Pleural, peritoneal, and other localized mesotheliomas: clinical guidelines

List of Abbreviations

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

** – vital and essential drugs

AJCC – American Joint Committee on Cancer

AUC – area under the pharmacokinetic curve for carboplatin dose calculation**

ECOG – Eastern Cooperative Oncology Group

PD-L1 – programmed cell death 1 ligand

AFP – alpha-fetoprotein

PFS – progression-free survival

WHO – World Health Organization

EBRT – external beam radiotherapy

IHC – immunohistochemistry

IT – immunotherapy

CT – computed tomography

PM – pleural mesothelioma

PeM – peritoneal mesothelioma

MRI – magnetic resonance imaging

OS – overall survival

mOS – median overall survival

PET-CT – positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals

EPP – extrapleural pneumonectomy

Terms and Definitions

Thoracentesis is a puncture of the pleural cavity.

Pleurodesis is the obliteration of the pleural cavity.

Paracentesis is a minimally invasive diagnostic and therapeutic surgical procedure involving puncture and drainage of the abdominal cavity with fluid evacuation (ultrasound-guided abdominal drainage).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mesothelioma is an epithelial malignant tumor arising from mesothelial cells lining the natural cavities of the body and characterized by involvement of the parietal and visceral pleura, peritoneum, pericardium, and tunica vaginalis.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Pleural involvement is most common (80–90%), followed by peritoneal involvement (15–20%), while pericardial and testicular mesothelioma account for no more than 1% [1]. Exposure to asbestos plays a major role in the etiology of pleural mesothelioma (hereinafter referred to as PM). The risk of developing PM is 300 times higher in individuals exposed to asbestos. The latent period between initial asbestos exposure and tumor onset is usually 30–40 years. The disease is most commonly diagnosed at 60–70 years of age [2–4]. The literature also indicates a viral etiology (SV-40 virus), the effect of ionizing radiation (cases of pleural mesothelioma developing 20–30 years after radiation therapy for Hodgkin lymphoma), and genetic predisposition [5–8]. Such causal relationships have not been proven for mesotheliomas of other sites.

1.3 Epidemiology of the Disease or Condition

The incidence of mesothelioma among the population varies significantly across different regions of the world. In 2022, 30,870 new cases were registered worldwide [9]. The incidence rate in the USA and Canada differs from that in Australia, France, and the UK, where the number of cases is significantly higher and continues to rise [10–13]. In Europe, the incidence of PM is 18–20 cases per million per year with wide geographical variation. In Japan, it is 7 per 1,000,000 inhabitants per year. The peak incidence is expected in 2020–2025. Men are affected significantly more often, with a sex ratio of 6 : 1 [4]. In the Russian Federation, due attention is not paid to the epidemiology of mesotheliomas. There are no morbidity and mortality statistics [14, 15].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, mesothelioma is coded according to the site of the primary lesion [16].

Mesothelioma (C45):

• C45.0 Pleural mesothelioma;

• C45.1 Peritoneal mesothelioma;

• C45.2 Pericardial mesothelioma;

• C45.7 Mesothelioma of other sites;

• C45.9 Mesothelioma, unspecified.

Malignant neoplasms of heart, mediastinum and pleura (C38):

• С38.4 Malignant neoplasm of pleura

Neoplasms of uncertain or unknown behavior of middle ear, respiratory and intrathoracic organs (D38):

• D38.2 Neoplasm of uncertain or unknown behavior of pleura

Benign neoplasm of soft tissues of retroperitoneum and peritoneum (D20):

• D20.1 Benign neoplasm of peritoneum

Neoplasm of uncertain or unknown behavior of other and unspecified sites (D48):

• D48.4 Neoplasm of uncertain or unknown behavior of peritoneum

Comment: Since mesothelioma is a specific morphological tumor type, not every pleural and peritoneal neoplasm can be coded as C45. Neoplasms may be benign or have unknown/unspecified malignant potential. For example, peritoneal inclusion cyst (PIC) of the peritoneum is classified among tumor-like conditions (D20). It is a benign cystic lesion of the abdominal cavity or pelvis resulting from enhanced proliferative activity of the mesothelium. PICs occur in women of reproductive and premenopausal age. General surgeons and gynecologists most commonly treat patients with PIC. Because PIC formerly had alternative names such as benign peritoneal mesothelioma and multicystic mesothelioma, the disease was regarded as malignant mesothelioma and mistakenly coded as C45.1. PIC has no malignant potential, but cyst formation can be recurrent, prompting referral to oncologists. There is no separate diagnostic algorithm for PIC, as the diagnosis is established after obtaining a morphological report, most often incidentally during treatment for another abdominal surgical pathology. This is precisely why the treatment of PIC is discussed in these guidelines.

Other unspecified neoplasms of the pleura and peritoneum not classified as mesothelioma may be considered both in these guidelines and within the treatment principles for primary peritoneal cancer or mediastinal tumors, as there is no unified concept for their treatment.

