Narrative review of indication and management of induction therapy for thymic epithelial tumors

Introduction

Background

Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus and include thymomas, and thymic carcinomas (TCs). The annual incidence of TETs ranges from 1.3 to 3.2 persons per million per year, with similar rates in both sexes, and the average age at diagnosis is 50–60 years. Thymoma is the most common primary tumor of the anterior mediastinum, yet it is rare, with an incidence of 0.2 to 0.5 cases per million people per year. On the other hand, TC is extremely rare (1). Thymomas exhibit slow behavior and present as localized disease, but they have the potential for intrathoracic and extrathoracic metastasis. In contrast, patients with TC have a worse disease course and histology than patients with thymoma and a higher rate of nodal and systemic metastasis (2).

The World Health Organization (WHO) histological classification system is used to distinguish between thymomas, TCs, and thymic carcinoids and to distinguish between different histological types of thymomas (i.e., A, AB, B1, B2, and B3). Revised in 2021, this classification system categorizes TCs into the following larger subtype groups: squamous, adenocarcinomas, adenosquamous, and carcinomas not otherwise specified. Histology plays an important role in disease biology because poor differentiation is correlated with shorter disease-free survival and overall survival (OS) (3).

The Masaoka-Koga staging system has been widely accepted for the management and determination of the prognosis of thymomas and TCs (4). Patients with stages I, II, and III thymomas have 5-year survival rates of 100%, 98%, and 85%, respectively. On the other hand, patients diagnosed with stage IVa or IVb thymoma exhibit 5-year survival rates of 55% and 77%, respectively (4). The chances of survival for patients with TC vary based on the stage of diagnosis: the higher the Masaoka stage is, the lower the OS rate. Patients with stage IVb disease have a 5-year OS of only 17%, whereas those with stage I disease have a 5-year OS of 100%, demonstrating a statistically significant difference (P<0.001) (5). To achieve a positive prognosis, thorough removal of tumors is crucial, especially in patients with advanced stage III or IV tumors (6,7). Unfortunately, a considerable proportion of these tumors fall under the Masaoka-Koga III–IVa category, which indicates that R0 resection is difficult owing to extensive spread of the disease in the surrounding area. In stage III tumors, mediastinal and intrathoracic structures, including the pericardium, heart, major blood vessels, and lungs, are invaded. In stage IVa tumors, there are pleural and/or pericardial implants as well. Therefore, for treating TETs, complete resection is essential to ensure a positive outcome (8).

It is strongly recommended in the European Society for Medical Oncology (ESMO) guidelines that complete resection be conducted and that all patients be discussed with a multidisciplinary cancer board comprising medical oncologists, radiation oncologists, and thoracic surgeons (1,9). The decision to pursue additional treatments is based on factors such as histology, stage, and degree of radicality achieved during surgery (R1 vs. R0) (1).

Objectives

In cases where complete removal of a tumor is not possible because of advanced-stage involvement in areas such as the lung, vessels, or heart, induction therapy may be administered to downstage the tumor and achieve clear surgical margins. This therapy can include chemotherapy, radiotherapy, or chemoradiotherapy. The best treatment for locally advanced TETs is still under debate, but recent advancements in various therapies, such as immunotherapy and targeted drugs, have shown promise. Therefore, we conducted this narrative review to evaluate the current progress in induction treatment for locally advanced TETs. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-23-30/rc).

Methods

The literature search was performed using PubMed and Web of Science in June 2023. The keywords used for the research were “thymic epithelial tumors”, “thymoma”, “thymic carcinoma”, “locally advanced”, “neoadjuvant”, “preoperative”, “chemotherapy”, “radiotherapy”, “chemoradiotherapy”, “immunotherapy”, and “target therapy”. Prospective and retrospective published trials, systemic and narrative reviews, and meta-analyses were included. No limits regarding the years of publication were applied, and only papers written in English were accepted (Table 1). Sixty-two articles were selected according to the inclusion criteria and exclusion criteria from 1,091 PubMed references identified by keywords and 431 Web of Science references identified by keywords; case reports were excluded by keywords.

