Тимома и тимусная карцинома
Заболеваемость и смертность
Thymic malignancies are rare, slow growing tumors of the anterior mediastinum. Thymomas can spread locally, metastasize, and recur decades after therapy and should not be considered “benign”. They typically occur in the fourth to eighth decade with a peak in the seventh decade, and account for 50% of anterior mediastinal masses in patients older than 50. years of age. The ratio of males to females is essentially equal . In the United States (US), incidence rates are highest among Asian/Pacific Islander populations and African Americans, and lowest among Hispanics and non-Hispanic Whites . The incidence of thymomas is 0.13. per 100,000. person years in the US . Five-year survival rates are approximately 93%, 85%, 65%, and 53% for Masaoka stages I–IVa, respectively. Ten-year survival rates are 90%, 75%, 56%, and 38% for stages I–IVa, respectively . Thymic carcinomas are more aggressive and more likely to metastasize to lymph nodes and distant sites compared to thymomas. They have 5-year survival rates of approximately 30–50% [3, 4] and median survival of 6.6. years .
Этиология и факторы риска
No known environmental or lifestyle risk factors are associated with incidence of thymoma or thymic carcinoma. The only consistent associations are age and ethnicity
Thymomas are derived from the epithelial component (cortical and medullary) of the thymus. These neoplastic epithelial cells are mixed in various proportions with non-neoplastic lymphocytes, primarily T cells. The World Health Organization (WHO) histologic classification system includes several subtypes of thymomas (type A, AB, B1, B2, and B3), and thymic carcinomas (Type C) (Table 2.1). Thymic carcinomas can be distinguished from thymomas by their malignant cytologic and architectural features. Several subtypes of thymic carcinoma have been described including squamous cell, sarcomatoid, mucoepidermoid, papillary, basaloid, and undifferentiated carcinomas [6, 7].
Диагноз и стадийность
Approximately one-third of patients with thymic malignancies are asymptomatic with another one-third presenting with cough, dyspnea or chest pain . A mass in the anterior mediastinum could represent other benign and malignant tumors such as lymphoma, thymic carcinoids, germ cell tumors, thyroid goiters, thymic cysts, or metastatic lung cancer, which should be considered during the patient’s evaluation. Thymomas are relatively uncommon below the age of 20. but make up 15–40% of anterior mediastinal masses between the ages of 20. and 40. . Beta-human chorionic gonadotropin and alphafetoprotein levels should be determined if germ cell tumors are suspected in young males. Thyroid-stimulating hormone, triiodothyronine, or thyroxine levels should be assessed in those suspected to have intrathoracic thyroid goiters.
Approximately 40–45% of patients with thymomas will present with myasthenia gravis (MG) . Only 10–15% of patients with MG will have a thymoma . Patients present with a fluctuating degree of ocular (diplopia, ptosis), bulbar (dysarthria, dysphagia), limb, and respiratory muscle weakness. The weakness is a result of autoantibodies against the acetylcholine receptors or against muscle receptor specific tyrosine kinase. Adequate medical control of MG should be achieved prior to surgical resection. Other paraneoplastic conditions such as red cell aplasia and hypogammaglobulinemia occur in 2–5% of patients .
If an anterior mediastinal mass is suspected on chest X-ray, a computed tomography (CT) scan of the chest with contrast should be obtained. Thymomas are usually well defined, round or oval masses in the thymus. Magnetic resonance imaging can be considered in patients with severe iodine contrast allergies . Positron emission tomography (PET)/CT can be useful in detecting metastatic disease . Close attention should be made to vascular invasion or involvement of other mediastinal structures which can limit surgical resection and indicate the need for neoadjuvant therapy. If a thymic malignancy is suspected and deemed surgically resectable, patients should undergo resection without tissue biopsy. For locally advanced or unresectable lesions or in cases where lymphoma is suspected, fine-needle aspiration, core-needle biopsy, or open biopsy can be performed for tissue diagnosis .
The Masaoka-Koga staging system is the most commonly used classification system for thymic malignancies (Table 2.2), and was recommended by the International Thymic Malignancy Interest Group (ITMIG) . Historically, no standardized staging system for thymic malignancies has been defined by the American Joint Commission on Cancer or the Union for International Cancer Control until the new eighth edition classification system  (Table 2.3). The primary extent of involvement (T) is classified by the level of tissue involvement that is determined by microscopic invasion. A node map was developed by ITMIG and the International Association for the Study of Lung Cancer and is used for the new nodal staging system. N1. nodes are in the anterior mediastinum and lower cervical regions, while N2. nodes are deep cervical, supraclavicular, and middle mediastinal nodes. Metastatic disease is subclassified between separate pleural (visceral or parietal) or pericardial nodules (M1a) and pulmonary intraparenchymal or distant organ metastasis (M1b).
