Update on thymic epithelial tumors: a narrative review

Introduction

Thymic epithelial tumors (TETs) include thymomas, thymic carcinomas, and neuroendocrine tumors of the thymus (NETTs). Although their incidence is low, they are the most common tumors of the anterior mediastinum (1).

The most common subgroup of TET is thymoma, which represents almost 50%, followed by thymic carcinoma (14–22%) and NETTs (2–5%) (1).

Epidemiologically, even though the distribution by age is quite similar, there is a slightly higher incidence in patients over 50 years of age (2), with the mean age at diagnosis being 50–60 years. The incidence by gender is similar, prevailing in men. The frequency of metastasis at diagnosis is higher in thymic carcinoma and NETTs than in thymomas (2), due to their more aggressive behavior with a greater tendency to disseminate systemically (1,3). Risk of developing a secondary malignancy is increased in this population, especially patients with thymomas. This is possibly due to treatments for their primary malignancy which includes radiotherapy (2).

In terms of survival, thymoma has an overall 5-year survival of approximately 78% (1). Thymic carcinomas and NETTs, as they are more aggressive entities with worse prognosis, the 5-year survival is 30% and 23%, respectively (1-4). No differences in prognosis have been observed between men and women in TETs (2). It has been observed that prognosis may be affected by histology, stage and the presence or absence of paraneoplastic syndromes (1).

This review aims to summarize the existing literature regarding the management for TETs. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-23-47/rc).

Methods

For this review, we searched EMBASE and MEDLINE until 6 September 2023. The search strategy is described in Table 1. The terms used in the search included thymoma, thymic carcinoma, thymic epithelial tumors, management, immunotherapy, multiple tyrosine kinases inhibitors. One of the main methodological limitations that we found when conducting the literature search and in the preparation of this manuscript is the lack of randomized clinical trials in this type of rare tumors. Many of the articles included are older, reviews or retrospective case series.

Clinical and diagnostic

For the diagnostic management, we must consider the clinical presentation and the findings in the diagnostic tests, being of special interest the radiological and histopathological findings (1).

Concerning the clinical presentation, about 33% of patients with thymic tumors are asymptomatic at the time of diagnosis. In those patients who are symptomatic, 40% present with symptoms related to intrathoracic mass compression (chest pain, cough, hoarseness, superior vena cava syndrome or dyspnea), 30% present with neurological symptoms and 30% present with systemic symptoms (weight loss, night sweats or fever), which make them difficult to differentiate from lymphoma (2).

In thymic carcinomas, the usual clinical presentation is as described above, with no more frequent associations with other entities (5). However, in NETTs, in addition to the symptoms described, 50% are functionally active and can be associated with endocrinopathies, with up to 40% presenting associated Cushing’s syndrome, or less frequently, multiple endocrine neoplasia (MEN) I in 19 to 25% (3). The association of MEN type IIA with NETT is an unusual presentation, known in a few cases, and considered a variant of Sipple’s syndrome (described as incomplete Sipple’s syndrome) (6,7).

The most frequent thymoma’s association is myasthenia gravis (1), present in up to 82% (8), in contrast to non-thymoma TETs, where the association with myasthenia gravis is exceedingly rare (9).

Preoperative diagnosis of these thymic masses can be complex, but currently, imaging tests are available to assist in this process (10).

Despite the fact that chest radiography is used for the initial study to confirm the presence of a thymic mass (1), the most useful and frequently used diagnostic test is contrast enhanced computed tomography (CT). CT scans provide information on clinical tumor local stage with an evaluation of the organs and structures adjacent to it (1). It also provides information on the presence of pleural parietal deposits (also called “droplet metastases”), as well as on the density characteristics of the thymic neoplasm. The identification of areas whose density is different from thymoma, such as hemorrhage, calcification or necrosis, provides relevant information for staging-for instance, the presence of calcifications suggesting B1, B2, and B3 types of thymoma (2).

