Prognostic value and adverse events of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in primary advanced and platinum-sensitive recurrent epithelial ovarian cancer: a systematic review and meta-analysis

Abstract Background The original meta-analysis of hyperthermic intraperitoneal chemotherapy (HIPEC) is already outdated, owing to the latest trial results. This study aimed to clarify the efficacy and adverse events of cytoreductive surgery with HIPEC compared to conventional therapy for advanced and platinum-sensitive recurrent epithelial ovarian cancer (OC). Methods In this meta-analysis, phase II/III controlled trials regarding ‘HIPEC’ and ‘ovarian cancer’ were searched for in electronic databases from inception to March 2022. Results Twenty-one studies were included in the quantitative synthesis. The pooled hazard ratio [HR] in the HIPEC group for progression-free survival (PFS) (HR = 0.61, 95% confidence interval [CI]: 0.45–0.83, p = .002) and overall survival (OS) (HR = 0.65, 95% CI: 0.51–0.82, p < .001) were improved in the HIPEC group compared with the non-HIPEC group. For primary advanced disease, OS and PFS were significantly increased in patients receiving interval debulking surgery + HIPEC, whereas PFS was not significantly different between primary debulking surgery (PDS) + HIPEC and PDS alone. For platinum-sensitive recurrent disease, no correlation was observed for PFS and OS between the HIPEC and non-HIPEC groups (p < .05). The incidence of procedure-related complications was higher in the HIPEC group than in the non-HIPEC group (odds ratio = 1.93, 95% CI: 1.24–3.01, p < .01). The morbidity of leukopenia, neutropenia, nausea, hypoalbuminemia, and grades III–IV electrolyte disturbance was higher in the HIPEC group than in the non-HIPEC group. However, HIPEC administration reduced the risk of intra-abdominal bleeding and constipation. Conclusion HIPEC-based regimens improved the clinical prognosis for primary advanced OC, whereas no significant value was elicited for recurrent OC.


Introduction
Ovarian cancer (OC) is the most lethal gynecological cancer, and >95% of cases are epithelial ovarian cancer (EOC).Optimal surgical cytoreduction and platinum-based chemotherapy are significant treatments for primary advanced ovarian cancer (AOC).More than 75% of patients are diagnosed at an advanced stage (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV) because of the absence of screening and specific symptoms when tumors usually have peritoneal cavity and upper abdominal organ metastasis [1].Under these circumstances, approximately 70 % of patients with advanced diseases develop recurrence within 3 years after surgery and chemotherapy, and the 5-year relative survival rate is <45% [2].The main reason for the high recurrence rate of AOC is that cancer cells frequently spread from the primary tumor into the peritoneal cavity and are implanted in abdominal organs, which makes complete cytoreductive surgery (CRS) difficult to achieve.
Previous research has established that optimal debulking prolong the overall survival (OS) of AOC and recurrent ovarian cancer (ROC).Harter et al. reported that total resection of ROC (R0 resection) was associated with an OS improvement of approximately 3 months for every 10% improvement in total resection [3].Therefore, optimal debulking is particularly crucial for improving survival in OC.However, when optimal debulking cannot be achieved, intraperitoneal chemotherapy (IPC) may be a supplemental treatment strategy.Compared with systematic chemotherapy, IPC via direct delivery of anticancer agents to peritoneal seeding lesions not only provides higher peritumoural drug concentrations by eliminating the hepatic first-pass effect but also reduces the systemic toxicity of agents.However, the incidence of IPC-related adverse events (AEs) was not negligible.Catheter-related complications, such as intra-abdominal infections, dislodgement of catheters, and catheter clogging, are particularly serious.Moreover, there are also severe AEs with regard to abdominal pain, fever, and gastrointestinal effects, which have proven difficult for patients to tolerate.The aforementioned AEs would contribute to diminishing the quality of life of patients with OC, and in turn, approximately 60% of the administration of IPC is forced to be discontinued or modified [4].Consequently, the use of IPC as routine treatment remains controversial.Recently, HIPEC has been administered in patients under anesthesia at the end of cytoreductive/debulking surgery for OC.Not only does this procedure require intraperitoneal catheterization, but patients are also assured to experience painless operative processes.Consequently, the HIPEC procedure is well-tolerated.Intraperitoneal perfusion was performed to increase the tumor drug concentration before the end of the operation when tissue adhesion was not formed [5].Additionally, mild hyperthermia (temperatures between 40 C and 44 C) is cytotoxic to cells by enhancing DNA damage and endoplasmic reticulum stress [2,6].Besides, it has been demonstrated that combining chemotherapy with regional hyperthermia can sensitize tumor tissues to anticancer agents, resulting in improved OS prolongation [7].Moreover, the heat shock protein gp96 is produced by thermal effects, which activate CD4 þ T and CD8 þ T cell proliferation, in turn increasing antitumor immunity [8].
Recently, a meta-analysis reported the benefits of HIPEC in prolonging OS and PFS in patients with AOC.However, whether this can improve progression-free survival (PFS) or OS remains controversial.Morbidity has rarely been reported in previous studies.Therefore, we conducted a systematic review and meta-analysis to investigate the prognostic value and AEs of CRS þ HIPEC in AOC and platinum-sensitive ROC.

