The effectiveness and safety of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-1425702/v1

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The effectiveness and safety of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-1425702/v1

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Objectives: This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) on colorectal peritoneal metastasis (CRPM) and provide more reliable evidence for clinical practice.

Methods: We searched for relevant randomized controlled trials (RCTs), case-control studies and cohort studies in PubMed, Web of Science, Cochrane Library, and Embase databases from their inception to 1 January 2022. Hazard ratio (HR) and odd ratio (OR) with 95% confidence intervals (CIs) were performed a meta-analysis using RevMan 5.3 software.

Results: A total of twelve studies, of which three RCTs, eight cohort studies and one case-control study were included, and 3605 participants were involved. The results showed that CRS plus HIPEC was better than other remedial measures at improving the overall survival (OS) (HR=0.46, 95% C1:0.35-0.61, P=0.02). However, the heterogeneity was obvious (P<0.0001, I²=73%). According to different control measures, it is divided into three subgroups of CRS, CRS plus intraperitoneal chemotherapy (IPC) and palliative chemotherapy (PC). The results of subgroup analysis showed that CRS plus HIPEC was better than CRS plus IPC at enhancing the OS (HR=0.58, 95% CI :0.36-0.93, P=0.02) and was more effective than PC at improving the OS (HR=0.29, 95% CI :0.24-0.35, P<0.00001). On the contrary, CRS plus HIPEC was no significant effect than CRS at improving the OS (HR=0.76, 95% CI :0.57-1.01, P=0.06). In addition, CRS plus HIPEC had more adverse events than CRS (OR=1.69, 95% CI : 1.06-2.70, P=0.03).

Conclusions: This systematic review and meta-analysis suggests that CRS plus HIPEC might be effective to CRPM in improving the OS. However, compared with CRS alone, the efficacy of CRS plus HIPEC has not improved much, and CRS plus HIPEC may bring more adverse events.

cytoreductive surgery

hyperthermic intraperitoneal chemotherapy

colorectal peritoneal metastasis

meta-analysis

Colorectal cancer (CRC) is currently the third most common cancer worldwide and the second most common cause of cancer-related death[1]. According to global cancer statistics, there are approximately 1.93 million new cases and 930,000 deaths in 2020[1]. The most common metastatic site of colorectal cancer is the peritoneum, and about 8–13% of colorectal cancer patients develop peritoneal metastases sometime after initial diagnosis[2, 3]. Colorectal cancer peritoneal metastasis (CRPM) is an almost incurable end-stage disease with a median survival of only 3–6 months[4, 5]. The primary treatment strategies are systemic chemotherapy and palliative support, but they have limited efficacy[6].

With further understanding of CRPM, it is no longer generally considered to be advanced cancer metastases but rather a regional tumor progression[7]. CRS plus HIPEC has been gradually applied for the treatment of CRPM. In 2003, Verwaal et al. published a randomized controlled trial of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treating CRPM. This study showed CRS plus HIPEC were nearly twice as long as systemic chemotherapy in prolonging survival time[8]. A total of three systematic reviews have been published on CRS plus HIPEC in treating CRPM [9–11]. The results showed that CRS plus HIPEC can prolong the survival time of CRPM patients without severe adverse events, but lacked inclusion of high-quality studies. In 2021, François Quénet et al. reported a multicenter randomized controlled trial in The Lancet Oncology including 265 patients with CRPM. Their results showed that CRS plus HIPEC was no overall survival benefit for CRPM and had higher complication rates in late stage of disease[12]. The study are likely to affect the reliability of the results of the systematic reviews and even may change the conclusion, especially in CRS alone compared with CRS plus HIPEC. Therefore, the effectiveness and safety of CRS plus HIPEC in the treatment of CRPM should be reevaluated to provide more reliable evidence for clinical practice.

This systematic review and meta-analysis performed as per the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. And its protocol was registered in PROSPERO (number CRD42022303110)[13].

Eligibility criteria

This systematic review and meta-analysis included randomized controlled trials (RCTs) , case-control trials and cohort studies. There were no language, the published status, or length of follow-up restrictions. The participants were diagnosed with CRPM. The intervention of the experiment group was CRS plus HIPEC and the control group was CRS, palliative chemotherapy (PC) , or intraperitoneal chemotherapy (IPC). The primary outcome of this study was the overall survival (OS) and adverse events was the secondary outcome. We excluded reviews, uncontrolled studies, without survival analysis data trials, conference abstracts and no full text.

