A systematic review and meta-analysis on mortality rate following total pelvic exenteration in cancer patients

Background Total pelvic exenteration (TPE), an en bloc resection is an ultraradical operation for malignancies, and refers to the removal of organs inside the pelvis, including female reproductive organs, lower urological organs and involved parts of the digestive system. The aim of this meta-analysis is to estimate the intra-operative mortality, in-hospital mortality, 30- and 90-day mortality rate and overall mortality rate (MR) following TPE in colorectal, gynecological, urological, and miscellaneous cancers. Methods This is a systematic review and meta-analysis in which three international databases including Medline through PubMed, Scopus and Web of Science on November 2023 were searched. To screen and select relevant studies, retrieved articles were entered into Endnote software. The required information was extracted from the full text of the retrieved articles by the authors. Effect measures in this study was the intra-operative, in-hospital, and 90-day and overall MR following TPE. All analyzes are performed using Stata software version 16 (Stata Corp, College Station, TX). Results In this systematic review, 1751 primary studies retrieved, of which 98 articles (5343 cases) entered into this systematic review. The overall mortality rate was 30.57% in colorectal cancers, 25.5% in gynecological cancers and 12.42% in Miscellaneous. The highest rate of mortality is related to the overall mortality rate of colorectal cancers. The MR in open surgeries was higher than in minimally invasive surgeries, and also in primary advanced cancers, it was higher than in recurrent cancers. Conclusion In conclusion, it can be said that performing TPE in a specialized surgical center with careful patient eligibility evaluation is a viable option for advanced malignancies of the pelvic organs.


Introduction
Total pelvic exenteration (TPE), an en bloc resection is an ultraradical operation for malignancies which was performed for the first time in 1946 by Alexander Brunschwig [1], and refers to the removal of organs inside the pelvis, including female reproductive organs, lower urological organs and involved parts of the digestive system (rectosigmoid) [2][3][4].
TPE procedure is used in the treatment of advanced gynecological cancers as well as primary advanced and recurrent rectal cancers [3,5].Even though TPE is infrequently performed, it may be considered as the last hope for the treatment of recurrent or advanced cancers [6,7].
TPE technique was associated with significant complications and mortality in the first decades, but in recent decades due to the improvement of preoperative planning (whole-body positron emission tomography), intraoperative and postoperative care, the survival rate, surgical complications and mortality of candidate patients has improved significantly [4,8,9].
Overall survival and disease-free survival rate significantly improved following TPE, especially in wellselected patients [3].To the best of our knowledge, the highest 5 years overall survival rate was reported as 65.8% [10] in cervical cancer patients following pelvic exenteration and in colorectal cancer patients, one year survival rate was more than 80% in several previous studies [11][12][13][14] and the highest five year survival rate was reported as 92.9% in a study by Mark Katory et al. in the United Kingdom [14].
Considering that this surgical technique is considered a rare and advanced technique, significant complications and mortality rate (MR) have been reported for it.Intraoperative mortality, in-hospital mortality, 30-and 90-day mortality are important consequences that are reported for the management of the complications of this surgery.In addition to the survival rate, mortality and complications are also changing over time and depend on the equipment of the surgical center as well as the experience of the surgical team, and different studies have reported different mortality rates and there is no comprehensive review in this regard.The aim of this meta-analysis is to estimate the intra-operative mortality, in-hospital mortality, 30-and 90-day mortality rate and overall mortality rate following TPE in colorectal, gynecological, urological, and miscellaneous.

Study design
This is a systematic review and meta-analysis in which international databases were searched to find the relevant studies.Standard guideline of "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed to prepared the report.This study was registered in the PROSPERO (CRD42023467479).

Eligibility criteria
In this study, all observational studies related to the MR after TPE surgery with English full-text were included in the study.There was no time limit for entering the articles, and also in terms of the study design, all the articles that reported the MR including cohort studies, crosssectional studies and case series studies were included.However, studies which had not defined the surgical procedure of TPE routinely were excluded.Additionally, we excluded case reports, letters to the editor, and review studies from our analysis.Although, we thoroughly screened the full texts of these articles to ensure that any relevant studies that were initially overlooked, were included in our primary search.Further details of the excluded articles are defined in Fig. 1.

Information sources and search strategy
Articles published in English were searched.To retrieved relevant articles, the search was carried out using keywords for three international databases including Medline through PubMed, Scopus and Web of Science on November 2023.Different keywords were used to search the databases, and the search strategy in PubMed is given as an example.

Data collection process
To select relevant studies, retrieved articles were entered into Endnote software and duplicate articles were removed at this stage.Then the titles and abstracts of the remaining articles were screened and irrelevant articles were discarded.After that, the full text of the remaining articles was evaluated and irrelevant articles were removed.Finally, the required information was extracted from the remaining related articles.

