Abstract
Background/Aim: The aim of the study was to determine outcomes and overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for malignant peritoneal mesothelioma (MPM). Patients and Methods: This was a retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for MPM from April 1999 to December 2021. Results: A total of 81 patients were identified with MPM. Median OS was 53 months with a 1-, 3- and 5-year OS of 76%, 55% and 49% respectively. Multivariate analysis identified lymph node status, PCI and CC score as statistically significant prognostic factors that impact survival. Median OS for PCI 0-20 was 103 months vs. 33 months for PCI 21-39 (p=0.005). Median OS for CC0, CC1 and CC2 were 104, 30 and 2.7 months respectively (p<0.001). Hazard ratio for node-positive disease over node-negative was 2.14 (95% CI=1.07-4.31, p<0.033). Grade III/IV complication rate was 43.2% and mortality 4.9%. Conclusion: CRS/HIPEC remains the gold standard for treating patients with MPM with excellent patient OS. Lymph node status, PCI and CC score were independent prognostic factors that affect OS.
Mesothelioma is a rare malignancy of the serosal membranes. The majority of mesotheliomas arise from the pleura and only up to 30% originate from the peritoneum (1, 2). First described in 1908 by Miller and Wynn, malignant peritoneal mesothelioma (MPM) is a rapidly progressing primary malignancy of the abdomen. Left untreated, median survival ranges from 6 to 12 months (3).
Unlike pleural mesothelioma, in which 80% of cases are associated with asbestos exposure, over 50% of patients with MPM report no prior history of asbestos exposure (4). Patients often present with vague, nonspecific symptoms including abdominal distention, pain, nausea, and weight loss. Consequently, this leads to a delay in diagnosis and many patients have diffuse disease on presentation.
Prior to introduction of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic chemotherapy was the treatment of choice with median overall survival (OS) ranging from 12-28 months (5, 6). However, CRS/HIPEC has emerged as a standard of care for MPM in select patients, with studies reporting median OS ranging from 34-92 months (3).
The peritonectomy unit at St George Hospital, Sydney, Australia is the country’s highest volume centre in treating patients with MPM. This study aims to report the unit’s survival outcomes as well as identify prognostic factors that impact OS.
Patients and Methods
Patient selection. Patients with MPM who underwent CRS/HIPEC from April 1999 to December 2021 at St. George Hospital (Sydney, Australia) were identified. Data were collected retrospectively from a prospectively maintained database at the Peritonectomy Unit of St George Hospital. All patients underwent pre-operative staging with contrast-enhanced computer tomography (CT) of chest, abdomen, and pelvis, fluorodeoxyglucose positron emission tomography (PET) and gadoxetate disodium-enhanced (Primovist™) magnetic resonance imaging (MRI). Tumour markers including CEA, CA 125 and CA 19.9 were included in the pre-operative workup. All patients were discussed at a multidisciplinary meeting which included radiologists, medical oncologists, surgeons, and allied health staff in order to determine suitability for surgery.
Histological diagnosis. Resected specimens were submitted to anatomical pathology for examination. Tumours were classified as one of three histological subtypes (epithelioid, sarcomatoid, or biphasic) in accordance with the World Health Organization classification of MPM (7). Standard immunohistochemical staining was conducted for the following markers: calretinin, cytokeratin (CK) 5/6, Wilms tumour (WT)-1, Epithelial membrane antigen (EMA) and HBME-1. Intra-abdominal lymph nodes were all sampled and classified as positive or negative for MPM.
Cytoreductive surgery. All patients underwent CRS in accordance with the principles set out by Sugarbaker (8). The peritoneal cancer index (PCI) was calculated at the beginning of each operation in order to determine burden of disease. The abdomen is divided into 13 sections and a score of 0 to 3 (which is based on tumour size) is allocated to each region to give a total out of 39 (9). At the completion of the procedure, a completeness cytoreductive (CC) score is recorded from 0 to 3 to quantify the amount of remaining disease (CC 0=no macroscopic residual cancer to CC 3=nodules >2.5 cm remaining) (9).
Intraperitoneal chemotherapy. All patients undergoing CRS were administered HIPEC in a standardised manner. At our Institution, an open method (also known as the “Coliseum technique”) is implemented as described by Sugarbaker (10). The abdomen is primed with Dianeal PD4 (1.5%) Peritoneal Dialysis Solution and heated to 41.5 OC. Once this temperature is reached, the chemotherapeutic agent is administered. Either Cisplatin (50 mg/m2) and/or mitomycin C (12.5 mg/m2) are instilled for 90 minutes, with stirring performed every 15 mins in order to provide a more even distribution throughout the abdomen.
