A real-world cohort study comparing chemotherapy and surgery in the treatment of stage IVA thymomas with pleural dissemination

Introduction

Thymic epithelial tumors (TETs), including thymomas (TMs) and thymic carcinomas (TCs), are rare but unique anterior mediastinal malignancies. Pleural dissemination is a common pattern of disease dissemination and treatment failure of TETs, especially in TMs (1), which is stage IVA (pleural-IVA) in both Masaoka-Koga (2) and the tumor-node-metastasis (TNM) staging system by International Association for the Study of Lung Cancer (3). Currently, platinum-based chemotherapy is recommended as the first-line treatment for both pleural-IVA and other stage IV TETs in the National Comprehensive Cancer Network (NCCN) (4) and the European Society for Medical Oncology (ESMO) guidelines (5), with upfront surgery (US) followed by adjuvant chemotherapy or radiation as an alternative in the NCCN guideline (4,5). However, TMs differ significantly from TCs in biological behavior and clinical manifestations. TCs are more aggressive, with a 60% distant metastasis rates, while TMs are relatively indolent with loco-regional recurrence accounting for 87% treatment failure (pleural dissemination being predominant) (6).

At this point, chemotherapy is still recommended as first-line treatment for pleural-IVA TMs, while none of the existing literature has ever studied specifically the efficacy of chemotherapy in this subset of patients. The actual response of pleural lesions to chemotherapy actually remains unknown. Moreover, it has never been verified whether chemotherapy is indeed a satisfactory approach in terms of disease control. And if not, whether there is a better way to improve the prognosis of patients with pleural-IVA TMs. We therefore retrospectively conducted a real-world study to evaluate the efficacy of first-line chemotherapy and to analyze the outcomes of different treatment modalities in patients with pleural-IVA TMs. We present this article in accordance with the STROBE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-73/rc).

Methods

Ethics

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shanghai Chest Hospital (approval No. IS24008). Informed consent was waived as this was a retrospective study using only de-identified information.

Patients eligibility

Clinical data of patients with pleural-IVA TETs treated during January 1, 2007 and December 31, 2018 were retrieved from a prospectively kept mediastinal database. Designed as a real-world study, all consecutive patients registered in this prospective database were included if they had: (I) histologically confirmed TMs; (II) pleural-IVA disease; (III) chemotherapy or surgery as first-line treatment; (IV) platinum-based regimens recommended by guidelines in chemotherapy cohort. Patients were excluded if they had: (I) unavailable imaging data; (II) TCs; (III) radiation as first-line treatment. Two types of IVA disease were categorized. Primary IVA was defined as presence of both mediastinal and pleural lesions upon first diagnosis, while recurrent IVA was defined as the occurrence of pleural dissemination during follow-up after surgical resection of primary mediastinal lesion. The World Health Organization (WHO) criteria was used to classify histological subtypes (7). Type A, AB and B1 were categorized as low-grade histological subtypes, and Type B2 and B3 as high-grade ones (8).

Study design

Complete imaging data before and after treatment was essential to evaluate the therapeutic effect. The primary endpoint was objective response rate (ORR) in pleural lesions to chemotherapy. The response in mediastinal and pleural lesions were thus assessed separately in the primary-IVA group. Treatment response evaluation for mediastinal and pleural lesions were evaluated according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (9) and the modified RECIST version 1.1 (10) respectively. Responses to chemotherapy were classified into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The secondary endpoints were long-term outcomes in terms of disease-control time (DCT), progression-free survival (PFS) and overall survival (OS). DCT was defined as the time from the start of treatment, either chemotherapy or surgery, to tumor progression or last follow-up. PFS was defined from the start of treatment to tumor progression, patient death or last follow-up. OS was defined from the start of treatment to patient death or last follow-up.

