Advertisement

Impact of centralization of care for malignant peritoneal mesothelioma: A historical cohort study from the Dutch mesothelioma expert centers

Open AccessPublished:October 27, 2022DOI:https://doi.org/10.1016/j.ejso.2022.10.003

      Abstract

      Background

      Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. An earlier population-based study found that the majority of Dutch patients do not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in two expert centers. We reviewed treatment patterns at these centers, to assess the impact of centralization of MPM care in the Netherlands.

      Methods

      Data from all patients referred to the Dutch MPM expert centers from 2014 to 2020, were retrospectively collected. Descriptive statistics regarding referrals, patient and tumor characteristics, and treatment patterns were provided. Population-based incidence rates were provided by the Netherlands Cancer Registry.

      Results

      From 2014 to 2020, 78 patients were referred to the Dutch Mesothelioma expert centers, of whom 32 were female (41%). From 2014 to 2017, 27 patients were referred, whereas 51 patients were referred from 2018 to 2020. This represents about 24% and 61% of the estimated population incidence, respectively. Treatment patterns were comparable between both periods. Between 2014 and 2018, 33% of patients underwent surgery, 44% systemic therapy, and 22% received best supportive care (BSC), while this was 29%, 37%, and 33% respectively from 2018 to 2020.

      Conclusion

      Centralization of care for patients with MPM resulted in an increase of annual referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. This might be considered a first important step towards better treatment for patients with this fatal disease.

      Keywords

      1. Introduction

      Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that primarily arises from the peritoneal lining. Comprising about 10–15% of cases, it is the second most common malignant mesothelioma (MM) location, after malignant pleural mesothelioma. Most cases are confined to the abdominal cavity, though a small percentage extends through the diaphragm into the thoracic cavity, or metastasizes to distant lymph nodes [
      • Baratti D.
      • et al.
      Lymph node metastases in diffuse malignant peritoneal mesothelioma.
      ,
      • Kim J.
      • et al.
      Malignant peritoneal mesothelioma: a review.
      ]. Exposure to asbestos is the main risk factor for developing MPM, but other risk factors such as germline BAP1 mutations have recently been identified [
      • Attanoos R.L.
      • et al.
      Malignant mesothelioma and its non-asbestos causes.
      ,
      • Testa J.R.
      • et al.
      Germline BAP1 mutations predispose to malignant mesothelioma.
      ]. MPM can be stratified into three main histological subtypes: the epithelioid subtype is the most common (90%) with the best prognosis, while the sarcomatoid and biphasic subtypes comprise about 5% of cases each [
      • Schulte J.J.
      • Husain A.N.
      Update on the pathologic diagnosis of malignant mesothelioma.
      ,
      • Cerruto C.A.
      • et al.
      Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma.
      ,
      • Yan T.D.
      • et al.
      Prognostic indicators for patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma.
      ]. Well-differentiated papillary mesothelioma (WDPMP) and multicystic peritoneal mesothelioma are other, more rare subtypes, that most often present as indolent tumors and have good prognosis [
      • Vogin G.
      • et al.
      Well-differentiated papillary mesothelioma of the peritoneum: a retrospective study from the renape observational registry.
      ,
      • Noiret B.
      • et al.
      Multicystic peritoneal mesothelioma: a systematic review of the literature.
      ].
      Currently, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), is considered to be the best available treatment for a selected group of MPM patients [
      • Alexander Jr., H.R.
      • et al.
      Current management and future opportunities for peritoneal metastases: peritoneal mesothelioma.
      ,
      • Magge D.
      • et al.
      Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis.
      ,
      • Yan T.D.
      • et al.
      Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience.
      ]. However, most patients are considered ineligible to undergo this major procedure, due to extent of disease, poor prognostic factors or performance status. Another treatment option is systemic chemotherapy with the anti-folate pemetrexed and a platinum derivative (e.g. carboplatin, cisplatin) [
      • Vogelzang N.J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      ,
      • Janne P.A.
      • et al.
      Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.
      ,
      • Simon G.R.
      • et al.
      Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial.
      ]. More recently, several clinical trials have been initiated, exploring the possible use of various immunotherapies [
      • de Boer N.L.
      • et al.
      Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial.
      ,
      • Antoniu S.A.
      • et al.
      Immune therapies for malignant mesothelioma.
      ].
      Earlier, we explored the incidence, treatment, and survival for patients with MPM in the Netherlands over a period of 25 years up to 2016 [
      • de Boer N.L.
      • et al.
      Malignant peritoneal mesothelioma: patterns of care and survival in The Netherlands: a population-based study.
      ]. This study demonstrated that survival slightly improved over the years, though it is still poor. However, it also revealed that up to 60% of patients did not receive anti-tumor treatment. We stated that centralization of care for MPM in expert centers could benefit patients as patients would likely receive treatment more often. Centralization of cancer care has previously been demonstrated to increase the treatment rate, and improve survival in other solid tumors [
      • Palmqvist C.
      • et al.
      Increased disease-free and relative survival in advanced ovarian cancer after centralized primary treatment.
      ,
      • Noiret B.
      • et al.
      Centralization and oncologic training reduce postoperative morbidity and failure-to-rescue rates after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies: study on a 10-year national French practice.
      ,
      • van Putten M.
      • et al.
      Overall survival before and after centralization of gastric cancer surgery in The Netherlands.
      ].
      Since 2015, there have been two officially acknowledged mesothelioma expert centers in the Netherlands. These are the Erasmus MC Cancer Institute (EMC) in Rotterdam, and the Netherlands Cancer Institute (NKI) in Amsterdam. The aim of this study was to review treatment and survival of patients referred to the two Dutch expert centers in recent years, in relation to centralization of care for patients with MPM in the Netherlands.