Search strategy
We performed a comprehensive literature search of electronic databases, including PubMed, Embase, Cochrane, Medline, and Web of Science, from inception to March 2022.The following combination of medical subject heading-terms and entry-terms strategy was used: 'hyperthermic intraperitoneal chemotherapy', 'HIPEC', 'ovarian neoplasms', and 'ovarian cancer'.All retrieved abstracts were independently screened by two authors, and any disagreements between the reviewers were resolved by consensus through discussion.

Selection criteria
In this meta-analysis, comparative clinical trials were included, and the language was restricted to English.The following inclusion criteria were applied: (1) the study participants included patients with primary advanced or platinum-sensitive recurrent EOC; (2) the patients received CRS plus HIPEC in the experimental arm; (3) the patients received only CRS without HIPEC in the control arm, and all enrolled patients received appropriate chemotherapy; and (4) PFS and OS were the primary outcomes, and the AEs were the secondary outcomes.The exclusion criteria were as follows: (1) literature reviews and systematic reviews; (2) case reports or series; (3) animal or cell experiments; (4) phase I clinical trials; and (5) studies that included only a HIPEC group for OC.Available data provided the frequency and severity of AEs and sample size.Importantly, treatment-related AEs were defined by the fifth version of the Common Terminology Criteria for Adverse Events of the National Cancer Institute.

Data extraction and quality assessment
The following data were extracted: first author, year of publication, country, study design, number of study participants, patient characteristics, surgical debulking and systemic chemotherapy strategies, HIPEC regimens, temperature and duration of treatment, and outcomes.The Newcastle-Ottawa Scale was used for the quality assessment of comparative studies.Studies with scores from 0 to 3, 4 to 6, and 7 to 9 were considered to be low, moderate, and high quality, respectively.The Jadad scale was used to assess the quality of randomized controlled trials (RCTs).Studies with scores of 1 or 2 were considered low quality, and those with scores of 3-5 were considered high quality.

Statistical meta-analysis
Hazard ratios (HRs) and odds ratios (ORs) were used to measure the prognostic value and safety of treatment.The HRs of the publications were obtained using Engauge Digitizer (version 11.3).All data were evaluated using Stata software (version 14.0; StatCorp) and Review Manager (version 5.3; Cochrane Training).Forest plots were generated to display outcomes for each study with their corresponding 95% confidence intervals (CIs) and the overall effects pooled estimate with 95% CIs.Statistical heterogeneity was evaluated using the I2 statistic, and an I 2 value <50% indicated that the heterogeneity was not statistically significant; thus, the fixed-effects model was used.When the opposite occurred, a random-effect model was applied.Subgroup analyses were performed according to the study design.We evaluated publication bias for each of the pooled study groups using a funnel plot, and the publication bias of the studies was further appraised using the Egger test.

Primary outcome
Fourteen studies were eligible to assess the effect of HIPEC on PFS, and HIPEC improved the outcome (HR ¼ 0.61, 95% CI: 0.45-0.83,p ¼ .002).Pooled data from 16 studies demonstrated that there was an improvement in OS in the HIPEC groups compared with the non-HIPEC groups for all populations (HR ¼ 0.65, 95% CI: 0.51-0.82,p < .001)(Figure 3(a,b)).