Таблица 2.1. Гистологическая классификация ВОЗ.
|A||A tumor composed of a population of neoplastic thymic epithelial cells having spindle/oval shape, lacking nuclear atypia, and accompanied by few or no nonneoplastic lymphocytes|
|AB||A tumor in which foci having the features of type A thymoma are admixed with foci rich in lymphocytes|
|B1||A tumor that resembles the normal functional thymus in that it combines large expanses having an appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla|
|B2||A tumor in which the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes. Perivascular spaces are common and sometimes very prominent. A perivascular arrangement of tumor cells resulting in a palisading effect may be seen|
|B3||A type of thymoma predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia. They are admixed with a mild component of lymphocytes, resulting in a sheet like growth of the neoplastic epithelial cells|
|C||A thymic tumor (thymic carcinoma) exhibiting clear-cut cytologic atypia and a set of cytoarchitectural features no longer specific to the thymus, but rather analogous to those seen in carcinomas of other organs. Type C thymomas lack immature lymphocytes; whatever lymphocytes may be present are mature and usually admixed with plasma cells|
Table 2.2. Masaoka-Koga clinical staging of thymoma [13, 14, 15].
|I||Макроскопически и микроскопически полностью инкапсулированная опухоль|
|IIA||Микроскопическая транскапсульная инвазия|
|IIB||Макроскопическая инвазия в тимусную ткань или окружающий жировую ткань, или макроскопически адгерентный, но не пересекающий, медиастенальную плевру или перикард|
|III||Макроскопическая инвазия в соседний орган (перикард, крупные сосуды или легкое)|
|IVA||Плевральная или перикардиальная диссеминация|
|IVB||Лимфогенное или гематогенное метастазирование|
Таблица 2.3. TNM стадийность тимусного рака.
|Первичная опухоль (T)|
|T0||Нет свидетельства первичной опухоли|
|T1||Tumor encapsulated or extending into the mediastinal fat; may involve the mediastinal pleura|
|T1a||No mediastinal pleura involvement|
|T1b||Direct invasion of mediastinal pleura|
|T2||Tumor with direct invasion of the pericardium (either partial or full thickness)|
|T3||Tumor with direct invasion into any of the following: lung, brachiocephalic vein (innominate vein), superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins|
|T4||Tumor with direct invasion into any of the following: aorta (ascending, arch or descending), arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus|
|Региональные лимфатические узлы (N)|
|NX||Региональные лимфатические узлы не оценены|
|N0||Нет метастазов в региональные лимфоузлы|
|N1||Metastases in anterior (perithymic) lymph nodes|
|N2||Metastases in deep intrathoracic or cervical lymph nodes|
|Отдаленный метастаз (M)|
|M0||No pleural, pericardial, or distant metastasis|
|M1a||Separate pleural or pericardial nodule(s)|
|M1b||Pulmonary intraparenchymal nodule or distant organ metastasis|
|Any T||N0, N1||M1a|
|IVB||Any T||N2||M0, M1a|
|Any T||Any N||M1b|
Patients with thymic malignancies should be evaluated and managed by a multidisciplinary team that includes thoracic surgeons, medical oncologists, radiation oncologists, chest radiologists, surgical pathologists, and pulmonologists . Surgery is the recommended treatment for all clinically resectable thymomas and thymic carcinomas. For locally advanced and metastatic disease, multimodality therapy with or without surgery is recommended .
The goal of surgery is en bloc R0. resection (complete resection with no microscopic residual tumor) of the lesion with total thymectomy including contiguous and noncontiguous disease. The ability to achieve a complete macroscopic and microscopic resection varies with stage . Locally advanced tumors may require resection of adjacent structures such as the pericardium, pleura, lung, phrenic nerve, and possibly vascular structures to achieve a R0. resection. Bilateral phrenic nerve resection results in respiratory morbidity and should be avoided. Routine evaluation of pleural surfaces should be performed for metastatic disease. For patients who develop a resectable recurrence, surgery is recommended and provides excellent long-term survival (72– 77%, 5-year) if complete resection can be achieved [19, 20].
Thymectomy can be performed through a sternotomy, thoracotomy, or with minimally invasive approaches such as a transcervical approach, video-assisted, or robotic-assisted thoracoscopic surgery. Minimally invasive approaches lack robust long-term data on recurrence or survival, but can be considered if the standard oncologic principles are met . The ITMIG has proposed a policy on the handling and reporting of surgical and pathological findings by surgeons and pathologists so future validation studies can be performed .
Thymomas are relatively radiosensitive. Neoadjuvant radiotherapy with or without chemotherapy is indicated in cases of marginally resectable tumors to enhance the ability to achieve complete resection .
Although surgery is the treatment of choice for stage I–III thymoma, many physicians advocate the use of adjuvant radiotherapy, particularly in cases of: incomplete resection; extension beyond the capsule; extensive pleural adherence; microscopic pleural invasion; macroscopic invasion of the pericardium, large vessels, or lung; or aggressive histology (WHO grade B3. or C) .