1.5 Classification of the disease or condition

Histological classification of mesothelioma (ICD-O)

The 2021 WHO international histological classification of tumors (5th edition) introduced new terms and approaches to the morphological diagnosis of mesotheliomas. Primarily, a fundamental difference from the 2015 and 2017 classifications is the understanding that all mesotheliomas are malignant. Pleural mesothelioma and pericardial mesothelioma were combined into a single chapter, whereas previously pericardial mesothelioma was classified as a heart tumor. Well-differentiated mesothelial tumor is no longer considered malignant and has been moved to the category of precancerous neoplasms; however, the treatment approach is still addressed in these guidelines. (Thoracic Tumours. WHO Classification of Tumours, 5th Edition, Volume 5. 2021)

Benign and preinvasive tumors

• 9054/0 Adenomatoid tumor

• 9052/1 Well-differentiated papillary mesothelial tumor

• 9050/2 Mesothelioma in situ

Mesothelioma

• 9050/3 Localized mesothelioma

• 9050/3 Diffuse mesothelioma, NOS

• 9051/3 Sarcomatoid mesothelioma

• 9052/3 Epithelioid mesothelioma

• 9053/3 Biphasic mesothelioma

TNM staging of pleural mesothelioma

The classification proposed by the International Mesothelioma Interest Group (IMIG) (AJCC, 8th ed. – 2017) is used to determine the stage of the disease. TNM staging is applicable only to pleural mesothelioma (Table 1). Although pleural effusion in PM occurs in 40–70% of patients, the presence of pleuritis is not taken into account during staging [17, 18].

Primary tumor:

• Tx – primary tumor cannot be assessed;

• T0 – no evidence of primary tumor;

• T1 – tumor is limited to the ipsilateral parietal pleura, with or without involvement of the visceral, mediastinal, or diaphragmatic pleura;

• T2 – tumor involves any surface of the ipsilateral parietal pleura, with at least one of the following characteristics:

– invasion of diaphragmatic muscle;

– invasion of underlying lung parenchyma.

• T3 – locally advanced, but potentially resectable tumor involving any surface of the ipsilateral parietal pleura, with at least one of the following characteristics:

– invasion of endothoracic fascia;

– invasion of mediastinal fat;

– single tumor nodule invading chest wall soft tissues

– pericardial involvement, but without full-thickness invasion.

• T4 – locally advanced yet technically unresectable process. The tumor invades all surfaces of the parietal pleura on the affected side. One of the following characteristics is present:

– diffuse or multifocal soft tissue invasion of the chest wall with or without rib involvement;

– invasion through the diaphragm into the peritoneum;

– invasion into any mediastinal organ(s);

– direct extension to the contralateral pleura;

– invasion into the spine;

– extension to the inner surface of the pericardium;

– pericardial effusion with positive cytology;

– myocardial invasion;

– brachial plexus involvement.

Regional lymph nodes:

• Nx – regional lymph nodes cannot be assessed;

• N0 – no regional lymph node metastases;

• N1 – metastases in bronchopulmonary lymph node(s) and/or ipsilateral hilar lymph node(s), mediastinal lymph nodes including ipsilateral parasternal, phrenic, pericardial fat, and intercostal lymph nodes;

• N2 – in ipsilateral or contralateral supraclavicular lymph node(s). Contralateral mediastinal lymph nodes.

Distant metastases:

• M0 – no distant metastases;

• M1 – distant metastases present (liver, lung parenchyma, bones, brain).

For peritoneal mesothelioma, regional lymph nodes are the retroperitoneal lymph nodes. For testicular mesothelioma, regional lymph nodes are the inguinal and iliac lymph nodes.

Table 1. Stage grouping of pleural mesothelioma

To specify the localization of distant metastatic lesions (M), an additional gradation is used:

PUL – lung                       PER – abdominal cavity

MAR – bone marrow          BRA – brain

OSS – bone                        SKI – skin

PLE – pleura                      LYM – lymph nodes

ADP – kidney                      SADP – adrenal glands

HEP – liver                       OTH – other

When clinically assessing the extent of the tumor process, the prefix "c" is placed before the TNM symbols, and "p" for pathohistological classification. The requirements for determining pT, pN, and pM categories are similar to those for cT, cN, and cM.

1.6 Clinical presentation of the disease or condition

Pleural mesothelioma tends to have locoregional growth, often confined to a hemithorax. Mesothelioma growth is usually slow, so symptoms appear in the late stages of the disease. Fluid is frequently detected in the pleural cavity, which is generally the primary reason for seeking medical attention. Typical symptoms include: dyspnea and ipsilateral chest pain; cough, hoarseness, Horner's syndrome, and superior vena cava syndrome are less common. The disease not only spreads to the opposite side of the chest but also metastasizes to the liver (31.9%), kidneys and adrenal glands (31%), spleen (10.8%), thyroid gland (6.9%), brain (3%), and bones (3%) [19].

Peritoneal mesothelioma is characterized by increased abdominal girth due to ascites, poorly localized abdominal pain, and a tendency toward constipation.

Metastases of peritoneal mesothelioma may be found in regional lymph nodes, lungs, liver (often along the capsule), intestines, ovaries, brain, bone marrow, pericardium, and myocardium.

In testicular mesothelioma, hydrocele comes to the forefront.

In pericardial mesothelioma, there are no specific symptoms; the clinical picture resembles chronic heart failure. Patients experience loss of appetite, general weakness, dull chest pain, dry cough, anemia, fever, and tachycardia. Mesothelioma may be localized in the pericardium or diffusely encase the heart. The tumor can invade the myocardium, atria, coronary sinuses, coronary arteries, and the cardiac conduction system. It can metastasize to regional lymph nodes and the lungs (30–50%).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: there are no pathognomonic symptoms.

There are no screening programs for detecting mesothelioma. The diagnosis of pleural mesothelioma is complex, especially regarding differential diagnosis with breast, lung, kidney, colon, and ovarian cancer metastases, as well as synovial sarcoma of the pleura. Peritoneal mesothelioma must be differentiated from peritoneal carcinomatosis in ovarian cancer; testicular mesothelioma must be differentiated from benign hydrocele or germ cell tumors.

