The latest global cancer burden data in 2022 released by the International Agency for Research on Cancer (IARC) of the World Health Organization showed that there were 30,618 new cases of malignant mesothelioma worldwide in 2022, accounting for 0.2% of the global new malignant tumors, and 25,372 deaths, accounting for 0.3% of the global deaths from malignant tumors^[13]. Peritoneal mesothelioma occurred more frequently in males, with a male-to-female incidence ratio of (4-5):1. An epidemiological study conducted by domestic scholars in MPeM patients in China from 2000 to 2013 found that the age-standardized incidence rate of MPeM in 2013 was 1.71 per million, with a yearly increasing trend in incidence^[14].

At present, the carcinogenic factors associated with mesothelioma include chemical carcinogenic factors, such as asbestos and other mineral fibers, physical carcinogenic factors, such as chronic peritonitis and therapeutic radiation, and biological carcinogenic factors. Among them, asbestos is the main carcinogen, but only 33% ~ 50% of patients have a history of asbestos exposure^[15]. Both occupational asbestos exposure and non-occupational asbestos exposure are unsafe for humans, especially adolescents and children^[16].

The lifetime risk of developing mesothelioma among asbestos practitioners is as high as 10% and the latency period from asbestos exposure to the occurrence of mesothelioma is 20-40 years^[17,18]. However, the association between asbestos exposure and MPeM is weaker than that between asbestos exposure and pleural mesothelioma, particularly in women^[18,19]. The cumulative exposure required for asbestos-induced MPeM, compared with asbestos-induced pleural mesothelioma, is generally higher^[20,21]. As asbestos use has not been completely banned in China, and the latency period of the asbestos-induced disease is long, it is indicated that the incidence of mesothelioma may continue rising.

Although asbestos exposure is the leading clear risk factor, there have been case reports revealing the occurrence of MPeM within radiotherapy fields, only with a small total number of cases and unclear risk degree^[22,23]. An analysis to investigate the association between radiation exposure and mesothelioma found that cancer patients whose peritoneum was directly exposed to external radiation showed a slight increase in the risk of peritoneal mesothelioma, whereas patients exposed to scattered radiation due to radiotherapy at other sites did not show any increase^[24]. MPeM can also occur in the context of chronic peritonitis^[25].

BRCA-associated protein 1 (BAP1) mutations are common in MPeM patients, and this tumor suppressor gene has also been reported in pleural mesothelioma^[26]. Mice with BAP1 germline heterozygous mutation have been shown to have increased susceptibility to MPM^[27]. Based on this, it is speculated that individuals with BAP1 mutations are predisposed to malignant mesothelioma upon asbestos exposure. Some patients with mesothelioma carry both BAP1 mutations and other germline mutations that induce other cancers^[28]. The significance of identifying these patients lies in the fact that both the patients and their relatives may be prone to other cancers, and it is beneficial for them to conduct genetic counseling and cancer screening.

In China, Chuxiong, Yunnan and Ningbo, Zhejiang are two areas with a high incidence of malignant mesothelioma. Although released epidemiological data in Chuxiong, Yunnan were limited, on-site investigations indicated that the disease types and sexes of malignant mesothelioma in Chuxiong were highly consistent with foreign data, but Yuyao and Cixi, Ningbo, were the opposite of Chuxiong, with peritoneal mesothelioma being predominant^[29,30]. The in-depth investigation found that the predominance of peritoneal mesothelioma in Yuyao and Cixi was related to the occupational environment, and in Zhejiang, asbestos processing was mainly carried out in small workshops where both diet and daily life took place, with a significantly increased probability of accidental ingestion of asbestos, in additional to inhaling asbestos; in Yunnan, mainly relying on mining, diet and daily life took place at home and the mine field was just a workplace, with a high probability of inhalation and a low probability of accidental ingestion^[31].

