Efficacy and survival of photodynamic treatment for tracheal adenoid cystic carcinoma: a two-center retrospective analysis

Introduction

Tracheal adenoid cystic carcinoma (TACC), a rare malignancy originating from secretory glands, is the second most frequent primary tracheal tumor and predominantly occurs in individuals aged between 40 and 60 years (1). Complete surgical resection (R0) remains the primary curative approach for adenoid cystic carcinoma (ACC), significantly improving survival (2,3). For patients with unresectable tumors or incomplete resection, definitive radiotherapy offers local control, while systemic therapies—chemotherapy, targeted agents, and immunotherapy—aim to delay progression. Yet, a limited long-term efficacy highlights the need for more effective strategies (4). Previous research on TACC has mainly focused on basic studies, examining therapeutic targets and signaling pathways (5-7). Notably, case reports have suggested that photodynamic therapy (PDT) may be a potential therapeutic option for patients with TACC undergoing palliative care (8-10).

PDT operates by utilizing photosensitizers to produce reactive oxygen species, which induce substantial cytotoxic effects. This mechanism can disrupt tissue structure and cause necrosis at the lesion site. Importantly, PDT has been shown to significantly reduce the risk of functional decline and improve the quality of life for patients (11). Furthermore, PDT is reproducible and can be effectively combined with other treatment modalities. However, there is a notable lack of large-scale clinical studies evaluating the efficacy and safety of PDT for treating TACC.

Given these considerations, we aimed to conduct a two-center retrospective analysis to evaluate the efficacy and safety of PDT in the treatment of TACC. In addition, this study also analyzed the factors that might affect the efficacy of PDT, with the aim of identifying the characteristics of potential PDT-high-benefit TACC patient groups and meeting the future personalized treatment needs of TACC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-757/rc).

Methods

Patients

This study included 39 patients with pathologically confirmed TACC who underwent PDT at Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine and Emergency General Hospital between August 2011 and September 2023. Figure 1 shows the inclusion and exclusion criteria for participant enrollment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine (No. 2024DZMEC-039-02) and Emergency General Hospital (No. K24-24). The requirement for informed consent was waived due to the retrospective nature of the analysis.

Figure 1 The flowchart of inclusion and exclusion for this study. ACC, adenoid cystic carcinoma; CT, computed tomography; TACC, tracheal adenoid cystic carcinoma.

PDT

Preoperative preparation

For preoperative preparation, all patients underwent standard laboratory evaluations, pulmonary function tests, and imaging studies to exclude contraindications. Tumor location and size were confirmed via bronchoscopy. Following this, patients provided written informed consent for the surgical procedure and received education on the photoprotection protocols. They were subsequently admitted to a light-shielded ward. Hematoporphyrin derivative (HpD) was administered intravenously at a dose of 2 mg/kg. A skin test for drug hypersensitivity was performed prior to administration, and only patients with negative results proceeded with infusion

Operative procedure

The initial laser irradiation was performed 48 hours after photosensitizer administration. Under fiberoptic bronchoscopy guidance, a cylindrical diffuser fiber was positioned directly at the tumor site. The laser wavelength was set to 630±3 nm with an energy density of 100–200 J/cm² and delivered in an intermittent mode (single irradiation duration: 3–8 minutes; interval: 1–3 minutes).

Prior to the second and third irradiations—administered on postinjection days 2 and 3, respectively, necrotic tissue was debrided from the lesion surface. Energy densities for subsequent sessions did not exceed that of the initial irradiation. The irradiation field encompassed the entire lesion, extending 0.5 cm beyond each end. For lesions longer than the diffuser tip (2–6 cm), segmented irradiation was applied. In cases of posttreatment respiratory distress, emergency bronchoscopy was performed to remove obstructive necrotic debris. On day 30 postadministration, a local skin photosensitivity test was conducted. Photoprotection restrictions were lifted only for patients who tested negative, allowing for resumption of sunlight exposure. The treatment protocol is illustrated in Figure 2.

Figure 2 Schematic diagram of photodynamic therapy. The patient was intravenously infused with HpD. After 48 hours, the photosensitizers were enriched around the tumor cells and then exposed to 630 nm infrared light. HpD, hematoporphyrin derivative.