2.1 Complaints and Anamnesis

Comments: Symptoms and medical history are described in the "Clinical presentation" section

2.2 Physical Examination

Comment: special attention should be paid to the patient's appearance during the examination, the assessment of the patient's severity status according to WHO/ECOG and/or the Karnofsky scale (Appendix G2), and the nutritional status assessment. It is also necessary to evaluate body temperature, pain syndrome, the presence of pleural effusion, and ascites. Physical examination findings are described in the "Clinical presentation" section

2.3 Laboratory Diagnostics

Comments: Elevated lactate dehydrogenase is not characteristic of testicular mesothelioma

Comments: Elevation of the CA-125 tumor marker is characteristic. Elevated alpha-fetoprotein and human beta-chorionic gonadotropin are not characteristic of testicular mesothelioma.

2.4 Instrumental Diagnostics

Comments: Computed tomography is the primary method in the diagnosis and staging of pleural and peritoneal mesothelioma, possessing high sensitivity and specificity in assessing pleural and pulmonary tumor changes, as well as pleural effusion. At the same time, CT has low sensitivity and specificity in assessing mediastinal lymph node status.

• Additional diagnostic methods such as whole-body bone scintigraphy or contrast-enhanced magnetic resonance imaging (the choice depends on the localization of the pathological focus and clinical manifestations) are recommended in the presence of symptoms in the patient or at stages I-III of the disease to rule out distant metastases before surgery. Contrast-enhanced cardiac MRI is also informative in the diagnosis of pericardial and myocardial involvement [36, 37, 38, 39, 40].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: Contrast-enhanced magnetic resonance imaging is a second-line diagnostic method for assessing local tumor spread. Contrast-enhanced chest CT with IV bolus administration and contrast-enhanced chest MRI play an important role in assessing tumor spread to the diaphragm, mediastinum, and upper thorax. In the non-invasive stage, it is very difficult to differentiate between T1 and T2.

2.5 Other Procedures

To accurately determine the histological type of the tumor, a pathomorphological examination of biopsy (surgical) material using immunohistochemical methods must be performed.

Comments: diagnostic thoracoscopy is the most important diagnostic method, allowing to obtain a sufficient amount of material for subsequent pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods and to visually assess the nature of pleural changes. Mesothelioma is characterized by the presence of a number of markers. Positive markers: calretinin, WT-1 antigen, vimentin, mesothelin, D2-40; negative markers: TTF-1, claudin-4, CEA

According to the WHO histological classification (1999), malignant mesotheliomas are divided into epithelioid (up to 70%), sarcomatoid (7–20%), and mixed (biphasic, 20–25%) [46, 47].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Surgical treatment

Surgery is the main treatment method for localized disease and the epithelioid tumor type. As with other types of tumors, surgical treatment aims to remove the tumor manifestations of the disease. The goal of cytoreduction in pleural mesothelioma is the "maximum possible macroscopic removal" of the tumor. In other words, all "visible" manifestations of the disease must be removed. R0 resection is considered questionable. The options for surgical management are: 1) pleurectomy/lung decortication with mediastinal lymphadenectomy using video-endoscopic techniques with/without pericardial and/or diaphragmatic resection and reconstruction, and 2) extrapleural pneumonectomy (EPP) with or without resection of the lung, pleura, pericardium, and diaphragm.

Comments: the sarcomatoid histological type of the tumor and N2 lymph node involvement are controversial factors for surgical intervention. EPP with resection of the pericardium and diaphragm can be associated with a high incidence of complications and should be performed by experienced thoracic surgeons. Surgical treatment of pleural mesothelioma is performed subject to selection criteria, which are: early stage of the disease and satisfactory ECOG performance status (0-1) (Appendix G).

• For patients with pleural mesothelioma and satisfactory functional status, pleurectomy is recommended at any stage of the disease to relieve continuous fluid accumulation in the pleural cavity, as a stage in multimodal treatment to achieve the maximum therapeutic antitumor effect and improve quality of life [54, 55].

Level of Recommendations CLevel of Evidence 5Level of Recommendations C – (Level of Evidence – 5).

Comments: pleurectomy has not shown an increase in survival compared to extended pneumonectomy, but it was able to reduce the recurrence of pleural fluid accumulation better than talc pleurodesis. Parietal pleurectomy or pleurodesis are indicated for the management of recurrent pleurisy.

Comments: Treatment options to control malignant pericardial effusions or tamponade must be individualized to maximize symptom relief. There are several different methods: percutaneous pericardiocentesis, subxiphoid pericardial window, pericardiectomy, or pericardiectomy via thoracotomy or video-assisted thoracoscopic surgery (VATS). Drainage is preferred in patients with intrapericardial hemorrhage and in patients with hemopericardium clots that make needle drainage (pericardiocentesis) difficult or ineffective. Unfortunately, recurrence of pericardial effusion occurs in 21-50% of cases [59, 60]

Comments: Local excision of the tunica vaginalis is associated with a local recurrence rate of 36%, and local control often requires a unilateral scrotal and tunica vaginalis incision with scrotal plastic surgery (hemiscrotectomy), whereas local recurrence after orchiectomy is noted in 10.5-11.5% of patients. Surgical treatment is the most common option [62]. Since in most cases malignant testicular mesothelioma is diagnosed intraoperatively or as a result of pathomorphological examination of removed specimens, if a hemiscrotectomy was initially performed, the scope of surgery is expanded to radical at the second stage. The issue of the need for ilioinguinal lymphadenectomy remains controversial [63, 64].