      2. Methods

      2.1 Study design and participants

      This retrospective cohort study included all MPM patients who were referred to the two Dutch mesothelioma expert centers from 2014 until 2020. At the Erasmus MC Cancer Institute, a phase 2 clinical trial (MESOPEC), investigating the safety and feasibility of adjuvant dendritic cell based immunotherapy (DCBI) after CRS-HIPEC for patients with MPM, was initiated in 2018 [
      • de Boer N.L.
      • et al.
      Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial.
      ]. For the purpose of prompt patient accrual, it was agreed upon within the ‘Dutch Peritoneal Oncology Group’ (DPOG) to preferentially refer all MPM patients to this center from 2018 onward.

      2.2 Data collection and approval

      Data were retrospectively obtained from patients’ electronic medical records. At the Erasmus MC, patient and tumor characteristics as well as data regarding treatment, treatment response, disease progression and overall survival were collected from patient charts. At the NKI patient and tumor characteristics were provided by the central research department, who performed a search in the Dutch Cancer Registry and original patients charts were reviewed by the local study investigators. The Dutch Personal Records Database was consulted in March 2021 for survival analyses. To describe the impact of centralization on a national level, the number of referrals was compared to the estimated population incidence of MPM, retrieved from the Dutch Cancer Registry (NKR). The NKR provides incidence numbers by identifying cancer patients in the Dutch Pathological Anatomical National Automated Archive (PALGA) and the National Registry of Hospital Discharge Diagnoses.
      All data were collected and managed according to the latest European privacy regulations (General Data Protection Regulation (GDPR), EU 2016/679). The study was approved by both the EMC local ethics committee (MEC 2018–1286) and the Dutch NKI-AVL Institutional Review Board (IRBd20-176).

      2.3 Statistical analysis

      Because the number of referred patients increased upon starting the MESOPEC study, we tabulated characteristics of the study population according to their period of referral (2014–2017 vs 2018–2020). These groups were not statistically compared because of a lack of rationale. Continuous variables were presented as medians with interquartile ranges [IQR]. Categorical variables were shown as absolute numbers with percentages. Overall survival was calculated for all patients from date of diagnosis until death or last date of follow-up. Progression free (PFS) and disease free survival (DFS) were calculated from the start of treatment until progression or last date of follow-up. Comparison of survival between subgroups was not performed due to the large number of confounding factors caused by the retrospective design. To illustrate survival estimates, Kaplan Meier overall survival-curves were created using R version 3.5.1 (http://www.r-project.org). Other figures were also constructed using R. Statistical analyses were performed with Statistical Package for Social Sciences (SPSS) version 25.0.0.1 (IBM corporation, Armonk, NY, USA).

      3. Results

      3.1 Referrals

      Between January 2014 and July 2020, a total of 78 patients with histologically proven MPM were referred to the EMC and NKI. The number of referrals markedly increased after starting the phase II MESOPEC trial, from about 5 to 9 cases per year between 2014 and 2017, to a total of 15, 20 and 16 referrals in 2018, 2019 and 2020 respectively (Fig. 1). National population based incidence did not increase during the study period, with a mean annual incidence of 28.7 cases (95%CI = 18.6–37.0). The proportion of referred patients compared to the population incidence, was 24% between 2014 and 2017, and 61% from 2018 to 2020, a more than two-fold increase.
      Fig. 1
      Fig. 1Annual peritoneal mesothelioma referrals to Dutch mesothelioma expert centers MPM patients referred to the Dutch mesothelioma expert centers from 2014 to 2020. EMC: Erasmus MC Cancer Institute. NKI: Netherlands Cancer Institute.

