Outcomes of minimal access cytoreductive surgery (M-CRS) and HIPEC/EPIC vs. open cytoreductive surgery (O-CRS) and HIPEC/EPIC in patients with peritoneal surface malignancies: a meta-analysis

Abstract Introduction Minimal Access Surgery (MAS) has shown better peri-operative outcomes with equivalent oncological outcomes in gastrointestinal and thoracic oncology. Open CRS (O-CRS) procedure accompanies inevitable and significant surgical morbidity in patients. The aim of the review article is to compare outcomes of M-CRS and HIPEC/EPIC with open procedure in peritoneal surface malignancies. Content Comprehensive search of databases was done and total 2,807 articles were found (2793-PubMed and 14-Cochrane review). PRISMA flow chart was prepared and 14 articles were selected. Meta-analysis was performed according to PRISMA guidelines using random-effects model (DerSimonian Laird) and fixed effect model. Publication bias was tested with Funnel plot and Egger’s regression test. Quality of studies was assessed by Newcastle–Ottawa scale. Summary and Outlook Patients in both groups [total (732), M-CRS(319), O-CRS(413)] were similar in demographic characteristics. Peri-operative outcomes were significantly better in M-CRS group in terms of blood loss SMD=−2.379, p<0.001 (95 % CI −2.952 to −1.805), blood transfusion RR=0.598, p=0.011 (95 % CI 0.402 to 0.889), bowel recovery SMD=−0.843, p=0.01 (95 % CI −1.487 to −0.2), hospital stay SMD=−2.348, p<0.001 (95 % CI −3.178 to −1.519) and total morbidity RR=0.538, p<0.001 (95 % CI 0.395 to 0.731). Duration of surgery SMD=−0.0643 (95 % CI −0.993 to 0.865, p=0.892) and CC0 score RR=1.064 (95 % CI 0.992 to 1.140, p=0.083) had no significant difference. Limited studies which evaluated survival showed similar outcomes. This meta-analysis shows that M-CRS and HIPEC/EPIC is feasible and has better peri-operative outcomes compared to open procedure in patients with limited peritoneal carcinoma index (PCI) peritoneal surface malignancies. Survival outcomes were not calculated. Further studies are warranted in this regard.


Introduction
In the last two to three decades the management of patients with peritoneal surface malignancies has transitioned from palliative care to therapeutic and often curative intent [1].Cytoreductive surgery (CRS) for removal of macroscopic disease and intra-peritoneal chemotherapy to treat the microscopic remnant disease has become a standard for treatment of peritoneal surface malignancies [2][3][4][5].Although survival outcomes have improved, these complex surgical procedures accompany inevitable high morbidity and mortality in patients, which is comparable to other high risk open oncological procedures [6,7].The morbidity of these procedures can be reduced to an extent by better perioperative optimisation of patients, still the complication rates are high and management becomes a challenge [8,9].
The role of minimal access surgery like laparoscopic surgery, hand assisted laparoscopic surgery and robotic surgery has already been established in gastrointestinal and thoracic oncology.The oncological and survival outcomes are similar but the complication rates and morbidity is significantly lower in minimal access surgery [10][11][12][13][14][15].The role of minimal access surgery in peritoneal surface malignancies is evolving rapidly due to early referral of patients to tertiary centres with early stages and low peritoneal burden.Feasibility of laparoscopic CRS and HIPEC in low peritoneal carcinoma index (PCI) patients with low grade and borderline tumours have been described since 2011 [16,17].For high grade tumours like ovary and colorectal, literature is limited yet better peri-operative outcomes with minimal access surgery have been described [18].
The purpose of this meta-analysis is to assess the current literature and studies comparing open CRS and intraperitoneal chemotherapy procedure with minimal access CRS and to determine whether minimal access surgery is feasible and has better peri-operative outcomes compared to open procedure.

Search methodology and selection criteria
A comprehensive search of the published literature was done using databases of PubMed and Cochrane review.Key words used for identifying studies for this meta-analysis were 'Cytoreductive surgery', 'HIPEC', 'EPIC', 'Laparoscopic', 'Robotic' and 'Minimal access'.Key words and search terms were kept broad so as to encompass all possibilities of studies applicable.Manual search of relevant publications was done to supplement the data.There were no restrictions of the date of publication in the included studies.This search was done on 22/03/2023.