Comments: In partial pericardiectomy, the affected part of the heart lining is removed, whereas in total pericardiectomy, as much of the affected heart lining as possible is removed within healthy tissues. In some cases, this procedure can increase the patient's life expectancy [66].

Combined treatment methods

The issue of combination therapy is decided on an individual basis.

Comments: If the patient has no comorbidities that could lead to a high surgical risk, and if complete cytoreduction or significant debulking is anticipated, it is advisable to perform maximal cytoreduction (the scope of surgery depends on the extent of the lesion). The procedure should be performed by an experienced surgical team, with the understanding that complete cytoreduction may require up to six peritonectomy procedures and multiple visceral resections [68]. The surgical team must have experience in making necessary intraoperative judgments regarding various surgical maneuvers that may be required. Although the extent of peritonectomy in most institutions is limited to the peritoneal surfaces affected by the disease (selective peritonectomy) or performed as total parietal peritonectomy (systematic peritonectomy) [69, 70, 71, 72]. Intraperitoneal chemotherapy can be administered intraoperatively as HIPEC, or in the early postoperative period as EPIC (early postoperative intraperitoneal chemotherapy), or as normothermic intraperitoneal chemotherapy (NIPEC), although HIPEC is used in the majority of cases. Chemotherapeutic agents used for HIPEC as monotherapy may include #cisplatin**, mitomycin**, doxorubicin**, #paclitaxel, #oxaliplatin**, #fluorouracil**, #irinotecan**, #docetaxel**, #carboplatin**. The dose and concentration of the drug are calculated in mg/m2 and L/m2. Perfusion temperature also varies—from 31 to 44 °C. The duration of perfusion ranges from 30 minutes to 2 hours. To date, there is no consensus on a standardized HIPEC technique and antineoplastic drug dosing for it. This results in a wide range of OS data following HIPEC use: from 30 to 92 months [73] with 5-year OS rates ranging from 41 to 67% [74].

Lymph node assessment in areas evaluated surgically is performed by some, but not all, centers. All enlarged lymph nodes should be removed (lymphadenectomy) and submitted for pathological examination (pathological examination of lymph node biopsy (surgical) material). The exact anatomical zones to be used for lymphadenectomy have not been clearly defined. Lymph node groups recommended for histopathological evaluation to rule out the presence of involved abdominal or pelvic lymph nodes include deep epigastric lymph nodes, external iliac lymph nodes at the internal inguinal ring, common iliac lymph nodes, lymph nodes along the gastroepiploic vessels, or accessible lymph nodes present in the mediastinum directly above the upper surface of the diaphragm [75, 76, 77].

Comments: this treatment method makes it possible to achieve a median overall survival of 15.4 months.

3.2. Radiation therapy

External beam radiation therapy as a standalone treatment does not improve efficacy or increase survival in patients with pleural mesothelioma.

For peritoneal mesothelioma, radiation therapy has limited options. There are no data on the efficacy of radiation therapy (either curative or adjuvant) in pericardial or testicular mesothelioma.

• When performing postoperative adjuvant external beam radiation therapy, it is recommended to include the entire parietal pleura (in case of lung decortication), the boundaries of surgical clips (after pneumonectomy), and areas with potential residual manifestations in order to achieve the maximum antineoplastic effect and improve the patients' quality of life [79, 80, 81, 82].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: Administering external beam radiation therapy to mediastinal and supraclavicular lymph nodes is not advisable. Postoperative external beam radiation therapy is possible in patients with an ECOG score of 0–1, with adequately preserved pulmonary function such that the patient does not require oxygen therapy, without signs of renal failure, and in the absence of distant metastases.

Table 2. Recommended doses of external beam radiation therapy in pleural mesothelioma [79, 83 - 88, 127].

3.3. Drug Treatment

If surgery is not feasible in early stage, mixed or sarcomatoid subtype, and in advanced tumor process (stages IIIB–IV for pleural mesothelioma), medical treatment is used (Table 3).

1. Optimal 1st-line medical treatment regimen: pemetrexed** + #cisplatin** (or #carboplatin**) [89, 90, 141].

   Level of recommendation A (evidence level – 2 for #cisplatin** and 3 for #carboplatin**).

2. Alternative 1st-line medical treatment regimen: #gemcitabine** + #cisplatin** [91, 92].

   Level of recommendation B (evidence level – 3).

3. Combination regimen of pemetrexed** + #cisplatin** (#carboplatin**) + targeted drug #bevacizumab** [93, 94, 95].

   Level of recommendation A (evidence level – 2 for #cisplatin** and 4 for #carboplatin**).

4. Immunotherapy with #nivolumab** and #ipilimumab** (especially preferred for the sarcomatoid tumor variant) [96].

   Level of recommendation A (evidence level – 2).

5. Combination of the pemetrexed** + #cisplatin** (#carboplatin**) + #pembrolizumab** regimen for the epithelioid tumor variant [103, 104].

Comments: The phase III MAPS study showed that the addition of #bevacizumab** to pemetrexed**+#cisplatin** chemotherapy improved both PFS (9.2 vs. 7.3 months, HR, 0.61, 95% CI 0.50–0.75) and OS (18.8 vs. 16.1 months, HR, 0.77, 95% CI 0.62–0.95), but resulted in increased toxicity. The addition of #bevacizumab** to the #gemcitabine** + #cisplatin** regimen did not improve OS and PFS in patients with pleural mesothelioma [97].

