Surgical outcomes of patients with locally advanced thymic epithelial tumor undergoing induction therapy followed by surgery: a narrative review

Introduction

Thymic epithelial tumors (TETs), including thymomas and thymic carcinomas, are relatively rare, with an annual incidence of approximately 3.2 cases per million (1). Although complete surgical resection remains the gold standard treatment for TETs, achieving this is generally easier in the early stages. Based on the Masaoka (-Koga) staging system, invasion into neighboring structures or the presence of diffuse pleural or pericardial disseminations can hinder radical resection in stage III or IV locally advanced TETs. Patients with locally advanced TETs have poorer outcomes than those with early stages, highlighting the clinical need for multimodal approaches (2-5). For patients with marginally resectable TETs, the neoadjuvant approach can decrease the tumor burden to allow for successful resection. In advanced cases deemed inoperable during preoperative evaluations, the preference leans toward induction therapy, as it may increase the resection rate and decreases the incidence of systemic relapse. However, published data of the managing of locally advanced TETs is lacking, indicating that no standardized management guidelines exist. Given the paucity of robust evidence and the small sample sizes in published studies, we aimed to conduct a narrative review to thoroughly characterize the long-term survival outcomes of patients who underwent induction therapy followed by surgical resection 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-23-57/rc).

Methods

The search strategy is summarized in Table 1. Briefly, we searched PubMed without date restrictions up to January 31, 2024. We only considered manuscripts written in English. The search strategy included the terms “surgery”, “survival”, “thymoma”, “thymic cancer”, and “induction therapy”. This strategy allowed for a selection of representative studies emphasizing tumor characteristics, types of induction therapy, adjuvant therapy, surgical outcomes, recurrences, and overall survival (OS) for stage III to IV TETs. As there is no definitive definition for locally advanced TETs, most studies addressing this topic include stage III (macroscopic invasion into neighboring organ) and IVa (pleural and pericardial metastases) TETs, however, treatment strategies involving preoperatively determined induction therapy, followed by surgical resection, have been employed even for stage IVb diseases (lymphogenous or hematogenous metastasis). This prompted us to collect reports on stage III and IV diseases, with the inclusion of invasive thymomas and thymic carcinoma and the exclusion of thymic neuroendocrine tumors. The article types included retrospective studies, prospective studies, and review articles. Articles without full texts or those with incomplete or irrelevant data were excluded.

Literature review method

We identified 37 studies that met our inclusion criteria. Table 2 enumerates the studies related to thymoma, Table 3 details studies concerning thymic cancer, and Table 4 compiles studies addressing both thymoma and thymic cancers. We also referred to a meta-analysis on induction therapy for locally advanced TETs written by Hamaji et al. and a systematic review on overall treatment for TETs published by Falkson et al. (2,4). To date, no randomized trials have addressed the management of locally advanced TETs.

Patient and disease characteristics

The mean age at TET diagnosis is typically 50–60 years; however, these tumors can be diagnosed in both children and older individuals. A consistent sex bias for thymomas is generally not seen, although a mild female predominance is observed for type A, AB, and B1 subtypes, whereas carcinomas tend to show male predominance (5,43-46). In the 11 retrospective and two prospective studies addressing locally advanced thymoma, patient numbers varied between 7 and 370, as detailed in Table 2. For thymic cancer, the seven retrospective studies included patient counts ranging from 7 to 31, as shown in Table 3. A total of 14 retrospective and 3 prospective studies encompassing both invasive thymoma and thymic cancer reported patient numbers ranging from 6 to 301, as detailed in Table 4. Among the 37 studies, all but two reported an average patient age within the 40s and 50s. Specifically, the age range was 43.5–58 years for thymoma (Table 2), 47.3–60.8 years for thymic cancer (Table 3), and 41.8–65.2 years for studies including both thymoma and thymic cancer (Table 4). In the studies focusing on patients with thymoma, four studies targeted stage III disease, four studies examined stage IV disease, and the remaining studies included both stage III and IV diseases (Table 2). For thymic cancers, all studies encompassed stage III and IV diseases (Table 3). Specifically, three studies concentrated on stage III disease, one study was exclusive to stage IV disease, and the remaining studies investigated both stage III and IV diseases (Table 4). Stage IV diseases could not be classified based on disease status, such as local invasion or dissemination, due to a lack of information in some studies. However, many studies involved cases of stage IV diseases that were initially considered unresectable. Despite these initial assessments, the primary therapeutic goal remained to achieve complete surgical resection, aiming for long-term survival.