Postoperative care and follow-up. Following CRS/HIPEC, all patients are cared for in the ICU until they are ready to be transferred to the ward. All post-operative complications are recorded according to the Clavien-Dindo classification system (11). On discharge, patients are followed-up every 3 months in the first postoperative year, 6-monthly in the second and third years, then yearly until the fifth postoperative year. At each follow-up appointment, a history and examination are conducted and investigations including tumour markers and imaging are reviewed.
Statistical analysis. All statistical analyses were performed using SPSS for Windows version 22 (IBM Corporation, New York, NY, USA). Survival curves were calculated using the Kaplan-Meier method. Log-rank testing was used to determine statistically significant differences between the curves. Multivariate analysis of factors was performed using the Cox proportional hazard model. Categorical variables were compared using Chi-square test and Fisher’s exact test where appropriate. A p-value <0.05 was considered to be statistically significant.
Results
Patient and surgical characteristics. A total of 81 patients were identified with MPM. Thirty patients (37%) were male and 51 (63%) were female. An overview of the patient characteristics is provided in Table I. The majority of the patients (85.9%) had epithelioid histology with 14.1% having biphasic. 58% of the patients had a PCI of 21 or higher and a CC 0 was achieved in 53.1% of patients. The mortality rate was 4.9%, and 43.2% of patients suffered a Grade III/IV complication.
Patient characteristics.
Overall survival. Median OS was 53 months with a 1-, 3- and 5- year OS of 75.9%, 55.3% and 48.6% respectively (Table II). Multivariate analysis demonstrated lymph node status, PCI and CC score as independent factors that impacted OS (Table III). Hazard ratio for positive lymph nodes over node negative disease was 2.14 (95% CI=1.07-4.31, p<0.033). Median OS was less in those with increasing PCI (103 months for PCI 0-20 vs. 33 months for PCI 21-39, p=0.005). Patients with higher CC score had worse median OS (104 month for CC O vs. 30 months for CC 1 and 2.7 months for CC 2, p<0.001) (Figure 1). Biphasic histopathology resulted in a reduced median OS to 11 months (vs. 62 months for epithelioid) but it was not statistically significant (p=0.07).
Survival outcomes.
Cox proportional hazards model for overall survival.
Survival curves. (A) Kaplan-Meier plot of overall survival in 81 patients treated for MPM. (B) Comparison of survival by lymph node status. (C) Comparison of survival according to PCI (PCI 0-20 vs. PCI 21-39). (D) Comparison of survival according to CC score (CC0 vs. CC1 vs. CC2). PCI: Peritoneal cancer index; CC: cytoreduction completeness.
Discussion
CRS/HIPEC has become the standard of care for MPM. This was established at two international consensus meetings in 2004 and 2006 (12, 13). Prior to this, MPM was considered a fatal disease and early management focused on palliation. In 1980, Antman et al. (14) suggested the use of systemic chemotherapy to manage the disease and since then, studies demonstrate modest overall survival benefits ranging from 10-26 months (6, 15, 16). The introduction of CRS/HIPEC has resulted in significant improvement in survival, with a systematic review by Yan et al. demonstrating median survival ranging from 34-92 months (3).
Our unit has demonstrated a median OS of 53 months for patients with MPM. Positive lymph nodes, Increasing CC score and PCI were important prognostic factors that negatively impacted OS. In our cohort, the mortality rate was 4.9 % whilst grade III/IV complications were 43%.
Patient survival outcomes for our unit parallel those by other international centres. Similarly to our centre, Sugarbaker demonstrated a median OS of 52 months in 100 patients with a 1, 3 and 5-year OS of 78%, 55% and 46% respectively (17). A study by Elias et al. showed a median OS that exceeded 100 months and a 5-year OS of 63% (18). The largest and most recent multi-institutional study across 8 centres demonstrated a median OS of 53 months with 1-, 3- and 5-year survival rates of 81%, 60% and 47% respectively (19). Our findings, in conjunction with the existing literature, demonstrate the benefit of CRS/HIPEC in MPM and the significantly higher OS when compared to systemic chemotherapy alone.