A benefit of immunotherapy in the CheckMate-743 study was observed in patients with non-epithelioid histotype (mOS 18.1 months vs. 8.8 months in the chemotherapy group) and with PD-L1-positive (> 1%) tumors (mOS 18.0 months with immunotherapy vs. 13.3 months with chemotherapy).

Median OS with immunotherapy in epithelioid pleural mesothelioma was 18.7 months vs. 16.5 months in the chemotherapy group. No significant difference was observed between the two treatment approaches in the PD-L1-negative variant (mOS with immunotherapy was 17.3 months vs. 16.5 months with chemotherapy). These patients did not derive a clear benefit from combination immunotherapy, and therefore, platinum-based pemetrexed** chemotherapy, possibly with the addition of #bevacizumab**, remains a reasonable first-line treatment option for them for now.

The KEYNOTE-483 study demonstrated a statistically significant improvement in OS in patients receiving #pembrolizumab** with chemotherapy compared to those receiving chemotherapy alone. Median OS was 17.3 months (95% CI: 14.4, 21.3) compared to 16.1 months (95% CI: 13.1, 18.2) (hazard ratio [HR] 0.79 [95% CI: 0.64, 0.98]; p = 0.0162).

Median PFS was 7.1 months (95% CI: 6.9, 8.1) vs. 7.1 months (95% CI: 6.8, 7.7) in the #pembrolizumab** plus chemotherapy group and the chemotherapy-alone group, respectively (HR 0.80 [95% CI: 0.65, 0.99]; p = 0.0194). Confirmed objective response rate was 52% (95% CI: 45.5, 59.0) in the #pembrolizumab** plus chemotherapy group and 29% (95% CI: 23.0, 35.4) in the chemotherapy-alone group. Median duration of response was 6.9 months (95% CI: 5.8, 8.3) and 6.8 months (95% CI: 5.5, 8.5), respectively.

IND.227 trial data indicate that the combination of #pembrolizumab** and platinum-based chemotherapy improves overall survival and progression-free survival compared with platinum-based chemotherapy alone in patients with untreated unresectable pleural mesothelioma. The hazard ratio (HR) comparing the arms was 0.79 (95% CI [0.64, 0.98]; P = .0324). Median overall survival for patients receiving chemotherapy and #pembrolizumab** was 17.28 months compared with 16.13 months for patients in the chemotherapy-only group. Three-year overall survival in the chemotherapy plus #pembrolizumab** groups and the chemotherapy-only groups was 25% and 17%, respectively.

Comments: There are no standards for II and subsequent lines. For mesotheliomas of other localizations, the same treatment regimens are used as for pleural mesothelioma.

Administration of 6 cycles of chemotherapy followed by active surveillance is prescribed. A change in chemotherapy regimen should only be carried out upon documented disease progression or in case of drug intolerance. In the event of disease progression 6 months or more after the last cycle of chemotherapy, re-induction of the 1st-line treatment regimen is preferred. In case of early progression (during chemotherapy or less than 6 months after the completion of chemotherapy), a second line of therapy is prescribed. Since #gemcitabine** is administered on days 1 and 8 of a 3-week cycle, and pemetrexed** is administered only on day 1 of a 3-week cycle, pemetrexed** involves a lower frequency of hospital visits, which benefits patients. There are no data on the re-administration of immunotherapy after a prolonged remission. The algorithm for the diagnosis and treatment of disseminated pleural mesothelioma is presented in Appendix B.

Table 3. Most common systemic treatment regimens for pleural mesothelioma [89 - 104]

Comments: #Pembrolizumab** is approved in the Russian Federation for solid tumors in the presence of microsatellite instability (MSI-high) in the tumor, while in peritoneal mesothelioma this marker occurs in 1–2% of cases. The efficacy of #pembrolizumab** in pericardial and testicular mesothelioma has not been studied. Pembrolizumab in patients without MSI-H showed no advantage over chemotherapy.

Comment: a #nivolumab** dosage of 240 mg has also been studied in clinical trials [111].

Comments: Since surgical cytoreduction for pleural mesothelioma is not expected to achieve an R0 resection, combination therapy with chemotherapy and/or radiation therapy is indicated. Patients with pleural mesothelioma with transdiaphragmatic disease, multifocal chest wall invasion, or histologically confirmed contralateral mediastinal or supraclavicular lymph node involvement should receive neoadjuvant therapy before maximum surgical cytoreduction is considered; in the context of multimodality treatment, four to six cycles of chemotherapy can be administered before or after surgery; combination treatment provides a median overall survival of 43.3 months and a 2-year survival rate of 77% [114, 115]. Targeted therapy with #bevacizumab** and immunotherapy are not used in the neoadjuvant setting.

Comments: If adjuvant chemotherapy is planned, it is necessary to ensure that the patient is able to undergo this treatment following radical surgery for pleural mesothelioma. Postoperative chemotherapy should be initiated no later than 3 months [118]. If the patient is considered to be borderline operable, for example, with a poor performance status according to the ECOG scale, it may be more appropriate to start treatment with neoadjuvant chemotherapy, given that functional status will deteriorate immediately after surgery regardless of the extent of the surgery.

Following orchiectomy for testicular mesothelioma and pericardiectomy for pericardial mesothelioma, the issue of adjuvant chemotherapy is decided on an individual basis.

3.4. Pain Management and Diet Therapy

The principles of pain management and optimal selection of analgesic therapy in patients with mesothelioma and chronic pain syndrome correspond to the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients in Need of Palliative Medical Care".