Statistical analysis

Categorical variables were analyzed by Chi-squared test or Fisher’s exact test when appropriate. Continuous variables were compared by the Student-t test or Wilcoxon rank sum test according to the distribution of the data. The McNemar test was used to evaluate if there was any difference in chemotherapy response between mediastinal lesions and pleural lesions. Propensity-score matching (PSM) was used to balance differences in factors which were potential selection biases in this study. Kaplan-Meier method was used to estimate OS and PFS curves. Log-rank test was used to evaluate differences in survivals between groups. Data processing and visualization was performed using ‘R’ statistical software (version 4.3.1). A two-sided P value of <0.05 was considered statistically significant. Since treatment modality has changed over time in this study, its impact on treatment outcomes during the earlier [2007–2015] and later [2016–2018] time periods was also compared. Posterior probability of achieving better results in different time periods would be reported with Bayesian analysis (11).

Results

Patients and treatment modality

Of the 329 patients with pleural-IVA TETs registered in our prospective database, a total of 168 eligible patients were enrolled (Figure S1). Primary IVA TM was seen in 86 (51.2%) patients, with recurrent IVA TM in 82 (48.8%) patients. Patient and tumor characteristics are listed in Table S1.

Altogether 124 patients (76.2%) received first-line chemotherapy. Paclitaxel (PTX)-containing regimens accounted for 63.7% (79/124), anthracycline-containing regimens accounted for 28.2% (35/124), etoposide (VP-16)-containing regimens accounted for 6.5% (8/124) and other regimens accounted for the rest 1.6% (2/124, gemcitabine + cisplatin in 1 case and irinotecan+carboplatin in the other). Among them, 66 (53.2%) received chemotherapy without surgery, including 35 with chemotherapy alone and 31 with radiation, and the other 58 (46.8%) received neoadjuvant chemotherapy followed by subsequent surgery. Altogether 367 cycles of chemotherapy were administered (median 2 cycles, ranging from 1 to 7 cycles per patient). Chemotherapy was safely delivered in general, with no patient died because of toxicity. All patients received at least 70% dosage of standard chemotherapy and 95% (118/124) completed at least 2 cycles of chemotherapy. Forty-four patients (26.2%) received US. Seventeen (38.6%) of them received surgery alone, 24 (54.5%) received adjuvant radiation and 3 (6.8%) received adjuvant chemotherapy. All the 102 patients who underwent surgery, either after neoadjuvant chemotherapy or upfront, achieved macroscopic R0 resection of the pleural disseminated lesions.

Tumor response to first-line chemotherapy

Of the 124 patients who received first-line chemotherapy, ORR in pleural lesions was merely 6.5%. Only 8 patients experienced PR (6.5%), with no CR observed. PD was seen in 9 patients (7.3%), with the rest had SD (86.2%, 107/124) (Figure 1). ORR in pleural lesions was slightly higher in the primary-IVA group than in the recurrent-IVA group but without significant difference (9.2% vs. 3.4%, P=0.28). ORR in mediastinal lesions in patients with primary-IVA TMs was 7.7% (5/65, Table 1). No difference was found in chemotherapy responses between mediastinal lesions (7.7%) or pleural lesions (9.2%) in the primary-IVA group (P>0.99).

Figure 1 Change of pleural lesion size from baseline in 124 patients with pleural-IVA TM after first-line chemotherapy. Eight of them (6.5%) had PR; 9 (7.3%) patients had PD and 107 (86.2%) patients had SD. PD, progression disease; PR, partial remission; SD, stable disease; TM, thymoma.

Upon adjusted analysis, no statistically significant difference in ORR was detected between patients with primary-IVA (9.2%) and recurrent-IVA TMs (3.4%, P=0.14), or between those who received 1–2 (9.1%) and more than 2 cycles of chemotherapy (8.6%, P=0.28) (Figure S2). No other predictor of response to chemotherapy was found, including sex, age, autoimmune disease or size of pleural lesion.

Long-term outcomes and subgroup analyses

With a median follow-up time of 46 [interquartile range (IQR): 3–141] months, most patients had PDs, with a 3-year PFS of only 37.6%. But long-term survival was still observed, with 5-year OS being 77.9% for the entire cohort.