Two prospective phase II studies specifically targeted locally advanced thymoma (Table 2). Kunitoh et al. demonstrated that a weekly dose-dense chemotherapy regimen with cisplatin, vincristine, doxorubicin, and etoposide, followed by surgical resection, was safely administered to 21 patients with stage III thymomas (9). This approach resulted in an 82% complete surgical resection rate (9). Conversely, Kim et al. found that induction chemotherapy using cyclophosphamide, doxorubicin, cisplatin, and prednisone, followed by surgical resection, achieved response rates of 80% and complete resection rates of 76% among 22 patients with stage III or IV thymomas (17). Shintani et al. reported the outcomes of a multimodal treatment approach for stage III and IV thymic carcinomas (19). Their study included 13 squamous cell carcinomas, two neuroendocrine carcinomas, and one undifferentiated carcinoma, and all patients underwent neoadjuvant chemotherapy. This study found that incomplete surgical resection and pathological vessel invasion were significant unfavorable factors for OS (19). In contrast, Kawasaki et al. administered weekly chemotherapy using a combination of cisplatin, vincristine, doxorubicin, and etoposide (CODE), followed by surgery, in seven cases of thymic cancers (20). These included six squamous cell carcinomas and one adenosquamous cell carcinoma. Notably, 4 of the 7 patients achieved an extended OS, surpassing 100 months after surgical resection (20).

The median percentages for each histologic subtype, based on the World Health Organization classification, were as follows: type A, 5% (range, 2–15%); type AB, 11% (2–18%); type B1, 15% (1–30%); type B2, 28% (2–88%); type B3, 22% (5–50%); type B1+2, 9% (6–11%); type B1+3, 9% (6–11%); type B2+3, 11%; and type C, 25% (12–67%). The predominant histologic subtype was type B, and approximately 15% of cases exhibited a type A element. Studies have indicated that approximately 30% of patients with thymoma have myasthenia gravis (MG), and approximately 20% of patients with MG are diagnosed with thymoma (5). In this review, 13 retrospective studies referred to the presence of MG preoperatively, with a median prevalence of 22% (range, 0–46%).

Induction therapy

One of the standard treatment approaches for locally advanced TETs preoperative induction therapy followed by radical resection. Induction therapy is thought to diminish tumor size and surgical complexity, facilitating more comprehensive surgical resections, reducing local recurrence rates, and improving long-term survival in a subset of patients with locally advanced TETs. However, the efficacy of induction therapies, such as chemotherapy, radiotherapy (RT), and chemo-radiotherapy (CRT) remains uncertain. Falkson et al. found no significant difference in OS among patient with thymoma who received neoadjuvant therapy compared to those who did not (hazard ratio =1.53, 95% confidence interval: 0.77–3.33, P=0.29) (2). Very few studies have been conducted on induction therapy for thymic carcinomas and none have demonstrated significant differences in survival between patients who received neoadjuvant therapy and those who did not. Questions persist regarding the combination of modalities that is most effective and whether postoperative therapy is necessary for patients who have undergone induction treatment.

