OS (HR 0.96; 95%CI 0.81–1.14; p = 0.64; I2 = 0) and disease free survival (DFS) (HR 1.04; 95%CI 0.76–1.43; p = 0.79; I2 = 53%) are similar for both simultaneous and delayed resections. The simultaneous group had a lower incidence of postoperative complications (modified RR = 0.77; 95%CI: 0.67–0.89; p = 0.0002; I2 = 10%).
3. Results 3.1. 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 followup 5 yrs. The outcomes of interest are PFS, OS and quality of life (QoL). There are no data on PFS. OS did not significantly differ at 1, 3 or 5 yrs (1 yr: OR 0.77; 95%CI 0.51–1.16, p = 0.21; 3 yrs: OR 1.12; 95%CI 0.85–1.47, p = 0.43, 5 yrs: OR 1.14; 95%CI 0.86–1.50, p = 0.37).
3.2. Neoadjuvant, peri-operative and adjuvant chemotherapy Since RCTs comparing neoadjuvant to adjuvant CT combined with resection of CRC liver metastases are lacking, the research question can only be addressed indirectly. Outcomes are OS and depending on the study PFS, recurrence free survival (RFS) or DFS. QoL could be appreciated from surrogate outcomes such as morbidity, adverse events, hospital stay, etc. RCTs have compared adjuvant CT to none (n = 7) and peri-operative CT to none (n = 1). Adjuvant CT can be systemic or loco regional i.e. administered by hepatic artery infusion (HAI). Wieser et al. performed a meta-analysis on 8 RCTs [13] including different regimens (systemic and loco regional) of peri-operative and adjuvant CT. Ciliberto et al. published a meta-analysis focusing on the 3 RCTs involving
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Table 5 Amstar checklist for systematic reviews. AMSTAR question Chen 2011 Chua 2010 Ciliberto 2012 Nelson 2009 Wieser 2010 Quan 2012 Lehman 2012
1
2
3
4
5
6
7
8
9
10
11
Included
Yes No Yes Yes Yes Yes Yes
Yes Yes Yes No Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes No
Yes Yes Yes No No Yes Yes
Yes Yes Yes Yes Yes Yes Yes
Yes No Yes Yes Yes No No
Yes Yes Yes Yes Yes Yes Yes
Yes na Yes Yes Yes na na
Yes No Yes Yes Yes No No
Yes No No Yes Yes No Yes
Yes Yes Yes Yes Yes Yes Yes
Table 6 Evidence table: systematic reviews synchronous CRC liver metastases. Study ID
Method
Chen, 2011 • Design: MA • Sources of funding: not stated • Search date: 1/1966–12/2009 • Searched databases: PubMed, Embase, Cochrane Library, Ovid, and Web of Science • Included study designs: comparative • Number of included studies: 14
Patient characteristics • Eligibility criteria: CRC with resectable synchronous hepatic metastasis • Patients characteristics: 2204 patients: 1384 (ages 56–64.9) having received simultaneous resection, 817 (ages 58–61) staged resection • Median FU: 2.5 yrs (total 5 yrs)
Intervention(s) • Intervention • Simultaneous resection • Comparator • Staged resection
systemic adjuvant CT [14] whereas Nelson’s meta-analysis reports on adjuvant HAI [15]. The above mentioned RCTs were included in the SR by Quan et al. [18]. The effect of neoadjuvant CT has only been reported in observational studies that were reviewed by Chua et al. [16]. The single available RCT on peri-operative CT by the EORTC reported first on PFS in 2008 and was included in the SRs of neoadjuvant as well as adjuvant CT [20]. A full intention to treat analysis for survival of this RCT was recently published and included in our de novo meta-analysis (Fig. 2) [22]. Chua et al. performed a SR including the 2008 analysis of the RCT by EORTC, three phase 2 and 19 observational studies [16]. A later review by Lehman et al. details the different systemic regimens for 14 studies, of which 11 were included by Chua et al. This report adds no new information related to the research question [17]. The last SR discusses the three RCTs on systemic peri-operative and adjuvant CT and 28 retrospective and prospective studies on neoadjuvant and adjuvant CT [18]. The authors state that heterogeneity and poor quality of the evidence were incompatible with a meta-analysis comparing different sequences of CT. The CCO guidelines are based on this last review [4]. In conclusion, neo adjuvant and adjuvant CT have not been compared directly. Studies on neo adjuvant and adjuvant CT are discussed separately.
