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The therapeutic efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is still under debate. This meta-analysis and systematic review of published literature on this comprehensive strategy aims to evaluate its efficacy on CRC patients with PC.
A systemic review with meta-analysis of published literatures on treatment of CRS plus HIPEC for patients with PC from CRC was performed. In addition, a summary of study results of published literatures concerning CRS plus HIPEC treating patients with PC from CRC was also conducted.
A total of 76 studies were selected, including 1 randomized controlled trial, 14 non-randomized controlled studies, and 61 non-controlled studies. The pooled hazard ratios (HRs) for overall survival (OS) in the 15 researches for meta-analysis was 2.67 (95% CI, 2.21-3.23, I2= 0%, P < 0.00001), and no significant evidence of publication bias was found. The difference of chemotherapy regimens of HIPEC was not associated with OS and DFS (disease-free survival) after CRS and HIPEC, with no significant difference of heterogeneity (P = 0.27, I2 = 24.1%). In both groups of mitomycin C based HIPEC group and oxaliplatin group, patients received HIPEC had significant better survival (P < 0.00001). The mean mortality and morbidity for HIPEC program were 2.8% and 33.0%, respectively.
This meta-analysis revealed that comprehensive therapeutic strategy of CRS plus HIPEC could bring survival benefit for selected patients with PC from CRC with acceptable safety.
Peritoneal carcinomatosis (PC), as a lethal regional progression for patients with colorectal cancer (CRC), has long been considered as a terminal condition with few effective treatments. In the past, the median overall survival (OS) of PC from colorectal cancer is 4 to 7 months after palliative surgery or 5-FU-based systemic chemotherapy with best supportive care [1-3]. Current systemic chemotherapy focusing on new chemotherapeutic agents such as oxaliplatin and irinotecan, along with anti-angiogenesis molecular targeting agents cetuximab and bevacizumab [4-7], could extend the median OS up to about 12 months . However, long-term survival is still hard to be achieved by systemic chemotherapy alone.
Researches on treatment of CRC PC did not reveal promising progress until the development of a comprehensive treatment strategy including cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative chemotherapy.[8-15] This new comprehensive treatment improves the median OS of selected patients with CRC PC up to 21-63 months, and 5-year survival rate up to approximately 40% [16-28], or even 58% according to the American Society of Peritoneal Surface Malignancies (ASPSM) multi-institution study . It has been widely recognized in North America, Europe, Australia, and Japan [14, 24, 26, 30-32]. In the 9th International Congress on Peritoneal Surface Malignancies in Amsterdam in 2014, peritoneal surface oncology group international (PSOGI) reached a consensus that CRS+HIPEC should be considered as the standard therapy for the selected patients with mild-to-moderate CRC PC .
Nevertheless, therapeutic efficacy of this comprehensive treatment strategy for CRC PC patient remains controversial due to insufficient convincing evidence. Therefore, we conducted this meta-analysis of published clinical studies to verify the efficacy of this strategy against CRC PC.
Literature search identified 326 researches, 76 of which met the inclusion criteria, including 1 randomized controlled trail (RCT) (87 patients) , 14 non-randomized controlled studies (3,092 patients) [13-15, 26, 28, 29, 34-40, 99], and 61 non-controlled studies (6,857 patients) [16, 19-21, 41-92, 100-104]. The other 250 studies were excluded for miscellaneous reasons, and the flowchart of search strategy is showed in Figure Figure1.1. We conducted a meta-analysis on the 15 controlled studies (3,179 patients) and a summary of 76 HIPEC-related studies (10,036 patients).