Search strategy

Two reviewers searched the following four databases from their inception through January 1, 2022 according to the Cochrane handbook guidelines[14]. The databases comprise PubMed, Cochrane Library, Web of Science, and Embase. We searched MeSH terms and synonyms such as “cytoreduction surgical procedures,” “hyperthermic intraperitoneal chemotherapy,” and “colorectal peritoneal metastases”. The search strategy is shown in the Supplementary search terms and strategies. In addition, we also searched the conforming literature through published systematic reviews.

Data extraction

Two researchers independently extracted the data using predesigned tabulation and checked the extraction results together. Any disagreement was judged by a third author. Two reviewers extracted the following information from the included literature: general characteristics of this study (the first author’s name, sample size, publication year, etc.), methods, interventions, follow-up time, hazard ratio (HR), 95% confidence intervals (CIs) and adverse events. If HR (95% CIs) was not mentioned in the study, we calculated HR (95% CIs) through the follow-up time and survival rate in the survival curve graph.

Risk of Bias Assessment

Two authors independently assessed the methodological quality of the included RCTs using the Cochrane Handbook for Systematic Reviews[15]. The disputes were resolved by a third author. And each study was estimated as high, low, or unclear risk of bias. Two reviewers independently assessed the methodological quality of the included cohort studies and case-control studies using the Newcastle-Ottawa Scale (NOS)[16]. The score was from 0 to 9 and 5 to 9 score was rated as high-quality.

Statistical Analysis

We used RevMan 5.3 software (International Business Machines Corporation, China) for data analysis. The overall survival (OS) data were analyzed using HR and 95% CIs. Adverse events data were analyzed using OR and 95% CIs. Heterogeneity was analyzed using I² and Q-test. When the heterogeneity was no significant (P>0.10, I²<50%), we applied the fixed-effect model. When there was obvious heterogeneity (P≤0.10, I²>50%), a random-effects model was used. Moreover, we analyzed the cause of heterogeneity by subgroup analysis or sensitivity analysis. Subgroup analysis was conducted according to types of interventions in control groups. Sensitivity analysis was performed derived from types of study methods and different contrast schemes. A funnel plot was used for assessing publication bias.

Study selection

Figure 1 shows the flow diagram of the search and selection process. A total of 1256 records were identified, of which 385 duplicates were removed. We excluded 849 records for not meeting eligibility criteria by screening the titles and abstracts. After screening the full text, 10 trials were excluded. A total of 12 studies were included.

Study Characteristics

Table 1 shows the characteristics of included twelve trials. There were three RCTs[8, 12, 17], eight cohort studies[6, 18-24], and one case-control study[25]. The sample sizes ranged from 34 to 2277. A total of 3605 participants were included in the twelve studies, and they were diagnosed as CRPM. The intervention in the experimental group was CRS plus HIPEC. One RCT, one case-control trial and one cohort study used CRS as the intervention in the control group. Two cohort studies included CRS plus IPC as the control group. Two RCTs and four cohort studies included PC as the control group, and one study did not mention the intervention of the control group. For the primary outcome, five studies reported HRs and 95% CIs. The seven studies extracted HRs and 95% CIs based on survival curves. For the secondary outcome, four trials reported adverse events in the experimental and control groups. Eleven studies mentioned follow-up time, and the median follow-up time ranged from 21.6 to 113 months.

Risk of bias

Figure 2 shows the quality assessment of the included RCTs. Three RCTs reported the generation of random sequences was performed by computer. None of the three studies describe allocation concealment. None of the three trials mentioned blinding of the investigators, participants, and outcome assessors. Only one study reported the quantity of dropouts. The result of the quality assessment of the included cohort studies and case-control study was presented in supplementary the characteristics of the included trials. The five cohort studies were seven score and one cohort study was eight score. Both of them were high-quality studies. Two cohort studies were six score. One case-control study was seven score. The funnel plots of the included studies showed no significant publication bias (Figure 3).