Results primary outcome
Results secondary and other outcome(s)
Critical appraisal of review quality
3. Overall survival No statistical difference at 1 year (OR, 0.77; 95%CI, 0.51–1.16, P = .21) 3 years (OR, 1.12; 95%CI, 0.85–1.47, P = .43) 5 years (OR, 1.14; 95%CI, 0.86–1.50, P = .37)
1. Operative factors: A: operative time (weighted mean difference [WMD], −34.19; 95% confidence interval [CI], −81.32–12.95, P = .16) B: intraoperative blood loss (WMD, −161.33; 95%CI, −351.45–28.79, P = .10). C: hospital stay (WMD, −4.77; 95%CI, −7.26–2.28, P < .01) 2. Postoperative complications: lower morbidity rate (odds ratio [OR], 0.71; 95%CI, 0.57–0.88, P = .002
• Results critical appraisal • High quality studies • Heterogeneity
3.2.1. Neoadjuvant chemotherapy Outcomes for neoadjuvant CT were reported without comparison group. The review by Chua et al. 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 [16]. Lehman et al. report on 11 studies that were included in the review by Chua et al. and three others. Retrospective comparisons suggest improved outcome for neoadjuvant CT compared to surgery alone and for adjuvant compared to neoadjuvant therapy. However these conclusions are not evidence based [17]. A SR of all types of publications on systemic CT [18] describes the outcomes of interest for the three RCTs that were analysed separately [14]. In 28 observational studies, 14 of them on neoadjuvant CT, these outcomes are lacking. A meta-analysis was not possible due to heterogeneity. A single study reports 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 CT, GRADE profiles could not be provided. 3.2.2. Adjuvant chemotherapy 3.2.2.1. Systemic adjuvant chemotherapy. The metaanalysis by Wieser et al. includes the largest number of patients: a total of 1058 patients from which 525 were randomised to surgery with peri-operative or adjuvant
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Table 7 Evidence table: systematic reviews synchronous and metachronous CRC liver metastases. Study ID Chua, 2009
Nelson, 2009
Method • Design: SR • Sources of funding: not stated • Searched databases and dates: MEDLINE, PubMed • Included study designs: RCT and non-randomised trials • Number of included studies: 23
• Design: meta-analysis • Sources of funding: not stated • Search date: 1966 to December 2008 • Searched databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, the Cochrane Hepato-Biliary Group Controlled Trials Register. • Included study designs: RCT • Number of included studies: 7 • Included studies: • Kemeny 1999 • Kemeny 2002 • Lorenz 1998 • Lygidakis 1995 • Rudroff 1999 • Tono 2000 • Wagman 1990
Patient characteristics
Intervention(s)
• Eligibility criteria: -publications where systemic CT was used in patients with resectable CLM, more than 20 patients, English • Patient characteristics: 3278 patients with majority of hepatic-only metastases (5 studies including patients with extra-hepatic disease) Median number of lesions: 2 (range 2–7), median maximum size of the lesion 4 cm (range 3–5)
• Intervention: neoadjuvant CT • Comparator: none
• Eligibility criteria: resectable hepatic mCRC synchronous and metachronous • Patients characteristics: total of 592 patients with in 289 intervention group • Median FU: 81 months
• Intervention: postoperative intra arterial chemotherapy • Comparator: no postoperative chemotherapy
Results primary outcome
Results secondary and other outcome(s)
Critical appraisal of review quality
• DFS (reported in 12 studies): median 21 mo (range 11–40 mo) • OS (reported in 13 studies): median 46 mo (range 20–67 mo) • Peri-operative mortality: median rate: 2% (range 0–5%) • Peri-operative morbidity: median rate: 27% (range 11–50%)
Radiological assessment: (reported in 14 studies): median rate of objective response • (Complete/partial) 64% (range 44–100%). • Median rate of complete response: 4% (range 0–38%). • Median rate of partial response 52% (range 10–90%). • Median rate of stable disease 26% (range 0–47%).