MPeM is a rare invasive disease. Most MPeM patients have the manifestation of diffuse peritoneal involvement, while a minority have localized diseases, with distinct clinical manifestations and natural courses^[32]. Diffuse MPeM is highly invasive, and patients with localized MPeM usually have a favorable prognosis after total resection. MPeM patients have no specific symptoms or vital signs. Common symptoms include abdominal distention, abdominal pain, weight loss, dyspnea and chest pain. The average interval from symptom onset to diagnosis is approximately 5 months^[33]. The clinical manifestations of diffuse MPeM are associated with ascites or intra-abdominal tumor progression^[34]. Common complaints include abdominal distention and/or increased abdominal circumference, abdominal pain or discomfort, nausea, anorexia, and weight loss. Gastrointestinal complications, such as intestinal obstruction, typically occur in the advanced stage of the disease. Because symptoms complained of are non-specific, many patients are already in advanced stages at the time of diagnosis. Abdominal distention (increased abdominal circumference) is the most common initial symptom, occurring in 30% to 80% of patients^[35]. Pain is the second most common initial symptom, occurring in 27% to 58% of patients^[36]. In most patients, the pain is diffuse and non-specific. Localized MPeM presents as a focal, borderline mass that may locally invade and extend to adjacent organs, but generally does not spread diffusely throughout the peritoneal cavity. The patients may complain of localized abdominal pain or palpable abdominal/pelvic mass^[37].

MPeM may occasionally metastasize to lymph nodes in the abdominal and pelvic cavities. Lymph node metastases occur in 20% to 28% of patients undergoing cytoreductive surgery due to diffuse MPeM^[38]. Distant metastases are rare^[39]. In a multi-institutional registry data-based study, 294 diffuse MPeM patients were included, among whom only 12 (4%) developed extra-abdominal metastases^[40]. Patients with MPeM may present with a variety of paraneoplastic manifestations: pyrexia, thrombocytosis, malignancy-related thrombosis, and hypoglycemia^[41].

Correct staging of malignant peritoneal mesothelioma requires a combination of imaging examinations and invasive exploratory procedures, which can be categorized into non-invasive and invasive examinations. Non-invasive examinations include CT, MRI, ultrasonography, PET-CT, or PET-MRI; invasive examinations include peritoneal biopsy (CT-guided or ultrasound-guided) and laparoscopy.

Enhanced CT of the whole abdomen remains the preferred imaging method for diagnosis, staging, surgical assessment, treatment monitoring, follow-up and complication evaluation of MPeM^[42]. Other imaging techniques such as ultrasonography, MRI, PET-CT and PET-MRI also have their respective advantages and features. It should be noted that in clinical practice, a single imaging method sometimes cannot meet the needs for diagnosis and treatment of MPeM, and the combination of two or more methods can improve the accuracy of diagnosis and evaluation of MPeM. Therefore, methods may be recommended to be used on the basis of the patient’s condition (strongly recommended, Level II evidence).

Ultrasonography is recommended for the extraction and localization of peritoneal fluid.

If conditions permit, it is recommended to choose to complete PET-CT or whole abdominal MRI [especially diffusion-weighted imaging (DWI) sequences], which is helpful for accurately assessing tumor burden and extent. From a health economics perspective, PET-CT is not recommended as a routine follow-up method for MPeM patients due to its high cost.

Malignant peritoneal mesothelioma is a group of heterogeneous tumors, and its characteristic histological manifestations are similar to those of pleural mesothelioma. According to the classification criteria for pleural tumors issued by World Health Organization (WHO) in 2021, the histological subtypes of malignant peritoneal mesothelioma mainly include epithelioid type, sarcomatoid type and biphasic type, of which the epithelioid type is the most common, and the diagnosis of biphasic MPM requires that both epithelioid and sarcomatoid components be > 10%^[52]. Tubulopapillary (well differentiated) mesothelioma is a rare subtype, more common in the peritoneum (rather than the pleura). In all pathological diagnoses, the above-mentioned major pathological subtype diagnoses should be provided. The pathological detection techniques for malignant peritoneal mesothelioma mainly include immunohistochemistry, fluorescence in situ hybridization (FISH), and DNA + RNA next generation sequencing (NGS).

Complete clinical information of patients, such as occupational exposure history, imaging manifestations, tumor history and treatment history, should be provided when specimens are submitted. Incomplete clinical information will affect the initial judgment, specimen handling, sampling procedures, and subsequent ancillary analysis.