Discussion
This study focused on the prognosis of CRS þ HIPEC versus CRS in patients with AOC and platinum-sensitive ROC.
Considering that patient tolerability is a critical factor for HIPEC application in routine clinical practice, we also analyzed the morbidity of CRS þ HIPEC compared with the control.Consequently, we are confident that this meta-analysis will provide useful clinical evidence for the treatment of AOC and platinum-sensitive ROC.
Our meta-analysis indicated that HIPEC prolonged OS and PFS for AOC compared to non-HIPEC.Optimal cytoreduction, especially complete surgical debulking, is considered the most important factor for improving the prognosis of patients with AOC [30].Our results revealed that HIPEC, as an additional therapy, effectively improved OS and PFS by partially eliminating the macroscopic and microscopic residual disease.The results of our meta-analysis are HIPEC-carboplatin and HIPEC-paclitaxel group was separately analyzed for PFS and OS.Platinum-sensitive relapse was included and platinum-resistance relapse was excluded from the analysis of OS. a The outcome of HIPEC-carboplatin and HIPEC-paclitaxel was dividually evaluated.
Only the PS patients were included in the final assessment.
c Jadad score.
consistent with those of previous studies [31][32][33][34].Therefore, it is reasonable to believe that HIPEC following CRS is a meaningful treatment strategy for AOC.However, Ceresoli et al. and Jou et al. did not find any advantages of HIPEC for AOC compared to non-HIPEC [11,12].The reason for their statistically insignificant result was probably due to the small sample size of patients.There are some other reasons for the lack of statistically significant differences between the HIPEC and control groups in some trials.First, the patients in the HIPEC group might have a higher disease burden than those in the control group.GOG182 showed that the baseline character of disease burden remains an independent prognostic indicator despite complete cytoreduction [35].In addition, patients with a higher disease burden might be confronted with a higher surgical complexity, which might lead to shorter survival times.A recent study indicated that compared with low surgical complexity scores (SCS), intermediate/high SCSs for debulking operations were associated with worse PFS and OS despite achieving no residual disease [36].In summary, it can be concluded that HIPEC is significant for extending the survival of patients with AOC under conditions of equal tumor burden and surgical complexity compared with CRS alone.In the subgroup analysis, the pooled outcomes verified the prominent advantage of IDS þ HIPEC in patients with AOC in our meta-analysis.Van Driel, Lim, and Antonio reported identical superiority in their RCTs [14,15,21].Nevertheless, there are inadequate RCTs to confirm that PDS þ HIPEC performs well in AOC.
Regarding platinum-sensitive ROC, no difference was observed between the HIPEC and non-HIPEC groups for PFS and OS in our meta-analysis.The latest RCT performed by Zivanovic et al. had the maximum weight among all studies.When we removed this study, OS was prolonged in the HIPEC group compared to the control group, which was consistent with the finding of other meta-analyses [31][32][33][34].Zivanovic et al. reported negative PFS and OS of carboplatin- based HIPEC regimens during secondary CRS for platinumsensitive ROC [27].Nevertheless, some confounding factors resulted in negative outcomes, e.g., residual disease after surgery was smaller in the control group than in the HIPEC group.The treatment for patients with ROC is not standardized currently, such as the omission of maintenance treatment, shorter platinum-free interval, and inclusion of higher-risk patients.These reasons may have resulted in the negative outcomes of this trial.According to the National Comprehensive Cancer Network guidelines (NCCN Guidelines V R Insights: Ovarian Cancer, Version 3.2022), patients with ROC are recommended to undergo testing for biomarker mutations, such as the breast cancer susceptibility gene, homologous recombination deficiency, mismatch repair, and microsatellite instability [37].Biomarker testing is used to determine whether OC has any targetable changes to guide treatment.Currently, bevacizumab and poly (adenosine diphosphate-ribose) polymerase inhibitors are considered maintenance treatments following standard chemotherapy for platinum-sensitive ROC [38][39][40][41].Besides, there are two ongoing trials (ClinicalTrials.govstudy IDs: NCT01376752 and 01539785) assessing the effect of HIPEC on the first relapse of OC, which would further provide evidence of the effect of HIPEC in patients with ROC [42,43].
In this study, we reported a higher risk of procedurerelated complications in the HIPEC group than in the non-HIPEC group.Jou et al. reported that the frequencies of morbidities of postoperative complications and abdominal infection were higher in the HIPEC group than in the control group in their study [12].Aggressive upper abdominal procedures, long operation durations, and surgical complexity are the main causes of these complications.These are leading factors for infectious morbidities, thromboembolic events, anastomotic leakages, and intraoperative hypothermia, rather than HIPEC administration.Lim et al. reported that the frequency of morbidities of fistula, perforation, or leakage of the bowel was higher in the HIPEC group for FIGO stages III-IV disease than for other FIGO stages [15].
HIPEC could be administered safely after maximal CRS, and the initiation of adjuvant chemotherapy was not delayed.In contrast, we found a lower incidence of abdominal bleeding in the HIPEC group because surgeons could discover potential bleeding points while performing abdominal perfusion.Consequently, selecting patients with suitable indications to undergo HIPEC is pivotal for improving survival prognosis and reducing surgical complications.Regarding AEs, we found that leukopenia was apparent due to the use of HIPEC, whereas refractory leukopenia was uncommon.Electrolyte imbalance have been reported in several trials, which may have resulted from fluid resorption during peritoneal perfusion [13].The approaches to avoid this situation were as follows: control the flow rate, perfusion pressure, and infusion time.However, these factors affect drug absorption and tissue penetration, thus affecting the efficacy of HIPEC.Therefore, further clinical trials are required to verify the optimal administration of HIPEC.Unexpectedly, we discovered that morbidity associated with constipation was lower in the HIPEC group than in the non-HIPEC group.Opioid pain relievers, forbidden diets, and water and narcotic drug suppression are likely to cause intestinal mucosa desiccation, which in turn leads to constipation.During peritoneal perfusion, the intestinal mucosa can absorb perfusion fluid and stay moist due to constipation.Although nephrotoxicity has rarely been reported in previous studies, the RCT performed by Lim et al. reported a higher risk of acute kidney injury and increased creatinine levels in the HIPEC group than in the non-HIPEC group [15].The incidence of these AEs decreased significantly after 21 patients received STS.Additionally, STS can effectively decrease the incidence of ototoxicity secondary to platinum medicines [44].
There are some limitations to this study, including a lack of high-quality trials with available evidence to support our outcomes.Most of the studies were single-center retrospective trials.In addition, the heterogeneity of patient characteristics, HIPEC regimen, debulking surgery, and chemotherapy agents may have led to obvious heterogeneous outcomes in studies and affected the results of the pooled analysis.Further studies are needed to address how best to incorporate HIPEC with optimization of the intraoperative random assignment process to exert the therapeutic effect of HIPEC.This directly influences the efficiency of HIPEC in OC.Specifically, prospective RCTs are needed to assess the prognostic value of HIPEC in patients with OC.

