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Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis
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ScienceDirect EJSO xx (2015) 1e7
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Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis Z.-M. Wang, Y.-Y. Chen, F.-F. Chen, S.-Y. Wang, B. Xiong* Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key of Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, PR China Accepted 31 May 2015 Available online - - -
Abstract Aims: The purpose of this meta-analysis is to assess the value of peri-operative chemotherapy for patients who have resectable colorectal cancer with liver metastases (CRCLM). The clinical effectiveness of peri-operative chemotherapy for CRCLM patients remains controversial. Methods: A literature review was performed to compare CRCLM patients receiving peri-operative chemotherapy plus surgery with patients receiving surgery alone. The Hazard ratio (HR), odds ratio (OR) and 95% confidence intervals (95% CIs) were set as effect measures. Results: There were 10 studies included in this meta-analysis, with a total of 1896 patients. There was no advantage in overall survival (OS) for patients receiving peri-operative chemotherapy compared with those who underwent surgery alone (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07). However, there was significant benefit in disease-free survival (DFS) in patients who received chemotherapy compared with surgery alone (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007). In a subset analysis, the systemic chemotherapy group showed a DFS benefit (HR, 0.81; 95% CI, [0.69, 0.96]; P ¼ 0.01) compared with different regional chemotherapy. The incidence of post-operative complications was significantly higher in patients who also received chemotherapy compared with the surgery alone group (OR, 1.42; 95% CI, [1.05, 1.92]; P ¼ 0. 02). Conclusions: There was no significant improvement in OS in CRCLM patients who received peri-operative chemotherapy compared with surgery alone, and chemotherapy significantly increased the post-operative complications. However, this requires further clinical study. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Peri-operative chemotherapy; Surgery; Resectable; Colorectal cancer; Hepatic metastasis; Meta-analysis
Introduction Colorectal cancer (CRC) is a common disease, and it is responsible for 10% of cancers and mortality worldwide. Of the 569,490 patients who died from CRC in the United States 1,2, more than 50% might have had liver metastases during the course of their disease.2 Surgery can prolong the overall survival (OS) time, but the 5-year relapse rate * Corresponding author. Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key of Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, PR China. Tel.: þ86 027 67813152; fax: þ86 027 67812892. E-mail addresses: [email protected] (Z.-M. Wang), [email protected] (Y.-Y. Chen), [email protected] (F.-F. Chen), [email protected] (S.-Y. Wang), binxiong1961@ gmail.com (B. Xiong).
remains at nearly 66%.3 As an important treatment strategy, chemotherapy plays a crucial role in comprehensive therapy. Studies have shown that the response rates of CRC patients receiving systemic chemotherapy is approximately 40e55% and the median survival time approaches 2 years.4,5 Recently, different peri-operative chemotherapy strategies for patients with resectable colorectal liver metastasis (CRCLM) have been used in clinical practice. However, there is conflicting information on the outcomes of peri-operative chemotherapy for patients with resectable CRCLM.6e10 In 2006, Nelson11 published a systematic review that showed a hazard ratio (HR) for OS of 1.089 (95%CI, [0.887e1.334]). A meta-analysis by Wieser12 in 2010 had a similar negative conclusion for the benefit of OS (0.94;
http://dx.doi.org/10.1016/j.ejso.2015.05.020 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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95%CI, [0.8e1.10]). Although the results for recurrencefree survival (RFS) showed a significant difference between the groups (HR, 0.77; 95% CI, [0.67e0.88]; P ¼ 0.0001), most trials included in the meta-analyses used outdated 5fluorouracil (FU)-based systemic chemotherapies. In 2013, a new randomized trial13 was conducted that reported an updated outcome for OS and disease-free survival (DFS) using a more active FOLFOX4 chemotherapy regimen and a larger number of patients. Although this study demonstrated a significant improvement in DFS for the perioperative chemotherapy group in the intent-to-treat population, there was no assessment of the role of peri-operative chemotherapy in increasing the risk of peri-operative morbidity. The purpose of this study is to perform a meta-analysis to evaluate the effect of peri-operative chemotherapy for resectable CRCLM patients using data from the trials used were carefully selected, and the selection process is described below. Methods Search strategy We searched the PubMed, Embase, Ovid and ScienceDirect databases for eligible clinical studies published in English from January 1979 to May 2014, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement.14 The following key words were used: “chemotherapy”, “colorectal”, “cancer”, “liver metastasis”, “surgical”, “resection” and “hepatectomy”. Two reviewers (ZM Wang and YY Chen) independently screened and retrieved the literature list. We then listed all review articles, original articles and references of the articles to avoid missing any relevant publications. References within the articles were hand-searched for relevant articles. Any disagreement was resolved by discussing with another author (FF Chen).