Results critical appraisal • No comparator
(1) Overall survival HR (Fixed, 95% CI) 1.09 [0.89, 1.34] 8.9% survival advantage in favour of control group (2) Adverse events related to the chemotherapy No result
• Median rate of disease progression: 15% (range 0–37%) Hepatectomy: • Median rate of complete resection: 93% (range 39–100%); • Median rate of hepatectomy involving resection of 3 or more segments: 68% (range 23–97%) (1) Intra-hepatic tumour recurrence (2) Time to recurrence (3) Extra-hepatic tumour recurrence (4) Time to recurrence and disease specific survival: for all: no results (lack of denominator)
• Various types of chemotherapy
Includes 1 poor quality study Results lack significance
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Table 7 (Continued) Study ID
Method
• Design: SR and MA • Sources of funding: P.U.R.E. Research Programme funded by the State Ministry for Innovation, Science, Research and Technology of NorthrhineWestfalia and the FoRUM foundation of the Ruhr-University Bochum • Search date • 1980-23 January 2009 • Searched databases: Medline (PubMed), the Cochrane Library, the Latin American and Caribbean Literature on Health Sciences (LILACS) • Included study designs: RCTs • Number of included studies: 8 • Included studies: Nordlinger,2008 Lorenz, 1998 Portier, 2006 Langer, 2002 Kemeny, 2002 Rudroff, 1999 Lygidakis, 1995 Wagman, 1990 Ciliberto, 2012 • Design: SR and MA • Sources of funding: not stated • Search date: 1982 to May 2010 • Searched databases: Pubmed, CancerLit, Embase, Medscape, Cochrane, abstracts from cancer meetings • Included study designs: RCT • Number of included studies: 3 • Studies included: • Langer, 2002 • Portier, 2006 • Nordlinger, 2008
Wieser, 2010
Patient characteristics • Eligibility criteria: Resectable stage IV CRC synchronous and metachronous • Patients characteristics: median/mean age 50 cases • Number of included studies: 30
• Eligibility criteria: • Patients characteristics: CRC liver metastases with or without lung metastases, portal node metastases or other extrahepatic disease, resectable and non-resectable metastases • Median FU: not reported
• Intervention: chemotherapy before or post surgery • Comparator: surgery alone
• For RCT see Ciliberto 2012 • For non randomised trials: no significant difference in mortality in any of the reported studies, all operative mortality
Pooled analysis of the surgical treatment for colorectal cancer liver metastases G. Veereman a , J. Robays a , L. Verleye a , R. Leroy a , C. Rolfo b,∗ , E. Van Cutsem c , D. Bielen d , W. Ceelen e , E. Danse f , M. De Man g , P. Demetter h , P. Flamen i , A. Hendlisz j , I. Sinapi k , D. Vanbeckevoort d , D. Ysebaert l , M. Peeters b a
Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium Department of Digestive Oncology, University Hospital Antwerp (UZA), Edegem, Belgium c Department of Digestive Oncology, University Hospitals Leuven (UZLeuven), Leuven, Belgium d Department of Radiology, University Hospitals Leuven (UZLeuven), Leuven, Belgium e Department of Digestive Surgery, University Hospital Gent (UZ Gent), Gent, Belgium f Department of Radiology, Catholic University Leuven (UCL), Woluwe, Belgium g Department of Digestive Oncology, OLV Ziekenhuis, Aalst, Belgium h Department of Pathology, Free University Brussels (ULB), Brussels, Belgium i Department of Nuclear Medicine, Jules Bordet Institute, Brussels, Belgium j Department of Digestive Oncology, Jules Bordet Institute, Brussels, Belgium k Department of Oncology, Grand Hôpital de Charleroi, Charleroi, Belgium l Department of Hepatobiliary Surgery, University Hospital Antwerp (UZA), Edegem, Belgium b
Accepted 10 December 2014
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Scoping, literature search, study selection and critical appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Scoping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Search for guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Search for systematic reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Search for primary studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Critical appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data extraction and statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Grading evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Timing of surgical resection of primary tumour and synchronous liver metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Neoadjuvant, peri-operative and adjuvant chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Neoadjuvant chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Adjuvant chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions based on grade profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123 125 125 125 125 125 125 127 127 127 127 127 127 128 128 133
Abbreviations: CCO, Cancer Care Ontario; CRC, colorectal cancer; CT, chemotherapy; DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; FU, fluorouracil; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HAI, hepatic artery infusion; HR, hazard ratio; IKNL, Integraal Kankercentrum Nederland; MDT, multidisciplinary team; NICE, National Institute for Health and Care Excellence, UK; OR, odds ratio; OS, overall survival; PFS, progression-free survival; PICO, Population-Intervention-Comparator-Outcome; QoL, quality of life; RFS, recurrence free survival; RCT, randomized controlled trial; RFA, radio-frequency ablation; SIGN, Scottish Intercollegiate Guidelines Network; SR, systematic review; WMD, weighted mean difference; yrs, years. ∗ Corresponding author at: Head of Phase I – Early Clinical Trials Unit, Oncology Department, University Hospital Antwerp UZA, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3 821 36 46; fax: +32 3 825 15 92. E-mail address: [email protected] (C. Rolfo). http://dx.doi.org/10.1016/j.critrevonc.2014.12.004 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