Data assessment and inclusion and exclusion criteria
After elimination of duplicate abstracts, two investigators independently reviewed all abstracts and full text of articles which were regarded as potentially eligible for further consideration.Handsearched reference lists of relevant articles were performed to identify further articles for analysis.Thereafter, eligible articles were selected for final analysis according to predefined inclusion and exclusion criteria.Disagreements were resolved by consensus.
Studies comparing outcomes of minimal access cytoreductive surgery like laparoscopic cytoreductive surgery, hand-assisted laparoscopic cytoreductive surgery or robotic cytoreductive surgery and HIPEC with open cytoreductive surgery and HIPEC were included.Studies which used EPIC instead of HIPEC were also included.Studies which did not have a comparative or control group with open CRS and HIPEC were not included.Studies with feasibility and peri-operative outcomes were focussed instead of survival outcomes due to limited follow up and data.Further inclusion and exclusion criteria is presented in the table in Figure 1.Authors of studies were not contacted for lack of data or missing data.

Extraction of data
Data from all finalised articles and studies was extracted and tabulated in google spread sheet under headings as follows: first author, title of study, country, year of publication, study duration, type of minimal access surgery, HIPEC/EPIC, HIPEC/EPIC protocols, demographic characteristics, type of primary, median PCI, CC score, duration of surgery, blood loss, blood transfusion, bowel recovery, post-operative grade 1-4 complications, hospital stay, follow up, mortality, disease free survival and overall survival.

Assessment of risk of bias
The risk of bias and quality of studies was assessed using Newcastle-Ottawa scale [19].Two authors independently performed the scores and the results were compared.Agreement was reached by consensus.According to the scale, articles having stars more than five are considered good articles.

Statistical analysis and data synthesis
The meta-analysis was performed in line with recommendations from the PRISMA (preferred reporting of items for systematic review and meta-analysis) guidelines [20].A fixed-effect (weighted with inverse variance) or a random-effects model was used where appropriate in our meta-analysis.We evaluated heterogeneity between articles using the χ 2 and I 2 statistic with Higgins and Thompsons method.Heterogeneity between articles was assessed to be greater with higher χ 2 and I 2 .When the p-value was <0.05, the assumption of homogeneity was rejected and a random-effects model of DerSimonian and Laird was adopted.Otherwise, a fixed-effects model of Mantel and Haenszel was used.For calculating publication bias, Funnel plot and Egger's regression test was used.Comparison of data between M-CRS and control group i.e.O-CRS, was done using relative risk (RR) and standardized mean difference (SMD) as the summary statistic.The point estimate of the RR and SMD was considered to be statistically significant at the p <0.05 level if the 95 % confidence interval did not cross the value of 1 for RR and 0 for SMD.All statistical analyses were made assuming a twosided test at the 95 % level of significance using Medcalc software (Microsoft, USA).

