Efficacy and safety in the use of intraperitoneal hyperthermia chemotherapy and peritoneal cytoreductive surgery for pseudomyxoma peritonei from appendiceal neoplasm: A systematic review

Highlights • Hyperthermia chemotherapy and cytoreductive surgery in patients with peritoneal pseudomyxoma.


Introduction
Peritoneal Pseudomyxoma (PMP) was first described by Rokitansky in 1842; 1 Werth, in 1884, 2 introduced the term peritoneal pseudomyxoma, describing ovarian mucinous carcinoma and presence of gelatinous ascites "("jelly belly""). In 1901, Frankel described the first case of peritoneal pseuxomyxomatous syndrome resulting from cystic rupture in cecal appendix.
This disease is a rare type of cancer that involves the peritoneal surface, whose most common origin is the cecal appendix, but also occurs in other places such as stomach, colon, meso or ovarian. It is characterized by the large production of mucin, with consequent mucinous ascites.
The Consensus 6 was achieved on the pathologic classification of PMP, defined as the intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon and classified: Intraoperative adjuvant treatment can be applied through Peritoneal Hyperthermic Chemotherapy (HIPEC). The technique described by Spratt et al. 7 Mitomycin, Oxaliplatin, or Cisplatin chemotherapy are currently used intraoperatively, which have been heated for 42 degrees.

Objective
To evaluate the efficacy and safety in the application of intra-abdominal hyperthermic chemotherapy and cytoreductive surgery for patients with pseudomyxoma peritonei from the cecal appendix.

Methods
The protocol of this study has been registered in PROSPERO (CRD42021252820). This systematic review will be prepared according to recommendations contained in PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). 8 The eligibility criteria of the studies are: 1 Adult patient with PMP from cecal appendix; 2 Treatment − CRS and HIPEC; 3 Outcomes -Mortality, disease-free survival, and adverse events of any cause, degree ≥ 3; 9 4 Follow-up time up to 60-months; 5 Randomized controlled trials, comparative non-randomized studies and case series; 6 No period or language limit; 7 Full text available for access.
The search for evidence will be conducted on the following virtual scientific information databases, using the search strategies: Medline/PubMed: ([Pseudomyxoma peritonei OR syndrome of pseudomyxoma peritoneal OR gelatinous ascites] AND [hyperthermic intraperitoneal chemotherapy]); Central Cochrane: (Pseudomyxoma peritonei AND hyperthermic intraperitoneal chemotherapy).
The information obtained from the characteristics of the studies were: 'author's name and year of the study, study design, number of patients, population, methods of intervention and comparison, absolute number of outcomes, and follow-up.
The measurement used to express benefit and damage varied according to outcomes expressed by means of continuous variables (mean and standard deviation) or expressed by categorical variables (absolute number of events). In continuous measurement, the results are of difference in means and standard deviation, and in categorical measures, the results are of absolute risks, differences in risks, and number needed to treat or to produce damage, considering the number of patients. The confidence level used will be 95%. When in the presence of common outcomes among the included studies, the results will be expressed through meta-analysis.

Bias assessment and quality of evidence
Case series studies or before and after will have their risk of bias analyzed according to the Joanna Briggs Institute Critical instrument. 10 Cohort and case-control studies will be evaluated with the Robins − I instrument 11 tool, while randomized clinical trials will have their risk of bias analyzed using the RoB 2 instrument. 12 The results of comparative observational clinical trials will be aggregated and meta-analyzed using Revman 5.4 13 software, while non-comparative studies will be meta-analyzed using the Comprehensive Metanalysis software.
Furthermore, the quality of evidence will be graded as high, moderate, low, or very low using the Grade instrument 14 and considering the risk of bias, the presence of inconsistency, inaccuracy, or indirect evidence in the meta-analysis of the outcomes, and the presence of publication bias.   Table 1). The result was extracted in absolute numbers and meta-analyzed in absolute risk, without comparison.