Table 1 The characteristics of the included trials

Reference	Country	Research types	Sample sizes (T/C)	HR (95%CI)	Control	Follow-up (Median follow-up)	Adverse events	Outcomes	NOS
Franko2010	American	Cohort study	105 (67/38)	0.42 (0.19-0.91)	PC	-	-	OS	6
Razenberg2015	Netherland	Cohort study	2277 (297/1980)	0.29 (0.23-0.36)	PC	-	-	OS	7
Elias2007	France	Cohort study	46 (23/23)	0.46 (0.13-1.67)	CRS+IPC	113 months (range, 70-188)	T: 4; C: 9	OS	8
Cashin2012	Sweden	Cohort study	126 (69/57)	0.60 (0.36-0.99)	CRS+IPC	49 months (range, 0.5-200)	-	OS	7
Larentzakis2019	Britain	Cohort study	286 (117/169)	0.36 (0.24-0.52)	-	8 years	-	OS	7
Elias2009	France	Cohort study	96 (48/48)	0.35 (0.19-0.64)	PC	T: 95.7 months; C: 63 months	-	OS	7
Baratti2020	Italy	Cohort study	96 (48/48)	0.73 (0.47-1.15)	CRS	T: 31.6 months; C: 39.9 months	T: 27; C: 28	OS	7
Gervais2013	Canada	Cohort study	34 (25/9)	0.21 (0.12-0.52)	PC	22.8 months (range, 2-81)	-	OS	6
Huang2014	China	Case-control study	62 (33/29)	0.43 (0.21-0.89)	CRS	T: 36.6 months(range, 15.5-82.9) C: 41.5months(range, 11.5-70.9)	T: 10; C: 3	OS	-
Verwaal2008	Netherland	RCT	105 (54/51)	0.60 (0.38-0.97)	PC	94months (range, 72-115)	-	OS	-
Verwaal2003	Netherland	RCT	105 (54/51)	0.55 (0.32-0.95)	PC	21.6months	-	OS	-
Quenet2021	France	RCT	267 (135/132)	1.00 (0.63-1.58)	CRS	63.8months	T: 25; C: 16	OS	-

RCT: randomized controlled trial; T: treatment group; C: control group; HR: Hazard ratio; 95% CI: 95% confidence interval; PC: palliative chemotherapy; CRS: cytoreductive surgery; CRS+IPC: cytoreductive surgery plus plus intraperitoneal chemotherapy; OS: overall survival.

Primary Outcome

Twelve trials included 3605 participants reported the OS. The meta-analysis of twelve trials showed that CRS plus HIPEC had a greater effect than other therapeutic measures (random-effect estimates; HR: 0.46; 95% C1: 0.35~0.61; P=0.02), with significant heterogeneity (I²=73%) (Figure 4). The assessment of primary outcome was divided into three subgroups according to the different interventions of the control group. One study not mentioned intervention in the control group used the descriptive analysis.

Subgroup 1 included three trials[12, 19, 25]. The meta-analysis of the three trials showed that there was no significant difference between CRS plus HIPEC and CRS, with no significant heterogeneity (fixed -effect estimates; HR: 0.76; 95% C1:0.57~1.01; P=0.06; I²=48%) (Figure 5).

Subgroup 2 included two studies[18, 24]. The meta-analysis of the two trials showed that CRS plus HIPEC had a better effect than CRS plus IPC, with no significant heterogeneity (fixed-effect estimates; HR: 0.58; 95% C1: 0.36~0.93; P=0.02; I²=0%) (Figure 6).

Subgroup 3 included six studies[8, 17, 20-23]. The meta-analysis of the six trials showed that CRS plus HIPEC had a greater effect than PC, with significant heterogeneity (random-effect estimates; HR: 0.37; 95% C1: 0.27~0.52; P<0.00001; I²=64%) (Figure 7). The source of heterogeneity was considered to be due to two RCTs as identified by sensitivity analysis. The meta-analysis of remaining four cohort studies showed CRS plus HIPEC had a better effect than PC, with no significant heterogeneity (fixed-effect estimates; HR: 0.29; 95% C1: 0.24~0.35; P<0.00001; I²=0%) (Figure 8). Descriptive analysis was applied for the two RCTs. The results showed that CRS plus HIPEC had a greater effect than PC (HR: 0.55 and 0.6; 95% C1: 0.32~0.95 and 0.38-0.97).