Evaluation and follow up

In accordance with the 2019 efficacy evaluation standard for PDT for respiratory tumors (12), the most recent efficacy evaluation was conducted 1 month after PDT. The evaluation criteria were as follows: (I) complete response (CR; complete elimination of the cancerous lesion in the bronchial lumen and no tumor cells visible in the mucosal biopsy pathology); (II) partial response (PR; reduction in the length and thickness of the intrabronchial lesion by at least 30% compared to before treatment, with tumor cells still present in the mucosal biopsy pathology); and (III) progressive disease (PD; an increase in the extent of cancerous lesions beyond the original focal area, accompanied by the presence of tumor cells in the biopsy).

Overall survival (OS) and progression-free survival (PFS) were employed as long-term efficacy evaluation indices. OS was defined as the time (in months) from the commencement of PDT treatment to death or the last follow-up, while PFS was defined as the time (in months) from the commencement of PDT to tumor progression or death. The dates of treatment initiation were obtained from the electronic medical records of the two hospitals, while the dates of death were obtained by telephone follow-up or from the Chinese Center for Disease Control and Prevention (CDC). The final follow-up was completed on December 31, 2023.

Statistical analysis

Data were analyzed with SPSS 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables are described as the mean ± standard deviation. The Kaplan-Meier method was used to construct survival curves and to calculate the 5-, 10-, and 15-year survival rates and median survival times. The differences in survival between groups were compared via log-rank tests. Finally, a multifactorial Cox regression model was employed to assess the relationship between covariates and TACC prognosis. All statistical tests were conducted with a two-sided hypothesis, and results were considered statistically significant when P<0.05.

Results

Patient characteristics

This study enrolled 39 patients diagnosed with TACC, comprising 17 males and 22 females, with a mean age of 47.5±14.0 years (range, 19–79 years). A positive smoking history was reported in 9 patients. At presentation, all patients exhibited respiratory symptoms, including cough (n=17), hemoptysis (n=6), dyspnea (n=14), tracheal foreign body sensation (n=1), and hoarseness (n=1).

Tumor infiltration was classified into mural, intraluminal, and mixed types, with lesions involving eight anatomical airway regions (13,14). Based on the TNM staging system, 1 patient was classified as stage I, 9 as stage II, 16 as stage III, and 13 as stage IV. The severity of pretreatment tracheal stenosis was assessed using the Myer-Cotton grading system, including grade II (n=4), grade III (n=9), grade IV (n=22), and grade V (n=4) (Table 1).

Tracheal features and clinical response

All patients underwent endoscopic airway tumor resection prior to PDT. The lesions were mainly located in the trachea in 31 cases and involved the tracheal carina and main bronchus in 16 cases. These lesions resulted in varying degrees of airway stenosis, with 26 cases being grade IV or V and 13 cases being grade III or below. All patients received PDT for 3 consecutive days, resulting in a significant reduction in tumor size and airway stenosis (Figure 3). The most recent efficacy evaluation of 39 patients after 1 month of PDT treatment showed CR in 5 patients, PR in 25 patients, and PD in 9 patients (Table 2).

Figure 3 Comparison of TACC before and after PDT. (A) Tumor tissue located in the untreated airway regions II–III of Patient A, causing >50% luminal stenosis. Initial cytoreductive therapy was performed under bronchoscopy, followed by three sessions of PDT delivering a total energy of 3,030 J. (B) Posttreatment image of the same airway region. (C) Residual tumor mass in airway region V obstructing the right main bronchus opening. After tumor resection, three PDT sessions were administered with a cumulative energy of 2,113 J. (D) Corresponding follow-up image. PDT, photodynamic therapy; TACC, tracheal adenoid cystic carcinoma.

Following treatment, clinical symptoms such as cough, dyspnea, and hemoptysis were significantly alleviated. A total of 10 deaths were recorded during the follow-up period.

In the CR group, one patient developed pulmonary and pleural metastases in 2014, 3 years after PDT, and achieved temporary remission through multiple bronchoscopic interventions. This patient ultimately died in 2021, with an OS of approximately 10 years.

In the PR and PD groups, 14 and 5 patients, respectively, received additional treatments including local injections, chemoradiotherapy, and immunotherapy. Two of these patients underwent a second course of PDT. One patient declined further follow-up and died. A total of nine patients in the PR and PD groups died during the study period.

Complications

In terms of adverse reactions and complications (Table 1), there were no operation-related adverse reactions in 39 patients treated with PDT; there were only 3 cases of photoallergic reactions, 1 case of dyspnea, 1 case of scarring stenosis, and 2 cases of granulomatous hyperplasia. There were no deaths or serious complications following PDT.