Data extraction Articles were independently reviewed by two authors (ZM Wang and YY Chen). The following information was collected from each report: year of publication, number of patients, patient characteristics, resection status, chemotherapy regimen, OS, DFS and follow-up period. We used the Downs and Black quality assessment method to evaluate the study quality. This method includes 27 criteria to assess both randomized and non-randomized comparative studies.15 Statistical analysis We used the Review Manager 5.2 (Cochrane Collaboration, Oxford, UK) to perform the meta-analysis. To statistically evaluate the prognostic effect of peri-operative chemotherapy, we extracted the Hazard ratio (HR) and the associated standard error for DFS and/or OS from the included studies that provided these statistics. If HRs and their relative standard errors, P values or confidence intervals (CIs) were not provided in the original articles directly, the HRs were approximated according to the method described by Tierney.16 By convention, an HR < 1 suggests a better prognosis in the peri-operative chemotherapy group compared with the surgery alone group. The pooled extracted HRs were entered into the generic inverse variance method available in the Review Manager. The odds ratio (OR) was calculated during the analysis of the association between peri-operative chemotherapy and peri-operative complications. We defined the statistical result with a P value <0.05 as significant. The inter-study heterogeneity was evaluated using the chi-square test and quantified using the I2 statistic. A fixed-effect model was used if there was no heterogeneity, whereas a random effect model for secondary analysis was used if the heterogeneity was statistically significant (P < 0.10, I2 > 50%). Potential publication bias was assessed using a funnel plot and further quantified by Egger17 and Begg’s tests18 using STATA software (Version 12.0, College Station, TX).
Inclusion and exclusion criteria Results Studies were included based on the following criteria: (i) a randomized controlled trial (RCT) or comparative study in which patients were assigned to one of at least two groups (peri-operative chemotherapy plus surgery and surgery alone); (ii) patients had pathologically confirmed CRC and underwent curative resection; and (iii) at least one of the following was reported in the study: DFS, OS or complications outcomes. The exclusion criteria were as follows: (i) a review or non-comparative study; (ii) duplicate reports by the same institution; (iii) the patients in the study were less than 20 years old; (iv) patients had extrahepatic metastasis or recurrence on the chest or abdomen; and (v) studies where patients were assigned to receive different chemotherapy regimens.
Search results and characteristics of eligible studies The literature search retrieved 641 related references. After evaluating the studies against the inclusion/exclusion criteria, 10 studies including 7 RCTs and 3 non-randomized comparative studies were eligible to be included in this meta-analysis (Fig. 1). We categorized the 10 articles into 3 subgroups based on their treatment chemotherapy strategies: subgroup 1 included 3 trials on hepatic arterial infusion (HAI) chemotherapy7e9; subgroup 2 included 3 trials on regional (hepatic arterial or portal vein infusion) together with systemic chemotherapy10,19,20; and subgroup 3 included the other 4 trials on systemic chemotherapy.13,21e23 The groupings were unanimously agreed-
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
Z.-M. Wang et al. / EJSO xx (2015) 1e7
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Figure 1. Flow chart of literature selection.
upon by the two reviewers. The basic descriptions of the 10 studies are shown in Table 1. Meta-analysis of overall survival The OS outcome reported by the 10 studies indicated no reduction in overall mortality that was attributable to perioperative chemotherapy (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07) (Fig. 2) There was no statistical heterogeneity (I2 ¼ 0%). Publication bias, tested by Egger’s test (P ¼ 0.684) and a funnel plot (Fig. S1), was negligible for the pooled analysis of OS. In the subgroups (Fig. 2), trials involving regional combined systemic chemotherapy showed no survival benefit (HR, 0.67 95% CI, [0.39, 1.14]; P ¼ 0.14; I2 ¼ 0%). Neither of the other subgroups, HAI and systemic chemotherapy, showed a significant improvement in long-term OS compared with surgery alone. The results for HAI are: HR, 0.95, 95% CI, [0.78, 1.17]; P ¼ 0.64; I2 ¼ 43%. The results for systemic chemotherapy are: HR, 0.85; 95% CI, [0.70, 1.03]; P ¼ 0.10; I2 ¼ 0%. We further evaluated the effect of these results by considering only the seven RCTs,7e10,13,22,23 and the results (HR, 0.89; 95% CI, [0.77, 1.03]; P ¼ 0.03) did not differ significantly compared with all trials in the pooled analysis (Fig. S2). Meta-analysis of disease-free survival The outcome generated from data that was extracted from all the studies showed that peri-chemotherapy treatment had a statistically significant positive effect on DFS (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007) (Fig. 3). We did not find