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5.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123
133 134 134 134 134 134
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. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colorectal cancer; Liver metastasis; Hepatic metastasis; Synchronous metastasis; Metachronous metastasis
1. 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) [4–6]. 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. Table 1 P.I.C.O. What is the best therapeutic sequence for patients with resectable CRC metastases to the liver? P (patient) I (intervention)
C (comparison)
O (outcome)
Patients with resectable colorectal liver metastases Simultaneous resection followed by systemic therapy (adjuvant chemotherapy) Simultaneous resection without systemic therapy or staged resection with or without chemotherapy PFS, OS, QoL
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Table 2 Search strategy: surgery and adjuvant treatment for liver-restricted metastatic colorectal cancer. Date Database Search strategy
Date Database Search strategy
November 2012 Medline via OVID 1. exp colorectal neoplasm/(136562) 2. (colo$ adj5 cancer$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (80489) 3. (colo$ adj5 neoplasm$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (108715) 4. (colo$ adj5 carcin$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (35295) 5. (colo$ adj5 tumo$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (25817) 6. (colo$ adj5 malign$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (4670) 7. (colo$ adj5 metast$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (15760) 8. exp neoplasm metastasis/(146094) 9. (metasta$ adj3 liver$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (19042) 10. (metasta$ adj3 hepa$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (9391) 11. *Liver Neoplasm/sc (9071) 12. 1 or 2 or 3 or 4 or 5 or 6 or 7 (171426) 13. 8 or 9 or 10 or 11 (167564) 14. 12 and 13 (22488) 15. exp antineoplastic agents/(764651) 16. exp Antineoplastic Combined Chemotherapy Protocols/(96569) 17. Chemotherap$.mp. (286438) 18. Colorectal neopl$/dt, th, su (0) 19. Systemic therap$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (6518) 20. systemic treatment.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (4377) 21. neo$adjuvant.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (16191) 22. exp Colorectal Surgery/(1767) 23. colorectal surgery.mp. (3969) 24. exp laparotomy/(14832) 25. resect$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (207462) 26. excis$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (135326) 27. metastatec$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] (71) 28. 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 (1206077) 29. 14 and 28 (12143) 30. Animals/(5091368) 31. Humans/(12693665) 32. 30 not (30 and 31) (3717557) 33. 29 not 32 (11614) 34. Meta-analysis.mp,pt. or review.pt. or search:.tw. (1902527) 35. 33 and 34 (1899) 36. limit 35 to yr=“2009-Current” (469) November 2012 Embase via embase.com ‘colorectal cancer’/exp OR (colo* NEAR/3 cancer* AND [2009–2013]/py) OR (colo* NEAR/3 neoplas* AND [2009–2013]/py) OR (colo* NEAR/3 carcin* AND [2009–2013]/py) OR (colo* NEAR/3 tumo* AND [2009–2013]/py) OR (colo* NEAR/3 malign* AND [2009–2013]/py) OR (colo* NEAR/3 metast* AND [2009–2013]/py) AND ‘liver metastasis’/exp AND (‘liver metastasis’/exp AND [2009–2013]/py OR (‘cancer chemotherapy’/exp AND [2009–2013]/py) OR (‘cancer combination chemotherapy’/exp AND
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125
Table 2 (Continued) Date
Date Database Search Strategy
November 2012 [2009–2013]/py) OR (‘molecularly targeted therapy’/exp AND [2009–2013]/py) OR (‘cancer palliative therapy’/exp AND [2009–2013]/py) OR (‘surgery’/exp AND [2009–2013]/py) OR (resect* AND [2009–2013]/py) OR (metastatec* AND [[2009–2013]/py)) NOT (‘animal experiment’/exp AND [2009–2013]/py) AND [2009–2013]/py AND ‘systematic review’/de November 2012 Cochrane library #1 MeSH descriptor: [Colorectal Neoplasms] explode all trees #2 MeSH descriptor: [Neoplasm Metastasis] explode all trees #3 #1 and #2 #4 MeSH descriptor: [Drug Therapy] explode all trees #5 MeSH descriptor: [General Surgery] explode all trees #6 MeSH descriptor: [Colorectal Surgery] explode all trees #7 #4 or #5 or #6 #8 #3 and #7 from 2009 to 2012, in Cochrane Reviews (Reviews only), Other Reviews and Cochrane Groups (Word variations have been searched)
2. Methods 2.1. Scoping, literature search, study selection and critical appraisal 2.1.1. 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 liver metastases has therefore been considered as one entity despite the overall better prognosis for metachronous liver metastases [11]. The use of CT to enhance resectability in case of initially unresectable liver metastases was out of scope for this review. The sequence of surgical resection of the primary tumour and synchronous liver metastases has been addressed separately. The term ‘simultaneous’ resection is commonly used but the term ‘concomitant’ may be more appropriate. Staged resection involves the classical approach with initial resection of the primary tumour.