Data items
The required information was extracted from the full text of the retrieved articles by the authors, and in cases of disagreement, decisions were made in consultation with other authors.The data extracted from each article included the name of the first author, year of publication, type of study design, sample size, type of cancer, location of the study, MR, included sample size, quality score of studies and the study population.
Our results were divided into four groups based on type of cancer: colorectal, gynecological, urological, and miscellaneous.The miscellaneous category included data on MR of TPE regardless of cancer type.Other cancers indicated for TPE in this study included squamous cell carcinoma, soft tissue sarcoma, perineal skin cancer, anal cancer, leiomyosarcoma, etc.
MR for intra-operative mortality, in-hospital mortality, 30-and 90-day mortality, was defined as reported deaths due to the surgical procedure and MR for overall mortality included death of the patients during the follow-up period due to surgery or cancer.Notably, patients who died due to other causes or were lost to follow-up were omitted from the analysis.

Study risk of bias assessment
The Joanna Briggs Institute Critical Appraisal (JBI) checklists were used to assess the quality of the included studies [15].For each type of article, either cohort studies or case series, we utilized the relevant checklists provided by JBI.Each item on the checklist was assigned a score of 1 if the response was "yes", and 0 if the response Fig. 1 Flow diagram of the literature search for studies included in meta-analysis.TPE: Total Pelvic Exenteration was "no", "unclear", or "not applicable".The quality indicators were converted to 100%, Studies addressing ≥ 75% of the checklist items were considered as having a low risk of bias [16].One author (MSF) carried out the quality assessment.

Effect measures
Effect measures in this study was the intra-operative, inhospital, 30-day and 90-day and overall MR following TPE.The included sample size and the number of dead people were extracted from the studies, and the MR and 95% confidence interval were calculated.

Synthesis methods and statistical analysis
To check the heterogeneity among the studies, the I 2 statistic was used and it was tested using the chi-square test, and if there was significant heterogeneity between the studies, the random-effects model was used to merge the data.Although, based on the heterogeneity between the studies, from a methodological point of view, the fixed effects model was used, but considering that the mortality rate may be different based on the center expertise, surgeon experience, and postoperative care, in addition to the fixed effects model, random effects model was also performed and its results were reported.Egger's linear regression test, Begg's test and funnel plot were used to check publication bias.All analyzes are performed using Stata software version 16 (Stata Corp, College Station, TX).

Study selection
In this systematic review, 1751 primary studies (772 papers via Medline, 936 via Scopus and 43 papers via additional search) retrieved.Of the total articles, 695 duplicate articles were identified and removed.Then, the titles and abstracts of the remaining 1153 articles were screened and at this stage, 744 articles were excluded due to the lack of fulfilling the inclusion criteria and the full text of 409 remained articles was evaluated, of which 98 articles entered into this systematic review.All the process was presented in Fig. 1.

Study characteristics
As it was shown in Tables 1 and 98 studies [6,7,[12][13][14] (5343 cases) were included in the analysis.The oldest one was published in 1967 and the most recent in 2023.Both case series (23 studies) and cohort studies (75 studies) were included in the analysis.The sample size of included studies ranged from 2 to 2305 cases and colorectal, gynecological, urological and miscellaneous cancers were included in the analysis.More details in this regard were presented in Table 1.

Risk of bias within studies
All the articles we reviewed met over 80% of the criteria in the JBI checklists and were thus included in the study.Tables 2 and 3 describe the details of evaluating the included studies according to JBI checklist for cohort studies and case series, respectively.

Urological cancers mortality rate
In the case of urological cancers, there have been fewer studies, but still, the results showed that 30-day MR is estimated as 2.07% (n = 4, 95%CI = 1.37-3.13%,I-square = 0.0%).