In addition, one study[6] did not mention intervention of the control group. Descriptive analysis was applied for the trial. The results showed that CRS plus HIPEC had a better effect (HR: 0.36; 95% C1: 0.24~0.52).

Secondary Outcome

Four studies reported adverse events[12, 19, 24, 25]. The meta-analysis of the four studies showed that CRS plus HIPEC had a higher adverse effects than other therapeutic measures, with significant heterogeneity (random-effect estimates; OR: 1.15; 95% C1: 0.45-2.96; P=0.77; I²=72%) (Figure9). The source of heterogeneity was considered to be due to the study of control group for CRS plus IPC as identified by sensitivity analysis. The meta-analysis of remaining three studies showed CRS plus HIPEC had a higher adverse effects than CRS, with no significant heterogeneity (fixed-effect estimates; HR: 1.69; 95% C1: 1.06~2.70; P=0.03; I²=40%) (Figure 10).

Principal findings

This systematic review and meta-analysis suggests that CRS plus HIPEC may have an effect on improving the OS, but the combination of CRS and HIPEC may not have significant synergistic effect. Moreover, CRS plus HIPEC might have more adverse events than CRS alone.

Summary of results

For primary outcomes, this meta-analysis included twelve studies. Comparing CRS plus HIPEC with other normal treatments, it showed that CRS plus HIPEC was more effective at increasing the OS. However, there was obvious heterogeneity (I²=73%). Three trials compared CRS plus HIPEC versus CRS. This meta-analysis found that there was no significant difference and no obvious heterogeneity (I²=48%). Two trials compared CRS plus HIPEC versus CRS plus IPC. This meta-analysis found that CRS plus HIPEC was more effective than CRS plus IPC. There was no heterogeneity (I²=0%). Six studies (two RCTs and four cohort studies) compared CRS plus HIPEC versus PC. But there was obvious heterogeneity (I²=64%). Four cohort studies compared CRS plus HIPEC with PC. This meta-analysis found that CRS plus HIPEC was more effective than PC and no heterogeneity (I²=0%).

For secondary outcomes, this meta-analysis included four trials. The results of this meta-analysis showed that CRS plus HIPEC had higher adverse events than other normal treatments. But there was significant heterogeneity (I²=72%). Three studies compared CRS plus HIPEC with CRS. This meta-analysis found that CRS plus HIPEC had higher adverse effects than CRS alone. And there was no significant heterogeneity (I²=40%).

Comparison with other studies

Three analogous systematic reviews were published [9-11]. Their results showed CRS plus HIPEC might bring survival benefit for the treatment of CRPM and have acceptable safety. However, their studies lacked high-quality clinical trials. Furthermore, the safety was not clearly evaluated and needed to be further assessed. In our research, first we included the high-quality study. Then, the meta-analysis was performed on safety. Most of all we found that CRS alone was as effective as CRS plus HIPEC in the treatment of CRPM, and had a lower adverse effects. This was the latest finding of this study that seted it apart from other studies.

Limitation of study

This systematic review and meta-analysis has several limitations. First, the included trials included observational studies and RCTs that may induce heterogeneity in results. Second, the inclusion of low-quality studies might have biased the analysis. Third, the included studies lacked uniform standards for the severity of the subjects' diseases and chemotherapy regimen, which might cause potential sources of heterogeneity. Fourth, there was a lack of high-quality RCTs of CRS plus CHIEC versus CRS alone in the treatment of CRPM.

This meta-analysis suggests that CRS plus HIPEC might be effective to CRPM in improving the OS. However, compared with CRS alone, the efficacy of CRS plus HIPEC has not improved much, and CRS plus HIPEC may bring more adverse events. Furthermore, high-quality RCTs with multi-center and larger sample sizes are needed in future.

Contributions

Z.X., X.W. and X.F. contributed to design the research and amend the article. Z.X. and X.W. contributed to the literature search. Y.W. and C.W. screened the title, abstract and full text. Y.W. and C.W. extracted the data and evaluated the risk of bias. Z.X. and X.W. analyzed the data. All authors had made a final reading of the article before submission.

Disclosure

The authors report no potential conflicts of interest in this study.

Funding

The research did not receive any financial support.

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The effectiveness and safety of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis: a systematic review and meta-analysis

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