According to whether they had surgery or not, patients were divided into a surgery group (102 cases), including surgery after neoadjuvant chemotherapy and US, and a no-surgery group (66 cases). After PSM, factors including sex, age, autoimmune disease, pleural lesion size, histological subtype and type of IVA were well-balanced in the two groups (Table S2). After a median follow-up time of 46 [7–129] months, significantly longer DCT and better survivals were seen in the surgery group than those in the no-surgery group {median DCT: 39.0 vs. 23.0 months, P<0.001; PFS, hazard ratio (HR): 0.457 [95% confidence interval (CI): 0.298–0.700], P<0.001, Figure 2A; OS, HR: 0.402 (95% CI: 0.178–0.906), P=0.03, Figure 2B}. Three-year PFS rate (54.4% vs. 17.2%, P<0.001) and 5-year OS rate (88.9% vs. 62.6%, P=0.02) were both significantly higher in the surgery group than in the no-surgery group.

Figure 2 Surgery was associated with significantly better PFS (A) and OS (B) compared to no-surgery in patients with stage IVA TMs after propensity score matching. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; TM, thymoma.

To study the efficacy of surgery or chemotherapy alone, long-term outcomes were also compared between patients who received surgery-alone (SA subgroup, 17 cases) or chemotherapy-alone (CA subgroup, 35 cases). More patients with autoimmune diseases (52.9% vs. 14.3%, P=0.006) and primary IVA disease (64.7% vs. 34.3%, P=0.04) were seen in the SA subgroup compared to those in the CA subgroup (Table S3). With a median follow-up time of 48 [7–135] months, significantly longer DCT and better survivals were seen in the SA subgroup than those in the CA subgroup [median DCT: 36.0 vs. 12.0 months, P=0.002; PFS, HR: 0.375 (95% CI: 0.191–0.738), P=0.004, Figure 3A; OS, HR: 0.224 (95% CI: 0.051–0.975), P=0.046, Figure 3B]. Three-year PFS rate (45.2% vs. 9.1%, P=0.003) and 5-year OS rate (86.3% vs. 51.8%, P=0.03) were both significantly higher in the SA subgroup than those in the CA subgroup.

Figure 3 Patients received SA had better PFS (A) and OS (B) than those received CA. Meanwhile, patients received US had a similar PFS (C) and a better OS (D) than those received neoadjuvant CS. CA, chemotherapy alone; CI, confidence interval; CS, chemotherapy; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; SA, surgery alone; US, upfront surgery.

To further investigate the role of neoadjuvant chemotherapy in pleura-IVA TMs, patients who received surgery were divide into an US (44 cases) subgroup and a neoadjuvant chemotherapy (CS, 58 cases) subgroup. After PSM, factors including sex, age, autoimmune disease, pleural lesion size, histological subtype and type of IVA were all balanced in the two groups (Table S4). After a median follow-up time of 50 [3–127] months, median DCT (40.0 vs. 27.0 months, P=0.20) and PFS [HR: 0.707 (95% CI: 0.409–1.221), P=0.21, Figure 3C] were similar in the two subgroups. But a significantly better OS [HR: 0.201 (95% CI: 0.042–0.952), P=0.04, Figure 3D] was seen in the US subgroup than that in the CS subgroup. Three-year PFS rate was 58.7% in the US subgroup, numerically better than that in the CS subgroup (41.4%, P=0.20). Five-year OS rate was significantly higher in the US subgroup than that in the CS subgroup (94.3% vs. 76.9%, P=0.03).

Treatment modality changed over time during the study period, with an increasing percentage of patients receiving surgery in later years (Figure 4). Patient and tumor characteristics were similar in the earlier and the later time periods, while the only difference was the percentage of patients receiving surgery (44.4% in the earlier period vs. 72.9% in the later period, P<0.001, Table S5). Compared to those in the earlier period, patients treated in the later period had a numerically better PFS [HR: 0.746 (95% CI: 0.533–1.065), P=0.11; 3-year PFS: 46.1% vs. 26.9%, P=0.10, Figure 5A] and a significantly better OS [HR: 0.263 (95% CI: 0.098–0.705), P=0.008; 5-year OS: 92.4% vs. 69.4%, P=0.002, Figure 5B]. The posterior probability of the hazard ratio of PFS <1 (the later versus the earlier period) was 0.9423, indicating a probability of 94.23% that treatment in the later period was associated with better PFS than that in the earlier period (Figure 5C).