The characteristics of 15 controlled studies [8-15, 26, 28, 29, 34-40, 99] were shown in Table Table11--5,5, and all 76 selected studies [12-16, 19-21, 26, 28, 29, 34-92, 99-104] were summarized in Table Table66--10.10. All these studies were published between 1993 and 2016 as full texts, performed in 19 countries and regions (Table (Table1111--19).19). Fifty-eight studies were single-center studies [12, 16, 19, 21, 35, 36, 38-43, 45, 43-53, 55-57, 60-63, 66-71, 74-83, 86-92, 99, 100, 102-104], and the other 18 were multicenter studies (participating institutions from 2 to 28) [13-15, 28, 29, 34, 37, 44, 46, 54, 58, 59, 64, 65, 72, 73, 84, 85, 101]. In these multicenter studies, 6 studies were performed by over 10 participating institutions included studies conducted by Glehen et al (n = 28, a central database) , Glehen et al (n = 25, a central database) , Elias et al (n = 25, a central database) , Esquivel et al (n = 21, The American Society of Peritoneal Surface Malignancies (ASPSM)) , and Prada-Villaverde et al (n = 15) . A total of 63 articles were retrospective studies, in which 11 articles were included in this meta-analysis [13-16, 19-21, 28, 29, 34, 37-40, 43-48, 50-52, 54-57, 59-66, 68-72, 74-88, 91, 99-104]. Thirteen articles were prospective studies, in which 4 were included in this meta-analysis [12, 26, 35, 36, 42, 49, 53, 58, 67, 73, 89, 90, 92]. According to the North-England evidence-based guidelines [34, 35], there was one evidence level Ib in this meta-analysis , the rest cohort studies or “outcome” researches were evidence level II.[13-15, 26, 28, 29, 34-40, 99]
In this meta-analysis, the median complete cytoreduction (CC0-1) rate was 72.2% (range, 32.4% - 100%), including 4 studies with 100% CC0 [28, 35, 36, 40], 7 studies with 50% - 99% CC0 [14, 15, 26, 29, 34, 37, 99], and 4 studies with <50% CC0 [12, 13, 38, 39]. Major clinico-pathologic characteristics of the 6,857 CRC PC patients (sample size ranging from 11 to 660) in 61 non-controlled studies are listed by Table Table66--1010.
Major technical features of HIPEC procedures in each institution are summarized in Table Table1111--19.19. HIPEC was performed using only open technique in 22 institutions and only closed techniques 10 institutions, with 41 institutions used both open and closed techniques. The commonly used chemotherapy agents were mitomycin C (MMC) alone (n = 63, dosage of 30-50 mg/m2 in 88% of institutions, median temperature 41.5°C, ranging from 40 - 43°C, and median duration 90 min, ranging from 60 - 90 min), oxaliplatin (L-OHP) alone (n = 43, dosage of 460 mg/m2 in 60% of institutions, median temperature 43°C, ranging from 40 - 43°C; and median duration 60 min), and a combination of MMC and cisplatin (CDDP) (n = 24, dosage of 30-50 mg/m2 + 50-100 mg/m2 in 33% of institutions).
The summarized HRs for OS in the 15 controlled researches was 2.67 (95% CI, 2.21-3.23, I2 = 0%, P < 0.00001) (Figure (Figure2a),2a), suggesting that CRC PC patients could obtain more benefits from CRS plus HIPEC than traditional therapy, without apparent heterogeneity among the studies (P = 0.81, I2 = 0%).
Sensitivity analysis of summarized HR and 95% CI showed no difference after choosing random effects model and fixed effects model. In terms of sample size difference, 15 researches were divided into three subgroups (sample size <50, 50-100, >100) by a sensitivity study for a stratified meta-analysis. The summarized HR and 95% CI showed no difference, with no between-subgroup heterogeneity (P = 0.48, I2 = 0%) (Figure (Figure2b).2b). In a sensitivity analysis, four studies with potential heterogeneity was removed due to small sample size  or asymmetrical sample size between two groups [14, 26, 40, 99], but the summary HR was 2.81 (95%CI, 2.28-3.48, I2 = 0%, P heterogeneity = 0.56).
Regarding the effect of different chemotherapy regimens in HIPEC procedure on the efficacy on OS or DFS, 15 researches were divided into 3 subgroups: group of MMC based chemotherapy, group of L-OHP based chemotherapy, and group of other regimens. The heterogeneity showed no significant difference (P = 0.27, I2 = 24.1%), which revealed that difference of chemotherapy regimens of HIPEC was not associated with OS and DFS after CRS and HIPEC in this meta-analysis (Figure (Figure3a).3a). A further analysis of difference in median year survival rate between group of CRS plus HIPEC and group of traditional treatment was conducted by independent-samples T test stratified by MMC and L-OHP subgroups (Figure (Figure3b3b and Figure Figure3c3c).