Thymomas frequently appear as well-defined rounded masses located anterior to the great vessels and heart. In contrast, thymic carcinoma is characterized by irregular margins and associated lymph nodes (2). In the case of NETTs, a lobulated thymic mass with heterogeneous enhancement and central areas of decreased attenuation secondary to areas of necrosis or hemorrhage are observed (3).

Magnetic resonance imaging (MRI) is usually reserved for cases where iodinated contrasts cannot be administered or to examine for the presence of cystic lesions or areas of local invasion (1,2). Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT may be considered for thymic carcinoma, given the high metabolism of this tumor, for the detection of occult metastases (1) or to characterize lesions suspicious for recurrence (5).

NETTs exhibit an overexpression of somatostatin receptors (SSTRs) on their cell membrane. Imaging techniques targeting SSTRs, such as 68Ga-DOTATOC/DOTATATE-PET, are employed to identify hormonally active tumors of this nature and devise suitable therapeutic strategies. This holds significance as the verification of receptor affinity through diagnostic imaging serves as a crucial determinant of the potential for peptide receptor radionuclide therapy (PRRT). PRRT, involving the use of receptor agonists or antagonists within the context of a theranostic approach, has gained widespread acceptance as an effective treatment modality for neuroendocrine neoplasms (NENs) since its introduction (11). While 68Ga, a positron emitter radionuclide, is exclusively utilized for diagnostic imaging, 90Yttrium-DOTA octreotide and 177-Lutetium DOTA octreotide are the most commonly employed regimens for PRRT (12).

Pathology

At the histological level, moderate atypicality with little associated mitosis and immature T-cell lymphocytes can be observed in thymoma. Vascular invasion and necrosis are usually absent. In contrast to thymomas, the histology of thymic carcinomas is characterized by marked atypicality, frequent mitosis, mature T- and B-cells and vascular invasion and necrosis. Immunohistochemically, thymoma is c-KIT (CD117) negative whereas in thymic carcinoma, in 60–80% of cases, epithelial cells are c-KIT positive, with frequent CD5-associated expression (13).

NETTs differ from the two previously described entities by the presence of elongated tumor cells, pleomorphic nuclei and arrangement in small, rosette-like acinar structures. Immunohistochemically, they are characterized by positivity for markers such as cytokeratin, Leu-7, synaptophysin and cytoplasmic chromogranin stain. Among the latter markers, TTF-1 positivity is noteworthy (3).

It is necessary to compare the histopathological differences among these tumor types, as they contribute to the postoperative diagnosis. This is imperative in scenarios where clinical presentation and imaging findings are merely suggestive (2).

Table 2 describes the histological classification for thymoma and Table 3, the histological classification for thymic carcinoma (1,14). NETTs are histologically classified into three categories: low grade (well differentiated), intermediate grade (moderately undifferentiated) and high grade (poorly differentiated) with well-differentiated (WD) carcinomas being the most frequent (3).

Despite the fact that there are relatively few studies on tumor mutational burden (TMB) in TETs, it is necessary to elucidate its role in this type of tumors. TMB stands as an indirect indicator of the ability and extent of tumors to produce new antigens, which is correlated to the suitability for immunotherapy (15).

Some of the most mutated genes in TETs are GTF2I, HRAS, TTN and TP53. GTF2I has been described as the predominant mutation in TETs, particularly in the case of the comparatively indolent type A and AB thymomas. However, its incidence is notably infrequent in the more aggressive types B and C. Patients with GTF2I mutations exhibit a more favorable prognosis, potentially attributable to their prevalence in relatively less aggressive subtypes (16). Comparing to thymomas, the incidence of GTF2I is decreased in thymic carcinomas (16).

Differential diagnosis and staging

The differential diagnosis of these tumors should be made primarily with: (I) lymphomas (both Hodgkin’s and non-Hodgkin’s), the most common, (II) extragonadal germ cell tumors and (III) metastatic carcinomas that may involve the mediastinum (1). In order to provide a differential diagnosis, the patient’s age, sex, clinical features and CT images should be considered (1,2).