Figure 4 Changes of treatment modality in the real-world for patients with stage IVA TMs during the study. Surgery showed a growing percentage compared to chemotherapy without surgery over time. The percentage of patients received surgery has been over 60% since 2016. TM, thymoma.

Figure 5 Patients treated between 2016 and 2018 had a numerically better PFS (A) and a significantly better OS (B) compared to those between 2007 and 2015. The posterior probability of the hazard ratio of PFS <1 was 0.9423 (C). CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Discussion

In this real-world study focusing on patients with stage IVA TMs with pleural dissemination, chemotherapy could be safely administered. But the response of pleural lesions to chemotherapy as the first-line treatment was poor in general, with an ORR of merely 6.5%, even lower than the PD rate (7.3%). Efficacy of chemotherapy was very limited, either as a definitive treatment or for neoadjuvant purpose. Instead, surgery appeared to be more helpful in improving patient prognosis comparing to chemotherapy.

Currently, chemotherapy is recommended either as the first-line treatment or as an adjuvant therapy after surgery for pleural-IVA TETs in the NCCN and the ESMO guidelines (4,5). As a rare tumor with relatively indolent nature, clinical trials on TETs are scarce and the chemotherapy efficacy in pleural lesions has yet to be assessed in large patient populations. Our study focused on the treatment outcomes for pleural dissemination in the largest patient cohort with pleural-IVA TM to date. According to our results, pleural implantation from TM had very low sensitivity to chemotherapy. The ORR of pleural lesions was merely 6.5%, with an even higher PD rate of 7.3%. The hypovascular nature of pleural lesions may be responsible for their poor response to chemotherapy. However in our study, ORR (7.7%) in mediastinal lesions in TMs was also much lower than previously reported, ranging from 25% to 91.8% (12,13). Most of these reports with higher ORR rates recruited white populations, while a phase II trial involving Asian patients with invasive thymic tumors reported an ORR of only 16.7% in 18 TMs (14). This indicated that ethnic difference might be one of the reasons for the low ORR in our patients with TMs. Although another phase II trial on chemotherapy for invasive TMs by Kim et al. (15) reported a high ORR of 77% (17/22), patients in that trial received high-dose prednisone (100 mg/d for day 1–5) for 3 cycles in addition to chemotherapy, and 68% of them had lymphocytic (45%) or mixed (23%) types of TMs. Drastic responses have been seen in both primary tumor and pleural dissemination to corticosteroids in several case studies (16-19). It is possible that some of the treatment response in Kim’s study might be attributed to corticosteroids rather than to chemotherapy per se. Further study is needed to clarify the mechanism and the efficacy of corticosteroids for advanced TMs.

US is an alternative to first-line chemotherapy for pleural-IVA TETs in the NCCN guideline (4). Moser et al. (20) reported surgical results in a pleural-IVA group with 5-year OS being 87.2% and 3-year freedom from recurrence rate being 57.9%. Choe et al. (21) also reported a surgical cohort with pleural-IVA disease. The median DCT was 2.2 years and 5-year OS was 73%. Both studies concluded that surgery might be an acceptable treatment for pleural-IVA TETs. However, these two studies mainly focused on surgical treatment, without any comparison to chemotherapy. In the current study, patients who received surgery had significantly better DCT (median 39.0 vs. 23.0 months, P<0.001), PFS (HR: 0.457, P<0.001) and OS (HR: 0.402, P=0.03) than those receiving chemotherapy without surgery. Also when comparing subgroups of patients who received surgery alone or chemotherapy alone, surgery was associated with significantly better prognosis than chemotherapy (PFS, HR: 0.375, P=0.004; OS, HR: 0.224, P=0.046). In addition, we also compared outcomes after shift of treatment modality in the real world. With baseline characteristics well-balanced between the two time periods, more patients received surgery in the later than in the earlier period (72.9% vs. 44.4%). PFS in the later period was numerically better than that in the earlier period (HR: 0.746, P=0.11), with a significantly better OS in the later period (HR: 0.263, P=0.008). Bayesian analysis revealed that the probability of better PFS in the later period than in the earlier was as high as 94.23%. These results indicated that compared to chemotherapy without surgery, surgery played a more important role in improving long-term outcomes in patients with pleural-IVA TMs.