Table 5 presents the types, detailed regimens, and response rates of induction therapy followed by surgical resection for patients with invasive thymoma. Of the 13 studies analyzed, 9 (69%) used chemotherapy as an induction option; 2 (15%) employed either chemotherapy, RT, or CRT, 1 (8%) opted for chemotherapy or CRT, and 1 (8%) used chemotherapy or RT. The 13 studies featured a total of 9 types of chemotherapeutic regimens: CAP (cyclophosphamide + doxorubicin + cisplatin), CAMP (cisplatin + doxorubicin + methylprednisolone), ADOC (cyclophosphamide + doxorubicin + cisplatin + vincristine), PE (cisplatin + etoposide), CP (cisplatin + docetaxel), CAV, cyclophosphamide + doxorubicin + vincristine, VIP (cisplatin + vincristine + ifosfamide), CODE (doxorubicin + cisplatin + vincristine + etoposide), and CAP + prednisolone. Generally, chemotherapeutic regimens that include adriamycin and/or platinum-based multi-agent combinations are recommended unless patients are ineligible for anthracycline. In terms of therapeutic response, induction chemotherapy had a complete response (CR) of 0–14%, a partial response (PR) of 4–86%, and an overall response rate of 4–93%. Falkson et al. reported that anemia (39%) and leukopenia (30%) were the predominant chemotherapeutic side effects in patients with stage III or IV thymomas who received induction chemotherapy prior to surgery (2).

For the studies focusing on thymic cancer, the types, regimens, and response rates of induction therapy are shown in Table 6. Of the four studies, all used chemotherapy as induction treatment. The observed response rates only in two studies were CR of 0% and PR of 71% and 75%, respectively. Regimens used for thymic cancer included CP, TP (paclitaxel + carboplatin), CODE, PE, and ADOC. Furthermore, adverse events exceeding grade 3 included neutropenia (10–61%), leukopenia (7–57%), diarrhea (11%), alopecia (4%), and anemia (8%).

Among the 16 studies involving both thymoma and thymic cancer, chemotherapy was the induction treatment in 11 studies (69%), while CRT was utilized in three studies (19%), shown in Table 7. One study (6%) allowed a choice between chemotherapy, RT, or CRT, and another study provided an option between chemotherapy or CRT. Regimens used in the studies included CAP, CP, TP, ADOC, CAP, PE, octreotide + prednisolone, and CEE (cisplatin + epirubicin + etoposide). Guan et al. compared concurrent and sequential CRT for the induction treatment of stage III or IV TETs (30). Their findings indicated no statistically significant differences in the response rate, radical surgical resection rate, or survival between the two treatments; however, sequential CRT was associated with a lower likelihood of adverse events. Across the studies, the observed adverse events from induction chemotherapy included neutropenia (27–71%) and vomiting (5–72%), with variations based on the specific regimens. In a phase II study conducted by Korst et al., induction CRT (PE and concurrent 45 Gy radiation) was administered to patients with stage III or IV TETs and 21 of 22 patients successfully completed the induction regimen (37).

Surgery and complication

Complete surgical resection is a critical determinant of survival for patients with TETs, regardless of the disease stage or histological type. Even for those presenting with locally advanced, initially deemed unresectable TETs, achieving complete surgical resection is the foremost therapeutic objective to secure long-term survival. Surgical outcomes, such as the extent of resection and the rate of complete surgical resection for studies specifically addressing thymoma, are detailed in Table 5. Among the five studies, after excluding those lacking detailed information on concomitantly resected organs, the lungs, blood vessels (specifically the innominate vein, superior vena cava, and aorta), and pericardium were the organs most frequently resected alongside the thymus, with each being involved in four studies. Other structures commonly resected included the diaphragm in three studies, phrenic nerve in two studies, and chest wall in two studies. The median rate of complete surgical resection was 76% (range, 22–100%). The phrenic nerve is an organ commonly invaded by locally advanced TETs. However, Aprile has reported techniques for sparing the phrenic nerve in the context of locally advanced TETs. These techniques can be applied even in cases undergoing induction therapy, particularly for patients with severe comorbidities or poor performance status (47).