Results
The present study included population was a total of 3.274 patients with PMP from the cecal appendix, submitted to HIPEC and CCR treatment, followed for analysis of outcomes death, disease-free survival, and adverse effects in a mean follow-up of 36 and 60 months. Characteristics of the selected studies are described in Table 2, in annexes.
NiKiforchin et al., 32 evaluated as prognostic factor cellularity in ascytic fluid in low-grade PMP: defined as acellular or cellular ascitic liquid, in the extraction of the results, both outcomes were added. Sugarbaker and Chang 37 evaluated complete and incomplete cytoreductive surgery, the results used for meta-analysis were only from complete surgery. Munhoz-Zuluaga et al., 31 evaluated High-Grade Peritoneal Mucinous Carcinoma (HGMCP) and High-Grade Peritoneal Mucinous Carcinoma with Synet cells (HGMCP-S). During the study data extraction, both results were added to the outcomes in HGMCP and HGMCP-S. Polanco et al., 33 evaluated High-Volume (HV) disease as defined as SPCI C < 12, while SPCI > 12 was considered Low-Volume (LV) disease, and the results used were the sum of both for high-grade PMP outcomes. Huang Y et al., 22 evaluated patients with PMP without histopathological classification, submitted to HIPEC or HIPEC associated with Was the condition measured in a standard, reliable way for all participants induced in the case series?
Were valid methods used for identification of the condition for all participants included in the case series?
Did the case series have consecutive inclusion of participants?
Was there clear reporting of the demographist of the participants in the study?
Were the outcomes or follow up results of cases clearly reported?
Was there clear reporting of the presenting site (s)/clink(s) demographic information?
Perioperative Chemotherapy (EPIC) (2-6 days), data were collected only from patients submitted to HPIEC. The judgments for the risk of bias of the 26 studies 15-40 were analyzed by the Joanna Briggs Institute Critical 10 instrument: 80% presented low risk, 16% moderate risk, and 4% high risk. Results were summarised in a risk of bias graph (Table 3).

Quality of evidence
Quality of evidence was assessed using the GRADE instrument 14 (Table 3) as very low quality for all outcomes, except for diseasefree survival 60-month (low-grade PMP) outcome was low quality. Table 4 Fig. 16. Comparison forest plot: without histopathological classification pseudomyxoma, outcome: adverse events ≥3 at 60-months.

Discussion
The absence of randomized and controlled studies results in the low incidence of the disease, 0.2 to 2 cases per 1.000.000 inhabitants per year. 41 In the present systematic review, with meta-analysis, the authors found only a series of cases, the fact that compromises the quality of the evidence presented.
Historically the prognosis of peritoneal pseudomyxoma is associated with origin (ovary, mesus, uric, stomach, colon, and appendix), and Cytological grading of malignancy (adenomatous, carcinomatous, and intermediate) and peritoneal dispersion index. 5 Currently, the treatment is performed through peritoneal cytoreduction with or without intrabdominal hyperthermic chemotherapy.
When the authors meta-analyze the low-grade PMP outcomes without histopathological classification, in 36-months, there was an observed improvement in survival for patients without histopathological classification, but in a 60-month outcome, there is a significant improvement in low-grade PMP patients; it can be justified by the slow progression of the disease in low-grade PMP in relation to high-grade, and it may increase the mortality in this group, reducing long-term survival.
When comparing DFS in the low-grade PMP groups and those without histopathological classification, in 60-months, the authors observed similar results, 57% and 56%, a fact that can be explained by the survival of patients with better surgical results, who are better likely to remain disease-free.
The studies evaluated individually present great differences between themselves, such as Masckauchan et al., 30 which reported a result of 0% in the mortality of patients with low-grade PMP in 60months, while Smeenk et al., 35 presented mortality of 34% of the patients. This important variation between the results may be correlated with the sample number, the chemotherapeutic drug used, the clinical and demographic characteristics of patients, surgical classification, and experience of the surgical team in the execution of the procedure.
Currently, there are difficulties in commercializing mitomycin chemotherapeutic drugs, being the most used for the execution of HIPEC. Marcotte et al. 29 and Masckauchan et al. 30 analyzed the survival of patients with PMP submitted to CRS and HIPEC with oxaliplatin, chemotherapy of the same family as cisplatin and carboplatin, obtaining results similar to mitomycin, and therefore, it can be used during the HIPEC procedure.