Survival analysis

In the CR group, the OS was 104.80±155 months, and the PFS was 44.60±47.75 months; in the PR group, the OS was 70.20±67.52 months, and the PFS was 35.52±17.69 months; and in PD group, the OS was 71.50±60.53 months, and the PFS was 0.42±0.36 months. Through statistical analysis of the data, it was determined that the OS (P=0.008) and PFS (P=0.005) were significantly different (P<0.05) between the PR and PD groups. The 5-, 10-, and 15-year survival rates were 73.2%, 64.1%, and 42.7%, respectively (Figure 4). The OS and PFS data are provided in Figure 4.

Figure 4 Kaplan-Meier curve. (A) Overall survival curve, including the 5-, 10-, and 15-year survival rates. (B) Overall survival of groups (P=0.008). (C) Progression-free survival of groups (P=0.005). P<0.05 was considered significantly different. CR, complete response; MST, median survival time; PR, partial response; PD, progressive disease.

Further statistical analysis revealed a significant correlation between energy density and patient survival outcomes (Table 2). When the energy density was ≥150 J/cm², patient survival was significantly improved, with a median OS of 34.0 months. This represented a 134% increase compared to patients with a <100 J/cm² energy density (absolute difference Δ=19.5 months; P=0.002). Although the 100 to 149 J/cm² group demonstrated a higher median PFS of 24.0 months, this finding should be interpreted with caution due to the extremely small sample size (n=2) and the fact that all patients achieved PR, resulting in a high specificity.

Cox regression

Univariate Cox regression analyses incorporated age, sex, treatment interval, smoking history, and family history. The results showed that the factors significantly associated with survival in patients with TACC were age [hazard ratio (HR) =6.40, 95% confidence interval (CI): 1.26–32.57; P=0.03] and treatment interval (HR =10.10, 95% CI: 1.19–85.59; P=0.03). However, no variable was found to be significantly associated with the survival of patients with TACC in the multifactorial Cox regression analysis (Table 3).

Discussion

In this study, we observed that these symptoms, including cough and dyspnea, were markedly reduced following PDT treatment. The mechanism responsible for this improvement is based on the ability of PDT to selectively target and destroy tumor cells while preserving surrounding healthy tissue. This selective action minimizes damage to critical structures within the respiratory tract, thereby reducing complications and enhancing patient comfort.

Furthermore, our findings indicate that patients treated with PDT had a low recurrence rate of symptoms, a reduced incidence of obstructive pneumonia, and a high remission rate. These outcomes highlight the effectiveness of PDT in managing both primary tumors and their associated complications. Notably, PFS and OS were substantially extended among the patients in this study. Specifically, the 5-, 10-, and 15-year survival rates were recorded at 73.2%, 64.1%, and 42.7%, respectively. Importantly, only 17.9% (n=7) of patients experienced complications during or after treatment, and no procedure-related fatalities were reported. This safety profile underscores the potential of PDT to be a viable alternative to conventional treatments.

TACC constitutes approximately 1.2% of upper respiratory tract neoplasms (15). Currently, surgery is the preferred treatment for TACC, followed by radiotherapy. According to previous studies (2,16), the survival of patients undergoing surgery alone is largely dependent on surgical margin status (positive vs. negative), with 5-year and 10-year survival rates ranging from 65.9% to 77.5% and 47.7% to 76.2%, respectively. However, adjuvant radiotherapy has not been shown to significantly prolong patient survival. Several studies (2,15) have found that radiotherapy does not significantly improve lesions, with an objective remission rate of approximately 6%. Patients undergoing high-dose radiotherapy have an average treatment cycle of 5 years (17) and may experience side effects such as chest tightness, chest wall tissue atrophy, pulmonary atelectasis, obstruction, and stenosis of the large airways and pain (15,18-20). Existing therapeutic regimens for TACC do not have satisfactory efficacy and no longer meet current clinical needs, highlighting the importance of developing novel therapeutic approaches. Spinelli et al. reported that tracheoscopy combined with adjuvant therapy significantly improved outcomes in patients with incompletely resected lesions (21,22).