Results

Induction chemotherapy

Recent studies have yielded promising results regarding surgical resection after induction therapy for advanced TETs. According to a meta-analysis by Hamaji et al. of 12 trials involving 266 patients, the pooled rate of response to induction therapy was 59%, with a pooled rate of complete resection of 73% and pooled 5- and 10-year OS rates of 87% and 76%, respectively (10). Park et al. (11) investigated the efficacy of neoadjuvant chemotherapy in 1,486 patients with surgically resected thymic tumors and reported that 110 patients (7.4%) underwent surgery after neoadjuvant chemotherapy, whereas 1,376 patients (92.6%) underwent upfront surgery. Propensity score matching was used to minimize differences in preoperative and intraoperative variables, and the two groups were compared for postoperative outcomes and survival.

The matched cohort analysis did not reveal significant differences in postoperative mortality (P value not calculated), postoperative complications (P=0.405), or length of hospital stay (P=0.821) between the neoadjuvant chemotherapy and upfront surgery groups. However, compared with those in the upfront surgery group, the patients in the neoadjuvant chemotherapy group exhibited significantly greater transfusion rates (P=0.003) and longer operation times (P<0.001). The pathological complete resection rate (P=0.382) and tumor size (P=0.286) were similar between the two groups. The 5-year OS rates were 77.4% and 76.7% (P=0.596) and the 3-year recurrence-free survival rates were 62.9% and 71.5% (P=0.070) in the neoadjuvant chemotherapy and upfront surgery groups, respectively (11).

The optimal neoadjuvant therapy regimen for minimizing operative morbidity and mortality and maximizing resectability and survival has not been established. Table 2 provides a comprehensive overview of the induction chemotherapy regimens, complete resection rates, and response rates for patients with locally advanced TETs (8,12-31). Platinum- and anthracycline-based chemotherapy are the most commonly used regimens in clinical practice, with response rates ranging from 37% to 100%. In patients for whom radical surgery (R0 resection) is feasible, a surgical approach is pursued, and complete resection is achieved in approximately 50–80% of patients. However, only limited data are provided by prospective randomized trials comparing chemotherapy with chemoradiotherapy in this specific setting and previous reports do not include sufficient information. In cases where there is substantial tumor shrinkage or transition from an unresectable tumor to a potentially resectable tumor occurs, extensive surgery should be offered, and postoperative radiotherapy should be considered. The most commonly prescribed platinum and anthracycline-based regimens in clinical practice are cisplatin + doxorubicin + cyclophosphamide (PAC), cisplatin + adriamycin + cyclophosphamide + vincristine (ADOC), and cisplatin + doxorubicin + methylprednisolone (CAMP). In a study by Shin et al., 12 patients with unresectable stage III–IVA thymoma received three courses of PAC + prednisolone; three patients achieved a complete response, while eight achieved a partial response. Of the 11 patients who underwent subsequent surgical intervention, nine achieved R0 resection (12). Similarly, in a study by Kim et al., 22 patients with stage III–IVb invasive thymoma received three courses of PAC + prednisolone; 17 exhibited major responses (complete responses, n=3; partial responses, n=14), and 21 were surgically treated (16 achieved R0 resection) (13). In a study by Rea et al., 16 patients with stage III–IVA invasive thymomas were treated with the ADOC regimen; 100% (seven complete and nine partial) of the patients achieved a response, followed by surgery, and 11 patients (68%) achieved complete resection (14). CAMP is also frequently used in clinical trials. In a study by Yokoi et al., the CAMP regimen was administered to 14 patients with invasive III–IVb stage thymoma in a neoadjuvant setting; 13 (92.9%) patients achieved a good response to this regimen, and nine underwent surgical treatment, with 2 (22.2%) achieving R0 resection (15).

Among these phase II trials or retrospective studies with a small number of patients, a pattern in the use of anthracyclines emerges when comparing platinum-based and anthracycline-based combination therapy with platinum-based and non-anthracycline-based combination therapy. In combination therapy with cisplatin and etoposide, the overall response rate (ORR) in both thymoma and TC patients were 51–62% (16,17). Carboplatin and paclitaxel have also shown promising results, with an ORR of 22–36% in patients with both thymoma and TC (18-20). Park et al. explored the impact of induction chemotherapy using docetaxel and cisplatin (TP) (21). In nine patients with thymomas (one with stage III disease and eight with stage IVA), five (55.6%) achieved a partial response, and four achieved a complete response. Moreover, seven patients were eligible for surgery, and all patients ultimately achieved R0 resection. For patients with thymoma who cannot tolerate anthracycline combination regimens, nonanthracycline regimens such as cisplatin + etoposide (EP), carboplatin + paclitaxel, or docetaxel and cisplatin (TP) can be used.

