Role of radiation alone vs. concurrent chemoradiotherapy in surgically ineligible patients with tracheobronchial squamous cell carcinoma

Introduction

Primary tracheobronchial cancer is extremely rare, accounting for only 0.1–0.4% of all malignancies (1). Most patients were diagnosed with adenoid cystic carcinoma or squamous cell carcinoma (SCC). Adenoid cystic carcinoma exhibits slow progression, while SCC displays a fast-growing nature, resulting in a significantly poor 5-year overall survival (OS) rate, ranging from 7% to 39% (2-4).

Traditionally, surgery has been the mainstay of treatment for patients with tracheal cancer (5). However, a significant proportion of the patients are ineligible for surgery, making radiotherapy (RT) an alternative treatment option. Local control is particularly critical in tracheobronchial SCC, as disease progression often leads to airway obstruction, which can significantly impact prognosis (6,7). Although some studies have reported the potential benefits of RT in improving survival outcomes, the rarity of the disease has hindered randomized controlled trials, leaving the optimal treatment approach undefined (8,9). Furthermore, the addition of concurrent chemotherapy to RT, primarily as a radiation sensitizer, has been sparingly described and is primarily reported in case reports. While this approach may have potential benefits in enhancing local control and reducing progression, robust clinical data are lacking. To date, no clinical studies have compared the outcomes of concurrent chemoradiotherapy (CCRT) and RT alone in this context.

Therefore, we aimed to comprehensively assess the disease characteristics, treatment approaches, and clinical outcomes in patients with primary tracheobronchial SCC. Our primary objective was to evaluate the survival outcomes of patients who were ineligible for surgery and received either RT alone or CCRT. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1911/rc).

Methods

Patients

We retrospectively reviewed the medical records of 159 patients with tracheobronchial malignancies who visited the Samsung Medical Center between January 1995 and April 2023. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Moreover, the study was approved by the Institutional Review Board of the Samsung Medical Center (#2023-07-104). The requirement for individual consent for this retrospective analysis was waived. The key inclusion criteria for the current study were as follows: (I) pathologically proven SCC; (II) treatment at Samsung Medical Center; and (III) no uncontrolled double primary malignancy. Finally, 19 patients were included in the final analysis (Figure 1). The location and size of the tumor were assessed using bronchoscopy and computed tomography (CT), with the transverse size representing the largest diameter measured on axial images, and the longitudinal size recorded as the tumor length on sagittal images. The clinical stages of patients were determined using the Bhattacharyya staging system (10).

Figure 1 Flow diagram. CCRT, concurrent chemoradiotherapy; OP, operation; RT, radiotherapy.

Treatments

Surgical decisions involving either endoscopic or open tracheal resection were made at a multidisciplinary team meeting, considering performance status, comorbidities, primary tumor location or size, and the presence of nodal or distant metastasis. Patients with close resection margins or those who did not achieve R0 resection underwent postoperative RT (PORT). PORT was initiated approximately 4–6 weeks after surgery, and a total radiation dose of 60 Gy was prescribed.

Fourteen patients who were ineligible for surgery underwent definitive or palliative RT of the trachea. The classification of RT intent was based on the presence of distant metastasis. Patients without distant metastases were classified as receiving definitive RT, with the goal of achieving curative outcomes. Conversely, patients with distant metastases were treated with palliative RT, aimed at symptom relief rather than cure. The decision between RT and CCRT was determined based on the clinical judgment of the treating physician, taking into account patient-specific factors such as performance status and comorbidities. Gross tumor volume (GTV) encompassed all visible lesions identified by bronchoscopy, neck or chest CT, and positron emission tomography-CT (PET-CT), including primary tracheal tumors and regional lymph nodes. The clinical target volume (CTV) was delineated using a craniocaudal margin of 1–2 cm and an axial margin of 5–7 mm from the GTV. The planning target volume included an additional 5–7 mm margin from the CTV. Brachytherapy was permitted as a boost therapy and was administered to two patients. Patients receiving palliative RT received 30 or 39 Gy in 3 Gy fractions, whereas those with a definitive aim received a median total dose of 66 Gy with 2.2 Gy per fraction. All the treatment plans were intended to deliver at least 97% of the prescribed dose to 95% of the CTV.