      3.2 Patient characteristics

      Fifty-nine percent of patients were male and median age at diagnosis was 62.5 years (IQR 52–69). History of (occupational) asbestos exposure was confirmed for 19 patients (24%), and 55% percent of patients had no history of asbestos exposure. For 22% of patients, history of asbestos exposure could not be retrieved (Table 1).
      Table 1Patient and tumor characteristics.
      Referred from 20142017 (n = 27)Referred from 20182020 (n = 51)Total (n = 78)
      Sex
       Female12 (44)20 (39)32 (41)
       Male15 (56)31 (61)46 (59)
      Age at diagnosis64 [51.5–68]62 [52–69]62.5 [52–69]
      Asbestos exposure
       Yes6 (22)13 (26)19 (31)
       No19 (70)23 (45)42 (69)
       Unknown2 (7)15 (29)17 (22)
      Histology
       Epithelioid22 (81)44 (86)66 (85)
       Biphasic04 (8)4 (5)
       Papillary1 (4)1 (2)2 (3)
       Sarcomatoid3 (11)1 (2)4 (5)
       Unknown1 (4)1 (2)2 (3)
      Ki67 proliferation index5 [2−20]10 [5–20]8 [5−20]
      Unknown10 (37)11 (22)21 (27)
      Ki67 high vs. low
       Ki67 < 10%7 (26)21 (41)28 (36)
       Ki67 ≥ 10%10 (37)19 (37)29 (37)
       Unknown10 (37)11 (22)21 (27)
      Peritoneal Cancer Index (PCI)
       Total34 [21–39]28 [20–38]30 [20–39]
       Determined by radiology27 [18–37]22 [15–28]22 [16–32]
       Determined by Surgery36 [30–39]38 [29–39]38 [29–39]
      Lymph node metastases
       Yes4 (15)10 (20)14 (18)
       No21 (78)41 (80)62 (79)
       Unknown2 (7)02 (3)
      Ascites
       Yes23 (85)37 (72)60 (77)
       No4 (15)14 (28)18 (23)
      BAP1 germline mutation
       Yes2 (7)2 (4)4 (5)
       No08 (16)8 (10)
       Unknown25 (93)41 (80)66 (85)
      Categorical variables are provided as number with (percentage). Continuous variables are provided as median with [interquartile range]. Some percentages do not accumulate to 100% due to rounding.

      3.3 Tumor characteristics

      Prognostic factors, such as histological subtype, Ki67 index, lymph node metastases and peritoneal cancer index (PCI), a measure for peritoneal disease load, did not show major differences between both periods. Epithelioid histology was the most common subtype (85%), while 5% of patients presented with sarcomatoid histology and another 5% with biphasic histology. WDPMP was diagnosed in 2 patients (3%). For 3% of patients the histology was unknown. One patient was first diagnosed with WDPMP over 20 years ago. After initial surgery, the disease recurred after 15 years. This patient was treated with CRS-HIPEC, after which the disease recurred after 5 years. This time pathological examination showed invasive growth. Therefore the tumor was re-classified as a malignant epithelioid mesothelioma, rather than WDPMP. The patient was again treated with CRS-HIPEC.
      Median proliferation index, determined by the percentage of Ki67 positive tumor cells, was 8 [IQR 4–20%]. Median PCI at diagnosis was 30 [IQR 20–39], based on 76 (97.4%) patients for whom PCI was available. Surgically determined PCI was available for 38 (48%) of patients. Median PCI was significantly higher when determined by surgery (i.e. diagnostic laparoscopy or laparotomy), compared to PCI determined by radiology (i.e. CAT scan). Median surgical PCI was 38 [
      • Blauwgeers H.
      • Kwast van der
      Zwan Kankerzorg in beeld: zeldzame kanker.
      ,
      • Baratti D.
      • et al.
      Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research.
      ,
      • Kusamura S.
      • et al.
      The role of ki-67 and pre-cytoreduction parameters in selecting diffuse malignant peritoneal mesothelioma (DMPM) patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
      ,
      • Gilani S.N.S.
      • et al.
      Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival.
      ,
      • Pillai K.
      • et al.
      Prognostic significance of Ki67 expression in malignant peritoneal mesothelioma.
      ,
      • Belderbos R.A.
      • et al.
      Ki67 (MIB-1) as a prognostic marker for clinical decision making before extended pleurectomy decortication in malignant pleural mesothelioma.
      ,
      • Sugarbaker P.H.
      • et al.
      Management of malignant peritoneal mesothelioma using cytoreductive surgery and perioperative chemotherapy.
      ,
      • Yan T.D.
      • et al.
      A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database.
      ,
      • Yan T.D.
      • et al.
      Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma.
      ,
      • Baumann F.
      • et al.
      Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
      ,
      • Esquivel J.
      • et al.
      Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.
      ], whereas median radiographic PCI was 22 [
      • de Boer N.L.
      • et al.
      Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial.
      ,
      • Antoniu S.A.
      • et al.
      Immune therapies for malignant mesothelioma.
      ,
      • de Boer N.L.
      • et al.
      Malignant peritoneal mesothelioma: patterns of care and survival in The Netherlands: a population-based study.
      ,
      • Palmqvist C.
      • et al.
      Increased disease-free and relative survival in advanced ovarian cancer after centralized primary treatment.
      ,
      • Noiret B.
      • et al.
      Centralization and oncologic training reduce postoperative morbidity and failure-to-rescue rates after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies: study on a 10-year national French practice.
      ,
      • van Putten M.
      • et al.
      Overall survival before and after centralization of gastric cancer surgery in The Netherlands.
      ,
      • van Kooten J.P.
      • et al.
      Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.
      ,
      • Yan T.D.
      • et al.
      Morbidity and mortality assessment of cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma--a prospective study of 70 consecutive cases.
      ,
      • Sugarbaker P.H.
      • et al.
      Comprehensive management of diffuse malignant peritoneal mesothelioma.
      ,
      • Le Roy F.
      • et al.
      Conversion to complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma after bidirectional chemotherapy.
      ,
      • Kepenekian V.
      • et al.
      Non-resectable malignant peritoneal mesothelioma treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) plus systemic chemotherapy could lead to secondary complete cytoreductive surgery: a cohort study.
      ,
      • Sugarbaker P.H.
      • Chang D.
      Cytoreductive surgery plus HIPEC with and without NIPEC for malignant peritoneal mesothelioma: a propensity-matched analysis.
      ,
      • Gatta G.
      • et al.
      Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.
      ,
      • Blauwgeers H.
      • Kwast van der
      Zwan Kankerzorg in beeld: zeldzame kanker.
      ,
      • Baratti D.
      • et al.
      Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research.
      ,
      • Kusamura S.
      • et al.
      The role of ki-67 and pre-cytoreduction parameters in selecting diffuse malignant peritoneal mesothelioma (DMPM) patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
      ,
      • Gilani S.N.S.
      • et al.
      Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival.
      ] (p < 0.0001). Ascites was present in 60 patients (76%). In 14 patients (18%) there were clinically suspected or pathologically confirmed lymph node metastases.