There are various types of samples used for diagnosis, including laparoscopic surgical specimens, open surgical specimens, CT-guided coarse needle biopsy specimens, ultrasound-guided coarse needle biopsy specimens, fine needle aspiration cytology specimens and ascitic fluid exfoliative cytology specimens. Peritoneal biopsy, usually performed by laparoscopy or CT- or ultrasound-guided percutaneous biopsy, is the primary method for specimen acquisition. For patients who may undergo surgery, single-port thoracoscopy at the potential incision is recommended.

MPeM often presents with peritoneal fluid at initial diagnosis. Ascitic fluid cytology is an initial diagnostic procedure that is easy to be performed, and is also one of the methods for early diagnosis of malignant pleural mesothelioma. However, due to the low sensitivity of cytology and the fact that sarcomatoid mesothelioma cells typically do not shed into the serous cavity, ascitic fluid cytology is not routinely recommended as a basis for definite diagnosis. However, for patients from whom peritoneal lesion tissues cannot be obtained, the diagnosis of MPeM can be made by preparing cell paraffin blocks for immunohistochemistry and FISH analysis, in combination with clinical, imaging and/or surgical examination, provided that the mesothelioma cells are sufficient in quantity and representative. The term “atypical mesothelial hyperplasia” may be used when the cellular morphology shows varying degrees of atypia (usually low grade) but the degree of malignancy cannot be determined. However, this is not sufficient to diagnose MPeM. Significant sampling bias may also occur in fine needle biopsy, often with false negative results and low accuracy, so fine needle biopsy is not routinely recommended as the basis for sample diagnosis^[53,54].

The immunohistochemical markers to be selected should at least include cell lineage origin markers, benign and malignant lesion judgment markers and differential diagnosis markers. The common first-line markers for judging the mesothelial origins include Pancytokeratin (AE1/AE3 and CAM 5.2), cytokeratin 5/6, Calretinin (CR), Podoplanin/D2-40, and Wilms tumor-1 (WT-1). It is essential to select, at a minimum, antibodies with a high specificity for mesothelial lineage in clinical application. Secondary markers include mesothelin (MSLN), thromboxane, caveolin, tenascin-X, and collagen III (COL3A1), but they are less frequently used due to their low specificity and sensitivity.

For the judgment of benign and malignant mesothelial hyperplasia lesions, although Glucose Transporter 1 (GLUT1), Insulin Like Growth Factor 2 mRNA Binding Protein 3 (IGF2BP3)/IGF-II mRNA Binding Protein 3 (IMP3), Desmin and Epithelial Membrane Antigen (EMA) can be used to assist in differential diagnosis, the latest markers are mainly the three protein molecules, BAP1, MTAP and P16 (CDKN2A), which are almost 100% lost in malignant MPeM, but almost all of them are positively expressed in benign reactive mesothelial hyperplasia^[55-57]. EZH2 can also be used as a reliable marker to differentiate benign mesothelial hyperplasia from malignant mesothelioma^[58].

It is recommended to use at least two mesothelioma markers and two carcinoma markers, and the diagnosis should be made by pathologists experienced in diagnosing MPeM^[59].

Sarcomatoid mesothelioma usually does not express any typical mesothelioma markers, but positive keratin may be helpful for the diagnosis of sarcomatoid mesothelioma. When other metastatic adenocarcinoma is differentiated, in addition to selecting adenocarcinoma markers (MOC31, BerEP4, BG8, B72.3 and CEA), organ-specific markers, such as estrogen receptor (ER), progesterone receptor (PR), GCDFP15 and Mamaglobin for breast cancer; PAX8, PAX2, RCC and CD15 for kidney cancer or PAX8, ER, PR, CA125 and HE4 for ovarian cancer, should also be included. It should be noted that most epithelioid mesotheliomas express GATA3, and some may also show positive PAX8. In immunohistochemistry, BAP1 and EZH2 are reliable markers for differentiating benign mesothelial hyperplasia from malignant mesothelioma^[55,56,58].

Currently, there is a lack of omics big data on MPeM genome and others, but existing studies have shown that the gene mutation spectrum of MPeM is similar to that of MPM, only with some differences in mutation frequency. According to TCGA data, the common somatic mutation genes in MPM include BAP1, NF2, CDKN2A, TP53, LATS1/2, and SETD2^[60]. BAP1 is the most common mutant gene in MPM. In patients with MPeM, no history of asbestos exposure, younger age, and a previous history of tumors, the BAP1 gene mutation rate is approximately 70%. Therefore, BAP1 genetic testing is firstly recommended in MPeM molecular testing^[61,62].