Unlike in patients with thymoma, in patients with TC, the ORR did not significantly differ between anthracycline and nonanthracycline regimens, and the key therapy was a platinum-containing regimen. Carboplatin + paclitaxel is the preferred choice for treating locally advanced TC. Anthracycline regimens, including CAP and ADOC, are also effective, but these regimens have greater toxicity.

Overall, neoadjuvant chemotherapy has proven to be effective in prospective and retrospective studies, with most regimens being well tolerated and resulting in a reasonable response rate in patients with locally advanced tumors. Thus, all available options must be discussed with patients and their medical team to make an informed decision regarding the ideal treatment plan.

Induction radiotherapy

Radiation therapy as a preoperative treatment for locally advanced thymic tumors has attracted considerable interest and research. However, most institutions currently favor chemotherapy as the preferred induction treatment. Radiation therapy poses a considerable challenge because of the potential damage it can inflict on adjacent tissues, particularly in patients where mediastinum radiation is involved. When administering radiation to this area, it is crucial to safeguard vital organs such as the heart, lungs, and esophagus. In addition, postoperative radiation therapy is generally considered for locally advanced thymic tumors. In cases where preoperative radiation therapy is considered, the risk of additional postoperative radiation therapy should also be considered.

In several studies, scholars have investigated the use of radiation therapy alone as an induction treatment for thymic tumors. In a multi-institutional study using the European Society of Thoracic Surgeons database, only 1% of patients (12 out of 2,030) received radiation monotherapy as induction therapy (32). Similarly, a review of the International Thymic Malignancy Interest Group database showed that only 6% of TC patients (48 out of 1,042) received induction radiation as the sole treatment (2).

Ribet et al. described a series of 113 patients, 19 of whom received preoperative radiation (33). Within this cohort, ten patients achieved complete resection, for a 5-year OS rate of 44%. Akaogi et al. reported 12 patients with thymic tumors that invaded the great vessels who underwent preoperative radiation. The cohort showed a 75% rate of complete resection, and ten patients also received adjuvant radiation, resulting in 5- and 10-year OS rates of 72% and 48%, respectively (34). The findings from various radiation experiences are summarized in Table 3.

In summary, radiation therapy as a preoperative induction treatment for locally advanced thymic tumors is not widely practiced. Most institutions prefer chemotherapy as the primary induction therapy. Based on the literature, radiotherapy may be effective to some extent. However, these previous studies involved a small number of patients; thus, there is little evidence that this treatment is more effective than preoperative chemotherapy or chemoradiotherapy. It should be used only in limited circumstances, such as severe organ dysfunction, where chemotherapy cannot be administered. In cases where radiation therapy is considered, the risk of additional postoperative radiation therapy should also be considered. Further research and well-designed studies are necessary to address these challenges and determine the optimal radiation therapy for the management of locally advanced thymic tumors.

Induction chemoradiotherapy

Preoperative chemoradiotherapy has emerged as a treatment strategy for TETs to increase the chances of complete tumor removal and improve response rates compared with chemotherapy alone. However, prospective randomized trials that directly compare chemotherapy with chemoradiotherapy in TET patients are rare, leading to inconclusive data (Table 4) (35-37). Concurrent chemoradiotherapy with 40–50 Gy radiation is often considered the optimal induction therapy for patients with TC (38). Several studies have reported encouraging results in investigating neoadjuvant chemoradiotherapy for locally advanced TETs. Korst et al. reported a phase 2 trial involving patients with thymoma or TC who underwent induction therapy with a combination of two cycles of cisplatin and etoposide combined with 45 Gy of thoracic radiotherapy. After induction therapy, computed tomography (CT) and positron emission tomography (PET) were performed, followed by attempted resection. The primary goal was to assess the pathologic response to induction therapy, while secondary endpoints included toxicity, surgical complications, radiographic response, and the rate of complete resection. Of the 22 patients enrolled, 21 completed induction therapy, and nine experienced severe toxicity. A partial radiographic response was observed in ten patients, while stable disease was detected in 11 patients. Approximately 77% of the patients underwent complete resection, 36% experienced surgical complications, and two died after the procedure. Although no patient achieved a pathological complete response, 24% of the specimens had <10% viable tumors (35). Chu et al. reported 114 TET patients who received chemotherapy or chemoradiotherapy as initial treatment and pre- and post-treatment scans at a tertiary academic cancer center between 2007 and July 2018. Of the 114 patients, 12 patients were in the chemotherapy group (ten with thymoma, one with TC, and one with an unclassifiable thymic tumor), and 12 were in the radiation therapy group (5 with thymoma, three with TC, and four with unclassifiable thymic tumors). All patients in both groups were in stage III–IV. After a median imaging follow-up of 15 months, chemoradiation led to a greater radiological response than chemotherapy alone (volume: −47.0 cm³ more, P<0.001; diameter: −0.8 cm more, P=0.03). Eight patients who received chemotherapy also experienced significant tumor shrinkage with additional radiation or chemoradiation. The median survival time was significantly longer for patients who ultimately underwent surgery than for patients who did not (46 vs. 14 months) (36).