      3.4 Treatment

      A comprehensive overview of treatment for the entire population, as well as treatment per time period (i.e. 2014-2017 vs. 2018–2020) is provided in figures two and three respectively. Treatment was first categorized into three main groups: 1. Surgery, 2. Systemic treatment only, and 3. Best supportive care (BSC). Within these categories, subcategories were created illustrating the multimodality of most treatment strategies.
      Most patients who received CRS-HIPEC, received some form of systemic therapy as well (79%), either as (neo) adjuvant or second line treatment after recurrence. Completeness of cytoreduction (CC-score) was assessed for 21 of 25 patients (86%) who underwent CRS-HIPEC. In nine patients (36%) complete cytoreduction was achieved (CC-0). Four patients (16%) had residual tumor nodules smaller than 2.5 mm (CC-1). In eight patients (32%), extensive residual disease was present after cytoreduction (CC-3). For five of these CC-3 patients, CRS-HIPEC was indicated for palliation. In the other two patients, the goal was to achieve complete cytoreduction. However, due to extensive small bowel involvement this was not feasible. Median progression free survival (PFS) from CRS-HIPEC was 23.1 months [IQR 5.6-NR months].
      CRS-HIPEC was not considered feasible in most patients (70%). Poor performance status or comorbidity (22%) and irresectability of the tumor (30%) were the most common reasons. Biphasic or sarcomatoid histology was considered a contraindication in nine percent of patients (Fig. 2) (see Fig. 3).
      Fig. 2
      Fig. 2Overview of treatment for peritoneal mesothelioma at the Dutch mesothelioma expert centers from 20142020. BSC: best supportive care. CRS-HIPEC: cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. CTx: systemic chemotherapy. Immuno: systemic immunotherapy. PS: performance score. PCI: peritoneal cancer index.
      Fig. 3
      Fig. 3Overview of treatment for peritoneal mesothelioma at the Dutch mesothelioma expert centers before and after centralization. BSC: best supportive care. CRS-HIPEC: cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. CTx: systemic chemotherapy. Immuno: systemic immunotherapy. PS: performance score.
      In total 40 patients (51%) received systemic chemotherapy at some point during treatment. The vast majority (95%) received pemetrexed combined with a platinum based agent (i.e. cisplatin, carboplatin, oxaliplatin). Median number of chemotherapy cycles was four (IQR 3–5). Median PFS of systemic chemotherapy was 6.2 months [IQR 3.4–22.8] (Table 2).
      Table 2Treatment characteristics.
      N = 78
      CCR-score
       CCR-09 (36)
       CCR-14 (16)
       CCR-20 (0)
       CCR-38 (32)
       Unknown4 (16)
      Palliative intent CRS-HIPEC
       Yes6 (24)
       No16 (64)
       Unknown3 (12)
      CRS-HIPEC median PFS
       Total23.1 [5.6 – NR]
       CCR-0NR [33.1 – NR]
       CCR-1NR [1 – NR]
       CCR-35.6 [4.6–16.8]
      Type of chemotherapy
       Pemetrexed + Platinum38 (95)
       Gemcitabine + Platinum2 (5)
      Number of chemotherapy cycles4 [4,5]
      Type of anti-PD1 immunotherapy
       Nivolumab6 (55)
       Pembrolizumab4 (36)
       Atezolizumab1 (9)
      Number of immunotherapy cycles5 [3–17]
      Months of PFS from systemic treatment
       Chemotherapy6.2 [3.4–22.8]
       Anti-PD1 immunotherapy3.7 [2.1–5.8]
      Categorical variables are provided as number with (percentage). Continuous variables are provided as median with [interquartile range]. CRS = cytoreductive surgery, HIPEC = hyperthermic intraperitoneal chemotherapy, NR = not reached. Some percentages do not accumulate to 100% due to rounding.
      Anti-PD1 immunotherapy was given to 11 patients (14%), of whom six (55%) received nivolumab, four (36%) received pembrolizumab, and 1 patient (9%) received atezolizumab. One patient received immunotherapy as first line treatment, all others received immunotherapy as second line treatment. The median number of immunotherapy cycles was five (IQR 3–17). Eventually all patients developed disease progression. Median progression free survival after start of anti-PD1 immunotherapy was 3.7 months [IQR 2.1–5.8] (Table 2).