CDKN2A mutation is associated with a poor prognosis, and its positive rate is nearly 100% in sarcomatoid mesotheliomas^[63]. Although the specificity of BAP1 and CDKN2A gene mutations for diagnosing malignant mesothelioma is not 100%, they are helpful for differentiating MPM from benign pleural lesions. Homozygous deletion of CDKN2A can be detected by p16 FISH^[64]. It is helpful for the diagnosis of mesothelioma in situ to detect the expression loss of BAP1 and/or MTAP via immunohistochemistry, and to detect the homozygous deletion of CDKN2A via FISH^[65]. Approximately 50% of patients harbored heterozygous or homozygous deletion mutations of NF2^[57]. NF2 inactivation has been found to be associated with a poor clinical prognosis of MPeM, and YAP hyperactivation was present in approximately 70% of MPM patients^[66].

It was found that KRAS mutation was present in 13.7% of MPM patients and was associated with shortened median survival time^[67].

TP53 gene mutations are relatively uncommon in MPeM, only accounting for about 14%, but more than 50% of MPM lesions showed TP53 protein overexpression, which was primarily caused by post-transcriptional phosphorylation or acetylation modifications of TP53 protein^[68].

Approximately 13% of MPeM lesions harbored large tumor suppressor kinase 2 (LATS2) mutation or deletion inactivation, and the inactivation of LATS2 could promote the development of malignant mesothelioma^[69].

In addition, in diffuse epithelioid MPeM, copy number gains or amplifications of some genes such as WT1, KDR, TNFAIP3, NFKBIZ, NTRK1 and MDM4 were also found (ranging from 12% to 50%), while some fusion genes including ALK rearrangement or EWSR1::ATF1 or EWSR1/FUS::CREB were found in tumor tissues from some young MPeM patients, but EWSR1::YY1 fusion was rare, and ALK rearrangement was almost absent in pleural mesothelioma, suggesting that these fusion genes may be driver variants for MPeM. It was also found in a recent study that high-frequency ARID1B mutations (56.5%) were present in MPeM^[61].

Although immunohistochemistry and FISH have now become routine techniques for the effective auxiliary diagnosis of MPeM, and next generation sequencing(NGS)-based sequencing techniques have not been widely used in the diagnosis of MPM, given the high heterogeneity and complexity in the morphology, gene profile and prognosis of MPeM, for certain morphological subtypes such as sarcomatoid and biphasic MPeM, the application of NGS techniques should be more helpful for the accurate identification of key driver variants and new targets of MPeM. Molecular pathological testing shall be conducted on a compliant and strictly quality-controlled platform, and the interpretation of complex results shall be discussed by the Molecular Tumor Board (MTB).

Consensus 6: Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the key treatment method for MPeM (Strongly recommended).

Consensus 7: It is recommended that the feasibility of surgery for MPeM patients be assessed through discussion by a Multidisciplinary Team (MDT) (Recommended).

Consensus 8: The decision on the feasibility of CRS + HIPEC for MPeM should be made in combination with pathological findings and tumor stage. Sarcomatoid MPeM is a contraindication for CRS (Recommended).

Consensus 9: Laparoscopic exploration can provide significant guiding value for the diagnosis, staging and surgical feasibility assessment of MPeM, and the puncture site should be selected along the medioventral line (Recommended).

Consensus 10: The goal of CRS for MPeM is to achieve R0 resection, or at least satisfactory cytoreduction - residual tumor lesion < 1 cm in diameter (Recommended).

Consensus 11: For MPeM patients, it is recommended to use a platinum-containing (cisplatin or carboplatin) combination regimen for HIPEC. For MPeM patients, the recommended temperature for HIPEC is 43 ℃ with the duration of 60-90 min, and should maintain stable during the entire perfusion process. For Chinese female MPeM patients receiving cisplatin for HIPEC, the maximum cisplatin dose should not exceed 85 mg/m². When cisplatin is used for HIPEC, sodium thiosulfate is recommended to mitigate the risk of renal injury (Recommended).