3.5. Supportive Care

The principles of treatment and prevention of nausea and vomiting in patients with mesothelioma correspond to the principles outlined in the guidelines "PREVENTION AND TREATMENT OF NAUSEA AND VOMITING" [119].

The principles of treatment and prevention of bone complications in patients with mesothelioma correspond to the principles outlined in the guidelines "USE OF OSTEOMODIFYING AGENTS FOR THE PREVENTION AND TREATMENT OF BONE PATHOLOGY IN MALIGNANT NEOPLASMS" [127].

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with mesothelioma correspond to the principles outlined in the guidelines "TREATMENT OF INFECTIOUS COMPLICATIONS OF FEBRILE NEUTROPENIA AND ADMINISTRATION OF COLONY-STIMULATING FACTORS" [128].

The principles of prevention and treatment of hepatotoxicity in patients with mesothelioma correspond to the principles outlined in the guidelines "MANAGEMENT OF HEPATOTOXICITY" [129].

The principles of prevention and treatment of cardiovascular complications in patients with mesothelioma correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF CARDIOVASCULAR TOXICITY OF ANTICANCER DRUG THERAPY" [130].

The principles of prevention and management of cutaneous complications in patients with mesothelioma correspond to the guidelines set out in the clinical practice guidelines "PRACTICAL GUIDELINES FOR THE MEDICAL MANAGEMENT OF DERMATOLOGICAL REACTIONS IN PATIENTS RECEIVING ANTITUMOR DRUG THERAPY" [131].

The principles of nutritional support in patients with mesothelioma correspond to the guidelines set out in the clinical practice guidelines "PRACTICAL GUIDELINES FOR NUTRITIONAL SUPPORT IN CANCER PATIENTS" [132].

The principles of prevention and management of nephrotoxicity in patients with cutaneous melanoma correspond to the guidelines set out in the clinical practice guidelines "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF NEPHROTOXICITY CAUSED BY ANTITUMOR DRUGS" [133].

The principles of prevention and management of thromboembolic complications in patients with mesothelioma correspond to the guidelines set out in the clinical practice guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND MANAGEMENT OF THROMBOEMBOLIC COMPLICATIONS IN CANCER PATIENTS" [134].

The principles of prevention and management of the consequences of drug extravasation in patients with mesothelioma correspond to the guidelines set out in the clinical practice guidelines "GUIDELINES FOR THE MANAGEMENT OF THE CONSEQUENCES OF ANTITUMOR DRUG EXTRAVASATION" [135].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation should be carried out based on the general principles of rehabilitation for patients following surgical interventions and/or chemotherapy.

Stages of rehabilitation after surgical treatment:

First stage of rehabilitation after surgical treatment

• Medical rehabilitation of a patient who has undergone surgical treatment for mesothelioma includes pain management, early enteral nutrition, avoidance of routine use of tubes and drains, and early mobilization of patients on the 1st postoperative day [142].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: the presented approach reduces the risk of early postoperative complications and shortens hospital stay. Early mobilization with elastic compression of the lower extremities helps prevent thromboembolic complications in the postoperative period.

Second stage of rehabilitation after surgical treatment

• Patients who have undergone surgery for mesothelioma are recommended adequate physical activity, aerobic and anaerobic exercise, and a combination of static and dynamic respiratory exercises to improve external respiration parameters, increase overall physical performance, expand the body's adaptive capabilities, and improve patients' quality of life [143].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients who have undergone surgery for mesothelioma are recommended regular physical therapy, which improves external respiration function, increases endurance, has a positive impact on the patient's psychological status, reduces the severity of anxiety, depression, fatigue, and pain, and improves mood [144].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: following combination treatment, the patient is advised to work with a medical psychologist; relaxation sessions and cognitive-behavioral therapy methods reduce symptoms of depression and anxiety.

Third stage of rehabilitation after surgical treatment

• Patients after combination treatment for mesothelioma are recommended to maintain an active lifestyle aimed at achieving a compensated functional state, social adaptation, and preventing the development of a chronic stress response [145].

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

Comments: Physical therapy and adequate physical activity lead to a reduction in fatigue, increased patient mobility, lower levels of depression, improved quality of life, and serve as prevention of cardiovascular and pulmonary complications. The use of audiovisual relaxation techniques reduces the severity of pain, fatigue, and anxiety, and improves the patient's quality of life and social adaptation.

Rehabilitation during chemotherapy

• Patients with peripheral polyneuropathy after chemotherapy are recommended acupuncture sessions, which increase IL-2, CD3+, and CD4+ levels, reduce bone marrow suppression, decrease fatigue and nausea, and improve quality of life scores [146].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

• In the event of chemotherapy-induced polyneuropathy, patients are recommended to perform physical exercises and practice walking therapy to control the clinical manifestations of polyneuropathy [147].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comment: balance training exercises are more effective for managing polyneuropathy than a combination of endurance and strength exercises; regular participation in physical therapy during chemotherapy reduces the incidence of cardiac complications.

• As part of the comprehensive treatment of chemotherapy-induced peripheral neuropathy, patients are recommended to undergo physiotherapy methods as indicated: low-level laser therapy (intravenous laser blood irradiation), general magnetotherapy, and transcutaneous electrical nerve stimulation (TENS) [120, 147].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• To prevent chemotherapy-induced oral mucositis, patients are recommended local hypothermia [148].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

5. Prevention and Dispensary Observation

No specific preventive measures exist.