      3.5 Survival

      The survival of patients referred between 2014-2017 and 2018–2020 was comparable (Fig. 4a). The survival of patients with lymph node metastases was worse compared to patients without positive lymph nodes (HR 2.2 [95% CI: 1.03–3.8], Fig. 4b). Patients with a low ki67 index had better survival (median 58 months) compared to patients with a high ki67 index (median 9.7 months, HR 0.34 [95% CI 0.15–0.76], Fig. 4c).
      Fig. 4a–c
      Fig. 4a–cKaplan Meyer overall survival curves for patients referred to the Dutch mesothelioma expert centers from 20142020 mOS: median overall survival. NA: not applicable. HR: hazard ratio. Ki67: marker of proliferation Ki67.
      Fig. 4a–c
      Fig. 4a–cKaplan Meyer overall survival curves for patients referred to the Dutch mesothelioma expert centers from 20142020 mOS: median overall survival. NA: not applicable. HR: hazard ratio. Ki67: marker of proliferation Ki67.
      Fig. 4a–c
      Fig. 4a–cKaplan Meyer overall survival curves for patients referred to the Dutch mesothelioma expert centers from 20142020 mOS: median overall survival. NA: not applicable. HR: hazard ratio. Ki67: marker of proliferation Ki67.

      4. Discussion

      The aim of this study was to review the impact of centralization of care for malignant peritoneal mesothelioma (MPM) in the Netherlands. Therefore we reviewed referrals of, and treatment received by patients referred to the Dutch mesothelioma expert centers from 2014 to 2020. Officially, centralization took place in 2015, when both the Dutch Cancer Institute (NKI) and the Erasmus MC Cancer Institute (EMC) were officially accredited as mesothelioma expert centers by the Dutch Federation of University Hospitals (NFU). At first this centralization was mainly focused on pleural mesothelioma and peritoneal mestohelioma cases were mostly referred to one of seven CRS-HIPEC expert centers. However, by initiating a phase-II clinical trial for patients with MPM in 2018, centralization of care became truly effective in The Netherlands. For prompt patient accrual, it was agreed to refer all MPM patients to the Erasmus MC Cancer Institute. This caused a major boost in referrals to this expert center. We found a more than two-fold increase in the percentage of patients being referred to the expert centers, despite of the decreased number of referrals in 2020, likely caused by the COVID-19 pandemic. On the other hand, initiating a clinical trial would not have been possible without centralizing care, which illustrates the synergystic effect of centralization and clinical research with regard to patients being referred to expert centers. This positive feedback mechanism, where centralization stimulates research and this research stimulates patients being referred and treated, might improve the future management of this disease and might ultimately improve its outcome.
      As centralization of care became truly effective in 2018, we studied treatment patterns before and after 2018. We found that treatment patterns at our centers remained comparable between both periods, though logically a slight increase in the proportion of patients receiving best supportive care (BSC) from 22% to 33%, was observed. In an earlier population based study, we found that between 1989 and 2018 there were no trends in MPM incidence, with a median of 0.18 cases per 100.000 person years RESR (revised European standard population rate) [
      • van Kooten J.P.
      • et al.
      Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.
      ]. This study also showed that about one third of patients received anti-cancer treatment between 2013 and 2018, while about two-thirds received best supportive care only. Taking into account these steady population incidence rates, and comparing the observations of the current study to earlier observed treatment paterns, it appears that more MPM patients are eligible to undergo anti cancer treatment than earlier thought. Whether this will eventually result in better quality of life or better survival outcome can not be determined by this study. Nonetheless, centralization might be an important first step towards better treatment for MPM patients. Especially as there currently is no consensus on the optimal treatment for MPM. Systemic chemotherapy is the standard of care according to the Dutch mesothelioma guideline. However, in recent years the use of CRS-HIPEC has increased for patients that are considered eligible. The Dutch guideline on mesothelioma treatment is mainly based on studies in pleural mesothelioma that showed a survival benefit of platinum-doublet therapy, and extended access programs for peritoneal mesothelioma patients [
      • Vogelzang N.J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      ,
      • Janne P.A.
      • et al.
      Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.
      ]. There are countries however, in which CRS-HIPEC is considered the golden standard, which is mostly based on retrospective series published over a decade ago [
      • Yan T.D.
      • et al.
      Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience.
      ,
      • Yan T.D.
      • et al.
      Morbidity and mortality assessment of cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma--a prospective study of 70 consecutive cases.
      ,
      • Sugarbaker P.H.
      • et al.
      Comprehensive management of diffuse malignant peritoneal mesothelioma.
      ]. These studies showed that CRS-HIPEC is feasible, and results in good prognosis for a selected group of patients, though the benefit of CRS-HIPEC for MPM patients has never been investigated in randomized trials. A major problem of CRS-HIPEC remains the fact that the majority of MPM patients are not eligible, and recurrence rates are high. Therefore new strategies are being investigated to tackle these problems. Le Roy et al. have investigated the use of bidirectional neoadjuvant chemotherapy (both intraperitoneal and systemic chemotherapy) [
      • Le Roy F.
      • et al.
      Conversion to complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma after bidirectional chemotherapy.
      ]. They performed CRS-HIPEC in 50% of patients that were first considered ineligible due to extensive disease. Kepenekian et al. explored a similar strategy, but with pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy [
      • Kepenekian V.
      • et al.
      Non-resectable malignant peritoneal mesothelioma treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) plus systemic chemotherapy could lead to secondary complete cytoreductive surgery: a cohort study.
      ]. They achieved similar results. To battle early recurrence, Sugarbaker et al. use normothermic intraperitoneal chemotherapy (NIPEC) as an adjuvant treatment. In a recent propensity mathced analysis they observed significantly improved survival for patients receiving NIPEC, with a five year OS rate of 70% [
      • Sugarbaker P.H.
      • Chang D.
      Cytoreductive surgery plus HIPEC with and without NIPEC for malignant peritoneal mesothelioma: a propensity-matched analysis.
      ].
      For any treatment that is offered to MPM patients (surgical and/or systemic), patient selection is of great importance. Especially as both treatments are associated with considerable morbidity. However, selection of MPM patients who are eligible to undergo treatment is complex. Expert multidisciplinary assessment could provide a more tailored treatment plan with consideration for prognostic factors, comorbidity and patients' preferences. Centralization of care will likely improve this process and is considered an important measure to be able to provide high-quality care [