One of the main differential diagnoses for TETs is lymphoma, however patients presenting with lymphoma tend to be younger compared to those with TET. They usually have constitutional symptoms, different from parathymic syndromes, such as night sweats, fever, weight loss and malaise. In contrast to TET, the physical examination of a patient with lymphoma may reveal lymphadenopathy.

There are several staging systems for this group of tumors; however, the most commonly used are the TNM 8th edition and the Masaoka-Koga staging system. Tables 4–6 describe these systems, respectively (1,2).

In the most recent 2021 classification of thymic tumors by the World Health Organization (WHO), NETTs are categorized into three groups (17): low-grade typical carcinoids (TC), intermediate-grade atypical carcinoids (ACs), and two high-grade malignancies—specifically, large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCC).

Localized disease

Surgical approach of thymoma and thymic carcinoma

Surgery is the main treatment strategy of patients diagnosed with thymoma and thymic carcinoma (18) and a complete surgical resection (R0) is a prognostic factor for recurrence and survival in these patients (19,20). Survival may differ according to the resection margins: complete R0 resection has an excellent prognosis, microscopic R1 has shown a 64% 10-year survival compared with macroscopic R2 that has shown a 36% 10-year survival (21-26). The best surgical approach is debatable and both an open surgery or a minimally invasive surgery could be performed on a case-by-case basis. For an open surgery, a median sternotomy can allow an extensive evaluation of mediastinal structures and surgical manipulation as well (4). If structures of the posterior mediastinum or the pulmonary hilar are infiltrated, a horizontal incision would be a better option (4).

Minimally invasive surgery could be considered for patients with early clinical stages (I-II) if a complete resection is feasible, taking into account that long-term data of the benefits of minimally invasive surgery compared to open surgery are lacking (27,28). Depending on the surgical approach, minimally invasive surgery could be divided in different categories: (I) unilateral transthoracic video-assisted thoracic surgery (VATS) thymectomy; (II) conventional subxiphoid VATS thymectomy; (III) transcervical VATS thymectomy; (IV) subxiphoid VATS thymectomy with double elevation of sternum. Open surgery has been compared with VATS thymectomy and robotic VATS (R-VATS) thymectomy and has been shown to have acceptable oncological outcomes and less perioperative complications (29,30). However, it should be taking into consideration that resecability is the first evaluation that should be performed in patients with localized disease and it is mainly based on the expertise of the surgeon (4). A thymectomy which includes the resection of the thymic tumor, residual thymus and perithymic fat is recommended (31). Furthermore, the resection of pleura, pericardium, phrenic nerve, lung and major vessels that are close to the thymus may be required as well.

Lymphadenectomy in thymic tumors is controversial and there the data on the prognostic significance is lacking. Systematic lymphadenectomy is recommended in stage II or higher, WHO histology B2/3, C, tumors >6 cm and NETTs (32). N1 could be resected with the total thymectomy but, N2 with the station R 2/4 and L 5/6 depend usually on the suspicious intraoperative findings (4). After curative therapy, if there is persistent or recurrent disease, salve surgery could be performed but the oncological outcomes are not well defined (33).

Thymoma

Resectable disease

Thymomas are classified as type A, type AB, type B1/B2/B3 in the WHO fifth edition which includes gene mutations and gene fusions (17). The Masaoka-Koga staging has been associated with survival and is based on the extension of the tumor (34). The prognostic relevance of molecular changes in thymomas has been recently highlighted as a distinctive feature and may allow future targeted treatments (35).

The symptoms and underlying autoimmune diseases that are diagnosed in patients with thymoma can have an impact in the workup required for diagnosis and in the treatment strategy. Myasthenia gravis can be present in up to 50% of patients with thymoma (36) and require an evaluation and treatment by a neurologist before a surgery can be performed because these patients have an increased surgical risk and could require a specific treatment prior to the intervention (37-39). Patients with a strong suspicion of having a resectable thymoma do not require a surgical biopsy nor a transpleural approached biopsy because there could be tumor seeding when the tumor capsule is ruptured (40).