Neoadjuvant chemotherapy with subsequent surgery is also mentioned in NCCN guideline. However, Park et al. (22) found that neoadjuvant chemotherapy did not help improving prognosis of patients with stage IV TETs. Unfortunately specific outcomes in patients with pleural-IVA diseases were not reported and the pleural response to chemotherapy was not mentioned either. In our study, in patients who received surgery, DCT (40.0 vs. 27.0 months, P=0.20), PFS (HR: 0.707, P=0.21) were not different between US subgroup and surgery after neoadjuvant chemotherapy subgroup, and even a better OS (HR: 0.201, P=0.04) was seen in US subgroup compared to neoadjuvant chemotherapy subgroup. In addition to the low response to chemotherapy in pleural lesions, one potential reason for the worse OS in the neoadjuvant subgroup might be long-term toxicity of chemotherapy. Our results clearly indicated that for patients with pleural-IVA TMs, chemotherapy had limited efficacy either in disease control or in improving survival.

Despite the safety of chemotherapy, the ORR in pleural lesions to chemotherapy was unsatisfactory in our study. Although 5-year OS appeared acceptable, this might be attributed to the prolonged survival even after disease progression in our patients, due to the relative indolent nature of TM. DCT and PFS are considered more useful references than OS for indolent tumors like TMs (1). But both need further improvement with median DCT being 26.0 months and 3-year PFS being 37.6% in the current cohort. The results were even worse in the chemotherapy alone subgroup, being only 12 months and 9.1% respectively. Innovative therapies are thus in need to improve treatment outcomes. The recent decade has seen the attempts of using target therapy (23,24) and immunotherapy (25,26) in management of advanced TETs. However, a very high rate of immune-related adverse events (≥ grade 3, 71.4%) has been reported in TMs, which limited the use of immunotherapy. Besides, none of these studies described the details of the enrollment and response of pleural-IVA TMs. Therefore, novel systemic treatments for TMs need to be explored. Hyperthermic intrathoracic chemotherapy (HITHOC) in combination with surgery has been retrospectively reported to improve prognosis than surgery alone (local disease-free intervals, HR: 0.33, P=0.02) (27), while small-sample studies suggested that entire hemithoracic radiation (EHRT) combined with surgery might yield favorable efficacy in patients with pleural IVA TETs (28,29). Given the indolent nature of TM and localization of stage IVA disease, it would be interesting to examine the combination of surgery with HITHOC and EHRT as a fortified local therapy in this patient population.

There were unavoidable limitations due to the retrospective nature of this study. There was significant heterogeneity in chemotherapy regimens or courses. But only patients receiving recommended chemotherapy regimens according to guidelines were included and our results showed that the number of courses did not affect ORR. Besides, due to the limited cases of patients who received adjuvant chemotherapy after surgery, we were unable to analyze the role of adjuvant chemotherapy. Additionally, the role of radiation was not assessed since we focused on chemotherapy and surgery in this study. However, our study was a real-world study including all consecutive patients who had chemotherapy upfront with recommended regimens, which would help diminishing potential confounding biases to the greatest extent when evaluating the efficacy of chemotherapy. Also PSM was repeatedly used to minimize potential selection bias between different groups. And it is the first and the only study to date focusing on chemotherapy efficacy in pleural dissemination from TM. Our results would serve as an important and useful reference for future studies and treatment on pleural-IVA TMs.

Conclusions

Chemotherapy as the first-line treatment is far from satisfactory for stage IVA TMs with pleural dissemination and may not be appropriate as a routine recommendation. Surgery plays a more important role as an alternative option. Given the low rate of response and disease control by chemotherapy, more effective novel treatment needs to be explored so as to further improve management outcomes in this subset of patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-73/rc

Data Sharing Statement: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-73/dss

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-73/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-73/coif). W.F. serves as an Editor-in-Chief of Mediastinum from March 2017 to March 2027. The other authors have no 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shanghai Chest Hospital (IS24008) at Jan 18^th, 2024. And individual consent for this retrospective analysis was waived.

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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