Table 6 details the surgical outcomes, such as the extent of resection and the rate of complete surgical resection, for studies focused on thymic cancer. Among the three studies, after excluding one study that lacked detailed information on concomitantly resected organs, blood vessels were the most frequently resected organ, involved in all the remaining studies. The median rate of complete surgical resection was 79% (range, 69–86%).

Table 7 provides an overview of surgical outcomes, including the extent of resection and the rate of complete surgical resection, across studies that encompass both thymoma and thymic cancer. Among the eight studies, excluding those without detailed information on concomitantly resected organs, the lungs and blood vessels emerged as the most frequently resected organs, each being involved in all the analyzed studies. The pericardium was another structure commonly resected, being involved in seven of the studies. The median rate of complete surgical resection was 76% (range, 52–82%). Korst et al. detailed the extent of resection, indicating that the lungs, vessels, pericardium, and phrenic nerve were resected in addition to the thymus (37).

Postoperative complications were noted in 20 studies. Only three studies reported postoperative 30-day mortality rates (1.0–9.5%). The median rate of postoperative complications was 26% (range, 19–42%). These adverse events included pneumonitis, bleeding, cardiac failure, atrial fibrillation, sternal dehiscence, pulmonary embolism, pleural effusion, pulmonary infarction, and cardiac arrest. Mineo et al. highlighted that, within the same timeframe, postoperative morbidity rates following resection after neoadjuvant therapy were significantly elevated compared with surgery performed on thymomas without preceding neoadjuvant chemotherapy (8).

Adjuvant therapy

In their systematic review, Falkson et al. highlighted the relative benefits of postoperative radiation therapy (PORT) in patients with thymomas (2). PORT demonstrated favorable results for OS and disease-free survival compared with the absence of PORT. Furthermore, patients with thymic carcinomas exhibited prolonged survival after PORT compared with those who did not receive it. Although these findings do not conclusively establish the superiority of PORT for locally advanced TETs due to the low certainty of the data, the overall results are promising. In contrast, few studies have compared the outcomes of adjuvant chemotherapy and the absence of such therapy, and their review by Falkson et al. found no statistically significant differences in the OS between these two groups (2). However, for patients with thymic carcinomas, there was a slight trend toward improved OS with adjuvant chemotherapy, albeit with very low certainty.

Among the 12 studies focusing on thymoma, seven provided data on adjuvant therapy, with a median 71% of patients (range, 22–100%) receiving it. The adjuvant therapies utilized were diverse: two studies offered chemotherapy, RT, or CRT; two used chemotherapy or RT; one opted for CRT or chemotherapy; one exclusively used RT; and one study lacked detailed information. Yokoi et al. found that out of 14 patients who received induction chemotherapy (cisplatin, doxorubicin, and prednisolone), nine proceeded to surgical resection. Of these, only two achieved R0 resection, while the others had incomplete resections (15). PORT was administered to eight patients, including seven with incomplete resections. Notably, two of these patients with incomplete resections achieved long-term survival, lasting 72 and 180 months post-surgery (15).

Out of 17 studies addressing both thymoma and thymic cancer, nine offered data on adjuvant therapy, with a median of 66% of patients (range, 25–89%) undergoing treatment. The types of adjuvant therapy varied: two studies included chemotherapy, RT, or CRT; two employed chemotherapy or RT; two chose CRT or chemotherapy; and three studies did not specify the details. Filosso et al. noted that 62% of surgically treated patients received adjuvant therapy, which was linked to improved survival in multivariate analysis (35). However, the majority of the studies did not confirm adjuvant therapy’s prognostic value for locally advanced TETs, leaving its overall impact still under discussion.

OS and recurrence

The 5-year, 10-year, and median OS rates, calculated from the initiation of induction therapy or at the time of surgery, were analyzed across various studies. For thymoma, OS outcomes were reported in 12 out of 13 studies, as summarized in Table 5. The median 5-year OS was 85% (range, 78–95%), and the 10-year OS was 76.7% (range, 53–84.9%). In the case of thymic cancer, OS results were provided by only two studies, detailed in Table 6. Shintani et al. reported a 5-year OS of 71% following induction chemotherapy and surgery for thymic cancers, while Kawasaki et al. observed a median OS of 83 months (19,20). Among 16 studies addressing both thymomas and thymic cancers to evaluate OS, the median 5-year OS was 70% (range, 49.7–93%), and the 10-year OS was 51% (range, 19.9–76.2%).