Completely resected stage I thymomas have an excellent prognosis and adjuvant therapy is not indicated . Indications for postoperative radiotherapy for stage II thymoma are not well defined . Postoperative radiotherapy is generally indicated in the setting of incomplete resection. For completely resected stage II thymoma, results in the literature regarding the benefits of radiotherapy are conflicting [19, 26, 27]. Patients with stage III thymomas or thymic carcinomas have a higher risk of recurrence and should receive adjuvant radiotherapy to aid in local control [28, 29].
For unresectable disease, radiation with or without chemotherapy remains the treatment of choice. Radiotherapy also can be an effective palliative treatment for symptomatic metastatic disease .
Техника лучевой терапии
The planning target volume should include the surgical bed, any gross residual tumor, and areas suspected of harboring subclinical disease (including mediastinal nodes if high risk) with a 2. cm margin (Figure 2.1). Postoperative radiotherapy is delivered using standard fractionation with 1.8–2.0. Gy fractions to a total of 45–50. Gy for margin-negative resections, 54–60. Gy for microscopically positive margins, and 60–70. Gy for unresectable and macroscopically positive margins . For patients with pleural disease, the risk of developing pleural dissemination is high (38%). In this group of patients, the use of hemithoracic irradiation of 10–17. Gy over 2–3. weeks in conjunction with a mediastinal dose of 40. Gy should be considered to improve locoregional control . Neoadjuvant radiotherapy may be delivered using standard fractionation up to a total dose of 45. Gy [25, 32]. Palliative radiation courses such as 30. Gy in 10. fractions are administered for symptomatic local sites. Modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) or image-guided radiotherapy may allow more sparing of adjacent organs and structures than standard 3D conformal techniques [24, 25].
Chemotherapy is active in thymic malignancies, and is utilized in the primary, postoperative, and locally advanced or metastatic settings . Several different chemotherapy combinations have been used as the primary treatment modality in patients with stage III thymoma or in large tumors in an effort to improve the likelihood of a complete resection . The regimens used in thymic malignancies are usually platinum based, including cisplatin, doxorubicin, and cyclophosphomide (PAC); cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC); and cisplatin, etoposide, and ifosfamide (VIP) [35–37].
PAC is recommended as the frontline regimen by the National Cancer Care Network for advanced-staged thymomas, primarily based on treatment of 29. patients with metastatic, locally progressive, or recurrent thymoma [35, 38]. There was an overall response rate of 50% and a median survival of 37.7. months with this regimen . For those patients unable to tolerate cisplatinor anthracycline-based therapy, carboplatin and paclitaxel does have some activity on unresectable thymomas or thymic carcinomas .
Thymic carcinomas are more aggressive than thymomas, and are less responsive to chemotherapy. Although the ADOC regimen is active in thymic carcinoma, carboplatin and paclitaxel is a less toxic regimen and most commonly used [39, 40].
Targeted therapies have shown some promise in thymic malignancies, although in a very small number of patients. Thymomas have shown increased EGFR expression and thymic carcinomas have likewise shown high expression of c-KIT as well as programmed death 1. and programmed death ligand, which are potential therapeutic targets [34, 41, 42]. A recent phase II study indicated promising activity of sunitinib (a multitargeted receptor tyrosine kinase inhibitor) in previously treated patients with thymic carcinoma .
Figure 2.1. Three-dimensional intensity-modulated radiation therapy treatment plan for Masaoka stage IIB thymic carcinoma status post radical thymectomy with a positive margin in (a) axial, (b) coronal, and (c) sagittal planes. The preoperative PET scan has been fused to the computed tomography simulation scan for target delineation purposes. The red line delineates the preoperative gross tumor volume. The pink line delineates the postoperative tumor bed. The color-wash display demonstrates the clinical target volume in green and the planning target volume in blue. The orange line represents the 6000. cGy isodose line. Radiation was delivered with intensity-modulated radiation therapy using five fields of 6-MV photons to 6000. cGy over 30. fractions.
Local recurrence involving the pleural space, lung, or the mediastinum is more common than distant metastasis. The average time to recurrence for thymomas is 5. years [1, 19, 44]. A comprehensive review found recurrence rates of 3%, 11%, 30%, and 43% for Masaoka stage I–IVa thymomas, respectively . The ITMIG has recommended annual CT scans of the chest for 5. years after surgical resection. Subsequently, chest radiographs and CT scans can be obtained in alternating years until year 11. followed by annual chest radiographs to 20. years. Resected stage III or IVA thymoma, thymic carcinoma, or incompletely resected tumors should have CT scans of the chest every 6. months for the first 3. years .