Thymomas can invade local structures like pleura and lung but it is unlikely to spread to extrathoracic sites or lymph nodes (41,42). For patients with resected tumors the most important prognostic factor is the complete resection rate that depend on the adhesion to other structures (43): stage I and II have 10-year OS of 90% and 70%, respectively (40,44). Patients with tumors invading structures that can be resected or those patients with encapsulated tumors should be evaluated for surgery as the standard approach of resectable thymomas (45,46). A total resection of the thymus and a lymph node dissection is the most common surgical approach in patients with early stage without myasthenia gravis (47).

After surgery, clinicians should evaluate the benefit of postoperative radiotherapy (PORT) depending on the stage of thymoma and resection margins, these recommendations are summarized in Tables 7,8. Thymomas don’t usually metastasize to regional lymph nodes, therefore, extensive elective nodal radiation is not a recommendation (41-48). On the contrary, postoperative adjuvant chemotherapy has not demonstrated a benefit in the adjuvant setting (59,60).

The surveillance of patients with resected thymomas should be done with a chest CT scan every 6 months during the first 2 years followed by an annual chest CT scan for a total of 10 years (61).

Potentially resectable disease

Patients with locally advanced thymomas where a complete resection is not feasible, may benefit from induction chemotherapy, surgery and PORT (62-69). Table 9 summarizes studies with a multidisciplinary approach of unresectable malignant thymomas. The preferred chemotherapy regimen for thymoma as first-line combination is the CAP regimen: cisplatin, doxorubicin, cyclophosphamide administered every 3 weeks with response rates of approximately 44% (55,70-72). However, a recent cohort study did not report differences between upfront surgery alone versus induction chemotherapy followed by surgery (76.7% vs. 77.4%, respectively, P=0.596) (63). For patients with oligometastastic disease that are diagnosed with solitary metastasis or ipsilateral pleural metastases two therapeutic approaches can be considered: (I) upfront surgery alone; (II) induction chemotherapy followed by surgery for patients with resectable disease (36,37).

Neoadjuvant chemotherapy may be useful for achieving a complete R0 resection. Previous studies have reported response rates that range from 77–100% and an average R0 resection rate of 72%. One of the main controversies is that the data to recommend a multimodality approach with neoadjuvant therapy is based on small studies that could not be representative (73).

Thymic carcinoma

Resectable disease

Thymic carcinomas are infrequent tumors that harbor a worse prognosis than thymomas and can metastasize to lymph nodes and other organs (74-76). The main differences between thymomas and thymic carcinomas are based on histologic grounds because thymic carcinomas show malignant features as well as different genetic and immunohistochemical features (17,75). The standard of care of patients with resectable tumors at diagnosis is surgery. If a patient is resectable and undergoes resection the 5-year OS is 50–75% and survival rates vary according to stage: (I) stages 1 and 2: 91%; (II) stages 3 and 4: 31% (77).

As previously reported for thymomas, for most patients with thymic carcinomas the mainstay of surgery is a total resection of the thymus and a lymph node dissection (35). Tumor stage and the invasion of other structures can alter the possibility of performing a complete resection (47). In order to achieve an R0 resection, surgeons with specialized training may need to perform surgery over the pericardium and the adjacent lung parenchyma with the main goal of achieving negative margins that can impact long-term survival (47,78).

Thymic carcinomas have a higher risk of recurrence and adjuvant PORT is recommended in order to achieve local control (77). Therefore, after surgery, clinicians should evaluate the benefit of PORT depending on the stage of thymic carcinoma and the resection margins obtained: recommendations on PORT are summarized in Table 10. The benefit of PORT in thymoma and thymic neoplasms has been observed in retrospective data and is summarized in Table 11.

Thymic carcinomas with positive margins or residual disease may benefit of PORT supplemented with adjuvant chemotherapy with carboplatin and paclitaxel (84). Adjuvant chemoradiotherapy could be an option for patients with thymic carcinoma and macroscopic residual disease after surgery (84).