2.1.2. Search for guidelines An initial search and critical appraisal of guidelines on CRC performed in September 2012 yielded 5 guidelines: a 2006 guideline by IKNL on liver metastases [8], a 2008 guideline by IKNL that did not address treatment of liver metastases [12], a 2011 guideline by the Scottish Intercollegiate Guidelines Network (SIGN), a 2011 guideline by the National Institute for Health and Care Excellence, UK (NICE) [5] and a 2012 guideline by Cancer Care Ontario,
Canada (CCO) [4]. We decided to update the literature from the search date of the IKNL 2006 guideline. 2.1.3. Search for systematic reviews We first searched for SR published since February 2009 until January 14th, 2013. SRss and meta-analyses were searched in the following databases: OVID Medline and PreMedline, EMBASE, Cochrane Database of Systematic Reviews. RCT’s and clinical trials were searched in: OVID Medline, Pubmed and OVID PreMedline. Hand search was performed based on reference lists of retrieved manuscripts. There were no other sources. Languages were limited to English, German, French and Dutch. The search strategy can be found in Table 2. All citations retrieved from the systematic literature search were screened on title and abstracts by one researcher (GV). Possible citations of interest were further selected based on the full text article by two researchers (GV and LV). Study selection criteria are summarised in Table 3. Search for SRs and meta-analyses published between 2009 and 2012 retrieved 516 citations after removal of duplicates. The further selection process, summarised in Fig. 1, yielded 7 SRs and/or meta-analyses. All reviews on surgery with or without CT included synchronous and metachronous liver metastases. Adjuvant CT was the exclusive subject of 3 reviews [13–15], neoadjuvant CT the exclusive subject of 2 reviews [16,17] and all types of CT the subject of one review [18]. The treatment of synchronous CRC liver metastases was addressed in one review [19]. 2.1.4. Search for primary studies A search for RCT’s and all types of clinical trials between January1, 2010 (last search date of the SRs) and January 14, 2013 yielded 22 citations and an additional hand search for primary studies yielded 6 citations after removal of duplicates. The further selection process (Table 4) based
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Potentially relevant citations identified:
Additional potentially relevant citations (hand searching):
516
Based on title and abstract evaluation, citations excluded:
3
Studies retrieved for more detailed evaluation:
320
199
Based on full text evaluation, studies excluded: Reasons: Population Intervention Outcome Design Language other (duplicate information)
192 61 28 3 92 0 6
Relevant studies: 7 Fig. 1. Flow chart of the selection of retrieved literature for systematic reviews. Table 3 Selection criteria systematic reviews and meta-analysis.
Table 4 Selection criteria primary studies.
Review question
Review question
Selection criteria Population
Intervention
Outcome
Best therapeutic schedule for resectable synchronous and metachronous levermetastases of CRC Inclusion criteria Patients with resectable colorectal metastasis in liver Any sequence of metastatectomy ± systemic therapy PFS, OS, QoL
Design
SR, MA, evidence based GL
Language
English, French, German, Dutch No
Duplicate
Exclusion criteria
Selection criteria
Unresectable liver metastases, other organ involvement Chemotherapy for unresectable metastases
Population
Prognostic factors, biomarkers, cost, no outcome variables Narrative reviews, editorials, letters, consensus based GL Other languages
Outcome
Yes
on exclusion of non-resectable liver metastases, studies on predictive factors and types of treatments that were not CT resulted in a single retrospective review of patients receiving adjuvant CT following hepatic resection with no comparator [3] and one RCT which is a large study by the European Organisation for Research and Treatment of Cancer
Intervention
Design Language Duplicate Full text not available
Best therapeutic schedule for resectable synchronous and metachronous levermetastases of CRC Inclusion criteria Patients with resectable colorectal metastasis in liver Any sequence of metastatectomy ± systemic therapy PFS, OS, QoL
RCT, observational studies, case series English, French, German, Dutch No No
Exclusion criteria Unresectable liver metastases, other organ involvement Chemotherapy for unresectable metastases Prognostic factors, biomarkers, cost, no outcome variables Case report, editorial Other languages Yes Yes
(EORTC) on perioperative FOLFOX4 chemotherapy and surgery vs. surgery alone. Interim results from this study were published in 2008 and 2012 [20,21] and in 2013 the final analysis became available [22].