In 2011, Yan et al. proposed a TNM staging system based on abdominal tumor burden (T), abdominal lymph node metastasis (N) and distant metastasis (M) to standardize and guide the clinical treatment and prognosis assessment of MPM^[40], as shown in Table 1. By scoring the severity of the disease in a total of 13 areas, namely, 9 abdominal quadrants and 4 mesenteric segments (LS-0: no visible tumor; LS-1: tumor nodule ≤ 0.5 cm; LS-2: 0.5 cm < tumor nodule ≤ 5 cm; LS-3: tumor nodule > 5 cm) and adding up of scores of all quadrants, the PCI could be calculated. Based on the PCI quartiles (1-10, 11-20, 21-30, > 30), T1 to T4 stages were determined. The 5-year survival rates were 87%, 53% and 29% for stage I, II and III patients, respectively.

Consensus 12: For patients with unresectable peritoneal mesothelioma, the chemotherapy regimen should be based on that for pleural mesothelioma, and pemetrexed plus platinum, bevacizumab plus pemetrexed and platinum, and nivolumab plus ipilimumab are recommended for first-line treatment. For patients with epithelioid subtype, chemotherapy ± bevacizumab is still the preferred regimen; for patients with non-epithelioid subtype, nivolumab plus ipilimumab, pembrolizumab plus chemotherapy, and bevacizumab plus atezolizumab and chemotherapy are optional therapeutic regimens (Recommended).

Consensus 13: Second-line treatment should be stratified according to the first-line treatment regimen for individualized diagnosis and treatment. NGS may be considered to achieve precise treatment. Or patients may participate in a clinical study. Patients who have not received immunotherapy can choose nivolumab + ipilimumab or nivolumab regimen. Patients who have received immunotherapy can choose bevacizumab combined with pemetrexed and platinum-based regimen. Pemetrexed, vinorelbine, and gemcitabine are optional regimens (Recommended).

Only a few clinical trials have explored the effectiveness of systemic therapy in patients with unresectable peritoneal mesothelioma. A study showed that among 98 patients with peritoneal mesothelioma who received pemetrexed as monotherapy or pemetrexed/cisplatin regimen, the objective response rate was 25% in first-line treatment patients and the median survival time was not reached^[82]. The expanded sample analysis results revealed that among 109 patients with peritoneal mesothelioma who received pemetrexed, pemetrexed/cisplatin, or pemetrexed/carboplatin as first- or second-line treatment, the 1-year survival rate was 57.4% for pemetrexed/cisplatin and 41.5% for pemetrexed alone, with a median survival time of 10.3 months^[83]. Other small-sample studies suggested that the median survival time of pemetrexed plus cisplatin as first-line treatment of peritoneal mesothelioma ranged from 15.4 to 16.6 months^[84,85]. There were also studies exploring gemcitabine plus cisplatin in the first-line treatment of peritoneal mesothelioma which showed some effect but led to serious adverse reactions^[86].

The pathological types and pathogenesis of pleural mesothelioma and peritoneal mesothelioma are basically similar. There are many phase III clinical studies of pleural mesothelioma with high level of evidence. Therefore, foreign guidelines recommend that systemic treatment of peritoneal mesothelioma can be based on clinical trials in patients with pleural mesothelioma. Pemetrexed + cisplatin or pemetrexed + cisplatin + bevacizumab is the preferred first-line treatment for pleural mesothelioma. A phase III randomized controlled study indicated that for patients with pleural mesothelioma who were not suitable for surgery, the median OS of patients treated with pemetrexed + cisplatin was prolonged by 2.8 months compared with cisplatin monotherapy (12.1 and 9.3 months, P = 0.02), which established the cornerstone of the combination of pemetrexed + cisplatin in the medical treatment of pleural mesothelioma^[87]. Several phase II clinical studies showed that pemetrexed + carboplatin was also effective in patients with pleural mesothelioma^[88-90]. A comparison of 1,704 patients with unresectable pleural mesothelioma showed that the median PFS and OS were similar for pemetrexed + cisplatin and pemetrexed + carboplatin^[91]. Therefore, pemetrexed + carboplatin is an option for patients with poor functional status who cannot tolerate cisplatin.