PDT is a relatively safe, easy-to-operate, and highly selective antitumor therapy, which has been increasingly applied in different tumor treatments (23). In cases of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), PDT is used as an endobronchial therapy to cure tumors growing in the bronchi and relieve symptoms resulting from bronchial obstruction, such as pain, shortness of breath and hemoptysis (24). In one study, PS1-PDT in combination with doxorubicin at a single dose enhanced the long-term cure in severe combined immunodeficient (SCID) mice bearing SCLC 14,541 tumors, suggesting this approach can be applied in patients with lung cancer (25). Zeng et al.’s in vitro and in vivo studies demonstrated the excellent efficacy of the combination of PDT, chemotherapy, and immunotherapy for the regression of distant tumors and lung metastases (26). PDT provides significant clinical benefit by substantially improving airflow obstruction (27). In more detailed studies, PDT was found to be highly adaptable and effective in patients who are inoperable or unresponsive to radiotherapy, chemotherapy, immunotherapy, and targeted therapy (28,29). These studies suggest that PDT is a promising alternative therapy.

In our study, patients treated with PDT had a higher survival rate than did patients treated with surgery. In the NSCLC study by Jayadevappa et al., the mean OS in the radiotherapy + chemotherapy and ablation group was 502±582 and 417±497 days, respectively, both of which were lower than that in the PDT group (505±526 days); moreover, PDT delayed the recurrence time of endobronchial obstruction (30). In our follow-up of patients with ACC, the mean OS was 76.77±79.45 months, which was longer than that in previous studies (2,16). Numerous patients administered with PDT combined with other treatments received significant improvements in survival. More than half of the patients underwent radiotherapy, chemotherapy, immunotherapy, and other treatments before PDT, but the efficacy was not significant, and there was no survival benefit. After treatment, 29 patients did not undergo other treatments and showed satisfactory photodynamic results.

We also found no significant association between the occurrence of TACC and smoking, gender, or family history in this study, contrasting with other types of lung tumors, which is in line with the literature (31,32). Another interesting finding was that TACC occurred more frequently in younger individuals (HR =6.40, 95% CI: 1.26–32.57; P=0.03). Due to the insidious and slow progression of TACC, treatment options for advanced cases are limited. Regular physical examinations may reduce the risk associated with long symptom-diagnosis intervals (HR =10.10, 95% CI: 1.19–85.59; P=0.03), thereby improving survival prognosis. Recent scientific investigations have shed light on the complex relationship between the MYB-NFIB chimeric gene and ACC, a rare form of cancer that primarily affects salivary glands. According to recent findings (33), there appears to be a significant association between the expression levels of the MYB-NFIB chimeric gene and the age at which ACC is diagnosed. Specifically, the data suggest that as individuals grow older, the likelihood or intensity of MYB-NFIB gene expression increases, potentially contributing to the onset of this disease. The MYB-NFIB fusion gene, formed through chromosomal rearrangements, plays a critical role in tumor biology by enhancing two key processes: angiogenesis and cell proliferation. Together, these mechanisms significantly influence the development and metastasis of ACC, making the MYB-NFIB gene an important focus for understanding the disease’s behavior. However, it is essential to approach these findings with caution. The studies conducted thus far have been limited by relatively small sample sizes, which restrict the ability to draw definitive conclusions regarding the relationship between MYB-NFIB expression and patient prognosis. Although the evidence points to a clear connection between gene expression and disease progression, more extensive research involving larger cohorts is necessary to confirm whether MYB-NFIB expression can serve as a reliable prognostic indicator. Such studies would also help clarify how variations in gene expression might correlate with treatment outcomes or survival rates, ultimately paving the way for more personalized therapeutic strategies in the management of ACC.

Certain limitations to our study should be addressed. First, due to the low incidence of TACC, we employed a retrospective design spanning 12 years, and the follow-up of patients was not sufficiently comprehensive. Second, in the univariate and multifactorial analyses, the relatively small number of cases might have led to some factors being uncorrelated. We hope to collect more data for a more comprehensive analysis of variables.

Conclusions

Our study demonstrated that PDT in patients with TACC achieved satisfactory clinical efficacy and safety and was associated with extended survival and a reduced incidence of complications for the patients. Furthermore, it was found that the duration from disease diagnosis and age were risk factors contributing to the development of TACC. In conclusion, the intraoperative application of PDT can effectively delay the growth and progression of TACC, thereby prolonging survival and enhancing the quality of life of the patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-757/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-757/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-757/prf

Funding: The study was supported by Horizontal Research Project of Beijing University of Chinese Medicine (No. HX-DZM-202222).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-757/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 and its subsequent amendments. The study was approved by the Ethics Committee of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine (No. 2024DZMEC-039-02) and Emergency General Hospital (No. K24-24). 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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(English Language Editor: J. Gray)