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2.1.5. Critical appraisal The critical appraisal of guidelines was performed with the Agree II tool (http://www.agreetrust.org) SRs were appraised using the AMSTAR checklist (http://amstar.ca) (Table 5). To judge the possibility of publication bias we used information available in the identified SRs (e.g. funnel plots reported in the review) and other criteria suggested by Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (e.g. only small studies sponsored by industry sponsors available). 2.2. Data extraction and statistical analysis Data extraction was summarised for SRs (Tables 6 and 7 ) and for primary studies (Tables 8 and 9). A meta-analysis was performed on the data from the new RCT and the retrieved meta-analysis using Review Manager (RevMan, version 5.0; The Cochrane Collaboration, updated February 2011, Oxford, England) using a generic inverse variance method. Heterogeneity was statistically assessed using χ2 based on the Q statistic and I2 statistic as described by Higgins et al. [23]. A fixed-effect model was used as no statistical evidence for heterogeneity was found for progression-free survival (PFS) and overall survival (OS), Ahazard ratio (HR) was extracted from the reported analyses using the extraction methods following Parmar et al. [24] and I2 statistic. 2.3. Grading evidence We applied the grade methodology and terminology in evaluating the following quality elements for intervention studies: study limitations, inconsistency, indirectness, imprecision and publication bias [25]. The quality of evidence was evaluated using grade methodology by two reviewers and a level of evidence was assigned to each conclusion [26]. The assessors (gv, jr, lr, lv) decided on downgrading with −1 or −2 points and summarised the reasons in the grade profiles.
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The following variables can be considered as indirect QoL indicators. Operative time (weighted mean difference [WMD] −34.19; 95%CI −81.32–12.95, p = 0.16) and intra-operative blood loss (WMD −161.33; 95%CI −351.45–28.79, p = 0.10) were similar in both groups. Hospital stay (WMD, −4.77; 95%CI −7.26–2.28, p < 0.01) and postoperative morbidity rate (odds ratio (OR) 0.71; 95%CI 0.57–0.88, p = 0.002) 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 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 centre (n = 47) [3]. Simultaneous resection was performed in 53% of the non-referred patients. The median follow-up was 43 months treatment with CT or not was variable, as was the number of surgical interventions. OS and PFS were not significantly different between the two groups. OS at 3 and 5 yrs was 73.8% and 57.3% in the nonreferred group and 74.9% and 61.2% in the referred group respectively, P = 0.360). PFS at 3 and 5 yrs was 43.0% and 25.9% in the non-referred group and 34.8% and 23.2% in the referred group respectively (P = 0.422). Postoperative morbidity however, was significantly higher in the referred group (75 vs. 47%, P = 0.023). Multivariate analysis showed no significant confounding factor. Simultaneous resection was one of the many variables that may play a role in this improved outcome. This study was not included in the GRADE profile (Table 10). After completing the literature searches and analyses, a recent review came to our attention [28]. The conclusions of this meta-analysis of 2880 patients agree with the previous studies: OS (HR 0.96; 95%CI 0.81–1.14; p = 0.64; I2 = 0) and disease free survival (DFS) (HR 1.04; 95%CI 0.76–1.43; p = 0.79; I2 = 53%) are similar for both simultaneous and delayed resections. The simultaneous group had a lower incidence of postoperative complications (modified RR = 0.77; 95%CI: 0.67–0.89; p = 0.0002; I2 = 10%).
3. Results 3.1. 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 followup 5 yrs. The outcomes of interest are PFS, OS and quality of life (QoL). There are no data on PFS. OS did not significantly differ at 1, 3 or 5 yrs (1 yr: OR 0.77; 95%CI 0.51–1.16, p = 0.21; 3 yrs: OR 1.12; 95%CI 0.85–1.47, p = 0.43, 5 yrs: OR 1.14; 95%CI 0.86–1.50, p = 0.37).