A randomized, multicenter, phase III study demonstrated that the combination of bevacizumab-based chemotherapy with pemetrexed + cisplatin followed by maintenance with bevacizumab prolonged median OS from 16.1 months to 18.8 months compared with pemetrexed + cisplatin (HR = 0.77, P = 0.0167)^[92]. This study established the status of pemetrexed + cisplatin + bevacizumab regimen in the first-line treatment of unresectable pleural mesothelioma. A phase II clinical study demonstrated that the pemetrexed + carboplatin + bevacizumab regimen achieved a median OS of 15.3 months and could also be considered as a treatment option for unresectable pleural mesothelioma^[93]. The results from several clinical trials showed that gemcitabine + cisplatin, pemetrexed monotherapy, and vinorelbine monotherapy are all available as first-line options^[94-97].

The emergence of immunotherapy has revolutionized the landscape of oncotherapy. Several clinical studies of combination immunotherapy in pleural mesothelioma have shown a longer survival than the traditional treatment. CheckMate-743, an open-label, multicenter, randomized phase 3 clinical trial^[98], revealed that for nivolumab + ipilimumab and standard chemotherapy (pemetrexed + cisplatin or carboplatin), the median OS was 18.1 months and 14.1 months respectively (HR = 0.74, 96.6%CI: 0.60-0.91, P = 0.0020), with a 26% reduction in the risk of death in patients with unresectable pleural mesothelioma. The results of subgroup analyses showed a greater OS benefit in patients with non-epithelioid pleural mesothelioma (HR = 0.46) and programmed cell death-ligand 1 (PD-L1) ≥ 1% (HR = 0.69). Based on the positive results from the CheckMate-743 study, the FDA approved nivolumab + ipilimumab for the first-line treatment of MPM on October 2, 2020, and the NMPA approved nivolumab plus ipilimumab for the treatment of and treatment-naive adult patients with unresectable non-epithelioid malignant pleural mesothelioma on June 8, 2021.

With the approval of dual-immunotherapy regimens for the indication of pleural mesothelioma, a number of phase III clinical studies of immunotherapy combined with chemotherapy have been conducted worldwide, including the Keynote-483 study, the BEAT-meso study and the DREAM3R study. The Keynote-483 study was an open-label, international, randomized multicenter phase III trial^[99] in which one arm received pembrolizumab plus pemetrexed and cisplatin/carboplatin and the other received only pemetrexed and cisplatin/carboplatin. The final results suggested an overall survival of 17.3 months and 16.1 months in the pembrolizumab combined with chemotherapy group versus the chemotherapy alone group, respectively (HR = 0.79, P = 0.0324). The 3-year overall survival was 25% in the pembrolizumab group and 17% in the chemotherapy alone group. The FDA has accelerated the approval of pembrolizumab for the indication of pleural mesothelioma. To evaluate whether the combination with immunotherapy based on bevacizumab + pemetrexed + carboplatin can further improve the efficacy in patients, BEAT-meso, an open-label, randomized, double-arm, multicenter phase III clinical trial^[100], was verbally presented at the ASCO meeting in 2024. The study was designed to evaluate the efficacy of atezolizumab + bevacizumab + pemetrexed + carboplatin (ABC) vs. bevacizumab + pemetrexed + carboplatin (BC) in the first-line treatment of patients with unresectable pleural mesothelioma. The results showed that ABC significantly prolonged PFS compared with BC, with a median PFS of 9.2 months vs. 7.6 months (HR = 0.72, P = 0.0020), but a median OS of 20.5 months vs. 18.1 months (HR = 0.84, P = 0.14), and a 2-year OS rate of 40% vs. 38%, respectively, which did not reach statistically significant difference. ABC regimen only resulted in a significant benefit in PFS, which did not translate into a significant benefit in OS, but subgroup analyses showed that patients with non-epithelioid subtype (HR = 0.50), PD-L1 TPS ≥ 1% (HR = 0.66), and poor prognosis as reflected by EORTC score (HR = 0.60) had a significant OS benefit from ABC regimen. CheckMate 743, Keynote-483, and BEAT-meso all indicated that patients with non-epithelioid subtype benefited more from combination immunotherapy. Domestic and foreign guidelines recommend dual-immunotherapy combination regimen to be preferentially used in patients with non-epithelioid subtype, but further exploration is needed to determine which of the three treatment strategies (chemotherapy + immunotherapy, chemotherapy + bevacizumab + immunotherapy, and nivolumab + ipilimumab) will benefit which patients more. The phase 2 studies PrE0505^[101] and DREAM^[102], both of which used combination therapy of durvalumab + cisplatin + pemetrexed, demonstrated good efficacy of PDL1 monoclonal antibody combined with chemotherapy in pleural mesothelioma, and the phase 3 study DREAM3R is ongoing.

