Photodynamic therapy of lung cancer: the present and the future

To the Editor: Lung cancer is the leading cause of cancer-related mortalities worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases.[1] Photodynamic therapy (PDT) has been used in lung cancer for nearly four decades. Its relatively low risk and ablative abilities render it a favorable adjuvant treatment alternative for NSCLC. It has been integrated into the modern multidisciplinary treatment of lung cancer due to its promising clinical outcomes in combination with other therapies. Herein, we comprehensively review the available evidence regarding PDT, focusing on clinical efficacy and possible future development in lung cancer. Multidisciplinary management and novel strategies for PDT: PDT is well established in the domain of interventional pulmonology, and functions well as part of a multidisciplinary approach for treating lung cancer with the following advantages[2] [Supplementary Figure 1, https://links.lww.com/CM9/C162]: (1) minimally invasive; (2) nonionizing radiation causes limited injury to connective tissue structures, thus preserving framework for healing after treatment; (3) high selectivity for tumor tissue, with less impact on healthy cells; (4) low and transient systemic toxicity compared to some treatments, e.g., chemotherapy and radiotherapy; (5) no cross-resistance; reducing or reversing drug resistance by inhibiting escape pathways in standard therapies, e.g., chemotherapy and targeted therapy; (6) it can be repeated locally in the short term, which is unfeasible with some established treatments, e.g., surgery, chemotherapy, and radiotherapy; (7) immunogenic cell death induced by PDT can potentially augment the efficacy of immunotherapy. Combination with chemotherapy: In a single-institution study,[3] all patients with stage II–IV NSCLC receiving PDT and chemotherapy had improved clinical symptoms and Karnofsky Performance Scale (KPS) scores as a result of increased airway patency and reduced obstructive pneumonia. Usuda et al[4] used talaporfin sodium (NPe6)-PDT for 29 patients with 38 early central lung cancer (ECLC) lesions and found that all non-complete response (CR) lesions after PDT were finally converted to CR by following chemotherapy. A clinical study of cholangiocarcinoma showed that PDT combined with chemotherapy (gemcitabine or gemcitabine with cisplatin) resulted in a significant improvement in overall survival compared with PDT alone.[5] However, the above simple combination of current PDT and chemotherapy may not have fully realized their potential due to various technical limitations. Chemo-PDT will break through the barriers to maximize its effectiveness. Nanoparticles (NPs) or other vehicles have been used to encapsulate photosensitizer (PS) and chemotherapeutic drugs; and longer wavelengths of red light are currently being explored. Combination with radiotherapy: Previous studies utilized photofrin-PDT and/or radiotherapy in ECLC patients and found that over 60% of lesions achieved CR after PDT; CR was observed in over 90% of recurrent lesions receiving PDT and radiotherapy.[6,7] Jayadevappa et al[8] analyzed Surveillance, Epidemiology, and End Results (SEER)-Medicare data of over 43,000 patients with advanced NSCLC (stage III–IV). They found that compared with the external beam radiotherapy (EBRT) plus chemotherapy group, PDT plus EBRT and/or chemotherapy did not increase all-cause or disease-specific mortality and led to a longer survival time (16.6 months vs. 13.7 months); the PDT ablation group had longer remission period than the non-PDT ablation group. Imamura et al[7] carried out a retrospective study of 29 patients with ECLC treated with PDT and EBRT and showed that using EBRT after initial PDT could improve the complete remission rate from 64.0% to 89.7%. Lam S et al[9] conducted a prospective randomized trial of 11 patients with obstructive and inoperable NSCLC. They found that PDT before EBRT resulted in better local control and improved quality of life. However, the RT dose also needs to be considered carefully when using light irradiation. Complications, such as hemoptysis, are more likely to occur in patients with upper aerodigestive tract carcinoma who have received both EBRT and brachytherapy before.[10] The novel radio-PDT therapy will allow for precise targeting and can prevent excessive and prolonged exposure, which can reduce toxicity and enhance tolerance. Combination with target therapy: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI), anaplastic lymphoma (ALK)-TKI, vascular endothelial growth factor (VEGF)-TKI, and other TKIs are classic antitumor small molecule drugs.[11] Drug resistance is inevitable and has become a major obstacle to overcome in effectively treating NSCLC. Importantly, targeted PDT is being investigated to explore the optimum way to overcome resistance and improve therapeutic effects. Combination with immunotherapy: PDT and immunotherapy may have synergistic effects by either enhancing tumor immunogenicity or reducing immunosuppression in the tumor environment.[12,13] PDT can induce immunogenic cell death (ICD) to release tumor-specific antigens as an in situ vaccine, and can also cause damage-associated molecular patterns to enhance tumor immunogenicity.[14] A preclinical model of renal cell carcinoma treated with vascular-targeted PDT and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy obtained potent local and systemic antitumor responses.[13] In clinical settings, a patient with head and neck squamous cell carcinoma achieved sustained CR (15 months) after PDT and nivolumab combination therapy, but the mechanism was not investigated.[15] The future of immuno-PDT seems to be promising, though more preclinical and clinical data are needed to realize its full potential. Combination with surgery: Preoperative PDT has been shown to convert 50–80% of inoperable advanced cases into operable tumors and reduce the resection area for 27–86% of surgical candidates.[16,17] It can decrease pathological stage in 64% of surgical NSCLC cases when combined with chemotherapy and/or radiation, and increase the survival rate from 51% to 60% in patients with T3 disease compared with surgery alone.[16,17] PDT may provide an alternative to conventional methods. Mehta et al[18] performed postoperative PDT in 11 stage I NSCLC patients with R1 resection and showed an over 90% local control rate with a median survival of 45 months. PDT can reduce tumor burden and remove residual lesions, suggesting that it may serve as a complementary therapy to surgery. Due to the development of optical and material technology, as well as pharmaceutical medicine and interventional therapy, a substantial progress is made in PDT by overcoming light depth, targeted delivery, and hypoxia environment. We look forward to the development of better PS in clinical practice, with better efficacy and fewer side effects. Importantly, the role of immune mechanisms of PDT is increasingly prominent. Future research should look for a way to enhance and prolong immunity of PDT and focus on the timing issue of its combination therapy. In standardized management, early detection is the key to prevent and treat lung cancer, and thus, the timing of PDT should be considered to moved forward, which is still worth exploring vigorously in future. To conclude, available evidence currently supports that combining PDT and current antitumor therapy can provide more chances for symptom relief and survival. The limitations of current PDT still exist. More efforts are needed to bring about more precise targeting, increased oxygen concentrations in tumor regions, improved light sources and activation of immunogenicity. Novel PDT may substantially boost the potential of antitumor agents used in combination. PDT can improve surgery success and eliminate residual lesions after surgery, as well as enhance the treatment effect of endobronchial approaches. These strategies urgently need further proof of therapeutic superiority and safety to facilitate clinical translation. Importantly, consistent findings from extensive literature promote a broader clinical scenario, where PDT is ideally suited for current multidisciplinary approaches. We hope to have large-sample studies to demonstrate its safety and effectiveness. Acknowledgements We would like to offer gratitude to all our colleagues at the department of pulmonary and critical care medicine, for their helpful discussion and advice in the preparation of this manuscript. Figure was created with BioRender software (https://biorender.com). Conflicts of interest None.