statistical heterogeneity (I2 ¼ 18%). Egger’s test (P ¼ 0.603) and a funnel plot (Fig. S3) showed that this combined analysis had no publication bias. In the seven RCTs, the outcome also reached a statistically significant difference (HR, 0.77; 95% CI, [0.68, 0.87]; P < 0.0001) (Fig. S4). In the subgroup analysis, only the systemic chemotherapy group showed a statistical significance difference between the two groups (HR, 0.81; 95% CI, [0.69, 0.96]; P ¼ 0.01) (Fig. 3). The outcome in the regional combined with systemic chemotherapy group was as follows: HR, 0.70; 95% CI, [0.46, 1.06]; P ¼ 0.09; I2 ¼ 0% (Fig. 3). Because of the large amount of heterogeneity in the HAI group (I2 ¼ 58%), we chose the random effects model to adjust heterogeneity. The results were as follows: HR, 0.82; 95% CI, [0.57, 1.18] and P ¼ 0.09. Meta-analysis of post-operative complications No significant statistical heterogeneity was found in the meta-analysis that included 4 studies10,13,21,22 with 1291 patients. The incidence of post-operative complications tended to be higher among patients who had received pre-operative chemotherapy (OR, 1.42; 95% CI, [1.05, 1.92]; P ¼ 0.02) (Table 2). Also, no significant difference was found in the post-operative death rate in the pooled analysis of three studies10,13,21 (OR, 1.36; 95% CI, [0.59, 3.13]; P ¼ 0.90) (Table 2). Discussion This study was the first to assess the clinical effect value in different peri-operative chemotherapy treatments
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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Table 1 Characteristics of studies included in meta-analysis. First author
Therapy regimen
Patients analyzed (n)
Chemotherapy/ control
Number of metastases
Comparative outcomes
Follow-up (Months)
Design
Quality score
Nordlinger 201313 Bolton 201219 Pinto 201121 Portier 200622 Kemeny 200210 Langer 200223 Rudroff 19997 Lorenz 19988 Lygidakis 19959 Donato 199420
FOLFOX4, systemic HAI, FUDR; systemic systemic 5-FU, systemic
364 49
182/182 36/13
1e4 1e2
PFSa; OS; OS;
122 66
RCT Prospective
25 17
676 171
334/342 86/85
1e6 1e4
DFS; OS DFSa; OS
60 87.4
Retrospective RCT
19 23
FUDR,HAI; 5-FU, systemic 5-FU, systemic 5FU, HAI
109
53/56
1e3
RFSa; OS
51
RCT
17
107 30
52/55 14/16
1e4 1e4
DFS; OSa RFS; OSa
n.r. 144
RCT RCT
18 18
5-FU, HAI
226
113/113
1e6
DFS; OSa
18
RCT
23
5-FU, HAI
40
20/20
n.r.
DFS; OSa
n.r.
RCT
16
124
40/62
1e4
DFS; OS
n.r.
Retrospective
15
5-FU, regional; systemic
Abbreviations: n.r.: not reported; PFS: progression-free survival; DFS: disease-free survival; OS: overall survival; RFS: Recurrence-free survival; HAI: Hepatic arterial infusion; PVI: portal vein infusion; 5-FU: 5-fluorouracil; FUDR: fluorodeoxyuridine. a It was the primary end-point of observing.
for patients diagnosed with CRCLM. CRCLM patients receiving peri-operative chemotherapy were compared with CRCLM patients who were undergoing surgery alone.
Our results were consistent with a previous systematic review that was published in 2006 by Nelson.11 Seven trials addressed this issue and included 592 patients, who were randomized either to HAI or an alternative treatment. No
Figure 2. Forest plots for the results of meta-analysis for overall time of the three subgroups.
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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Figure 3. Forest plots for the results of meta-analysis for disease-free time of the three subgroups.
significant advantage in OS was found in the meta-analysis for hepatic artery chemotherapy (HR, 1.089; 95% CI, [0.887e1.334]). Another meta-analysis that used eight RCT studies was published in 2010 by Wieser,12 and their results suggested that peri-operative chemotherapy yielded no survival advantage over surgery alone (HR, 0.94; 95% CI, [0.8, 1.10]; P ¼ 0.43). In a subset analysis, the studies were divided into two subgroups (intra-arterial chemotherapy and systemic chemotherapy), and no survival benefit was evident. However, both peri-operative treatment groups mentioned above had a significant DFS benefit for the HAI subgroup (HR, 0.78; 95% CI, [0.65, 0.95]; P ¼ 0.01) and the systemic therapy subgroup (HR, 0.75; 95% CI, [0.62, 0.91]; P ¼ 0.003). The results were in agreement with our analysis of 7 randomized trials chosen as a result of less than 20 patients of 1 trial24 in the metaanalysis by Wieser.12 In our study, the OS did not show a statistically significant benefit (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07).