Wright et al. reported the therapeutic effect of concurrent induction chemoradiotherapy in ten patients with initially unresectable locally advanced thymic tumors (including 9 with thymomas and 1 with TC). The therapeutic protocol consisted of two cycles of EP chemotherapy with concurrent radiotherapy (33–49 Gy) before surgery. Adjuvant EP chemotherapy was administered for patients with incomplete resection and a high risk of recurrence. After completion of induction chemoradiotherapy, 4 (40%) patients achieved a partial response, while the remaining 6 (60%) patients presented no changes. All ten patients were directed toward surgery, and R0 resection was achieved in 8 (80%) patients. The examination of resected specimens revealed substantial (>90%) tumor necrosis in four (40%) patients. No postoperative deaths were observed, and the estimated 5-year survival was 69% (37).

Based on these reports, chemoradiotherapy as induction treatment for unresectable locally advanced TETs may be as effective as preoperative chemotherapy. However, there are only a few reports on the vagueness of the definition of “unresectable” and the regimen to be used. The indication for additional radiation should be carefully considered in terms of the stage and histology of the target tumor, as additional radiation may increase toxicity.

Yamada et al. analyzed the extracted data of a total of 310 stage III thymoma patients from the Japanese National Database. Among the thymoma tumors in these cases, 194 (62.6%) involved the lungs, 151 (48.7%) involved the pericardium, 1,236 (40.6%) involved the great vessels, and 247 (79.7%) were completely resected. The complete resection rate was significantly lower in patients with invasion of the great vessels than in the other patients (73.8% vs. 83.7%, respectively; P=0.011) (39). Hassan et al. explored the function of induction chemotherapy in nine patients with locally advanced thymoma who underwent three cycles of EP before surgery (16). In three patients (37.5%) with confirmed invasion of the great vessels, including the ascending aorta, main pulmonary artery, superior vena cava, and heart, via anterior mediastinotomy and radiology, there was incomplete resection after induction chemotherapy; extended full-thickness tumor invasion of the vessels remained during surgery, causing incomplete resection. Therefore, in TET patients with great vessel invasion, chemotherapy alone may be insufficient, while chemoradiotherapy may enhance antitumor activity and the possibility of total resection.

In summary, the use of chemoradiotherapy as a preoperative induction treatment for TETs may improve the likelihood of complete tumor removal and enhance response rates. However, further research, including prospective randomized trials, is necessary to determine the optimal treatment approach for different histological subtypes and to assess the long-term outcomes of induction chemoradiotherapy in TET patients.

Induction immunotherapy

Immunotherapy, specifically programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune therapy, has emerged as a revolutionary approach for the treatment of TETs. PD-L1 expression is commonly used as a predictor of PD-1/PD-L1 immune therapy efficacy, and high PD-L1 expression is associated with aggressive histological type, advanced disease stage, and worse prognosis (40-45). Padda et al. examined PD-L1 expression in tissue microarrays (TMAs) of TETs. TMAs were generated from 69 TETs and 17 thymic controls, and the PD-L1 scores of the epithelial cells were evaluated. A high PDL1 score was more frequent in patients with TETs than in controls (68.1% vs. 17.6%; P=0.0036). Histology and PD-L1 expression were significantly correlated, with higher intensity staining according to the WHO classification B2/B3/C TETs. According to an adjusted analysis (for age and sex), patients with PD-L1-high TETs had a markedly worse OS than patients with PD-L1-low TETs [hazard ratio: 5.40, 95% confidence interval (CI): 1.13–25.89; P=0.035] and had a trend toward worse event-free survival (hazard ratio: 2.94, 95% CI: 0.94–9.24; P=0.064) (46). Tumor-infiltrating lymphocytes, which are crucial for immune system activation, are abundantly present in patients with TETs (47). These factors support the potential efficacy of PD-1/PD-L1 therapy for TETs.