The studies of second-line treatment of peritoneal mesothelioma are mostly small-sample studies, and the data on second-line and subsequent treatments are relatively limited. A study evaluated 26 patients with peritoneal mesothelioma^[85] who received gemcitabine, paclitaxel, nivolumab, and other agents, indicating a median overall survival of 16.9 months. A phase 2 study evaluated atezolizumab in combination with bevacizumab as a posterior line treatment in patients with peritoneal mesothelioma who had progressed after or were intolerant to first-line pemetrexed/platinum-based chemotherapy^[103]; 90% of the patients were epithelioid type, with a response rate of 40%, and 1-year overall survival rate of 85%. Another study evaluated the efficacy of immune checkpoint inhibitor as posterior line treatment in 29 patients with peritoneal mesothelioma^[104]; 69% of the patients received nivolumab/ipilimumab during posterior line treatment and 31% of patients received immune checkpoint inhibitor monotherapy, including nivolumab, pembrolizumab, and atezolizumab. The median survival time was 19 months and the 1-year overall survival rate was 68%.

For second-line treatment of peritoneal mesothelioma, also refer to the treatment of patients with recurrent pleural mesothelioma. For patients who did not receive pemetrexed as first-line treatment, it is recommended use it as second-line treatment. After failure of first-line treatment with pemetrexed-based therapy, pemetrexed may be re-administered to young patients with a favorable PS score and a long progression-free survival time after first-line treatment^[105,106]. Retrospective studies showed that gemcitabine and vinorelbine had some benefit^[96,107], and can be used when no other options are available. For patients who have progressed after chemotherapy, immunotherapy may be a posterior line treatment option. CONFIRM, a phase III randomized clinical trial^[108], evaluated 332 patients with MPM who had progressed after platinum-based chemotherapy, and treated with nivolumab and placebo respectively, and the results revealed that the median overall survival was 10.2 months for nivolumab-treated patients and 6.9 months for placebo-treated patients. Another randomized phase II study evaluating nivolumab with or without ipilimumab as subsequent therapy in patients with pleural mesothelioma^[109] showed that the median overall survival was 15.9 months in the nivolumab plus ipilimumab group and 11.9 months in the nivolumab alone group, but the adverse events were increased in the combination therapy group.

Although 31% of MPM patients had EGFR overexpression^[110], the efficacy of tyrosine kinase inhibitors (TKIs) for MPM was not satisfactory, and axitinib, sorafenib and imatinib have failed to benefit the patients^[111]. In a phase II clinical study^[112], the median PFS was 9.7 months in the nintedanib group compared with placebo (HR = 0.49, P = 0.006); the median OS was 20.6 months (HR = 0.70, P = 0.197), reflecting certain efficacy, and the phase III clinical study is ongoing. Recently, it has been reported in the literature that a patient with MePM had ALK translocations with STRN as fusion partner. This paper reported a 17-year-old female MPeM patient with STRN-ALK gene fusion and no history of asbestos exposure, who had tumor progression after standard chemotherapy and was subsequently enrolled in a clinical study using tyrosine kinase receptor inhibitor, alectinib^[113]. Another recently published trial of alectinib investigated its use in unresectable malignancies, and the author reported that alectinib may be effective in ALK-positive cancers^[114].