Злокачественная мезотелиома плевры
Заболеваемость и смертность
Malignant pleural mesothelioma (MPM) is an uncommon cancer with an approximate incidence of 2,000–3,000. cases per year in the US . The mesothelioma incidence rate, based on cases diagnosed between 2009. and 2013, was approximately 1.8. per 100,000. men per year and 0.4. per 100,000. women per year . The incidence in the US is leveling off , but is expected to rise in countries with increased utilization and fewer regulations on exposure and mining of asbestos . Mesothelioma most commonly occurs in the pleura, but can occur on other serosal membranes (e.g., pericardium, peritoneum, tunica vaginalis testes).
Этиология и факторы риска
The link between MPM and asbestos exposure was noted in a landmark study in 1960.  and is the biggest risk factor for MPM. A latency period between exposure to asbestos and development of mesothelioma has been reported by different investigators to be approximately 40. years, with shorter periods in heavily exposed individuals . Previous radiation therapy also increases the risks of MPM . The median age at the time of diagnosis is 63. years. Median survivals are 21, 19, 16. and 12. months for stage I–IV, respectively . Recent studies indicate that germline mutations of the BAP1. tumor suppressor gene are responsible for a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma, and other cancers [54, 55].
Гистологические подтипы MPM включают эпителиоидную, саркоматоидную, двухфазную (эпителиоидную и саркоматоидную) и десмопластический. Эпителиоидные опухоли являются наиболее распространенными, в то время как десмопластическая MPM крайне редка. Иммуногистохимическое окрашивание помогает дифференцировать MPM от доброкачественных болезней и других первичных и вторичных злокачественных новообразований с вовлечением плевры. Кальретинин, цитокератин и виментин обычно экспрессируются в MPM [55, 57].
Диагноз и стадийность
Patients with MPM present with nonspecific symptoms. A thorough evaluation includes a detailed history of the patient’s asbestos exposure. Early-stage patients may complain of dyspnea associated with a pleural effusion. As the disease progresses, patients may note pain due to chest wall invasion followed by worsening dyspnea due to lung entrapment, chest wall restriction, or contralateral effusion and ascites. Physical examination may demonstrate decreased breath sounds, dullness to percussion or a palpable chest wall mass.
For patients presenting with a pleural effusion, thoracentesis can be both diagnostic and therapeutic. Pleural fluid cytology yields a positive diagnosis in approximately 60% of cases. Needle biopsy and thoracoscopic biopsy are diagnostic in 86% and 98% of cases, respectively [58, 59]. If the pleural space is obliterated making thoracoscopy impossible, an open biopsy can be pursued. Incisions should be aligned to allow for resection at the time of surgery as MPM tends to invade in to the chest wall at these sites.
Staging workup should include a CT scan of the chest and abdomen with contrast and a PET-CT. Mediastinal lymph node staging can be done either with mediastinoscopy or endobronchial ultrasound with fine-needle aspiration. Magnetic resonance imaging should be considered to identify mediastinal invasion, chest wall involvement, or transdiaphragmatic extension . PET-CT should be obtained before any pleurodesis procedure to lower the risk of a false-positive study [61, 62]. Video-assisted thoracoscopic surgery and laparoscopy can be performed if contralateral or peritoneal disease is suspected.
The TNM staging system for MPM was initially proposed by the International Mesothelioma Interest Group and in collaboration with the International Association for the Study of Lung Cancer has recently been updated for the eighth edition of the American Joint Commission on Cancer staging manual (Table 2.4) .
Patients should be evaluated by a multidisciplinary team with experience in managing MPM. Select patients with a good performance status and clinical stage I–III disease are candidates for multimodality therapy. Most patients present with advancedstage disease, making treatment difficult and cure rare. Surgery is recommended for medically operable patients with clinical stage I–III MPM as part of multimodality therapy where complete gross cytoreduction of the tumor can be achieved. Patients in the International Association for the Study of Lung Cancer mesothelioma database who had curative intent surgery plus either chemotherapy or radiation had better outcomes compared to surgery alone (median survival, 20. vs 11. months) . To determine medical operability, patients should have pulmonary function tests with a carbon monoxide diffusion capacity, a ventilation perfusion scan (if FEV1. < 80% predicted), and a cardiac stress test.
Surgery for MPM includes either extrapleural pneumonectomy (EPP) or a lung-sparing procedure with pleurectomy and decortication (P/D). EPP involves en bloc resection of the lung, pleura, pericardium, and ipsilateral diaphragm. Standard P/D removes the involved pleura and any gross disease. A radical or extended P/D includes the removal of the pericardium and ipsilateral diaphragm with the pleura. Mediastinal lymph node sampling should be performed with both EPP and P/D. Deciding which operation to offer a patient should take in to consideration the ability to provide a complete gross resection, the planned adjuvant therapy, and the patient’s prognosis.