To ensure occupational safety when working with asbestos, regulatory requirements and standards applied in high-dust environments are used. These rules regulate dust control methods, establish permissible concentration levels, and mandate the use of specific protective measures. Both international and Russian standards protect employees, equipment, and the environment from the negative impact of asbestos-containing dust. When working at asbestos-mining enterprises, individual dust protection measures are observed in accordance with Russian Sanitary Rules and Norms (SanPiN) 2.2.3.757-99 Work with Asbestos [121].

Following treatment, in accordance with the general principles of the oncological component of clinical examination (dispensary monitoring), patients should undergo active dynamic surveillance to detect early signs of disease progression/recurrence: every 3 months during the 1st year, and every 6 months during the 2nd year, including instrumental diagnostic examinations [122].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: the following diagnostic examinations are performed:

1. Complete blood count (CBC), differential CBC, and general clinical blood chemistry analysis;

2. Computed tomography (CT) of the chest cavity, CT of the lesser pelvis in women, and CT of the pelvic organs in men (depending on the location of the primary tumor and metastases);

3. Ultrasound examination of the abdominal cavity (comprehensive) and ultrasound examination of lymph nodes (one anatomical region);

4. Electrocardiography (ECG) + echocardiography in case of pericardial involvement.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation," is organized and provided:

1. in accordance with the regulations on the organization of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is not possible to perform pleural or peritoneal biopsies or other diagnostic examinations at the medical organization where the center for outpatient oncological care (primary oncology office) is organized, the attending physician shall refer the patient to an oncological dispensary (oncology hospital) or a medical organization providing medical care to cancer patients.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd Edition 8936, 906-909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, an oncologist at an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure), in order to determine the treatment tactics.

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

• digital images obtained from pathomorphological studies to the fourth-group pathologo-anatomical bureau (department) (reference center) via information interaction, including the use of teleconsultation technologies for remote interaction between medical personnel;

• of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

• Pathologo-anatomical examination of pleural biopsy (surgical) material using immunohistochemical methods and molecular genetic testing: sent to the fourth-group pathologo-anatomical bureau (department) (reference center) as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.

Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1. presence of oncological disease complications requiring emergency and urgent specialized medical care;

2. presence of complications from cancer treatment (surgical intervention, radiation therapy, drug therapy, etc.).

Indications for hospitalization in a medical organization in a planned form are:

1. the need to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-inpatient setting;

2. presence of indications for specialized antitumor treatment (surgical intervention, radiation therapy including brachytherapy, external beam radiation therapy, and other types of radiation therapy, drug therapy, etc.) requiring inpatient or day-hospital monitoring.

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2. refusal by the patient or their legal representative of specialized (including high-tech) medical care in an inpatient or day-inpatient setting prescribed by the concilium of the cancer-care medical organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

3. in cases of non-compliance by the patient with prescriptions or internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4. need to transfer the patient to another medical organization in the relevant medical specialty.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

Prognostic factors in pleural mesothelioma are presented in Table 4.

Table 4. Prognostic factors in pleural mesothelioma [123, 124, 125].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Barbolina Tatiana Dmitrievna, Candidate of Medical Sciences, Oncologist, Researcher at the Chemotherapy Department No. 3, N.N. Blokhin National Medical Research Center of Oncology, Assistant at the Department of Oncology, N.D. Yushchuk Scientific and Educational Institute of Continuous Professional Education, Russian University of Medicine of the Russian Ministry of Health, Associate Professor at the Department of Postgraduate Medical Education (specialty "Oncology"), Department of Professional Education, N.N. Blokhin National Medical Research Center of Oncology.

2. Barmin Vitaly Valerievich, Candidate of Medical Sciences, Associate Professor, Head of the Center for Mediastinal and Myasthenia Pathology, Head of the Myasthenia Group, Thoracoabdominal Oncology Surgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, member of AOR, ESTS, IASLC.

3. Bolotina Larisa Vladimirovna, Doctor of Medical Sciences, Associate Professor, Head of the Chemotherapy Department, Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

4. Vladimirova Lyubov Yuryevna, Doctor of Medical Sciences, Professor, Head of the Antineoplastic Drug Therapy Department No. 1, Rostov Research Oncological Institute of the Russian Ministry of Health.

5. Gamayunov Sergey Viktorovich, Doctor of Medical Sciences, Chief Physician, Nizhny Novgorod Regional Clinical Oncology Dispensary.

6. Grinevich Vyacheslav Nikolayevich, President of the Russian Society of Oncopathologists, Candidate of Medical Sciences, Head of the Oncopathology Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

7. Dengina Natalya Vladimirovna, Candidate of Medical Sciences, Head of the Radiological Department, Regional Clinical Dispensary, Ulyanovsk.

8. Drapkina Oksana Mikhailovna, Director of the National Medical Research Center for Preventive Medicine, Chief Freelance Specialist-Therapist of the Russian Ministry of Health, Doctor of Medical Sciences, Professor, Corresponding Member of the RAS.

9. Kozlov Nikolay Alexandrovich, Candidate of Medical Sciences, Pathologist at the Pathological Anatomy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

10. Levchenko Evgeny Vladimirovich, MD, PhD, Head of the Thoracic Surgery Department, Head of the Research Department of Thoracic Oncology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

11. Pikin Oleg Valentinovich, MD, PhD, Professor, Head of the Thoracic Surgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, oncologist (Working Group Chair).