Potentially resectable disease

Thymic carcinomas that invade phrenic nerve(s), innominate vein or heart/great vessels are usually not suitable for upfront surgery because it is difficult to achieve an R0 resection, thus, a multimodal approach incorporating induction chemotherapy and postoperative RT is recommended (85). Prior to the start of induction chemotherapy, a diagnostic biopsy is recommended (84). An extensive evaluation on the risk of iatrogenic phrenic nerve injury should be performed prior to surgery because it can impair respiratory function.

Multimodality therapy approach based on previous studies of unresectable malignant thymomas, summarized in Table 10:

• Induction chemotherapy based on combination regimens, with resecability rates that range from 36–69% (57,68,86) followed by complete surgery and adjuvant radiotherapy/chemotherapy has been shown to prolong free survival (55). The recommendation of chemotherapy regimen is the same as unresectable disease: cyclophosphamide/doxorubicin and cisplatin repeated every 3 weeks.
• Reevaluate with imaging techniques if surgery is feasible. Patients who require a pleurectomy or extrapleural pneumonectomy because of the extent of disease should be discussed since the evidence of prolonged disease survival after performing an aggressive surgical approach is controversial (84).
• If an R0 resection is not possible it should be discussed if a maximum debulking followed by adjuvant RT (PORT) can be performed (84). Patients with residual disease may benefit from adjuvant chemotherapy and PORT.

Recurrent disease

Patients who have a localized recurrent disease require an assessment of a radical approach of surgery and the consideration of PORT or chemotherapy (87-89). If an R0 resection is not feasible, the resection of resectable disease and radiotherapy for the non-resectable disease can be discussed (90). If the patient has metastastic widespread disease then the treatment approach should be palliative (84).

NETTs

NETTs are usually diagnosed in a more advanced stage compared to thymic carcinomas and are larger in size (91,92). In functional lesions, locally advanced invasive tumors or fast-growing mediastinal lesions a histological confirmation is recommended prior to the surgical approach (93). The resection should include invaded mediastinal structures to achieve an R0 resection. In advanced tumors where there is an invasion of great vessels, pleural deposits or lung invasion, a posterolateral thoracotomy combined with sternotomy could be performed (93).

NETTs harbor an aggressive behaviour and have a poor prognosis even when an R0 resection has been achieved. If a recurrence occurs, an extensive surgical approach should be considered at the multidisciplinary meeting and an adjuvant radiotherapy has been shown to be effective in this subgroup of patients (94-96).

Unresectable/advanced disease

Thymoma and thymic carcinoma

Unresectable disease is that which presents with extensive pleural and/or pericardial metastases, unreconstructable great vessel, heart, or tracheal involvement or otherwise technically unresectable disease, including those with distant metastases.

Treatments are individualized according to the symptoms, extent of disease, and performance status. A multidisciplinary team should evaluate on a case-by-case basis the best therapeutic approach for patients with TETs. Debulking surgery may also provide benefit to select patients with initially unresectable disease, so continued involvement of a multidisciplinary team, including a thoracic surgeon, is important.

Patients with locally advanced, unresectable disease (TNM stage IIIB or Masaoka-Koga stage IVB), thymoma, or thymic carcinoma should be treated with concurrent chemoradiotherapy (cisplatin and etoposide) when feasible. Extrapolating from treatment paradigms for locally advanced lung cancer, radiotherapy doses of 60 Gy are appropriate (5). In this setting, chemoradiotherapy can offer long-term survival benefit and control the symptoms of the disease (97).

In select patients with initially unresectable disease, it is appropriate to evaluate for debulking surgery, as this approach may improve survival outcomes (97).

First line

Chemotherapy is the primary palliative treatment modality for patients with more widespread disease (1). Up to six cycles of platinum-anthracycline based regimens as CAP (cyclophosphamide, doxorubicin, cisplatin), cisplatin and etoposide and carboplatin and paclitaxel are the chemotherapy regimens that have shown efficacy in this setting (1). Six first-line chemotherapy regimens are recommended, with the carboplatin-paclitaxel combination being the preferred regimen (84). In advanced thymoma, a pooled analysis of 10 prospective and 5 retrospective studies indicated that anthracycline-based and platinum chemotherapy was superior to platinum without anthracycline in overall response rate (ORR 69.4% vs. 37.8%) and cisplatin-based chemotherapy was superior to carboplatin-based chemotherapy (ORR 53.6% vs. 32.8%) (72).