Results
Search syntax described previously was used and total of 2,807 results were obtained (2,793 from PubMed and 14 from Cochrane library).Duplicate articles (n=6) were removed and 2,801 articles were reviewed.A total of 2,758 articles were excluded based on title and abstract review.Forty three articles were reviewed on the basis of their full text.According to exclusion criteria, 29 articles were rejected.Finally, 14 articles were included in this meta-analysis with total of 732 patients [15,[21][22][23][24][25][26][27][28][29][30][31][32][33] [Table 1].Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart and selection criteria is shown in Figure 1.The assessment of the quality of studies in this meta-analysis was done by Newcastle-Ottawa Quality Assessment Scale and all studies showed a score of five stars and above indicating 'good studies'.
There was a total 732 patients of which 319 (43.57%) were in the study group i.e. minimal access CRS and HIPEC/EPIC and 413 (56.43 %) were in the control group i.e. open CRS and HIPEC/EPIC group.The median age was 55.7 (48.1-63.3)years in the M-CRS group and 53.3 (47.3-59.3)years in the O-CRS group.The female to male ratio was 1.31:1 and 1.67:1 whereas median BMI was 26.4 and 27.5 in the M-CRS and O-CRS groups, respectively.As only studies with matched proportion of population were considered, there was little heterogeneity in the demography.Other demographic and patient factors are given in the table (Table 2).Of all the 732 patients 48.9 % had appendix as primary, 35.1 % had colorectal primary, 5.9 % had ovarian primary and 5.5 % had mesothelioma as primary.Remaining patients had miscellaneous primaries.Majority of patients in the study had PCI <10.Disease characteristics of both groups are given in (Table 3).
The parameter of duration of surgery from incision to closure was reported by all 14 studies.The statistical analysis for duration of surgery in minutes between the M-CRS and O-CRS groups showed significant heterogeneity by the Higgins and Thompsons method with I 2 95.99 % (95 % CI for I 2 94.54 to 97.05, p<0.0001) hence random effects model of DerSimonian and Laird was used to calculate relative risk.Funnel plot and Egger's regression test were used to test publication bias which was 0.7372 (p=0.8672,95 % CI −8.668 to 10.143).The Standardized Mean Difference for duration of surgery was −0.0643 (95 % CI −0.993 to 0.865, p=0.892).No significant difference was seen between two groups (Figure 2A).
Number of patients who required blood transfusions were reported in seven studies out of 14.The relative risk for blood transfusion in M-CRS and O-CRS was 0.598 with significant p-value of p=0.011 (95 % CI 0.402 to 0.889) fixed effects model with I 2 0.00 % (95 % CI 0.00 to 32.90, p=0.8835).Publication bias 0.07921 (95 % CI −1.5120 to 1.6704, p=0.8842).There were significantly less number of blood transfusions in the M-CRS group as compared to O-CRS group (Figure 2C).
Parameter of bowel recovery in terms of number of days to pass flatus or number of days to start oral feeding were reported by six studies.The standardized mean difference   Significantly less number of days in hospital was spent in the M-CRS group (Figure 3A).
The parameter of completeness of cytoreduction score [CC score] were reported directly or indirectly in all 14 studies.Both groups had low peritoneal burden with mean PCI of <10.The relative risk for CC0 score for M-CRS vs. O-CRS groups was 1.064 (95 % CI 0.992 to 1.140 with p=0.083) with I 2 0.00 % (95 % CI 0.00 to 40.92, p=0.8570) and publication bias 0.4821 (95 % CI −1.3639 to 2.3281, p=0.4668).No significant difference is seen between M-CRS and O-CRS groups hence strengthening the feasibility and oncological equivalence of both methods (Figure 3B).
The oncological and survival outcomes are shown in the table (Table 4).All studies didn't have long follow up hence   M-CRS and 100 % and 62.5 % in O-CRS groups respectively.He also reports 5-year survival of 100 % in both M-CRS and O-CRS groups [27].L. Rodriguez-Ortiz in their study report DFS and OS similar in both groups but Park SY et al. report better DFS in M-CRS group with similar OS in both groups [28,32].Chong Wang et al. mentions that there was no difference in DFS in both groups, OS was not reached due to limited follow up.Sang Hun Ha reports 3-year peritoneal recurrence free survival, DFS and OS of 51 %, 39 %, 67 and 53 %, 33 % and 66 % in M-CRS and O-CRS groups [30,33].30 day mortality in the M-CRS group was 0 % in 13 of 14 studies, only in one study by Ha et al. there was 90-day mortality of one patient (2.4 %) [33].Thirty-day mortality in the O-CRS group was 1(7.1 %) by Park et al., 4(16.6 %) by Koti et al. and 90-day mortality was 1(4.8 %) in the study by Ha et al. [25,32,33] Overall, the survival outcomes were not evaluated statistically but limited number of studies that evaluated survival outcomes showed that they were similar.

Discussion
Peritoneal surface malignancies comprise of a heterogenous group of malignancies which can be primary or secondarily spread to peritoneum from other organs with unique proclivity of peritoneal dissemination [34].Cytoreductive surgery and intra-peritoneal chemotherapy in the form of HIPEC/ EPIC/PIPAC has been proven to improve overall survival in these patients [35].Even in rare primary malignancies like sarcomas, GIST, etc. with peritoneal only dissemination, CRS and HIPEC has shown benefit [36].At present, open CRS and HIPEC has major morbidity of 22-34 % and mortality rates of 0.8-4.1 % [37].With the standardisation of this procedure, it becomes necessary to reduce the surgery related morbidity with the use of modern technologies without affecting the oncological outcomes.Minimal access surgery has revolutionised this concept in various oncological fields by significantly decreasing morbidity and mortality.Earlier there were concerns regarding increased peritoneal dissemination of cancer cells by laparoscopy but prospective randomised trials have shown no difference in port site or peritoneal recurrences [38].
The minimal access approach has a theoretical advantage of decreased adhesion formation post-surgery which may show benefit according to 'Fibrin entrapment hypothesis' [39].Also decreased hospital stay and complications in the post-operative period leads to decreased over all costs for the patient and hospital [25,40,41].Another important advantage of minimal access surgery is decreased time to adjuvant chemotherapy due to overall early recovery of patients and has shown to increase disease free survival [21].
This has a lesser role in low grade malignancies like appendiceal mucinous neoplasms and multi cystic mesothelioma but has a major impact on patients with high grade primaries like ovary and colorectal malignancies [42,43].
Initially the use of laparoscopy was limited to calculating PCI, to evaluate candidates for complete cytoreduction and therapeutic drainage of mucinous ascites for palliation and symptom control [44,45].In 2005, Ferron et al. first described feasibility of laparoscopic CRS and HIPEC in animals [46].In 2011, Esquivel et al. were first to show feasibility of laparoscopic CRS and HIPEC in patients with peritoneal surface malignancies [16].Since then many case series and small retrospective studies have shown feasibility of minimal access cytoreductive surgery and HIPEC.Further in this regard, Koti et al. and Fagotti et al. have shown feasibility of robotic CRS and HIPEC in their studies [25,31].
To our knowledge this meta-analysis is first of its kind which directly compares outcomes of minimal access vs. open CRS and HIPEC/EPIC across different peritoneal surface malignancies.This meta-analysis includes studies with laparoscopic, hand assisted laparoscopic and robotic CRS and HIPEC/EPIC procedures.The PSOGI international collaborative registry and ASPSM multi-institution analysis describe outcomes of patients undergoing laparoscopic CRS and HIPEC in various peritoneal surface malignancies but lack direct comparison with open CRS procedures [17,18].
In this meta-analysis peri-operative outcomes were compared in terms of duration of surgery, estimated blood loss, number blood transfusions, days for bowel recovery (time to pass flatus/time to start orals), hospital stay and morbidity [(minor=Grade I and Grade II) (major=Grade III and Grade IV) and (total=Grade I-IV)] according to Clavien-Dindo classification [47].Technical feasibility outcomes were compared in terms of completeness of cytoreduction score 0. Survival outcomes were not evaluated statistically.
A Arjona-Sanchez et al. in the PSOGI international collaborative registry have described outcomes of 143 patients with laparoscopic CRS and HIPEC and have shown similar peri-operative outcomes to our meta-analysis of 319 patients of M-CRS group [17].Our meta-analysis shows that peri-operative outcomes in terms of blood loss, blood transfusion, bowel recovery, hospital stay and morbidity are significantly better in the M-CRS group while duration of surgery have no significant difference.These findings are similar to the peri-operative outcomes of COLOR II trial and COREAN trial for colorectal cancers and MISSION trial for ovarian cancer comparing minimal access surgery to open surgery [48][49][50].The oncological safety of procedure in terms of CC0 had no significant difference in both groups when the median PCI was low i.e. <10.This infers that Table : Survival outcomes of studies in the meta-analysis.