3.2. Neoadjuvant, peri-operative and adjuvant chemotherapy Since RCTs comparing neoadjuvant to adjuvant CT combined with resection of CRC liver metastases are lacking, the research question can only be addressed indirectly. Outcomes are OS and depending on the study PFS, recurrence free survival (RFS) or DFS. QoL could be appreciated from surrogate outcomes such as morbidity, adverse events, hospital stay, etc. RCTs have compared adjuvant CT to none (n = 7) and peri-operative CT to none (n = 1). Adjuvant CT can be systemic or loco regional i.e. administered by hepatic artery infusion (HAI). Wieser et al. performed a meta-analysis on 8 RCTs [13] including different regimens (systemic and loco regional) of peri-operative and adjuvant CT. Ciliberto et al. published a meta-analysis focusing on the 3 RCTs involving
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Table 5 Amstar checklist for systematic reviews. AMSTAR question Chen 2011 Chua 2010 Ciliberto 2012 Nelson 2009 Wieser 2010 Quan 2012 Lehman 2012
1
2
3
4
5
6
7
8
9
10
11
Included
Yes No Yes Yes Yes Yes Yes
Yes Yes Yes No Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes No
Yes Yes Yes No No Yes Yes
Yes Yes Yes Yes Yes Yes Yes
Yes No Yes Yes Yes No No
Yes Yes Yes Yes Yes Yes Yes
Yes na Yes Yes Yes na na
Yes No Yes Yes Yes No No
Yes No No Yes Yes No Yes
Yes Yes Yes Yes Yes Yes Yes
Table 6 Evidence table: systematic reviews synchronous CRC liver metastases. Study ID
Method
Chen, 2011 • Design: MA • Sources of funding: not stated • Search date: 1/1966–12/2009 • Searched databases: PubMed, Embase, Cochrane Library, Ovid, and Web of Science • Included study designs: comparative • Number of included studies: 14
Patient characteristics • Eligibility criteria: CRC with resectable synchronous hepatic metastasis • Patients characteristics: 2204 patients: 1384 (ages 56–64.9) having received simultaneous resection, 817 (ages 58–61) staged resection • Median FU: 2.5 yrs (total 5 yrs)
Intervention(s) • Intervention • Simultaneous resection • Comparator • Staged resection
systemic adjuvant CT [14] whereas Nelson’s meta-analysis reports on adjuvant HAI [15]. The above mentioned RCTs were included in the SR by Quan et al. [18]. The effect of neoadjuvant CT has only been reported in observational studies that were reviewed by Chua et al. [16]. The single available RCT on peri-operative CT by the EORTC reported first on PFS in 2008 and was included in the SRs of neoadjuvant as well as adjuvant CT [20]. A full intention to treat analysis for survival of this RCT was recently published and included in our de novo meta-analysis (Fig. 2) [22]. Chua et al. performed a SR including the 2008 analysis of the RCT by EORTC, three phase 2 and 19 observational studies [16]. A later review by Lehman et al. details the different systemic regimens for 14 studies, of which 11 were included by Chua et al. This report adds no new information related to the research question [17]. The last SR discusses the three RCTs on systemic peri-operative and adjuvant CT and 28 retrospective and prospective studies on neoadjuvant and adjuvant CT [18]. The authors state that heterogeneity and poor quality of the evidence were incompatible with a meta-analysis comparing different sequences of CT. The CCO guidelines are based on this last review [4]. In conclusion, neo adjuvant and adjuvant CT have not been compared directly. Studies on neo adjuvant and adjuvant CT are discussed separately.
Results primary outcome
Results secondary and other outcome(s)
Critical appraisal of review quality
3. Overall survival No statistical difference at 1 year (OR, 0.77; 95%CI, 0.51–1.16, P = .21) 3 years (OR, 1.12; 95%CI, 0.85–1.47, P = .43) 5 years (OR, 1.14; 95%CI, 0.86–1.50, P = .37)
1. Operative factors: A: operative time (weighted mean difference [WMD], −34.19; 95% confidence interval [CI], −81.32–12.95, P = .16) B: intraoperative blood loss (WMD, −161.33; 95%CI, −351.45–28.79, P = .10). C: hospital stay (WMD, −4.77; 95%CI, −7.26–2.28, P < .01) 2. Postoperative complications: lower morbidity rate (odds ratio [OR], 0.71; 95%CI, 0.57–0.88, P = .002
• Results critical appraisal • High quality studies • Heterogeneity
3.2.1. Neoadjuvant chemotherapy Outcomes for neoadjuvant CT were reported without comparison group. The review by Chua et al. 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 [16]. Lehman et al. report on 11 studies that were included in the review by Chua et al. and three others. Retrospective comparisons suggest improved outcome for neoadjuvant CT compared to surgery alone and for adjuvant compared to neoadjuvant therapy. However these conclusions are not evidence based [17]. A SR of all types of publications on systemic CT [18] describes the outcomes of interest for the three RCTs that were analysed separately [14]. In 28 observational studies, 14 of them on neoadjuvant CT, these outcomes are lacking. A meta-analysis was not possible due to heterogeneity. A single study reports 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 CT, GRADE profiles could not be provided. 3.2.2. Adjuvant chemotherapy 3.2.2.1. Systemic adjuvant chemotherapy. The metaanalysis by Wieser et al. includes the largest number of patients: a total of 1058 patients from which 525 were randomised to surgery with peri-operative or adjuvant