However, the subgroup analysis showed that there was a strong tendency towards a better OS in the systemic chemotherapy subgroup. Our pooled analysis also revealed a distinct advantage for DFS for patients in the systematic chemotherapy group (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007). The OS and DFS results were not changed when we performed a pooled analysis of seven randomized trials. This result strongly supports our outcomes. Thus, these outcomes showed that systemic chemotherapy played a main role in a better patient OS or DFS. During this meta-analysis, we minimized heterogeneity by restricting the study design, sample characteristics and chemotherapy strategy. However, some degree of heterogeneity remained in the HAI group (I2 ¼ 58%). However, after adjusting for heterogeneity, the outcomes were not changed. The results suggested that two questions need to be answered. First, why isn’t the regional chemotherapy as beneficial as systemic chemotherapy in patients with
Table 2 Meta-analysis result of operative complications. No. of studies
Operative complication Operative death
4 3
Chemotherapy arm
Surgery arm
n/N
n/N
119/637 13/551
92/654 10/569
Or (95%CI)
1.42 (1.05, 1.92) 1.36 (0.59, 3.13)
P
0.02 0.47
Heterogeneity P
I2 (%)
0.72 0.90
0 0
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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CRCLM? This is important for the clinical use of regional chemotherapy in stage III CRC to prevent liver metastasis after surgery. The meta-analysis published by Tang25 revealed that HAI might be able to reduce the rate of liver metastasis in patients with advanced CRC, and patients with resected stage IV CRC might also benefit from HAI treatment. However, systemic chemotherapy after liver surgery was considered to be insufficient26 because in stage IV CRC patients, tumor cells are likely to generate in the other places, such as lung, brain and bone marrow, which decreases the patient’s survival time.27 The variable results may also be attributed to the lack of well-designed randomized trials, insufficient number of patients and a HAI treatment duration that is too short to see a clinical effect. Second, why did peri-operative chemotherapy with surgery not result in a better OS? The following discussion may explain these results. Most of the trials included in our meta-analysis were initially designed to detect a DFS benefit and they were not powered for OS, which was a secondary endpoint. In addition, a good long-term outcome in the surgery-only group meant that demonstrating a treatment benefit for peri-operative chemotherapy was needed, but difficult to obtain.28 When there was a recurrence, OS was strongly affected by the other treatment, either surgical or medical. Chemotherapy was administered frequently to patients in the surgery only group at the first progression. Moreover, patients were treated with FOLFOX chemotherapy only in the recent trial by Nordinger.13 Most trials used outdated 5-FU-based systemic chemotherapies. Also, some main elements, for example, the number of liver metastasis lesions, operative resection status (R0 or R1), negative margins and the optimal timing of chemotherapy (post- or pre-operative) in each group may lead to a different OS.6 Because there were not enough studies that could provide sufficient data, we could not perform a further meta-analysis of the subgroups. Further studies are required to resolve these critical issues. The impact of chemotherapy on the peri-operative outcome remains controversial.29,30 Because there was insufficient data in the current meta-analyses, researchers highlight the assessment of grade 3 and 4 toxicities in patients receiving peri-operative chemotherapy.11,25 The results showed that toxicities were generally mild and acceptable. We noted that the use of pre-operative chemotherapy was also associated with an overall increased risk of peri-operative morbidity. Our results initially showed a slight increase in peri-operative complications among patients treated with pre-operative chemotherapy. However, we did not find an increase in peri-operative mortality. There were some limitations to this study. First, we restricted the database search to studies published in English only. Second, data were extracted based on the published paper instead of the individual patient data (IPD). A meta-analysis based on IPD could have a more reliable outcome than one based on extracted data. Third, there were few high quality RCTs in the studies that were
included in this meta-analysis. Although there were some RCT studies and the RCT data was pooled for additional analysis, highly-scoring studies were rare. Thus, the results may still be insufficient even after pooling and must be interpreted with caution. Conclusions This is the first meta-analysis to assess the clinical effect and value of different regional chemotherapy treatments for patients with resected CRCLM. Better OS and DFS outcomes for patients who underwent peri-operative regional chemotherapy were not found. There was little support for requiring peri-operative regional chemotherapy in patients with resectable CRCLM. Thus, peri-operative regional chemotherapy should be used in caution in these patients. Because peri-operative systemic chemotherapy can improve DFS in patients, it may be better than regional chemotherapy and should be acceptable in patients where CRCLM is resectable. Moreover, peri-operative chemotherapy could significantly increase post-operative complications, which needs to be verified in future clinical practice. Conflict of interest There is no conflict of interest in relation to this study. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2015.05.020.