Sr.
No.  months minimal access approach can be used in patients with low PCI.As many of the studies in this meta-analysis were retrospective cohort studies, the follow up period was less and survival outcomes like disease free survival, peritoneal recurrence free survival and overall survival could not be compared across both groups with accuracy.But, few studies like Chang et [32].These finding may be attributed to the higher pressures reached during the minimal invasive HIPEC procedure which has shown to increase penetration and cytotoxicity of chemotherapeutic agents [51][52][53].

Author
Finally, we believe that the strength of our metaanalysis is that a fair number of patients (732 patients, M-CRS 319 and O-CRS 413) were included in the study and comparative analysis was made.Also, the demographic characteristics of the patients in both groups were comparable since only studies with matched population were included.The major limitation of this meta-analysis is that, majority of studies barring a few are retrospective cohort studies.This is due to paucity of comparative work, relatively novel approach of minimal access in cytoreductive surgeries and lack of randomised controlled trials.Another limitation is that survival outcomes were not calculated statistically as only few studies mentioned survival outcomes and different studies had different primaries and histology.

Conclusions
This meta-analysis shows that minimal access cytoreductive surgery and HIPEC/EPIC is feasible and has better perioperative outcomes compared to open procedure in patients having limited PCI peritoneal surface malignancies.However, further collaborative, prospective studies and randomised trials are warranted to confirm the results and for better assessment of survival outcomes.

Figure 1 :
Figure 1: The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart.

Figure 2 :
Figure 2: Forrest plots of relative risk and standardized mean difference of different peri-operative outcomes between M-CRS and O-CRS group.(A) Duration of surgery, (B) estimated blood loss, (C) blood transfusions; (D) bowel recovery.

Figure 3 :
Figure 3: (A) Forrest plot of SMD of hospital stay in days in M-CRS and O-CRS groups, (B) Forrest plot of relative risk of completeness of cytoreduction score 0 in M-CRS and O-CRS groups.

Figure 4 :
Figure 4: Forrest plots of relative risk of morbidity between M-CRS and O-CRS groups.(A) Minor morbidity, (B) major morbidity, (C) total morbidity.
al., Cho CY et al., Mercer et al., Rodriguez-Ortiz et al., Wang et al. and Ha et al. have shown that disease free survival and overall survival in both groups were similar [21, 22, 27, 28, 30, 33].Interestingly, Chang et al. have shown less early peritoneal recurrence (defined as peritoneal recurrence in less than 12 months) in the M-CRS group than O-CRS group (11.8 vs. 29.4%) [21].Similar results are shown by Salt et al. and Rodríguez-Ortiz et al. [26, 28].Also, Park et al. have shown better 3-year DFS in the M-CRS group than the O-CRS group (53.8 vs. 27.3%) in patients in whom complete cytoreduction was achieved (CC0)