OS data by MMC-based HIPEC procedure were available in 7 studies with 614 patients [12, 13, 15, 34, 35, 37, 39]. Due to more patients received MMC regimen in studies by Elias et al.  (21 patients for MMC regimen, while 6 patients for L-OHP regimen) and Glehen et al.  (322 patients for MMC regimen, while 32 patients for L-OHP regimen and 29 patients for others), these two studies were included in MMC subgroup. The stratification analysis showed that OS of patients receiving HIPEC by MMC was significantly improved (HR = 2.88, 95% CI, 2.26-3.68, I2 = 0%, P < 0.00001) (Figure (Figure3a),3a), with 1-, 3-, and 5-year survival rates of 79.5%, 38.8%, and 34%, respectively (Figure (Figure3b).3b). In comparison, the corresponding survival rates in the traditional group were 54.9%, 18.3%, and 9.7%, respectively (Figure (Figure3b3b).
Four studies using L-OHP based chemotherapy in HIPEC procedures of 283 patients [28, 36, 38, 40, 99]. A statistically significant benefit for OS was revealed in HIPEC group (HR = 2.18, 95% CI, 1.57-3.04, I2 = 0%, P < 0.00001) (Figure (Figure3a),3a), with the 1-, 3-, and 5-year survival rates of 93%, 59%, and 43%, respectively in HIPEC group vs. 63%, 25%, and 14%, respectively in traditional group (Figure (Figure3c3c).
Three trials [14, 26, 29] were identified as the subgroup of other regimen due to difficulties in identifying them as MMC subgroup or L-OHP subgroup since mixed chemotherapy regimens were used in HIPEC during the whole disease course. A significant survival benefit in HIPEC group vs. traditional group (HR = 3.90, 95% CI, 1.73-8.81, I2 = 0%, P < 0.00001) was demonstrated (Figure (Figure3a3a).
Publication bias was evaluated with funnel plot analyses, as shown in Figure Figure4,4, and the funnel plot was symmetric. No apparent publication bias was found in our OS meta-analysis with Begg's test (z continuity corrected = 0.99, Pr >|z|continuity corrected = 0.32) (Figure (Figure4a),4a), or with Egger's test (t = 0.82, P >|t|= 0.427, 95%CI of bias: -0.49˜1.1) (Figure (Figure4b4b).
In 15 controlled studies and 59 single-arm studies, HIPEC-related outcomes including survival rates, median OS and 95% CI, DFS/RFS, PFS, follow-up time, morbidity, and mortality, are summarized in Table Table2020--2525 and Figure Figure55
In controlled studies, the mean (± SD) mortality and morbidity rates were 4.3% (± 3.7%) and 19.8% (± 9.2%) in HIPEC groups, 6.2% (± 4.2%) and 20.5% (± 12.3%) in traditional groups, respectively (Table 20-25). No significant difference in mortality (P = 0.423) or morbidity (P = 0.815) was detected between HIPEC group and traditional group by T test. In the integrated HIPEC-related data of 76 studies, mean mortality and morbidity was 2.8% (± 2.9%) and 33.0 (± 13.4%), respectively.
Due to the tumor biologic characteristics of colorectal cancer, about 10-13% patients have already progressed to PC when CRC is diagnosed [3, 7], which has a poor prognosis. In order to improve the efficacy, a comprehensive treatment strategy with combination of CRS plus HIPEC had been developed. With wide application of this treatment, CRS plus HIPEC has been proved capable to achieve better survival in selected patients with PC from colorectal cancer.
This meta-analysis of 15 controlled studies demonstrated that CRS+HIPEC comprehensive therapeutic strategy could bring significant survival benefit for selected CRC PC patients than traditional treatment of palliative surgery alone or systemic chemotherapy (HR = 2.67, 95% CI 2.21-3.23, P < 0.00001). In addition, the summarizing analysis of these 76 studies showed that the median OS was about 29 months in HIPEC group, which is significant longer compared with median OS of 17.9 months for CRC PC patients receiving contemporary chemotherapy reported by Kerscher et al (n = 2,406) . These results provide further supporting evidence that CRS+HIPEC as the principal comprehensive treatment can bring more survival benefit to selected patients with CRC PC than traditional therapy.