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Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis Z.-M. Wang, Y.-Y. Chen, F.-F. Chen, S.-Y. Wang, B. Xiong* Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key of Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, PR China Accepted 31 May 2015 Available online - - -
Abstract Aims: The purpose of this meta-analysis is to assess the value of peri-operative chemotherapy for patients who have resectable colorectal cancer with liver metastases (CRCLM). The clinical effectiveness of peri-operative chemotherapy for CRCLM patients remains controversial. Methods: A literature review was performed to compare CRCLM patients receiving peri-operative chemotherapy plus surgery with patients receiving surgery alone. The Hazard ratio (HR), odds ratio (OR) and 95% confidence intervals (95% CIs) were set as effect measures. Results: There were 10 studies included in this meta-analysis, with a total of 1896 patients. There was no advantage in overall survival (OS) for patients receiving peri-operative chemotherapy compared with those who underwent surgery alone (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07). However, there was significant benefit in disease-free survival (DFS) in patients who received chemotherapy compared with surgery alone (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007). In a subset analysis, the systemic chemotherapy group showed a DFS benefit (HR, 0.81; 95% CI, [0.69, 0.96]; P ¼ 0.01) compared with different regional chemotherapy. The incidence of post-operative complications was significantly higher in patients who also received chemotherapy compared with the surgery alone group (OR, 1.42; 95% CI, [1.05, 1.92]; P ¼ 0. 02). Conclusions: There was no significant improvement in OS in CRCLM patients who received peri-operative chemotherapy compared with surgery alone, and chemotherapy significantly increased the post-operative complications. However, this requires further clinical study. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Peri-operative chemotherapy; Surgery; Resectable; Colorectal cancer; Hepatic metastasis; Meta-analysis
Introduction Colorectal cancer (CRC) is a common disease, and it is responsible for 10% of cancers and mortality worldwide. Of the 569,490 patients who died from CRC in the United States 1,2, more than 50% might have had liver metastases during the course of their disease.2 Surgery can prolong the overall survival (OS) time, but the 5-year relapse rate * Corresponding author. Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key of Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, PR China. Tel.: þ86 027 67813152; fax: þ86 027 67812892. E-mail addresses: [email protected] (Z.-M. Wang), [email protected] (Y.-Y. Chen), [email protected] (F.-F. Chen), [email protected] (S.-Y. Wang), binxiong1961@ gmail.com (B. Xiong).
remains at nearly 66%.3 As an important treatment strategy, chemotherapy plays a crucial role in comprehensive therapy. Studies have shown that the response rates of CRC patients receiving systemic chemotherapy is approximately 40e55% and the median survival time approaches 2 years.4,5 Recently, different peri-operative chemotherapy strategies for patients with resectable colorectal liver metastasis (CRCLM) have been used in clinical practice. However, there is conflicting information on the outcomes of peri-operative chemotherapy for patients with resectable CRCLM.6e10 In 2006, Nelson11 published a systematic review that showed a hazard ratio (HR) for OS of 1.089 (95%CI, [0.887e1.334]). A meta-analysis by Wieser12 in 2010 had a similar negative conclusion for the benefit of OS (0.94;
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95%CI, [0.8e1.10]). Although the results for recurrencefree survival (RFS) showed a significant difference between the groups (HR, 0.77; 95% CI, [0.67e0.88]; P ¼ 0.0001), most trials included in the meta-analyses used outdated 5fluorouracil (FU)-based systemic chemotherapies. In 2013, a new randomized trial13 was conducted that reported an updated outcome for OS and disease-free survival (DFS) using a more active FOLFOX4 chemotherapy regimen and a larger number of patients. Although this study demonstrated a significant improvement in DFS for the perioperative chemotherapy group in the intent-to-treat population, there was no assessment of the role of peri-operative chemotherapy in increasing the risk of peri-operative morbidity. The purpose of this study is to perform a meta-analysis to evaluate the effect of peri-operative chemotherapy for resectable CRCLM patients using data from the trials used were carefully selected, and the selection process is described below. Methods Search strategy We searched the PubMed, Embase, Ovid and ScienceDirect databases for eligible clinical studies published in English from January 1979 to May 2014, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement.14 The following key words were used: “chemotherapy”, “colorectal”, “cancer”, “liver metastasis”, “surgical”, “resection” and “hepatectomy”. Two reviewers (ZM Wang and YY Chen) independently screened and retrieved the literature list. We then listed all review articles, original articles and references of the articles to avoid missing any relevant publications. References within the articles were hand-searched for relevant articles. Any disagreement was resolved by discussing with another author (FF Chen).