Throughout the postoperative follow-up period in various studies, the median recurrence rate was observed to be 30%, with a range from 17.5% to 100%. It is important to note that follow-up durations varied among these studies. In a phase II study by Kunitoh et al., focusing on CODE therapy followed by surgery for stage III thymoma, a relapse rate of 61.9% was reported (9). The initial signs of recurrence in these patients were typically regrowth of the primary tumor or pleural or pericardial dissemination. Kawasaki et al. reported relapse sites in 3 out of 7 patients experiencing recurrence, identifying the pleura as the most common relapse site, followed by the liver and bones (20). Marulli et al. observed that among 203 patients who achieved R0 resection, 43 (21.2%) experienced recurrence, with a median time to relapse of 46 months (28). Intrathoracic relapse was seen in 13.3% of cases, while extrathoracic relapse occurred in 6.4%. Both intra- and extrathoracic relapses were noted in 1.5% of cases. Significantly, the recurrence rate was markedly higher in patients with histologic types B2-3 thymoma and thymic carcinoma compared to types A, AB, and B1 thymomas (28).

Strengths and limitations

The strengths of this narrative review lie in its approach of separately collating reports from retrospective and prospective studies. The prospective studies provided consistent sample sizes, induction treatment modalities, and regimens, enabling a detailed evaluation of therapeutic outcomes. These assessments shed light on the advantages and disadvantages of multimodal therapies for locally advanced TETs. However, enrolling patients proved challenging, resulting in smaller sizes than the retrospective studies. In contrast, the retrospective studies were much more abundant than the prospective ones, although they displayed higher variability in patient characteristics and induction treatments, such as RT, CRT, or chemotherapy. Nevertheless, upon consolidation of the data from both study types, factors such as curative resection rates, adverse events, postoperative complications, and prognosis were found to be comparable. This suggests that the strategy of induction treatment followed by surgical resection for locally advanced TETs with curative intent can be justified to a certain degree. This review emphasized the histological classification of thymoma and thymic cancer during data collection, given the relatively distinct biological nature of these two neoplasms. We analyzed studies that included both histological types and those that focused on one specific histology. Our findings suggested that multimodal strategies are feasible for both type of TETs from both prognostic and safety perspectives.

This narrative review faces multiple limitations. The inherent rarity of TETs leads to small sample sizes in the reviewed studies, which, along with the extensive time span these studies cover, contributes to the heterogeneity of their populations. Additionally, the positive outcomes observed post-surgery in patients with stage III–IV advanced diseases may be influenced by selection bias. Secondly, the absence of prospective randomized studies leaves the benefit of adding surgical resection for curative intent, as opposed to multimodal treatment without surgery, an open question. Conducting phase III studies is notably challenging given the infrequency of this condition. Finally, the inability to distinguish between stage IV tumors that are locally invaded and those with pleural nodules, due to the limited information available even after reviewing a large corpus of literature, remains a significant constraint. It is our hope that future reviews will differentiate these two statuses, thereby shedding light on the clinical significance of induction treatment for locally advanced TETs.

Conclusions

This narrative review underscored the potential for encouraging curative surgical rates and long-term OS in patients with locally advanced TETs who received induction therapy followed by surgical resection. These results, drawn from both retrospective and prospective studies, support the consideration of an induction regimen before surgical resection in selected patients with stage III and IV TETs. Henceforth, joint efforts are essential for obtaining more extensive data from prospective studies on this topic.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

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-23-57/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-57/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-57/coif). The series “Locally Advanced Thymic Epithelial Tumors” was commissioned by the editorial office without any funding or sponsorship. 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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