      • Gatta G.
      • et al.
      Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.
      ]. The ‘Dutch cancer registry’ (NKR) recently observed that survival outcomes for rare cancers trail behind on more common malignancies in the Netherlands [
      • Blauwgeers H.
      • Kwast van der
      Zwan Kankerzorg in beeld: zeldzame kanker.
      ]. They also recommended to centralize expertise for rare cancers and suggested this can lead to improved outcome.
      Several prognostic factors have been described in literature that might facilitate selection for treatment. For example, the proliferation index of the tumor, represented by the Ki67 index, has been shown to be associated with OS both in pleural and peritoneal mesothelioma [
      • Baratti D.
      • et al.
      Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research.
      ,
      • Kusamura S.
      • et al.
      The role of ki-67 and pre-cytoreduction parameters in selecting diffuse malignant peritoneal mesothelioma (DMPM) patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
      ,
      • Gilani S.N.S.
      • et al.
      Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival.
      ,
      • Pillai K.
      • et al.
      Prognostic significance of Ki67 expression in malignant peritoneal mesothelioma.
      ]. In the current study, patients with a low ki76 index had a better survival (Fig. 4C), though the independent effect could not be assessed in multivariable analysis due to patient and treatment heterogeneity. A recent study by Belderbos et al. investigated the ki67 index in patients with pleural mesothelioma [
      • Belderbos R.A.
      • et al.
      Ki67 (MIB-1) as a prognostic marker for clinical decision making before extended pleurectomy decortication in malignant pleural mesothelioma.
      ]. They also found that Ki67 could be utilized as a prognostic marker for patients with pleural mesothelioma undergoing extended pleurectomy/decortication. This is especially useful for identifying patients who are unlikely to benefit from surgery. They used a cut off value of 10% Ki67 positive cells, and found that tumors with Ki67 indexes below 10% resulted in better prognosis after surgery. Kusamura et al. used the same cut off and found a similar outcome for patients with MPM [
      • Kusamura S.
      • et al.
      The role of ki-67 and pre-cytoreduction parameters in selecting diffuse malignant peritoneal mesothelioma (DMPM) patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
      ].
      Other established prognostic factors are tumor histology and lymph node status. Patients with epithelioid MPM show better survival, when compared to patients with biphasic or sarcomatoid histology [
      • Cerruto C.A.
      • et al.
      Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma.
      ,
      • Magge D.
      • et al.
      Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis.
      ,
      • Sugarbaker P.H.
      • et al.
      Management of malignant peritoneal mesothelioma using cytoreductive surgery and perioperative chemotherapy.
      ,
      • Yan T.D.
      • et al.
      A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database.
      ]. The same applies to patients with lymph node metastases. Nodal dissemination has shown to be of great prognostic significance and has been adopted in a proposed TNM classification by Yan et al. [
      • Yan T.D.
      • et al.
      A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database.
      ] In a study by the same author, median survival after CRS-HIPEC for patients with positive lymph nodes was 6 months, and 2-year survival was 0% [
      • Yan T.D.
      • et al.
      Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma.
      ]. Others have shown similar results [
      • Baratti D.
      • et al.
      Lymph node metastases in diffuse malignant peritoneal mesothelioma.
      ]. Preferably, lymph node status is meticulously assesed for patient selection to prevent futile treatment.
      A feature that results in favorable prognosis, is being a carrier of a germline BAP1 mutation. Baumann et al. even showed that patients with a germline BAP1 mutation, have a sevenfold increased long term survival compared to other MPM patients [
      • Baumann F.
      • et al.
      Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
      ]. In our cohort, four patients (5%) were identified as carrier of such a mutation. Patients are not routinely tested for this mutation, but only by indication (such as a history of earlier malignancies or diagnosis at a very young age). The exact frequency of MPM patients that carry this germline mutation is unknown. It could have implications for choice of treatment and therefore it should be subject of further study.
      The extent of peritoneal involvement is also of prognostic significance. This is represented by the PCI which varies from 0 – no peritoneal lesions, to 39 – confluent or >5 cm lesions in all regions of the abdomen. For systemic therapy there are no data regarding the extent of disease in relation to survival, while for surgical treatment there is a clear relation between the PCI and survival [
      • Magge D.
      • et al.
      Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis.
      ,
      • Yan T.D.
      • et al.
      A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database.
      ]. In our cohort, PCI determined by radiology was significantly lower than PCI determined by surgery. This also has been reported for peritoneal metastases from colorectal cancer [
      • Esquivel J.
      • et al.
      Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.
      ,
      • Koh J.L.
      • et al.
      Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis.
      ]. Small lesions are not detected by CAT or MRI scans, likely resulting in an underestimation of the true PCI. Therefore, we first performed diagnostic laparoscopy (DLS) in every patient that was considered for CRS-HIPEC.
      As with every study there are limitations to the current work. Due to the retrospective data collection, there were missing data for various variables. Therefore it was not possible to perform unbiased comparative analyses between subgroups. For this reason we only provided descriptive statistics. Also, detailed population based treatment data were unavilable. Therefore we could not compare treatment at our centers with the population based treatment patterns, making it difficult to truly assess the impact of centralization. On the other hand, we were able to compare treatment at our centers with population based data that were reviewed earlier, which indicated that more patients undergo treatment when refferred to an expert center. Also, we could only estimate the proportion of referred patients compared to the population incidence, as recent incidence rates were yet unavailable. Moreover, patients diagnosed in a certain year might be referred in the following year, which made it impossible to compare the number of annual referrals with the annual population incidence (which was provided completely anominized). Therefore it can not be fully ruled out that the increased number of patients referred to our centers is caused by an increase of MPM incidence. However, earlier work showed that from 1989 to 2018 MPM incidence in the Netherlands did not significantly change, thereby making this scenario highly unlikely [
      • van Kooten J.P.
      • et al.
      Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.
      ].