Data extraction Articles were independently reviewed by two authors (ZM Wang and YY Chen). The following information was collected from each report: year of publication, number of patients, patient characteristics, resection status, chemotherapy regimen, OS, DFS and follow-up period. We used the Downs and Black quality assessment method to evaluate the study quality. This method includes 27 criteria to assess both randomized and non-randomized comparative studies.15 Statistical analysis We used the Review Manager 5.2 (Cochrane Collaboration, Oxford, UK) to perform the meta-analysis. To statistically evaluate the prognostic effect of peri-operative chemotherapy, we extracted the Hazard ratio (HR) and the associated standard error for DFS and/or OS from the included studies that provided these statistics. If HRs and their relative standard errors, P values or confidence intervals (CIs) were not provided in the original articles directly, the HRs were approximated according to the method described by Tierney.16 By convention, an HR < 1 suggests a better prognosis in the peri-operative chemotherapy group compared with the surgery alone group. The pooled extracted HRs were entered into the generic inverse variance method available in the Review Manager. The odds ratio (OR) was calculated during the analysis of the association between peri-operative chemotherapy and peri-operative complications. We defined the statistical result with a P value <0.05 as significant. The inter-study heterogeneity was evaluated using the chi-square test and quantified using the I2 statistic. A fixed-effect model was used if there was no heterogeneity, whereas a random effect model for secondary analysis was used if the heterogeneity was statistically significant (P < 0.10, I2 > 50%). Potential publication bias was assessed using a funnel plot and further quantified by Egger17 and Begg’s tests18 using STATA software (Version 12.0, College Station, TX).
Inclusion and exclusion criteria Results Studies were included based on the following criteria: (i) a randomized controlled trial (RCT) or comparative study in which patients were assigned to one of at least two groups (peri-operative chemotherapy plus surgery and surgery alone); (ii) patients had pathologically confirmed CRC and underwent curative resection; and (iii) at least one of the following was reported in the study: DFS, OS or complications outcomes. The exclusion criteria were as follows: (i) a review or non-comparative study; (ii) duplicate reports by the same institution; (iii) the patients in the study were less than 20 years old; (iv) patients had extrahepatic metastasis or recurrence on the chest or abdomen; and (v) studies where patients were assigned to receive different chemotherapy regimens.
Search results and characteristics of eligible studies The literature search retrieved 641 related references. After evaluating the studies against the inclusion/exclusion criteria, 10 studies including 7 RCTs and 3 non-randomized comparative studies were eligible to be included in this meta-analysis (Fig. 1). We categorized the 10 articles into 3 subgroups based on their treatment chemotherapy strategies: subgroup 1 included 3 trials on hepatic arterial infusion (HAI) chemotherapy7e9; subgroup 2 included 3 trials on regional (hepatic arterial or portal vein infusion) together with systemic chemotherapy10,19,20; and subgroup 3 included the other 4 trials on systemic chemotherapy.13,21e23 The groupings were unanimously agreed-
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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Figure 1. Flow chart of literature selection.
upon by the two reviewers. The basic descriptions of the 10 studies are shown in Table 1. Meta-analysis of overall survival The OS outcome reported by the 10 studies indicated no reduction in overall mortality that was attributable to perioperative chemotherapy (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07) (Fig. 2) There was no statistical heterogeneity (I2 ¼ 0%). Publication bias, tested by Egger’s test (P ¼ 0.684) and a funnel plot (Fig. S1), was negligible for the pooled analysis of OS. In the subgroups (Fig. 2), trials involving regional combined systemic chemotherapy showed no survival benefit (HR, 0.67 95% CI, [0.39, 1.14]; P ¼ 0.14; I2 ¼ 0%). Neither of the other subgroups, HAI and systemic chemotherapy, showed a significant improvement in long-term OS compared with surgery alone. The results for HAI are: HR, 0.95, 95% CI, [0.78, 1.17]; P ¼ 0.64; I2 ¼ 43%. The results for systemic chemotherapy are: HR, 0.85; 95% CI, [0.70, 1.03]; P ¼ 0.10; I2 ¼ 0%. We further evaluated the effect of these results by considering only the seven RCTs,7e10,13,22,23 and the results (HR, 0.89; 95% CI, [0.77, 1.03]; P ¼ 0.03) did not differ significantly compared with all trials in the pooled analysis (Fig. S2). Meta-analysis of disease-free survival The outcome generated from data that was extracted from all the studies showed that peri-chemotherapy treatment had a statistically significant positive effect on DFS (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007) (Fig. 3). We did not find