The different regimens used in chemotherapy may be one potential confounding factor for survival outcomes. In order to investigate the influence of chemotherapy regimens on postoperative survival, a stratification analysis between MMC based regimens and L-OHP based regimens was conducted. The results of heterogeneity showed no significant difference (P = 0.50). These results are inconsistent with the reports by Elias et al , which showed that OS advantage for L-OHP regimens over non-L-OHP regimens (32 vs. 25 months, P = 0.02). However, L-OHP used in HIPEC was not an independent prognostic factor for survival in the study of Elias and colleagues. A multi-center retrospective controlled study reported by Prada-Villaverde et al.  showed that of 539 patients undergoing CRS plus HIPEC, L-OHP based HIPEC and MMC based HIPEC achieved similar median OS (31.4 vs. 32.7 months, P = 0.925). Similarly, the study of Hompes et al.  yielded the same conclusion that there was not obvious benefit in OS for HIPEC with L-OHP (37.1 months) or MMC (26.5 months) (P = 0.45). Although different chemotherapy regimens in HIPEC may have an effect on stability and reliability of this meta-analysis, the result of heterogeneity analysis was in accordance with above studies. As a result, both MMC and L-OHP were the feasible chemotherapy drugs in HIPEC for CRC PC patients to achieve similar efficacy.
Moreover, there are also some doubts that different chemotherapy in intravenous or postoperative intraperitoneal therapy regimens, even targeted therapy, had interference on the survival outcomes in meta-analysis. The doubts were removed by the report of Kerscher et al . In 2,406 CRC patients of no-PC and PC, the survival outcomes for contemporary chemotherapy regimens (oxaliplatin or irinotecan) were compared with 5-FU regimens. For the CRC patients (without PC), survival outcomes for contemporary regimens were increased over 5-FU regimens (5-year survival rate 71.6% vs. 63.3%, P = 0.001). On the contrary, for patients with PC from CRC, the survival of L-OHP or irinotecan agent was similar to 5-FU regimens (P > 0.05), regardless of synchronous PC (2-year survival rate 31.1% vs. 19.1%, P = 0.092, and 5-year survival rate 20.8% vs. 5.8%, P = 0.081) or metachronous PC (2-year survival rate 71.5% vs. 58.5%, P = 0.329, and 5-year survival rate 28.1% vs. 24.4%, P = 0.411).
There were a few statistical flaws in this meta-analysis. For example, only one RCT  was included. It may be due to the difficulty of performing RCT. Therefore, we had to select meticulously current studies of best evidence level besides the only RCT. However, this meta-analysis showed acceptable outcomes of low heterogeneity and sensitivity. Regrettably, a patient-level (based on single patient data) meta-analysis as the gold standard for meta-analysis was not performed because of the difficulty in obtaining vast data from each database or institution. In addition to meta-analysis, this report provided a summary of 76 clinical studies published until today about CRS and HIPEC, which can get a review of published studies. In order to get the best evidence level results, more RCTs and prospective, multicenter, large-scale clinical trials need to be performed in future studies.
Observing available data from 6 controlled studies (a total of 470patients) [12, 35, 36, 38, 39, 99], mortality or morbidity were found similar in both groups of HIPEC and traditional surgery, which was 4.3% vs. 5.0% and 19.8% vs. 19.5%, respectively. The summarized HIPEC-related mortality and morbidity in 48 articles (the total number of patients, n = 4,809) [12, 16, 20, 35, 36, 38, 39, 46, 48-50, 52-54, 56, 58-62, 64-69, 71, 73, 75, 76, 79, 80, 82-90, 92, 100-104] were 2.8% (SD, ± 2.9%; range, 0-12%) and 33.0% (SD, ± 13.4%; range, 4-60%), respectively. Some large-sample retrospective studies and population-based analysis found a series of approximate results that the range of mortality was 2%-5.6% and morbidity was 25%-34% [93-97]. Furthermore, a systematic review of morbidity and mortality for CRS+HIPEC by Chua et al.  showed that the mortality and morbidity range from 0.9% to 5.8% and 12% to 52%, respectively. Though evidence proved that safety for CRS+HIPEC was acceptable, a meta-analysis on mortality and mortality for CRS+HIPEC may be able to provide more convincing results on the mortality and morbidity.
With the summary of 76 studies, it is found that although HIPEC is now widely accepted and performed in most institutions, details of performing HIPEC varies among different institutions. As we noted, there are several mainly different techniques concerning HIPEC including 1) “open” or “closed” technique, 2) using MMC and/or L-OHP, 3) mono-chemotherapy or combination of chemotherapy regimens, 4) temperature and duration of HIPEC. These can be further studied in future studies.