CRS/HIPEC has the potential to carry significant morbidity and mortality and thus should be performed in experienced centres. Our unit first published data on outcomes for MPM in 2009 on 20 patients (20). Three patients had grade III complications, 1 patient had a grade IV complication and 1 patient died in the ICU after 14 days from sepsis and multi-organ failure. The unit’s complication rate for CRS/HIPEC remains low with the most recent data demonstrating a morbidity and mortality rate of 43.2% and 4.9% respectively. This is similar to a study by Yan et al. in 2007 that reported on 70 patients a mortality rate of 3% and grade III and IV complications of 27% and 14% respectively (22). A study looking at 211 patients across three US institutions also showed a similar complication rate and perioperative mortality of 2.3% (23). A review of 7 studies from 6 well established CRS centres showed a perioperative mortality rate of 0 to 8% and morbidity of 25 to 40% (3). CRS/HIPEC is a major surgical procedure and in experienced centres such as ours, morbidity and mortality remain acceptable.
A number of prognostic factors have been identified that impact OS in MPM. In our study, node positive disease, a higher CC score and increasing PCI negatively impacted patient OS. Patients with node positive disease had a hazard ratio of 2.14 (95% CI=1.07-4.31) when compared to node negative disease. Our results demonstrated a 5-year OS of 71.3%, 28.8% and 0% for CC0, CC1 and CC2 respectively (p<0.001). Patients with a PCI of 0-20 had a 5-year OS of 67.3% compared to 35.1% in those with PCI of 21-39 (p=0.005).
Previous studies also demonstrated the negative impact of increasing CC score on OS. The analysis by Yan et al. (19) showed a median OS of 94 months for CC 0 and median OS of 67, 40 and 12 months for CC1, 2 and 3 respectively. A study by Sugarbaker showed a median OS of 67 months for CC 0-2 vs. 26 months for CC 3 (23). Finally, Alexander et al. demonstrated an almost doubling in the risk of death for those with CC 2 or 3 compared to those with CC 0 or 1 (HR=1.81, p=0.02) (22). A potential reason for our unit’s poor CC 2 patient survival compared to the existing literature could be due to the fact that all CC 2 patients had a PCI of 39. Aiming to achieve CC 0 resections in those with MPM is important, as it significantly improves patient OS.
Similarly to CC score, increasing PCI and positive lymph nodes have been shown to negatively impact OS. A previous study demonstrated a median OS of 119 months in patients with PCI ≤ 20 compared to 39 months in PCI ≥21 (19). Baratti et al. showed on univariate analysis that PCI <17 correlated with better OS (24). Although rare in MPM, there is evidence that nodal metastasis significantly impacts patient OS (25, 26).
There are a number of other factors that have been established which negatively influence OS that weren’t apparent in our study. Histological subtype has consistently been proven to be important in predicting OS. Although a survival difference between epithelioid and biphasic histopathology was noted in our study, it was not statistically significant. Multiple studies have demonstrated that epithelioid histology carries the most favourable prognosis when compared to biphasic or sarcomatoid (20, 24). Magge et al. showed a median OS of 51 months for epithelioid MPM versus 10 months for biphasic/sarcomatoid histology (27). Due to the poor prognosis associated with sarcomatoid disease, some centres consider it a contraindication to CRS/HIPEC as adequate survival benefit cannot be achieved.
Finally, even though not presented in our data, high expression of Ki67 has been shown to correlate with worse median OS (24, 28).
The authors recognise that several limitations exist with the study. First and foremost, the retrospective nature of the study does not allow establishment of cause and effect. All the data come from a single centre and thus an element of bias would exist. In addition, the patient group was not controlled and there is significant heterogeneity in patient characteristics. The authors also recognise that there were variables which are known to impact OS that were not included in the study. This was due to missing data and the unit has made steps to rectify this for future projects. Despite its limitations, considering the rarity of the disease, the relatively high volume of patients included in the study would be considered a strength. Furthermore, the extended period in which the unit’s data spans allowed for good survival analysis.
Conclusion
MPM is a rare disease and fatal if left untreated. CRS/HIEPC has become the mainstay of treatment and provides the best option for long term survival. A number of prognostic factors exist that affect patient survival and our study demonstrates the negative impact of increasing PCI, higher CC score and lymph node positive disease. In specialised centres such as ours, morbidity and mortality remain low. As future studies emerge on MPM, our understanding of the disease will continue to evolve and improve patient outcomes.
Acknowledgements
The Authors would like to thank Shoma Barat for the maintenance of the unit’s database.
Footnotes
Authors’ Contributions
Study conception and design: Shamavonian R, Ahmadi N, Morris DL. Data acquisition: Cheng E, Barat S, Karpes JB. Data analysis and interpretation: Cheng E. Manuscript preparation: Shamavonian R, Cheng E. Critical revision of manuscript: Karpes JB, Ahmadi N, Morris DL.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received March 31, 2022.
- Revision received April 22, 2022.
- Accepted April 29, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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