statistical heterogeneity (I2 ¼ 18%). Egger’s test (P ¼ 0.603) and a funnel plot (Fig. S3) showed that this combined analysis had no publication bias. In the seven RCTs, the outcome also reached a statistically significant difference (HR, 0.77; 95% CI, [0.68, 0.87]; P < 0.0001) (Fig. S4). In the subgroup analysis, only the systemic chemotherapy group showed a statistical significance difference between the two groups (HR, 0.81; 95% CI, [0.69, 0.96]; P ¼ 0.01) (Fig. 3). The outcome in the regional combined with systemic chemotherapy group was as follows: HR, 0.70; 95% CI, [0.46, 1.06]; P ¼ 0.09; I2 ¼ 0% (Fig. 3). Because of the large amount of heterogeneity in the HAI group (I2 ¼ 58%), we chose the random effects model to adjust heterogeneity. The results were as follows: HR, 0.82; 95% CI, [0.57, 1.18] and P ¼ 0.09. Meta-analysis of post-operative complications No significant statistical heterogeneity was found in the meta-analysis that included 4 studies10,13,21,22 with 1291 patients. The incidence of post-operative complications tended to be higher among patients who had received pre-operative chemotherapy (OR, 1.42; 95% CI, [1.05, 1.92]; P ¼ 0.02) (Table 2). Also, no significant difference was found in the post-operative death rate in the pooled analysis of three studies10,13,21 (OR, 1.36; 95% CI, [0.59, 3.13]; P ¼ 0.90) (Table 2). Discussion This study was the first to assess the clinical effect value in different peri-operative chemotherapy treatments
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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Table 1 Characteristics of studies included in meta-analysis. First author
Therapy regimen
Patients analyzed (n)
Chemotherapy/ control
Number of metastases
Comparative outcomes
Follow-up (Months)
Design
Quality score
Nordlinger 201313 Bolton 201219 Pinto 201121 Portier 200622 Kemeny 200210 Langer 200223 Rudroff 19997 Lorenz 19988 Lygidakis 19959 Donato 199420
FOLFOX4, systemic HAI, FUDR; systemic systemic 5-FU, systemic
364 49
182/182 36/13
1e4 1e2
PFSa; OS; OS;
122 66
RCT Prospective
25 17
676 171
334/342 86/85
1e6 1e4
DFS; OS DFSa; OS
60 87.4
Retrospective RCT
19 23
FUDR,HAI; 5-FU, systemic 5-FU, systemic 5FU, HAI
109
53/56
1e3
RFSa; OS
51
RCT
17
107 30
52/55 14/16
1e4 1e4
DFS; OSa RFS; OSa
n.r. 144
RCT RCT
18 18
5-FU, HAI
226
113/113
1e6
DFS; OSa
18
RCT
23
5-FU, HAI
40
20/20
n.r.
DFS; OSa
n.r.
RCT
16
124
40/62
1e4
DFS; OS
n.r.
Retrospective
15
5-FU, regional; systemic
Abbreviations: n.r.: not reported; PFS: progression-free survival; DFS: disease-free survival; OS: overall survival; RFS: Recurrence-free survival; HAI: Hepatic arterial infusion; PVI: portal vein infusion; 5-FU: 5-fluorouracil; FUDR: fluorodeoxyuridine. a It was the primary end-point of observing.
for patients diagnosed with CRCLM. CRCLM patients receiving peri-operative chemotherapy were compared with CRCLM patients who were undergoing surgery alone.
Our results were consistent with a previous systematic review that was published in 2006 by Nelson.11 Seven trials addressed this issue and included 592 patients, who were randomized either to HAI or an alternative treatment. No
Figure 2. Forest plots for the results of meta-analysis for overall time of the three subgroups.
Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020
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Figure 3. Forest plots for the results of meta-analysis for disease-free time of the three subgroups.
significant advantage in OS was found in the meta-analysis for hepatic artery chemotherapy (HR, 1.089; 95% CI, [0.887e1.334]). Another meta-analysis that used eight RCT studies was published in 2010 by Wieser,12 and their results suggested that peri-operative chemotherapy yielded no survival advantage over surgery alone (HR, 0.94; 95% CI, [0.8, 1.10]; P ¼ 0.43). In a subset analysis, the studies were divided into two subgroups (intra-arterial chemotherapy and systemic chemotherapy), and no survival benefit was evident. However, both peri-operative treatment groups mentioned above had a significant DFS benefit for the HAI subgroup (HR, 0.78; 95% CI, [0.65, 0.95]; P ¼ 0.01) and the systemic therapy subgroup (HR, 0.75; 95% CI, [0.62, 0.91]; P ¼ 0.003). The results were in agreement with our analysis of 7 randomized trials chosen as a result of less than 20 patients of 1 trial24 in the metaanalysis by Wieser.12 In our study, the OS did not show a statistically significant benefit (HR, 0.88; 95% CI, [0.77, 1.01]; P ¼ 0.07).