There is a lack of randomized controlled studies to prove a survival benefit of surgery. The Mesothelioma and Radical Surgery randomized feasibility study assessed the benefit of EPP after neoadjuvant chemotherapy compared to chemotherapy alone . EPP had increased morbidity but did not improve survival. The study has been criticized for its small sample size, lack of standardized chemotherapy regimens, and data relating to time from chemotherapy to EPP . A direct comparison of the effects of EPP versus P/D is hard to assess due to complex patient factors and clinical scenarios directing the type of surgical intervention. A retrospective review of 663. patients who had surgical resection for MPM noted a higher operative mortality for EPP (7%) compared to P/D (4%). P/D had a better survival (median survival, 12. vs 16. months: P <0.001), but this difference was thought to be related to selection bias and a difference in patient characteristics . The theoretical advantages of EPP are a more complete cytoreduction and allowing for higher doses of adjuvant radiation therapy resulting in lower rates of local recurrence (33% vs 65% compared to P/D) . A recent metaanalysis of EPP (1391. patients) and P/D (1512. patients), reported a significantly higher mortality associated with EPP (4.5% vs 1.7%; P <0.05). Median survivals favoring EPP were reported in 53% of the studies, but of those that reported at least a 2-year survival (seven of 24) the two cohorts had similar survivals . EPP has been recommended for select patients with a good performance status, minimal comorbidities, stage II–III disease, epithelioid histology, and no N2. disease [68, 69]. P/D should be considered for stage I disease  or for patients who cannot tolerate EPP . For patients who cannot tolerate any resection or have symptomatic effusions, palliative therapeutic options include pleurodesis or PleurX® catheter placement.
MPM has intermediate radiosensitivity, similar to nonsmall cell lung cancer. Radiotherapy alone is not curative, due to the large radiation doses needed for tumor sterilization, large target volumes, and proximity to radiosensitive normal structures.
Высокодозная лучевая терапия на всю половину грудной клетки после плеврэктомии и декортикации улучшает локальный контроль по сравнению с историческим контролем; однако, не было показано улучшение выживаемости . Significant radiation toxicities, primarily pneumonitis, pulmonary fibrosis, pericardial effusion, esophagitis, and esophageal stricture have been reported in patients treated with adjuvant radiotherapy following P/D [72–74]. Thus, adjuvant radiation in this setting should be considered with the goal of reducing locoregional failure, preferably on clinical trial.
Таблица 2.4. TNM стадийность злокачественной мезотелиомы плевры.
|Первичная опухоль (T)|
|TX||Первичная опухоль не может быть оценена|
|T0||Нет свидетельства первичной опухоли|
|T1||Tumor is limited to the ipsilateral parietal pleura with or without involvement of:
· Visceral pleura
· Mediastinal pleura
· Diaphragmatic pleura
|T2||Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
· Involvement of the diaphragmatic muscle
· Extension of tumor from the visceral pleura into the underlying pulmonary parenchyma
|T3||Locally advanced but potentially resectable tumor.
Tumor involving all the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
· Involvement of the endothoracic fascia
· Extension into the mediastinal fat
· Solitary, completely resectable focus of tumor extending into the soft tissue of the chest wall
· Nontransmural involvement of the pericardium
|T4||Locally advanced technically unresectable tumor.
Tumor involving all the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
· Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction
· Direct diaphragmatic extension of the tumor to the peritoneum
· Direct extension of the tumor to the contralateral pleura
· Direct extension of the tumor to a mediastinal organ
· Direct extension of the tumor into the spine
· Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium
|Региональные лимфатические узлы (N)|
|NX||Региональные лимфатические узлы не могут быть оценены|
|NO||Нет метастазов в региональные лимфоузлы|
|N1||Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes|
|N2||Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes|
|Отдаленный метастаз (M)|
|M0||Нет отдаленных метастазов|
|IIIB||T1, T2, T3||N2||M0|
|IV||Any T||Any N||M1|
Postoperative radiotherapy is given after EPP to improve local control and to prevent recurrence at the instrument-tract after pleural intervention. Adjuvant radiotherapy to 50–54. Gy reduces local recurrence rates after EPP in carefully selected patients . IMRT has allowed safe delivery of higher doses of up to 60. Gy in the adjuvant setting after EPP [76, 77]. Prophylactic radiation to surgical tracts has been shown to prevent local recurrences at these sites [78, 79].
Техника лучевой терапии
The target volume should include the entire hemithorax, thoracotomy incision, biopsy tracks, and sites of chest drains [75, 80]. Postoperative radiotherapy is delivered to this target volume using standard fractionation with 1.8–2.0. Gy fractions to total 50–54. Gy. A total dose of 54–60. Gy is recommended for microscopically positive margins. A total of 60. Gy or greater is recommended for macroscopic residual disease. Modern radiotherapy techniques such as IMRT or image-guided radiotherapy may allow more sparing of adjacent critical structures than 3D conformal techniques .
Prophylactic doses of 21. Gy in seven fractions help to prevent surgical tract recurrences [78, 79]. Palliative chest wall radiation to doses >40. Gy at doses of =4. Gy per fraction appear to be more effective in providing symptomatic relief than lower doses . Palliation of bone or brain metastases is treated with standard courses such as 30. Gy in 10. fractions.