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Table 7 Evidence table: systematic reviews synchronous and metachronous CRC liver metastases. Study ID Chua, 2009
Nelson, 2009
Method • Design: SR • Sources of funding: not stated • Searched databases and dates: MEDLINE, PubMed • Included study designs: RCT and non-randomised trials • Number of included studies: 23
• Design: meta-analysis • Sources of funding: not stated • Search date: 1966 to December 2008 • Searched databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, the Cochrane Hepato-Biliary Group Controlled Trials Register. • Included study designs: RCT • Number of included studies: 7 • Included studies: • Kemeny 1999 • Kemeny 2002 • Lorenz 1998 • Lygidakis 1995 • Rudroff 1999 • Tono 2000 • Wagman 1990
Patient characteristics
Intervention(s)
• Eligibility criteria: -publications where systemic CT was used in patients with resectable CLM, more than 20 patients, English • Patient characteristics: 3278 patients with majority of hepatic-only metastases (5 studies including patients with extra-hepatic disease) Median number of lesions: 2 (range 2–7), median maximum size of the lesion 4 cm (range 3–5)
• Intervention: neoadjuvant CT • Comparator: none
• Eligibility criteria: resectable hepatic mCRC synchronous and metachronous • Patients characteristics: total of 592 patients with in 289 intervention group • Median FU: 81 months
• Intervention: postoperative intra arterial chemotherapy • Comparator: no postoperative chemotherapy
Results primary outcome
Results secondary and other outcome(s)
Critical appraisal of review quality
• DFS (reported in 12 studies): median 21 mo (range 11–40 mo) • OS (reported in 13 studies): median 46 mo (range 20–67 mo) • Peri-operative mortality: median rate: 2% (range 0–5%) • Peri-operative morbidity: median rate: 27% (range 11–50%)
Radiological assessment: (reported in 14 studies): median rate of objective response • (Complete/partial) 64% (range 44–100%). • Median rate of complete response: 4% (range 0–38%). • Median rate of partial response 52% (range 10–90%). • Median rate of stable disease 26% (range 0–47%).
Results critical appraisal • No comparator
(1) Overall survival HR (Fixed, 95% CI) 1.09 [0.89, 1.34] 8.9% survival advantage in favour of control group (2) Adverse events related to the chemotherapy No result
• Median rate of disease progression: 15% (range 0–37%) Hepatectomy: • Median rate of complete resection: 93% (range 39–100%); • Median rate of hepatectomy involving resection of 3 or more segments: 68% (range 23–97%) (1) Intra-hepatic tumour recurrence (2) Time to recurrence (3) Extra-hepatic tumour recurrence (4) Time to recurrence and disease specific survival: for all: no results (lack of denominator)
• Various types of chemotherapy
Includes 1 poor quality study Results lack significance
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Table 7 (Continued) Study ID
Method
• Design: SR and MA • Sources of funding: P.U.R.E. Research Programme funded by the State Ministry for Innovation, Science, Research and Technology of NorthrhineWestfalia and the FoRUM foundation of the Ruhr-University Bochum • Search date • 1980-23 January 2009 • Searched databases: Medline (PubMed), the Cochrane Library, the Latin American and Caribbean Literature on Health Sciences (LILACS) • Included study designs: RCTs • Number of included studies: 8 • Included studies: Nordlinger,2008 Lorenz, 1998 Portier, 2006 Langer, 2002 Kemeny, 2002 Rudroff, 1999 Lygidakis, 1995 Wagman, 1990 Ciliberto, 2012 • Design: SR and MA • Sources of funding: not stated • Search date: 1982 to May 2010 • Searched databases: Pubmed, CancerLit, Embase, Medscape, Cochrane, abstracts from cancer meetings • Included study designs: RCT • Number of included studies: 3 • Studies included: • Langer, 2002 • Portier, 2006 • Nordlinger, 2008
Wieser, 2010
Patient characteristics • Eligibility criteria: Resectable stage IV CRC synchronous and metachronous • Patients characteristics: median/mean age 50 cases • Number of included studies: 30
• Eligibility criteria: • Patients characteristics: CRC liver metastases with or without lung metastases, portal node metastases or other extrahepatic disease, resectable and non-resectable metastases • Median FU: not reported
• Intervention: chemotherapy before or post surgery • Comparator: surgery alone
• For RCT see Ciliberto 2012 • For non randomised trials: no significant difference in mortality in any of the reported studies, all operative mortality
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