12. Sakaeva Dina Damirovna, MD, DSc, Professor, Deputy Chief Medical Officer for Oncology, Mother and Child Clinic Group, Oncologist, Department of Antitumor Drug Therapy 1, Clinic of the Bashkir State Medical University.

13. Snegovoy Anton Vladimirovich, MD, PhD, Professor, Head of the Department of Antineoplastic Drug Therapy, Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Falaleeva Natalya Aleksandrovna, MD, PhD, Head of the Department of Drug Treatment for Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

15. Filonenko Elena Vyacheslavovna, MD, PhD, Professor, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Healthcare Organization Section:

1. Gevorkyan Tigran Gagikovich, Deputy Director for the Implementation of Federal Projects, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

2. Ivanov Sergey Anatolyevich, Corresponding Member of the Russian Academy of Sciences, MD, PhD, Professor of the RAS, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Nevolskikh Alexey Alekseevich, MD, PhD, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Khaylova Zhanna Vladimirovna, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

5. Komarov Yury Igorevich, PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

Supportive Care Section:

1. Gladkov Oleg Alexandrovich, Professor, MD, PhD, Director of EVIMED Medical Center LLC.

2. Karaseva Vera Vitalievna, MD, PhD, Associate Professor, Professor at the Department of Oncology, Institute of Advanced Professional Education of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Conflict of interest. The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• pathologists.

Table 1. Levels of evidence rating scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence (LoE) rating scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grades of recommendation (GoR) rating scale for prevention, diagnostics, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnostics, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current instructions for medicinal products mentioned in this clinical guideline can be found on the grls.rosminzdrav.ru website and the RUSSCO website.

Appendix B. Physician Action Algorithms

Fig. 1. Primary diagnostic algorithm for suspected mesothelioma

Fig. 3. Treatment algorithm for disseminated pleural mesothelioma

Appendix C. Patient Information

Timely communication with your attending physician and nurse regarding your health status is an important part of helping your medical team protect you during treatment as safely as possible. It is very important that any symptoms (adverse events) associated with treatment are identified and treated at the very beginning of their manifestation; this will help prevent them from progressing to more severe grades. Report changes in your health status to your doctor in a timely manner.

In case of chemotherapy complications, you must contact your oncologist-chemotherapist.

1. If body temperature rises to 38 °C or higher:

• start systemic antibacterial drugs as recommended by your attending physician.

2. In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) – chamomile flowers, oak bark, sage leaves, lubricate the mouth with sea buckthorn (peach) oil;

• treat the oral cavity as recommended by your attending physician.

3. For diarrhea:

• diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods;

• lean meats, flour products, fermented dairy products, and rice water are permitted. Drink plenty of fluids.

• take medications as recommended by your attending physician.

4. In case of nausea:

• take medications as recommended by your attending physician.

Information for patients receiving PD-1 inhibitor monoclonal antibody therapy (ATC L01FF02, # pembrolizumab** (ATC – L01XC18)). Timely communication with your attending physician and nurse regarding your health status is an important part of helping the medical team protect you during treatment as safely as possible.

It is very important that any symptoms (adverse events) associated with treatment with PD-1 inhibitors (ATC L01FF02, #pembrolizumab** (ATC – L01XC18)) are identified and treated at the very beginning of their manifestations, which will help prevent them from progressing to more severe grades. PD-1 inhibitor mAbs (ATC L01FF02, #pembrolizumab** (ATC – L01XC18)) are designed to help your body's immune system fight the tumor process.

The most common side effects you may encounter during treatment are the result of high immune system activity. Such side effects are called immune-mediated and differ from the side effects you may observe with other types of cancer treatment.

Adverse events that you may experience usually occur during the first 12 weeks of treatment, but can also occur later. It is very important that you inform your attending physician of any symptoms that appear during treatment with PD-1 inhibitors. Recognizing side effects in the early stages enables your attending physician to immediately initiate appropriate therapy and prevent adverse events from progressing to more severe grades. If you experience any of the symptoms listed below after treatment with PD-1 inhibitor mAbs (ATC L01FF02, #pembrolizumab** (ATC – L01XC18)), please inform your attending physician immediately.

Potential adverse events following PD-1 inhibitor therapy:

• an increase in bowel movements to 2 or more per day, or any nighttime diarrhea, any stool containing mucus and blood;

• abdominal pain or chills, as well as pain requiring medical intervention;

• red, painful eyes or yellowish discoloration of the whites of the eyes, blurred vision, inflammation, or swelling of the eyes;

• yellow discoloration or redness of the skin, itchy rash, sun sensitivity of the skin;

• newly onset cough or shortness of breath;

• fatigue or drowsiness; • difficulty concentrating or confusion;

• headache, body aches, or pain at the tumor site;

• fever (elevation in body temperature up to +38 °C);

• sudden decrease or increase in body weight; 53

• newly onset erectile dysfunction or loss of interest in intimate life.

Please pay special attention to any changes during treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. WHO/ECOG performance status scale

Russian title: WHO/ECOG Performance Status Scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official developer website, publication with validation): https://ecog-acrin.org/resources/ecog-performance-status

Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology

Group. Am J Clin Oncol 1982;5(6):649–655.

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Table 9. WHO/ECOG Performance Status Scale

Key (interpretation): Provided within the scale itself.

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale.

Original title (if any): KARNOFSKY PERFORMANCE STATUS.

Source (official developer website, validation publication): [Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. edn. Edited by MacLeod C. New York: Columbia University Press; 1949: 191-205]

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Table 10. Karnofsky Performance Scale

Key (interpretation): Provided within the scale itself.