Химиотерапия и тримодальная терапия
The benefit of chemotherapy in MPM was first demonstrated in the metastatic or inoperable setting. Prior to 2000, it was unclear whether chemotherapy provided a benefit over supportive care. In 2003, the combination of cisplatin with pemetrexed was studied in a large (n = 456) chemotherapy naive population . Cisplatin plus pemetrexed produced a significantly superior response rate of 41.3%, and median survival of 12.1. months, compared to 16.7% and 9.3. months in the control group of single agent cisplatin. The National Cancer Care Network recommends four combination systemic therapy regimens that can be used either alone or as part of multimodality therapy for MPM. Cisplatin and pemetrexed is recommended as the first-line regimen (category I). Carboplatin can be substituted for patients with medical contraindications to cisplatin and gemcitabine is recommended for patients who are unable to receive pemetrexed. Cisplatin, pemetrexed, and bevacizumab can be used for patients with unresectable disease and are able to receive bevacizumab . There is no current standard second-line agent for MPM. Although multiple targeted agents are now playing a role in nonsmall cell lung cancer, no agent has yet proven to be beneficial to patients with MPM. There are currently multiple pathways being investigated in early clinical studies in patients with MPM .
Even with the added benefits of local control with adjuvant radiation therapy after EPP, distant recurrence remains a problem and affects survival . Multiple studies have investigated giving neoadjuvant cisplatin in the setting of trimodality therapy . Patients in the largest study that completed all three forms of therapy achieved a median survival of 29. months and 62% were alive at 2. years .
Intrapleural therapies such as hyperthermic intracavitary chemotherapy [85, 86], hyperthermic povidone-iodine lavage , photodynamic therapy , and immunogenetic therapy  have been studied but clear benefits of their use are still lacking .
No well-established, defined follow-up guidelines are available for MPM. Similar follow-up for lung cancer, including clinic visits with CT scans of chest and abdomen every 4–6. months for the first 2–3. years followed by annual imaging thereafter, seems appropriate due to the aggressive nature of the disease and the high risk for recurrence.
- Detterbeck FC. Evaluation and treatment of stage I and II thymoma. J Thorac Oncol 2010;5(10. Suppl 4):S318–22.
- Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010;5(10. Suppl 4):S260–5.
- Eng TY, Fuller CD, Jagirdar J, Bains Y, Thomas CR, Jr. Thymic carcinoma: state of the art review. Int J Radiat Oncol Biol Phys 2004;59(3):654–64.
- Weksler B, Dhupar R, Parikh V, et al. Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290. patients. Ann Thorac Surg 2013;95(1):299–303.
- Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015;149(1):95–101.
- Kelly RJ. Thymoma versus thymic carcinoma: differences in biology impacting treatment. J Natl Compr Canc Netw 2013;11(5):577–83.
- Marx A, Chan JK, Coindre JM, et al. The 2015. World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol 2015;10(10):1383–95.
- Muller-Hermelink HK, Marx A, Geuder K, Kirchner T. The pathological basis of thymoma-associated myasthenia gravis. Ann NY Acad Sci 1993;681:56–65.
- Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860–9.
- Marom EM. Imaging thymoma. J Thorac Oncol 2010;5(10. Suppl 4):S296–303.
- Sung YM, Lee KS, Kim BT, et al. 18F–FDG PET/CT of thymic epithelial tumors: usefulness for distinguishing and staging tumor subgroups. J Nucl Med 2006;47(10):1628–34.
- Marchevsky A, Marx A, Strobel P, et al. Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac Oncol 2011;6(Suppl 3):S1724–9.
- Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol 2011;6(Suppl 3):S1710–6.
- Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48(11):2485–92.
- Koga K, Matsuno Y, Noguchi M, et al. A review of 79. thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44(5):359–67.
- Detterbeck FC, Marom E. Thymus. In: MB Amin, SB Edge, FL Greene, et al. (eds) AJCC Cancer Staging Manual, 8th edn. New York: Springer Nature, 2017.
- Ruffini E, Van Raemdonck D, Detterbeck F, et al. Management of thymic tumors: a survey of current practice among members of the European Society of Thoracic Surgeons. J Thorac Oncol 2011;6(3):614–23.
- Thymomas and Thymic Carcinomas. National Comprehensive Cancer Network, 2013.
- Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 1997;113(1):55–63.
- Margaritora S, Cesario A, Cusumano G, et al. Single-centre 40-year results of redo operation for recurrent thymomas. Eur J Cardiothorac Surg 2011;40(4):894–900.
- Toker A, Sonett J, Zielinski M, et al. Standard terms, definitions, and policies for minimally invasive resection of thymoma. J Thorac Oncol 2011;6(Suppl 3):S1739–42.
- Detterbeck FC, Moran C, Huang J, et al. Which way is up? Policies and procedures for surgeons and pathologists regarding resection specimens of thymic malignancy. J Thorac Oncol 2011;6(Suppl 3):S1730–8.