In conclusion, this meta-analysis showed that CRS+HIPEC comprehensive therapeutic strategy was associated with improvement of OS in CRC PC patients, and the results of the meta-analysis were proved of good reliability by low heterogeneous and robust sensitivity. Meanwhile, CRS and HIPEC can be performed with acceptable safety according to summary results of all 76 studies.
The following databases were systematically searched up to July 31, 2016 including PubMed, Science Citation Index, EMBASE, and MEDLINE. The Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and conference proceeding articles from major oncologic and gastrointestinal cancer meetings were also sought for published results. The key words included “colon”, “rectum”, “colorectal”, “cancer”, “peritoneal carcinomatosis”, “hyperthermic intraperitoneal chemotherapy”, and synonyms and related terms for these words. The MeSH terms included “colon cancer”, “rectal cancer”, “colorectal cancer”, “peritoneal carcinomatosis”, “hyperthermic chemotherapy”, “hyperthermic intraperitoneal chemotherapy”, “HIPEC”, “intraperitoneal chemohyperthermia”, and “IPCH”. The combined application of “key words terms” and “MeSH terms” were conducted to improve the efficiency and accuracy of literature search.
For inclusion in the meta-analysis and summarized HIPEC-related data analysis, a study had to fulfill the following criteria: (1) According to the North-England evidence-based guidelines [105, 106], excluded from IV levels evidence of literatures were included; (2) All patients were diagnosed CRC PC; (3) For assessing CRS+HIPEC±SC/EPIC, the intervening measure group was CRS+HIPEC±SC/EPIC, while the control group was traditional therapy of surgery and/or SC; For systematic review of CRS+HIPEC to treat CRC PC, HIPEC-related literatures involving clinical efficacy evaluation were included; (4) The key outcome measures should be included in literatures, such as OS, disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), year survival rate, morbidity and mortality , multivariate analysis, follow-up times; (5) English language; (6) To reduce the effect of publication bias, both fully published articles and abstracts were eligible for inclusion.
Exclusion criteria: (1) Animal studies, pathological research, imageology research, pharmacokinetics research, quality of life assessment, literature review, commentary, letter, book, etc; (2) Duplicate publication or overlapping data (chose the largest and latest sample size); (3) The sample size is less than 10; (4) Multiple cancer; (5) Unresectable liver metastases or others distant metastasis; (6) missing rate of follow-up > 5%.
Three authors analyzed data from a meta-analysis of 15 controlled researches of CRS plus HIPEC group vs. surgery and/or SC group and a summarized analysis of 76 researches of HIPEC group. The following data were extracted from each article: (1) Major clinico-pathologic characteristics and detail HIPEC regimens; (2) Survival and advent events. All relevant text, tables, and figures were reviewed for data extraction. For equivocal literatures or discrepancies between two independently assessed reviewers, these were resolved by discussion and consensus with a third author.
All meta-analysis were performed using Review Manager 5. Overall survival (OS) or disease-free survival (DFS) in all studies were extracted from original literature. If not achieved accurate data in original text, hazard ratios (HRs) for time-to-event outcomes with 95% confidence intervals (95% CI) in two groups were estimated by Tierney's methods . The heterogeneity in the meta-analysis was evaluated by I2 statistics  and T test  was calculated for each result in summarizing analysis of all HIPEC-related data from the included 76 articles. If I2 >50%, it was defined as the unacceptable heterogeneity. If I2 <50%, fixed effect model was used to get pooled HR and 95% CI; otherwise, random effects model was used if moderate heterogeneity. For a sensitivity analysis, we investigated the different research features of eligible trials, which included statistical methods, methodological quality, sample sizes, and clinical factors on HIPEC-related effect, after that, summarizing each subgroup data in term of Mental-Haenszel stratification analysis. According to Egger's test  and Begg's test , publication bias was considered to be inevitable when P < 0.10. The funnel plot analyses using ‘STATA: Data Analysis and Statistical Software version 12.0’, was to observe the results of meta-analysis whether any publication bias.
This study was supported by the grants for the Young Teacher Foundation of the Fundamental Research Fund for the Central Universities (No. 413000009), the Wuhan Clinical Research Center for Peritoneal Carcinomatosis (No. 2015060911020462), the Hubei Province's Outstanding Medical Academic Leader Program (No. 4) and the Science Fund for Doctorate Mentors by China's Ministry of Education (No. 20120141110042).
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.