      5. Conclusion

      Centralization of care for patients with MPM in The Netherlands has provided the opportunity to perform clinical trials and has resulted in an increase of referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. Whether this will result in better quality of life or prognosis, remains to be determined. Nonetheless, centralization of care might be considered as a first important step towards better treatment for patients with this fatal disease.

      CRediT authorship contribution statement

      Job P. van Kooten: Data acquisition, Quality control of data and algorithms, Formal analysis, interpretation, Statistical analysis, Manuscript preparation, Writing – review & editing. Cornedine J. de Gooijer: Data acquisition, Quality control of data and algorithms, Formal analysis, interpretation, Statistical analysis, Manuscript preparation, Writing – review & editing. Jan H. von der Thüsen: Data acquisition. Arend G.J. Albers: Data acquisition. Max J. Lahaye: Data acquisition. Kim Monkhorst: Data acquisition. Jacobus A. Burgers: Manuscript preparation, All authors, Conceptualization, Study design, Writing – review & editing. Eva V.E. Madsen: Quality control of data and algorithms, Manuscript preparation.

      Conflict of interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JB reports reimbursements for his institution (Netherlands Cancer Institute) outside the submitted work from Roche, AstraZeneca and Boehringer Ingelheim. JA reports grants outside the submitted work from Amphera and Roche, ownership interest (including patents) from Amphera, and advisory roles for Amphera, Boehringer Ingelheim , Bristol Myers Squibb , Eli Lilly, MSD and Roche, outside the submitted work. All other authors declare no conflict of interest.