Although several regimens are acceptable, cyclophosphamide, doxorubicin, and cisplatin (CAP) and cisplatin and etoposide (PE) have been used successfully for thymomas or thymic carcinomas. Data suggest that the CAP and ADOC regimens could be effective for thymic carcinomas, but they are more toxic than carboplatin/paclitaxel (98,99). The combination of carboplatin and paclitaxel is also used extensively, especially in patients with thymic carcinoma, while the CAP regimen is preferred in patients with thymoma (84). Table 12 summarizes the different chemotherapy regimens (100-104).

Subsequent therapy

There are no further recognized standard lines of treatment for patients with TETs who progress on initial chemotherapy. Despite them, many patients are candidates to receive a second line. None of the agents studied in this context has been assessed in randomized phase 3 trials.

Pemetrexed, everolimus, octreotide [long-acting release (LAR)] with or without prednisone, paclitaxel, 5-fluorouracil (5-FU), gemcitabine with or without capecitabine, sunitinib, ifosfamide and etoposide are second-line chemotherapy options for thymomas (105-116).

Pemetrexed, 5-FU, sunitinib, everolimus, paclitaxel, lenvatinib, gemcitabine with or without capecitabine, ifosfamide and pembrolizumab are second-line chemotherapy options for thymic carcinomas (99,105,109,117-122). Table 13 summarizes the different chemotherapy regimens.

Although immunotherapy studies have shown efficacy in patients with advanced thymoma, we do not offer immunotherapy, as high rates of immune-related adverse events (irAEs) have been reported in these patients (121,122). In clinical trials, pembrolizumab demonstrated durable responses in patients with thymic carcinoma, which may be more pronounced those whose tumors express programmed death-ligand 1 (PD-L1) (121-123). These patients should be carefully monitored for possible severe irAEs, including myocarditis, myasthenia gravis, and hepatitis. There are no randomized trials directly comparing immunotherapy with other subsequent-line regimens, such as chemotherapy.

The elevated incidence of irAEs in TETs patients that receive immune checkpoint inhibitors warrant additional biomarker studies to identify patients who can benefit the most from immunotherapy and could present less irAEs (122). In this context, immunologic biomarkers for the early identification and prediction identification of irAEs are currently being investigated (124,125). Biomarkers like immune gene expression, IL-17 or peripheral eosinophil counts have been associated with the development of irAEs in solid tumors (124).

Sunitinib or lenvatinib are multiple tyrosine kinases inhibitors, including vascular endothelial growth factor (VEGF) and c-KIT, are an appropriate option in patients with thymic carcinomas refractory to initial chemotherapy, based on data from phase II trials and retrospective studies (109,110,120).

There is no clear role for nivolumab or avelumab in patients with relapsed thymic carcinoma, as clinical trials evaluating these agents showed limited activity and significant toxicity (126,127). Similarly, everolimus is not routinely used due to severe toxicity (pneumonitis), despite initial studies that suggest some efficacy in relapsed thymoma and thymic carcinoma (128).

Later-line options for treatment-refractory thymomas and thymic carcinomas include etoposide, ifosfamide, pemetrexed, octreotide, fluorouracil, S-1, gemcitabine plus capecitabine and paclitaxel.

Arunachalam et al. performed a meta-analysis focused on the efficacy and safety of subsequent treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy (123). From the nineteen trials identified in the systemic literature review, three trials with one or two TC patients were removed to reduce publication bias. The pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28%, 24%, and 21%, respectively. Pembrolizumab obtained an extended duration of response with a pooled median OS of 23.8 months [95% confidence interval (CI): 12, not reached]. Patients who had received lenvatinib, sunitinib, capecitabine + gemcitabine, S-1, everolimus or pembrolizumab reported a median PFS of at least five months. S-1 or pembrolizumab trials reported a median OS of at least 20 months; this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Therefore, the study found limited treatment options upon relapse, and there is a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.