Conclusions
The results of our meta-analysis provide encouraging evidence for the use of HIPEC in patients with primary advanced OC.However, current retrospective trials and RCTs lack the compelling proof to confirm the efficacy of HIPEC for patients with ROC.Although a high risk of procedurerelated complications has been reported, they are mainly caused by surgical complexity rather than HIPEC.Nevertheless, individual AEs must receive careful attention, especially electrolyte imbalance, leukopenia, and nephrotoxicity.Therefore, high-quality prospective randomized trials are needed to further clarify the efficacy and safety of HIPEC.

Disclosure statement
No potential conflict of interest was reported by the author(s)

Figure 1 .
Figure 1.PRISMA guided flow diagram of study selection for inclusion in this review and meta-analysis.

Figure 2 .
Figure 2. Funnel plot of studies evaluating the publication bias of PFS and OS between HIPEC and No-HIPEC.

Figure 3 .
Figure 3. Forest plots showing the effect of HIPEC on the survival of EOC.

Figure 4 .
Figure 4. Forest plots showing the effect of HIPEC on survival of EOC after subgroup analysis.

Table 1 .
The characteristics of the included studies.CRS þ HIPEC vs CRS.

Table 2 .
Meta-analysis estimates of adverse events between HIPEC and No-HIPEC.
2¼ /, only one study was included.