However, the subgroup analysis showed that there was a strong tendency towards a better OS in the systemic chemotherapy subgroup. Our pooled analysis also revealed a distinct advantage for DFS for patients in the systematic chemotherapy group (HR, 0.81; 95% CI, [0.72, 0.91]; P ¼ 0.0007). The OS and DFS results were not changed when we performed a pooled analysis of seven randomized trials. This result strongly supports our outcomes. Thus, these outcomes showed that systemic chemotherapy played a main role in a better patient OS or DFS. During this meta-analysis, we minimized heterogeneity by restricting the study design, sample characteristics and chemotherapy strategy. However, some degree of heterogeneity remained in the HAI group (I2 ¼ 58%). However, after adjusting for heterogeneity, the outcomes were not changed. The results suggested that two questions need to be answered. First, why isn’t the regional chemotherapy as beneficial as systemic chemotherapy in patients with
Table 2 Meta-analysis result of operative complications. No. of studies
Operative complication Operative death
4 3
Chemotherapy arm
Surgery arm
n/N
n/N
119/637 13/551
92/654 10/569
Or (95%CI)
1.42 (1.05, 1.92) 1.36 (0.59, 3.13)
P
0.02 0.47
Heterogeneity P
I2 (%)
0.72 0.90
0 0
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CRCLM? This is important for the clinical use of regional chemotherapy in stage III CRC to prevent liver metastasis after surgery. The meta-analysis published by Tang25 revealed that HAI might be able to reduce the rate of liver metastasis in patients with advanced CRC, and patients with resected stage IV CRC might also benefit from HAI treatment. However, systemic chemotherapy after liver surgery was considered to be insufficient26 because in stage IV CRC patients, tumor cells are likely to generate in the other places, such as lung, brain and bone marrow, which decreases the patient’s survival time.27 The variable results may also be attributed to the lack of well-designed randomized trials, insufficient number of patients and a HAI treatment duration that is too short to see a clinical effect. Second, why did peri-operative chemotherapy with surgery not result in a better OS? The following discussion may explain these results. Most of the trials included in our meta-analysis were initially designed to detect a DFS benefit and they were not powered for OS, which was a secondary endpoint. In addition, a good long-term outcome in the surgery-only group meant that demonstrating a treatment benefit for peri-operative chemotherapy was needed, but difficult to obtain.28 When there was a recurrence, OS was strongly affected by the other treatment, either surgical or medical. Chemotherapy was administered frequently to patients in the surgery only group at the first progression. Moreover, patients were treated with FOLFOX chemotherapy only in the recent trial by Nordinger.13 Most trials used outdated 5-FU-based systemic chemotherapies. Also, some main elements, for example, the number of liver metastasis lesions, operative resection status (R0 or R1), negative margins and the optimal timing of chemotherapy (post- or pre-operative) in each group may lead to a different OS.6 Because there were not enough studies that could provide sufficient data, we could not perform a further meta-analysis of the subgroups. Further studies are required to resolve these critical issues. The impact of chemotherapy on the peri-operative outcome remains controversial.29,30 Because there was insufficient data in the current meta-analyses, researchers highlight the assessment of grade 3 and 4 toxicities in patients receiving peri-operative chemotherapy.11,25 The results showed that toxicities were generally mild and acceptable. We noted that the use of pre-operative chemotherapy was also associated with an overall increased risk of peri-operative morbidity. Our results initially showed a slight increase in peri-operative complications among patients treated with pre-operative chemotherapy. However, we did not find an increase in peri-operative mortality. There were some limitations to this study. First, we restricted the database search to studies published in English only. Second, data were extracted based on the published paper instead of the individual patient data (IPD). A meta-analysis based on IPD could have a more reliable outcome than one based on extracted data. Third, there were few high quality RCTs in the studies that were
included in this meta-analysis. Although there were some RCT studies and the RCT data was pooled for additional analysis, highly-scoring studies were rare. Thus, the results may still be insufficient even after pooling and must be interpreted with caution. Conclusions This is the first meta-analysis to assess the clinical effect and value of different regional chemotherapy treatments for patients with resected CRCLM. Better OS and DFS outcomes for patients who underwent peri-operative regional chemotherapy were not found. There was little support for requiring peri-operative regional chemotherapy in patients with resectable CRCLM. Thus, peri-operative regional chemotherapy should be used in caution in these patients. Because peri-operative systemic chemotherapy can improve DFS in patients, it may be better than regional chemotherapy and should be acceptable in patients where CRCLM is resectable. Moreover, peri-operative chemotherapy could significantly increase post-operative complications, which needs to be verified in future clinical practice. Conflict of interest There is no conflict of interest in relation to this study. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2015.05.020.
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Please cite this article in press as: Wang Z-M, et al., Peri-operative chemotherapy for patients with resectable colorectal hepatic metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.020