The results of a phase III randomized controlled trial in 448 patients with pleural mesothelioma indicated that the combination of bevacizumab with cisplatin + pemetrexed significantly prolonged OS compared with cisplatin + pemetrexed alone, and the difference was statistically significant (median OS 18.8 vs. 16.1 months, P = 0.0167), demonstrating the value of bevacizumab in the treatment of mesothelioma^[92]. A phase II clinical trial of ramucirumab as second-line treatment in patients with MPeM showed that ramucirumab + gemcitabine significantly prolonged OS with good safety; the median OS was 13.8 months (70%CI: 12.7-14.4 months) in the ramucirumab + gemcitabine group and 7.5 months (70%CI: 6.9-8.9 months) in the gemcitabine + placebo group, with a statistically significant difference (P = 0.028)^[115]. This suggests that anti-VEGF therapy is promising in patients with MPeM.

Consensus 14: The efficacy of radiotherapy in patients with MPeM is uncertain, and radiotherapy may be considered for whole-abdomen or local irradiation in patients with residual disease after cytoreductive surgery or patients who cannot undergo surgery (Recommended).

The efficacy of radiotherapy in patients with MPeM is uncertain, and radiotherapy is only used as an adjunct for other treatments to achieve more active and effective control of the condition in patients with MPeM, and radiotherapy may be considered for whole-abdomen or local irradiation in patients with residual disease after cytoreductive surgery or patients who cannot undergo surgery^[116]. Most of the current studies are small-sample case reports. A pilot study with a limited number of 10 patients showed an improvement in disease-free survival of 19 to 78 months after cytoreductive surgery, chemotherapy and whole-abdomen irradiation^[117]. It was reported that 27 patients with MPeM treated with sequential therapy of intraperitoneal drug injection, surgery, HIPEC and whole-abdomen radiotherapy had a 3-year survival rate of 67%^[118]. Adverse reactions such as low tolerated dose, low response rate and adhesion of some vital organs in the abdomen and intestinal obstruction are the main reasons for hindering the implementation of radiotherapy^[117].

Consensus 15: Palliative and supportive treatment for malignant peritoneal mesothelioma focuses on pain management, as well as alleviation of gastrointestinal symptoms. For the management of cancer pain, refer to the principle of ladder medication for cancer pain management (Strongly Recommended).

Palliative and supportive treatment is an important part of the cancer prevention and control system, which focuses on relieving pain, other serious disease symptoms and emotional distress, so as to improve the quality of life. Drug therapy is the first choice for cancer pain management in patients with malignant peritoneal mesothelioma. For moderate pain, weak opioids, such as codeine or tramadol, are administered; for severe pain, strong opioids are administered.

The patients with malignant peritoneal mesothelioma usually have such clinical symptoms as abdominal pain, abdominal distension, intestinal obstruction, etc. Therefore, appropriate symptomatic treatment and nutritional support should be given during palliative and supportive treatment, and the adverse reactions due to hyperthermic intraperitoneal chemotherapy should be given corresponding drug therapy and clinical management.

Consensus 16: Patients with malignant peritoneal mesothelioma are recommended to be followed up every 3 months for the first 2 years after active surgical treatment, and a whole-abdomen CT reexamination should be performed (Strongly recommended). For patients with diffuse MPeM treated with CRS + HIPEC, follow-up may be extended to 15 years (Recommended).

At present, the follow-up model of malignant peritoneal mesothelioma is still lack of high-level evidence-based medical evidence. Considering the poor prognosis of malignant peritoneal mesothelioma, regular follow-up can can help detect tumor progression at an early stage. In 2021, Professional Committee of Peritoneal Tumor of Chinese Anti-Cancer Association, Professional Committee of Tumor Hyperthermia of Chinese Anti-Cancer Association and Professional Committee of Tumor Hyperthermia of Beijing Cancer Prevention & Treatment Society jointly issued the Chinese Expert Consensus on the Diagnosis and Treatment of Diffuse Malignant Peritoneal Mesothelioma^[8]. In combination with clinical practice, it is recommended that follow-up items include physical examination, CT scan of the whole abdomen and serum tumor markers. The frequency of follow-up is every 3 months for the first 2 years after surgery, every 6 months for 3 to 5 years after surgery, and every year after 5 years, and an extension to 15 years after surgery is possible. At present, PET-CT and MRI are not recommended as routine follow-up examinations; there is currently insufficient evidence to suggest that biomarkers can be used for follow-up of malignant peritoneal mesothelioma; the monitoring of disease progression should be guided by signs and symptoms that occur during clinical follow-up period.