- Yagi K, Hirata T, Fukuse T, et al. Surgical treatment for invasive thymoma, especially when the superior vena cava is invaded. Ann Thorac Surg 1996;61(2):521–4.
- Gomez DR, Fuller CD, Chennupati S, Thomas CR, Jr. Mediastinal and tracheal cancer. In: EC Halperin, LW Brady, CA Perez, DE Wazer (eds) Perez and Brady’s Principles and Practice of Radiation Oncology 6th edn. Baltimore: Lippincott Williams & Wilkins, 2013.
- Rengan R, Bonner Millar LP, Thomas CR Jr. Uncommon thoracic tumours. In: L Gunderson, J Tepper (eds) Clinical Radiation Oncology, 3rd edn. Philadelphia: Elsevier, 2011:859–89.
- Rena O, Papalia E, Oliaro A, et al. Does adjuvant radiation therapy improve disease-free survival in completely resected Masaoka stage II thymoma? Eur J Cardiothorac Surg 2007;31(1):109–13.
- Ogawa K, Uno T, Toita T, et al. Postoperative radiotherapy for patients with completely resected thymoma: a multiinstitutional, retrospective review of 103. patients. Cancer 2002;94(5):1405–13.
- Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol 1999;17(7):2280–9.
- Fuller CD, Housman DM, Thomas CR. Radiotherapy for thymoma and thymic carcinoma. Hematol Oncol Clin North Am 2008;22(3):489–507.
- Eng TY, Thomas CR, Jr. Radiation therapy in the management of thymic tumors. Semin Thorac Cardiovasc Surg 2005;17(1):32–40.
- Uematsu M, Yoshida H, Kondo M, et al. Entire hemithorax irradiation following complete resection in patients with stage II–III invasive thymoma. Int J Radiat Oncol Biol Phys 1996;35(2):357–60.
- Fuller CD, Ramahi EH, Aherne N, Eng TY, Thomas CR, Jr. Radiotherapy for thymic neoplasms. J Thorac Oncol 2010;5(10. Suppl 4):S327–35.
- Girard N, Lal R, Wakelee H, Riely GJ, Loehrer PJ. Chemotherapy definitions and policies for thymic malignancies. J Thorac Oncol 2011;6(Suppl 3):S1749–55.
- Rajan A, Giaccone G. Treatment of advanced thymoma and thymic carcinoma. Curr Treat Options Oncol 2008;9(4–6):277–87.
- Loehrer PJ, Sr., Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12(6):1164–8.
- Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer 1991;68(1):30–3.
- Loehrer PJ, Sr., Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001;91(11):2010–5.
- Ettinger DS, Riely GJ, Akerley W, et al. Thymomas and thymic carcinomas. J Natl Compr Canc Netw 2013;11(5):562–76.
- Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 2011;29(15):2060–5.
- Koizumi T, Takabayashi Y, Yamagishi S, et al. Chemotherapy for advanced thymic carcinoma: clinical response to cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC chemotherapy). Am J Clin Oncol 2002. Jun;25(3):266–8.
- Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G. Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol 2011;29(36):4820–7.
- Yokoyama S, Miyoshi H, Nakashima K, et al. Prognostic value of programmed death ligand 1. and programmed death 1. expression in thymic carcinoma. Clin Cancer Res 2016; 22(18):4727–34.
- Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2. trial. Lancet Oncol 2015;16(2):177–86.
- Blumberg D, Port JL, Weksler B, et al. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg 1995;60(4):908–13; discussion 914.
- Detterbeck F, Parsons AM. Thymic tumors: a review of current diagnosis, classification, and treatment. In: Pearson’s Thoracic and Esophageal Surgery, 3rd edn. Philadelphia: Elsevier, 2008:1589–614.
- Huang J, Detterbeck FC, Wang Z, Loehrer PJ, Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol 2011;6(Suppl 3):S1691–7.
- Price B, Ware A. Time trend of mesothelioma incidence in the United States and projection of future cases: an update based on SEER data for 1973. through 2005. Crit Rev Toxicol 2009;39(7):576–88.
- Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/ based on November 2015. SEER data submission, posted to the SEER web site, April 2016.
- Park EK, Takahashi K, Hoshuyama T, et al. Global magnitude of reported and unreported mesothelioma. Environ Health Perspect 2011;119(4):514–8.
- Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 1960;17:260–71.
- Robinson B. Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg 2012;1(4):491–6.
- De Bruin ML, Burgers JA, Baas P, et al. Malignant mesothelioma after radiation treatment for Hodgkin lymphoma. Blood 2009;113(16):3679–81.
- Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol 2012;7(11):1631–9.
- Ohar JA, Cheung M, Talarchek J, et al. Germline BAP1. mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer. Cancer Res 2016;76(2):206–15.