NETTs

Approximately 80% to 90% of WD thoracic NETTs express SSTRs on their cell surface, that bind with high affinity somatostatin analogs (SSAs) lanreotide autogel and octreotide LAR (2). SSAs should probably be chosen first line for patients with relatively low-volume, relatively asymptomatic, SSTR-positive disease (129-131).

There are other several systemic treatment options: everolimus, temozolomide-based chemotherapy, and peptide receptor radioligand therapy using a radiolabeled SSA such as lutetium Lu-177 dotatate (¹⁷⁷Lu-dotatate).

Beyond SSAs, there are no data for selecting or sequencing these treatments except that ¹⁷⁷Lu-dotatate is limited to SSTR-expressing tumors. Even in those tumors, there is no real basis for choosing ¹⁷⁷Lu-dotatate over everolimus, or viceversa, as the second-line treatment. Most of the data on the effectiveness of these drugs is extrapolated from thoracic, gastroenteropancreatic or intestinal neuroendocrine tumors, with only data available from retrospective studies of patients with NETTs. Table 14 summarizes the different treatment options in G1/G2 advanced/metastatic NETTs.

Patients with intermediate to poorly-differentiated tumors respond to platinum-based chemotherapy regimens (135,139). In particular, treatment of poorly-differentiated NETTs with platinum-based regimens, such as carboplatin and etoposide, as per treatment guidelines for poorly-differentiated NETs at other sites.

New combinations of SSAs and other investigational drugs are therefore warranted, with the aim to improve clinical outcomes, while maintaining a good tolerability profile.

New therapeutics options

Immunotherapy administered alone or in combination with other agents is currently under study in several trials including patients with advanced B3 thymoma and thymic carcinoma which relapsed after at least one line of platinum-based chemotherapy. One of the main lines of research is the combination of antiangiogenic agents with chemotherapy or immunotherapy. Table 15 summarizes the main ongoing clinical trials in patients with advanced TETs.

Conclusions

TETs are rare and heterogeneous tumors that arise in the anterior mediastinum. Thymomas may be an incidental diagnosis discovered at chest imaging, and patients may present with symptoms due to the presence of a mass in the thorax or to a paraneoplastic phenomenon such as myasthenia gravis. The management of TETS requires a multidisciplinary approach (pathologists, medical oncologists, radiation oncologists and thoracic surgeons). Complete surgical resection is the initial treatment approach for all patients when preoperative evaluation suggests that a complete resection will be feasible and there are no medical contraindications to surgery. For patients with resected disease, the approach to postoperative radiation therapy is based on stage. In case of potentially resectable disease the recommendation is initial treatment with neoadjuvant chemotherapy and local treatment depending on the response.

In unresectable disease, RT alone, chemotherapy, or the combination is appropriate for patients in whom surgery is not technically feasible or is contraindicated, and may be of curative potential. Platinum-based chemotherapy is the treatment of choice in case of metastatic disease. However, patients with metastatic TETs have limited treatment options beyond platinum-based chemotherapy, due to the poor effectiveness showed by several other agents administered in subsequent lines of therapy. New therapies have been explored in this clinical setting such as the antiangiogenic multikinase inhibitors, mammalian target of rapamycin (mTOR) inhibitor, ICIs and their combinations.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-23-47/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-47/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-47/coif). L.C.G. reports he received payment for presentations of Roche, Astra Zeneca, Brystol Myers Squibb, Merck Serono, Ipsen Pharma, Grunenthal, Kyowa Kirin, Pfizer and Eisai and received support for attending meetings from Roche, Merck, Eli Lilly, Bristol-Myers Squibb and Nutricia. V.P.B. reports she received a grant as an award from Merck and FSEOM, payment for presentations of Merck, Eli Lilly, Eisai and Pierre Fabre and received support for attending meetings from Roche, Eli Lilly, Bristol-Myers Squibb, Merck, Amgen, Merck Sharp and Dhome, and Nutricia. V.P.B. also reports she participated in an advisory board from advanced accelerator applications, a Novartis company. The other authors have no conflicts of interest to declare.

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