Table S1 provides details on the chemotherapy agents used in CCRT, with every patient receiving six cycles of chemotherapy during the course of RT. The doses for each regimen were as follows: cisplatin 35 mg/m² intravenously (IV) in the cisplatin regimen, paclitaxel 50 mg/m², and carboplatin with the target area under the curve 1.5 IV in the paclitaxel/carboplatin regimen, paclitaxel 50 mg/m² and cisplatin 25 mg/m² IV in the paclitaxel/cisplatin regimen, and docetaxel 20 mg/m² and cisplatin 20 mg/m² IV in the docetaxel/cisplatin regimen.

Response evaluation and outcomes

During regular follow-ups, patients underwent CT, bronchoscopy (with or without biopsy), and PET-CT and tumor response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. (11).

OS was defined as the time from treatment initiation to death from any cause. Freedom from local progression (FFLP) was defined as the time from treatment initiation to primary tracheal tumor progression, whereas freedom from distant progression (FFDP) was defined as distant progression encompassing the advancement of pre-existing distant metastatic lesions or the emergence of new distant lesions. Additionally, progression-free survival (PFS) was defined as the duration between the start of treatment and the initial disease progression or death.

We evaluated the toxicity associated with RT based on the Common Terminology Criteria for Adverse Events version 5.0. Toxicities occurring within three months of initiating treatment were classified as acute toxicity, while those appearing after 3 months were classified as late toxicity.

Statistical analyses

Statistical analyses were performed using R version 4.2.2 (R Development Core Team, Vienna, Austria). A chi-square test was performed for nominal variables and an independent simple t-test was performed for continuous variables to compare the distribution of patient characteristics in each treatment group. The Kaplan-Meier method was used to calculate FFLP, FFDP, PFS, and OS. Univariate analysis was performed using Cox regression analysis. Statistical significance was set at P<0.05 significant.

Results

Patient’s characteristics and treatments

Nineteen patients were included in the analysis, and their characteristics are summarized in Table 1. Among them, 5 (26.3%) were eligible for surgery, of whom two required PORT due to a close resection margin. Of the remaining 14 patients (73.7%), 9 were ineligible for surgery due to the extent of the disease, while 5 patients were excluded due to prior treatment history of the thorax, or they refused personally (Table S2). The median age of all patients was 62 years (range, 45–80 years). The primary tumor was located in the cervix in 7 patients (36.8%) and the thorax in 12 patients (63.2%), meanwhile, 7 patients (36.8%) had lymph node involvement and 3 patients (15.8%) had distant metastasis at the time of diagnosis. Most patients complained of dyspnea, and 7 patients (36.8%) underwent stent insertion before initiating treatment.

Survival outcomes and pattern of failure

The median PFS and OS of all patients were 28.2 and 43.3 months, respectively (Figure S1). The survival outcomes in each treatment group are presented in Figure 2, with the 3-year OS rates in the RT alone, CCRT, and surgery groups were 16.7%, 83.3%, and 60.0%, respectively.

Figure 2 Clinical outcomes of patients with tracheobronchial squamous cell carcinoma: (A) freedom from local progression, (B) freedom from distant progression, (C) progression-free survival, (D) overall survival. CCRT, concurrent chemoradiotherapy; RT, radiotherapy.

The failure patterns are listed in Table 2. Of the 19 patients, 8 (42.1%) experienced progression during a median follow-up period of 19.1 months. The first site of recurrence was the trachea in three patients and the lungs in five patients. Local and distant progression occurred in six patients each. Although there were no significant differences in the failure patterns among the treatment groups, the CCRT group tended to exhibit less local and distant progression than the RT alone group.