Several trials have explored the efficacy and safety of immunotherapy for advanced or recurrent thymomas. For example, a phase II study by Cho et al. evaluated the role of pembrolizumab in 26 patients with TC and seven patients with refractory thymoma and reported partial responses in two thymoma patients and 5 TC patients (48). In addition to efficacy, toxicity is also an important consideration for treatment. Five of seven (71.4%) patients with thymoma and four of 26 (15.4%) patients with TC reported grade 3 immune-related adverse events (irAEs), including myocarditis, hepatitis, myasthenia gravis, colitis, thyroiditis, and glomerulonephritis. Moreover, in another study, the administration of anti-PD-1 therapy resulted in a storm of irAEs (including myasthenia gravis, myositis, myocarditis, and death) after the administration of the first treatment cycle (49). Patients with TC and type B3 thymoma, characterized by mature T lymphocyte infiltration, have lower risks of irAEs during immune checkpoint inhibitor therapy. These entities should be preferred when considering the use of these agents. Pembrolizumab has been included as a possible therapeutic option for refractory TC in the National Comprehensive Cancer Network (NCCN) guidelines. However, caution is warranted when using immune checkpoint inhibitors in thymomas due to the increased risk of irAEs. Clinical trials are warranted to determine the exact role of induction immunotherapy in patients with TETs. A notable ongoing Korean phase II study (NCT03858582) is evaluating the efficacy and safety of neoadjuvant therapy with pembrolizumab plus chemotherapy (docetaxel and cisplatin) for three cycles every 3 weeks. Patients who undergo R0 resection are receiving pembrolizumab, while those who undergo R1 or R2 resection are receiving radiation therapy and pembrolizumab.

Immunotherapy studies for TETs are presented in Table 5. Clinical trials should be conducted to assess the exact effect of induction immunotherapy in patients with TETs. Currently, studies on the efficacy and safety of immunotherapy as a preoperative option are limited. Toxicity must be avoided during preoperative treatment, as it could hinder or delay surgery. Prospective clinical trials, including safety studies, are necessary to provide more comprehensive data on the potential benefits and risks of induction immunotherapy in patients with TETs.

Induction-targeted therapy

The advances in the research of the molecular biology of TETs have increased the number of targeted therapies in clinical trials (52). However, in the neoadjuvant setting for TETs, the use of targeted treatment is supported by limited evidence. One ongoing clinical trial is investigating the effects of combining cetuximab with traditional platinum and anthracycline-based chemotherapy as neoadjuvant therapy for locally advanced thymoma (Clinical Trials.gov NCT01025089). This phase II study was designed to evaluate the combination of cetuximab and the PAC regimen as neoadjuvant chemotherapy for locally advanced thymoma. Initially, patients receive cetuximab weekly for up to 4 weeks to evaluate the tumor response to cetuximab alone. Subsequently, the continue to receive weekly cetuximab along with concurrent PAC for four cycles before surgery. The primary endpoint of the trial is the frequency of complete pathological response, with secondary endpoints including toxicity, treatment response, and R0 resection.

The activation of the PI3K/AKT pathway in TETs (53) led to the investigation of the mammalian target of rapamycin (mTOR) inhibitor everolimus in a phase II trial, which demonstrated a median progression-free survival (PFS) of 10.1 months and OS of 25.7 months in advanced, treatment-refractory thymoma and TC (54). Although epidermal growth factor receptors are often overexpressed in TETs, activating mutations are rarely observed (55). A phase II study using gefitinib showed poor response rates in patients with chemorefractory TETs (56). KIT overexpression has been reported in TCs; however, under 10% of tumors harbor a KIT mutation, and no response has been reported with the use of imatinib to date (57). Thymic tumors exhibit insulin-like growth factor receptor overexpression (58). A phase II study of cixutumumab enrolled 49 patients (37 with thymomas and 12 with TCs) with recurrent or refractory disease, five with thymoma and a partial tumor response, 28 with stable disease, and four with progressive disease. Among the 12 TC patients who received treatment, none responded, five had stable disease, and seven had progressive disease (59).