- Betti M, Aspesi A, Biasi A, et al. CDKN2A and BAP1. germline mutations predispose to melanoma and mesothelioma. Cancer Lett 2016;378(2):120–30.
- Yanagawa J, Rusch V. Surgical management of malignant pleural mesothelioma. Thorac Surg Clin 2013;23(1):73–87.
- Galateau-Salle F, Churg A, Roggli V, Travis WD, for World Health Organization Committee for Tumors of the Pleura. The 2015. World Health Organization classification of tumors of the pleura: advances since the 2004. classification. J Thorac Oncol 2016;11(2):142–54.
- Adams RF, Gleeson FV. Percutaneous image-guided cuttingneedle biopsy of the pleura in the presence of a suspected malignant effusion. Radiology 2001;219(2):510–4.
- Boutin C, Rey F. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188. consecutive patients. Part 1: Diagnosis. Cancer 1993;72(2):389–93.
- Heelan RT, Rusch VW, Begg CB, et al. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. Am J Roentgenol 1999;172(4):1039–47.
- Nguyen NC, Tran I, Hueser CN, et al. F-18. FDG PET/CT characterization of talc pleurodesis-induced pleural changes over time: a retrospective study. Clin Nucl Med 2009;34(12):886–90.
- Ahmadzadehfar H, Palmedo H, Strunk H, et al. False positive 18F-FDG-PET/CT in a patient after talc pleurodesis. Lung Cancer 2007;58(3):418–21.
- Rusch VW, Chansky K, Nowak AK, et al. Malignant pleural mesothelioma. In: MB Amin, SB Edge, FL Greene, et al. (eds) AJCC Cancer Staging Manual, 8th edn. New York: Springer Nature, 2017.
- Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 2011;12(8):763–72.
- Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial: conclusions not supported by data. Lancet Oncol 2011;12(12):1093–4; author reply 4–5.
- Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663. patients. J Thorac Cardiovasc Surg 2008;135(3):620–6.
- Taioli E, Wolf AS, Flores RM. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma. Ann Thorac Surg 2015;99(2):472–80.
- Zauderer MG, Krug LM. The evolution of multimodality therapy for malignant pleural mesothelioma. Curr Treat Options Oncol 2011;12(2):163–72.
- Kaufman AJ, Flores RM. Surgical treatment of malignant pleural mesothelioma. Curr Treat Options Oncol 2011;12(2):201–16.
- Nakas A, von Meyenfeldt E, Lau K, Muller S, Waller D. Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma. Eur J Cardiothorac Surg 2012;41(5):1031–6.
- Baldini EH. Radiation therapy options for malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 2009;21(2):159–63.
- Rusch VW. Pleurectomy/decortication and adjuvant therapy for malignant mesothelioma. Chest 1993;103(4. Suppl):382S–4S.
- Gupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005;63(4):1045–52.
- Lee TT, Everett DL, Shu HK, et al. Radical pleurectomy/ decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2002;124(6):1183–9.
- Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122(4):788–95.
- Ahamad A, Stevens CW, Smythe WR, et al. Intensity-modulated radiation therapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003;55(3):768–75.
- Forster KM, Smythe WR, Starkschall G, et al. Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 2003;55(3):606–16.
- Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995;108(3):754–8.
- Di Salvo M, Gambaro G, Pagella S, et al. Prevention of malignant seeding at drain sites after invasive procedures (surgery and/or thoracoscopy) by hypofractionated radiotherapy in patients with pleural mesothelioma. Acta Oncol 2008;47(6):1094–8.
- Gupta V, Krug LM, Laser B, et al. Patterns of local and nodal failure in malignant pleural mesothelioma after extrapleural pneumonectomy and photon-electron radiotherapy. J Thorac Oncol 2009;4(6):746–50.
- Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21(14):2636–44.
- Ettinger DS, Wood DE, Akerley W, et al. NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016. J Natl Comp Canc Netw 2016;14(7):825–36.
- Nowak A. Chemotherapy for malignant pleural mesothelioma: a review of current management and a look to the future. Ann Cardiothorac Surg 2012;1(4):508–15.
- Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27(18):3007–13.
- Chang MY, Sugarbaker DJ. Innovative therapies: intraoperative intracavitary chemotherapy. Thorac Surg Clin 2004;14(4):549–56.
- Tilleman TR, Richards WG, Zellos L, et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study. J Thorac Cardiovasc Surg 2009;138(2):405–11.
- Lang-Lazdunski L, Bille A, Belcher E, et al. Pleurectomy/ decortication, hyperthermic pleural lavage with povidoneiodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma. J Thorac Oncol 2011;6(10):1746–52.
- Pass HI, Temeck BK, Kranda K, et al. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997;4(8):628–33.
- Haas AR, Sterman DH. Novel intrapleural therapies for malignant diseases. Respiration 2012;83(4):277–92.
- Bronte G, Incorvaia L, Rizzo S, et al. The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet? Crit Rev Oncol/Hematol 2016;107:20–32.