Univariate analysis

Univariate analysis revealed that large transverse tumor size, low radiation dose, and patients who had undergone stent insertion before any treatment exhibited poor PFS and OS (Table S3). Additionally, patients with preexisting distant metastases at the time of diagnosis and those with a large longitudinal tumor size demonstrated poor PFS and OS, respectively. Regarding treatment approaches, surgery demonstrated no significant association with survival outcomes compared to other treatment groups. In contrast, patients treated with RT alone had significantly worse OS compared to other treatment groups.

RT alone vs. CCRT

Among the 14 patients who were ineligible for surgery, 12 patients received RT alone or CCRT with curative intent, excluding 2 patients who had pre-existing distant metastasis at the time of diagnosis (Figure 1).

In the tumor response evaluation conducted 3 months after the completion of RT, both the RT alone and CCRT groups had two patients each who displayed a complete response (Table S4). Furthermore, in the RT alone group, five of six patients demonstrated an objective response, whereas all patients in the CCRT group exhibited an objective response. In the RT alone group, the median OS was 17.0 months, with 1-, 2-, and 4-year OS rates of 75.0%, 25.0%, and 25.0%, respectively. In the CCRT group, the median OS had not yet been reached, and the 1-, 2-, and 4-year OS rates were 100%, 83.3%, and 55.6%, respectively, displaying a trend of improved survival compared to the RT alone group (P=0.08) (Table 3, Figure 3).

Figure 3 Clinical outcomes after curative radiotherapy in patients with inoperable tracheobronchial squamous cell carcinoma (n=12): (A) freedom from local progression, (B) freedom from distant progression, (C) progression-free survival, (D) overall survival. CCRT, concurrent chemoradiotherapy; RT, radiotherapy.

Most patients reported only Grade 1–2 systemic symptoms, such as fatigue and nausea, with no Grade 3 or higher acute toxicities. Late toxicities of Grade 3 or higher were observed in one patient from each group. In the RT-alone group, one patient developed Grade 3 tracheal stenosis 2 years after treatment, which was resolved through bronchoscopic dilatation and ballooning. Similarly, in the CCRT group, one patient experienced Grade 3 tracheal stenosis 7 months after treatment, which was also successfully managed with bronchoscopic intervention.

Discussion

In the study, we demonstrated that tracheobronchial SCC is extremely rare and has a poor prognosis. Most treatment failures are attributed to local progression or distant metastasis to the lungs.

Curative surgery for resected SCCs of the trachea and carina has been reported to yield high 5- and 10-year survival rates of 39% and 18%, respectively (3). However, a substantial number of patients cannot undergo surgery due to factors such as lengthy tracheal tumors, involvement of adjacent organs, multiple lymph node involvement, distant metastasis, and a history of prior surgery or irradiation (2,12-14). Similarly, in our study, disease extent was identified to be the primary reason for inoperability, with only 26.4% of the patients being eligible for surgery. Therefore, while RT has been considered a crucial curative treatment option for patients with unresectable tumors, its outcomes remain controversial and are often limited to small case series (15-17). For patients with unresectable tumors, bronchoscopic interventions, such as laser therapy, argon plasma coagulation, and stenting, play a vital role in relieving airway obstruction and improving quality of life, potentially contributing to better prognosis (7,18). However, as these approaches are primarily supportive, they are not sufficient to achieve radical disease control. For this reason, RT remains a key treatment modality for unresectable tumors, despite the limited data available from small case series. Our current study revealed a tendency towards improved PFS and OS when concurrent chemotherapy was administered alongside RT, indicating that CCRT may be an effective treatment option for patients who are not eligible for surgery. Some hospital data-based studies and case reports have reported clinical outcomes of patients undergoing CCRT, but without systematic statistical analysis, while one study using the National Cancer Database found superior median OS for CCRT compared to RT alone (Table S5) (18-26). Therefore, to our knowledge, this is the first clinical report comparing CCRT with RT alone and demonstrating the benefits of CCRT exclusively in patients with SCC among tracheobronchial cancers.