Discussion
In this study, we investigated the MR after TPE using meta-analysis method, which included different types of cancers such as colorectal, gynecological, urological and miscellaneous cancers.The main findings of this study showed that the highest mortality rate was related to overall mortality.The overall mortality rate was 30.57% in colorectal cancers, 25.5% in gynecological cancers and 12.42% in Miscellaneous.In fact, the highest rate of mortality is related to the overall mortality rate of colorectal cancers.Naturally, the MR in open surgeries was higher than in minimally invasive surgeries, and also in primary advanced cancers, it was higher than in recurrent cancers.
Generally, TPE is used in the treatment of advanced gynecological cancers as well as primary advanced and recurrent rectal cancers, so it is mostly used in cases where conventional treatment modalities do not have a suitable prognosis.Due to the fact that the stage of cancer is higher and the prognosis is worse in patients who are candidates for this surgery, it is expected that the MR will be higher, on the other hand, this surgery is considered as an advanced surgery, and its success rate depends on the experience of the surgeon and the equipment of the surgical center.
In a study by Vigneswaran et al. [94] with the largest sample size conducted in the USA, 2305 cases of TPE between 2005 and 2016 were evaluated.Of these, 45% were urological malignancies, 33% colorectal, 15% gynecological and 9% other cancers.The authors have stated that despite the common complications in this surgery, the mortality rate is relatively low and the outcomes during and after the operation are dissimilar in different types of cancer.Also, the prevalence of major complications is 15%, 30-day mortality is 2%, the duration of hospitalization after surgery is 9 days, and blood transfusion is reported in 50% of cases.The results of the present meta-analysis estimated the 30-day mortality rate to be 2.61%, 5.89%, 1.59% and 2.07% in colorectal, gynecological, miscellaneous and urological cancer which is higher than the value reported in the aforementioned study in most cases.Part of this difference can be related to better equipment and care in USA medical centers and part of it to more experience of medical centers and surgical teams.In our study, the results showed that the overall mortality rate in gynecological malignancies is lower than that in colorectal cancers (25.5% vs. 30.57%).Although in the study of Vigneswaran et al. [94], no significant difference was reported in the 30-day mortality rate of different cancers, but the prevalence of complications was higher in gynecological cancers, and the return to the operating room due to complications was also higher in gynecological cancers than in colorectal cancer (12.8% vs. 8.7%), while it was 4.8% for urological cancers.
Intra-operative mortality rate in colorectal cancers with rate of 0.21% showed the highest rate among studied cancers and its value in all other cancers were 0.2% or less.In terms of in-hospital mortality, this rate was estimated at 3.11% for colorectal cancer, and the highest rate of in-hospital mortality rate was related to colorectal cancer.Therefore, the results of our study showed that in performing TPE for colorectal cancers, intraoperative, in-hospital, 30-day, 90-day and overall mortality rate is more than gynecological, urological, and miscellaneous cancers.
It is important to note that while recent advancements in surgical techniques and well-equipped surgical centers have improved mortality rates for TPE, the main rationale for such an aggressive surgery is the potential chance for a cure, which has been reported in up to 63% of patients [103].However, the effectiveness of alternative options such as robotic-assisted or laparoscopic surgeries in achieving this goal has not been thoroughly studied [104].One notable study by Bizzarri et al. [83] reported a 30-day mortality rate of 0% following minimally invasive TPE, demonstrating its feasibility in a small group of 5 patients.More research is needed to fully understand the outcomes of minimally invasive TPE compared to conventional surgical method.
The complexity of the TPE procedure makes it challenging to predict outcomes.Factors such as the purpose of surgery (curative or palliative), cancer type, patient comorbidities, and the expertise of the surgical team and center are known to be associated with morbidity and mortality [94,104,105].Patients undergoing TPE also require strong physical and emotional support.Therefore, a skilled multi-disciplinary team is essential for evaluating patient eligibility and performing the surgery.Previous studies have emphasized the use of specific guidelines, such as the enhanced recovery after surgery (ERAS) guideline, to reduce complications [94,106].Ultimately, individualized patient selection is recommended before performing TPE.
To the best of our knowledge, this is the largest metaanalysis of MR following TPE.However, several limitations should be acknowledged.Our data may be biased towards reporting more studies with a 0% MR.This is mainly because if a study reported a 0% MR for a

Table 2 (continued)
specific time period, the MR for previous periods would be assumed to be 0% as well, even if it wasn't reported in detail.However, if a study reported a MR higher than 0% for a specific time period and didn't report the previous MRs, those data points were labeled as missing.Furthermore, in this study we included as much studies as possible, to create a holistic picture of MR following TPE.Therefore, it might be subject to bias as all TPE performed since 1976 with proper definition of TPE were included in our analysis.Further studies are required to investigate the impact of surgical intention, surgical center expertise, post-operation care, and patients' comorbidities on MR following TPE.

Conclusion
In conclusion, it can be said that performing TPE in a specialized surgical center with careful patient eligibility evaluation is a viable option for advanced malignancies of the pelvic organs.JBI: Joanna Briggs Institute, NA: not applicable, Y: yes, N: no Q1: Were the two groups similar and recruited from the same population?Q2: Were the exposures measured similarly to assign people to both exposed and unexposed groups?Q3: Was the exposure measured in a valid and reliable way?Q4: Were confounding factors identified?Q5: Were strategies to deal with confounding factors stated?Q6: Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?Q7: Were the outcomes measured in a valid and reliable way?Q8: Was the follow up time reported and sufficient to be long enough for outcomes to occur?Q9: Was follow up complete, and if not, were the reasons to loss to follow up described and explored?Q10: Were strategies to address incomplete follow up utilized?Q11: Was appropriate statistical analysis used?Were there clear criteria for inclusion in the case series?Q2: Was the condition measured in a standard, reliable way for all participants included in the case series?Q3: Were valid methods used for identification of the condition for all participants included in the case series?Q4: Did the case series have consecutive inclusion of participants?Q5: Did the case series have complete inclusion of participants?Q6: Was there clear reporting of the demographics of the participants in the study?Q7: Was there clear reporting of clinical information of the participants?Q8: Were the outcomes or follow up results of cases clearly reported?Q9: Was there clear reporting of the presenting site(s)/clinic(s) demographic information?Q10: Was statistical analysis appropriate?

Table 2
Quality assessment of cohort studies according to JBI checklist Briggs Institute, U: unclear, Y: yes, N: no Q1:

Table 1
Characteristics of Included Studies

Table 3
Quality assessment of case series according to JBI checklist

Table 4
Summary of meta-analysis to estimate the mortality rate following TPE in colorectal cancers

Table 5
Summary of meta-analysis to estimate the mortality rate following TPE in gynecological cancers

Table 6
Summary of meta-analysis to estimate the mortality rate following TPE in Misc.cancers