Vascular endothelial growth factor (VEGF) and VEGF receptors have been identified as possible targets in high-risk thymomas and TCs (60), suggesting the potential use of antiangiogenic agents such as sunitinib. An open-label phase II study of sunitinib in patients with chemorefractory TETs demonstrated a partial response in 6 patients and stable disease in 15 patients among 23 TC patients. Among the 16 thymoma patients, 1 had a partial response, while 12 had stable disease (61). A retrospective review of 28 patients (20 with TCs and eight with thymomas) of sunitinib in the off-label cohort study showed a response rate of 22% and a disease control rate (DCR) of 63%, with a median PFS of 3.7 months and a median OS of 14.5 months (62). A phase II trial of lenvatinib, an oral multitargeted kinase inhibitor for VEGFR, FGFR, and c-Kit, enrolled 42 patients with advanced TC who had progressed after at least one platinum-based chemotherapy (63). The ORR was 38%, the DCR was 95%, and the median PFS was 9.3 months. Of the 42 patients, 30 (71%) had squamous cell carcinoma, and 14 out of these 30 (47%) had a partial response. Two ongoing clinical trials of lenvatinib were identified.

An open-label, single-arm phase II study will evaluate the efficacy and safety of the combination treatment of pembrolizumab and lenvatinib in pretreated type B3 thymoma or TC patients who have progressed after at least one course of platinum-based chemotherapy for advanced disease without any previous immunotherapy (previous bevacizumab allowed but not sunitinib) and who are not suitable for curative-intent radical surgery and/or radiotherapy regardless of PD-L1 status (Clinical Trials.gov NCT04710628). Another phase II, investigator-initiated, nonrandomized, open-label, single-arm, multicenter study will evaluate the efficacy and safety of carboplatin, paclitaxel, lenvatinib, and pembrolizumab in combination for previously untreated advanced or recurrent TCs that are judged to be incapable of radical resection (Clinical Trials.gov NCT05832827).

A list of the major molecularly targeted agents reported for TETs is shown in Table 6. Targeted therapy may be an option for heavily pretreated patients in clinical practice, and some agents have shown promising effects with tolerable side effects. However, no previous study has shown more pronounced responses compared to chemotherapy or chemoradiotherapy. However, further studies are needed to investigate the benefits of incorporating targeted therapy into preoperative chemotherapy for TETs.

Discussion

The management of locally advanced TETs remains challenging. Complete resection is crucial for improving the prognosis of these tumors, but achieving R0 resection can be difficult due to the invasion of surrounding structures and distant metastasis. In such cases, induction therapy plays an important role in downstaging the tumor and making it amenable to surgical resection. Currently, chemotherapy is the most widely used induction therapy for locally advanced thymomas, with platinum and anthracycline-based regimens being the standard approach; for TCs, chemotherapy with either platinum and anthracycline-based regimens or carboplatin and paclitaxel is favored. Furthermore, the emergence of immunotherapy and targeted therapies may provide additional options for the treatment of TETs.

Due to concerns about potential damage to surrounding tissues, radiation therapy as the sole induction treatment for locally advanced TETs is less common. However, combining modern radiation techniques with surgery has shown promising outcomes in some cases.

Preoperative chemoradiotherapy may be an emerging approach that is intended to improve the chances of complete tumor removal compared with chemotherapy in more advanced special situations, such as severe vessel invasion.

Neoadjuvant chemotherapy or chemoradiotherapy has shown promising results in terms of response rates and complete resection rates, although there are no prospective randomized trials comparing chemotherapy with chemoradiotherapy.

There is still insufficient evidence for the use of preoperative immunotherapy and preoperative targeted therapy. Close attention should be given to the emergence of irAEs during immunotherapy.

Since TETs are rare tumors, in most studies, there is clear selection bias with a shrinking denominator. Moreover, the level of evidence is limited in most publications. A multidisciplinary approach involving thoracic surgeons, medical oncologists, radiation oncologists, radiologists, immunologists, neurologists and pathologists is crucial for the comprehensive management of patients with TETs. Treatment decisions should be individualized based on factors such as histology, stage, and the feasibility of radical surgery. Close collaboration among medical teams and informed discussions with patients are essential for determining the most appropriate treatment plan.

Conclusions

In conclusion, the use of induction treatment for locally advanced TETs is evolving, highlighted by ongoing advancements in chemical regimens, radiotherapy technologies, immunotherapy, and targeted therapies. However, further research and well-designed studies are needed to address the remaining challenges and optimize the management of these rare tumors, ultimately improving patient outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Masatsugu Hamaji) for the series “Locally Advanced Thymic Epithelial Tumors” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-23-30/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-30/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-30/coif). The series “Locally Advanced Thymic Epithelial Tumors” was commissioned by the editorial office without any funding or sponsorship. Y.S. reports payment or honoraria from Chugai Pharmaceutical Co. Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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