It has been known that tracheal cancer exhibits not only a substantial occurrence of local failure but also significant rates of distant failure after RT (19,25). In the current study, we established that local progression was reduced from 42.9% to 28.6% and distant progression from 57.1% to 14.3% when concurrent chemotherapy was added to RT, although this was not statistically significant due to the small number of cases (Table 2). In addition, at the first site of failure, the CCRT group demonstrated no instances of distant progression, highlighting its distinction from the other treatment groups. The findings support the use of chemotherapeutic agents in treatment strategies aimed at maximizing locoregional control and effectively managing micrometastatic diseases. In addition, despite the limitations posed by the small sample size and rarity of the disease, the findings imply that concurrent use may hold a more favorable stance than sequential use, indicating a potential advantage in terms of improving local control. Numerous preclinical studies on non-small cell lung cancer have established the synergistic benefits of combining RT with chemotherapy (27,28). In particular, cisplatin-based chemotherapy is commonly used, as it is hypothesized that delaying recovery from RT-induced damage can enhance the effectiveness of RT. Furthermore, various randomized trials have provided evidence that CCRT is superior to RT alone, leading to improved PFS and OS in the treatment of locally advanced lung cancer (29,30).

In our study, the majority (71.4%) of the CCRT group patients received cisplatin-based chemotherapy, as in other studies (20,22,31). Videtic et al. reported a case in which a patient with unresectable disease achieved a complete response after receiving cisplatin based CCRT, maintaining a disease-free status at the 2-year follow-up (26). Furthermore, Joshi et al. reported three patients with tracheal cancer who underwent CCRT with a follow-up period of 28 months, and the median survival has not been reached yet (24). A study published by Hararah et al. based on the national cancer database demonstrated a median survival of 26 months for the CCRT group and 16 months for the RT alone group, indicating an improvement of more than 10 months (21). Furthermore, in the subgroup analysis of patients with nonmetastatic disease, CCRT demonstrated comparable outcomes to curative surgery with or without adjuvant therapy, whereas RT alone had significantly inferior results. Therefore, our study provides supporting evidence that CCRT is a warranted approach, as it aligns with the findings of large-scale population-based studies.

Our study had several limitations. First, it was a retrospective study. Second, the small sample size limited the ability to demonstrate statistical significance. Third, the extended study duration of nearly 30 years inevitably included significant advancements in treatment modalities, such as RT techniques and multidisciplinary care. These temporal variations may have introduced variability in treatment outcomes, which should be carefully considered. In addition, detailed recommendations regarding the optimal chemotherapy regimen, RT technique, and dosage are lacking. However, a notable strength of our study is the inclusion of a substantial number of patients with SCC from a single center, which allowed for a more focused analysis. As presented in a review article, many studies involve heterogeneous groups with various pathologies, and there are no statistical reports on outcomes based on treatment methods, specifically for patients who underwent CCRT (32).

Considering the rarity of the disease and the potential limitations of using national registries, such as incomplete information on the clinical stage, comorbidities, and recurrence status, our findings suggest the need for future multi-institutional studies to overcome the aforementioned limitations and obtain more comprehensive data on larger patient populations, thereby providing valuable insights for further research and clinical practice.

Conclusions

Although surgery is the preferred treatment for tracheobronchial SCC, many patients are ineligible, leading to a primary reliance on RT. The addition of concurrent chemotherapy to RT may have a potential for improving survival outcomes, offering an alternative to surgery.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1911/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1911/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1911/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1911/coif). The 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 (as revised in 2013). Moreover, the study was approved by the Institutional Review Board of the Samsung Medical Center (#2023-07-104), 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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