      References

        • Baratti D.
        • et al.
        Lymph node metastases in diffuse malignant peritoneal mesothelioma.
        Ann Surg Oncol. 2010; 17: 45-53
        • Kim J.
        • et al.
        Malignant peritoneal mesothelioma: a review.
        Ann Transl Med. 2017; 5: 236
        • Attanoos R.L.
        • et al.
        Malignant mesothelioma and its non-asbestos causes.
        Arch Pathol Lab Med. 2018; 142: 753-760
        • Testa J.R.
        • et al.
        Germline BAP1 mutations predispose to malignant mesothelioma.
        Nat Genet. 2011; 43: 1022-1025
        • Schulte J.J.
        • Husain A.N.
        Update on the pathologic diagnosis of malignant mesothelioma.
        Transl Lung Cancer Res. 2020; 9: 917-923
        • Cerruto C.A.
        • et al.
        Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma.
        Arch Pathol Lab Med. 2006; 130: 1654-1661
        • Yan T.D.
        • et al.
        Prognostic indicators for patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma.
        Ann Surg Oncol. 2007; 14: 41-49
        • Vogin G.
        • et al.
        Well-differentiated papillary mesothelioma of the peritoneum: a retrospective study from the renape observational registry.
        Ann Surg Oncol. 2019; 26: 852-860
        • Noiret B.
        • et al.
        Multicystic peritoneal mesothelioma: a systematic review of the literature.
        Pleura Peritoneum. 2019; 420190024
        • Alexander Jr., H.R.
        • et al.
        Current management and future opportunities for peritoneal metastases: peritoneal mesothelioma.
        Ann Surg Oncol. 2018; 25: 2159-2164
        • Magge D.
        • et al.
        Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis.
        Ann Surg Oncol. 2014; 21: 1159-1165
        • Yan T.D.
        • et al.
        Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience.
        J Clin Oncol. 2009; 27: 6237-6242
        • Vogelzang N.J.
        • et al.
        Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
        J Clin Oncol. 2003; 21: 2636-2644
        • Janne P.A.
        • et al.
        Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.
        Clin Lung Cancer. 2005; 7: 40-46
        • Simon G.R.
        • et al.
        Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial.
        J Clin Oncol. 2008; 26: 3567-3572
        • de Boer N.L.
        • et al.
        Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial.
        BMJ Open. 2019; 9e026779
        • Antoniu S.A.
        • et al.
        Immune therapies for malignant mesothelioma.
        Expert Rev Anticancer Ther. 2014; 14: 965-973
        • de Boer N.L.
        • et al.
        Malignant peritoneal mesothelioma: patterns of care and survival in The Netherlands: a population-based study.
        Ann Surg Oncol. 2019; 26: 4222-4228
        • Palmqvist C.
        • et al.
        Increased disease-free and relative survival in advanced ovarian cancer after centralized primary treatment.
        Gynecol Oncol. 2020; 159: 409-417
        • Noiret B.
        • et al.
        Centralization and oncologic training reduce postoperative morbidity and failure-to-rescue rates after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies: study on a 10-year national French practice.
        Ann Surg. 2020; 272: 847-854
        • van Putten M.
        • et al.
        Overall survival before and after centralization of gastric cancer surgery in The Netherlands.
        Br J Surg. 2018; 105: 1807-1815
        • van Kooten J.P.
        • et al.
        Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.
        Thorax, 2022
        • Yan T.D.
        • et al.
        Morbidity and mortality assessment of cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma--a prospective study of 70 consecutive cases.
        Ann Surg Oncol. 2007; 14: 515-525
        • Sugarbaker P.H.
        • et al.
        Comprehensive management of diffuse malignant peritoneal mesothelioma.
        Eur J Surg Oncol. 2006; 32: 686-691
        • Le Roy F.
        • et al.
        Conversion to complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma after bidirectional chemotherapy.
        Ann Surg Oncol. 2017; 24: 3640-3646
        • Kepenekian V.
        • et al.
        Non-resectable malignant peritoneal mesothelioma treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) plus systemic chemotherapy could lead to secondary complete cytoreductive surgery: a cohort study.
        Ann Surg Oncol. 2022; 29: 2104-2113
        • Sugarbaker P.H.
        • Chang D.
        Cytoreductive surgery plus HIPEC with and without NIPEC for malignant peritoneal mesothelioma: a propensity-matched analysis.
        Ann Surg Oncol. 2021; 28: 7109-7117
        • Gatta G.
        • et al.
        Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.
        Lancet Oncol. 2017; 18: 1022-1039
        • Blauwgeers H.
        • Kwast van der
        Zwan Kankerzorg in beeld: zeldzame kanker.
        in: Simons ˆ City: Dutch cancer registry. 2018
        • Baratti D.
        • et al.
        Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research.
        J Surg Oncol. 2011; 103: 822-831
        • Kusamura S.
        • et al.
        The role of ki-67 and pre-cytoreduction parameters in selecting diffuse malignant peritoneal mesothelioma (DMPM) patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
        Ann Surg Oncol. 2016; 23: 1468-1473
        • Gilani S.N.S.
        • et al.
        Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival.
        Int J Hyperther. 2018; 34: 578-584
        • Pillai K.
        • et al.
        Prognostic significance of Ki67 expression in malignant peritoneal mesothelioma.
        Am J Clin Oncol. 2015; 38: 388-394
        • Belderbos R.A.
        • et al.
        Ki67 (MIB-1) as a prognostic marker for clinical decision making before extended pleurectomy decortication in malignant pleural mesothelioma.
        JTO Clin Res REp. 2021; : 2
        • Sugarbaker P.H.
        • et al.
        Management of malignant peritoneal mesothelioma using cytoreductive surgery and perioperative chemotherapy.
        J Oncol Pract. 2016; 12: 928-935
        • Yan T.D.
        • et al.
        A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database.
        Cancer. 2011; 117: 1855-1863
        • Yan T.D.
        • et al.
        Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma.
        Eur J Surg Oncol. 2006; 32: 948-953
        • Baumann F.
        • et al.
        Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
        Carcinogenesis. 2015; 36: 76-81
        • Esquivel J.
        • et al.
        Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.
        J Surg Oncol. 2010; 102: 565-570
        • Koh J.L.
        • et al.
        Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis.
        Ann Surg Oncol. 2009; 16: 327-333