Background: Photodynamic therapy (PDT) is a relatively safe and highly selectivity antitumor treatment, which might be increasingly used as a supplement to conventional therapies. A clinical overview and detailed comparison of how to select patients and lesions for PDT in different scenarios are urgently needed to provide a basis for clinical treatment. Summary: This review demonstrates the highlights and obstacles of applying PDT for lung cancer and underlines points worth considering when planning to initiate PDT. The aim was to make out the appropriate selection and help PDT develop efficacy and precision through a better understanding of its clinical use. Key Messages: Increasing evidence supports the feasibility and safety of PDT in the treatment of non-small cell lung cancer. It is important to recognize the factors that influence the efficacy of PDT to develop individualized management strategies and implement well-designed procedures. These important issues should be worth considering in the present and further research.

Photodynamic therapy (PDT) is the use of certain wavelengths of light with photosensitizing agents to kill cancer cells. The roots of PDT can be traced to over 3,000 years ago [1], though it was not until 1982 when it was used to treat obstructing lung cancer in patients that this form of therapy took shape [2]. Since then, PDT has emerged as a promising approach for treating early stage cancers, reducing symptoms in late-stage cancers, and successfully ablating pulmonary nodules [3]. It exhibits distinct advantages over standard procedures, such as low invasive, high tumor selectivity, and low toxicity [3, 4].

The recommendations for PDT applications in the guidelines are different and inconsistent. The American College of Chest Physicians recommends PDT as an effective treatment for small, early stage lung cancers located centrally [5]. The National Comprehensive Cancer Network recommends PDT only to treat locoregional recurrences or relieve symptomatic local disease [6]. To date, no systematic summary or detailed analysis is available of what types of lesions may benefit from PDT and what combination therapy should be used with PDT to achieve good treatment expectations. Treatment success depends on selecting suitable candidates for PDT application in different clinical scenarios.

Hence, we systematically review PDT application in non-small cell lung cancer (NSCLC) to guide clinical patient selection and combination treatments to achieve better therapeutic effects. We also focus on new technology and drugs of PDT to provide further insight for clinicians and encourage wider use in clinical settings.

PDT needs a two-stage process. First, photosensitizer (PS) is administered and accumulated a higher concentration in tumors than in normal tissues [3, 7]. The selection of PS type should be based on clinical requirements (Table 1). The second stage starts after an interval of injection to make a concentration gradient between normal and tumor tissues, and it involves the use of lasers to emit specific wavelengths of light. The PSs are activated by exposure to certain light wavelengths and produce reactive oxygen species (ROS) by reacting directly with a substrate (type I reaction). Free radicals are then formed and transfer energy directly to form singlet oxygen radicals (type II reaction). The production can cause direct cell death, destroy tumor vessels, and activate antitumor immune responses, which contributes to inhibiting tumor growth in situ and preventing distant metastasis [3, 6] (shown in Fig. 1).

Table 1.

The characteristics and dosimetry of PSs

GenerationDrugLaserAdministered doseIrradiation intervalSkin photosensitivityLight dosesLight fluences
1st PSs Porfimer sodium 630 nm 1.5–5 mg/kg 24–72 h 4–6 weeks Recommends  
HPD 
DHE 
     Lens: 150 J/cm2 100–300 mW/cm2 
Diffuser: 200–300 J/cm 
     Review  
Superficial irradiation     90–675 J/cm2 80–500 mW/cm2 
Interstitial irradiation     200–400 J/cm 200–500 mW/cm 
2nd PSs mTHPC 652 nm 0.15 mg/kg 90–110 h 1–2 weeks 10–20 J/cm2 100–150 mW/cm2 
NPe6 664 nm 2.5–3.5 mg/kg 4 h 2–3 weeks 100 J/cm2 150 mW/cm2 
HPPH 665 nm 2.5–6 mg/m2 body surfaces area 24–48 h 2 weeks 125 J/cm2 300–400 mW/cm2 
GenerationDrugLaserAdministered doseIrradiation intervalSkin photosensitivityLight dosesLight fluences
1st PSs Porfimer sodium 630 nm 1.5–5 mg/kg 24–72 h 4–6 weeks Recommends  
HPD 
DHE 
     Lens: 150 J/cm2 100–300 mW/cm2 
Diffuser: 200–300 J/cm 
     Review  
Superficial irradiation     90–675 J/cm2 80–500 mW/cm2 
Interstitial irradiation     200–400 J/cm 200–500 mW/cm 
2nd PSs mTHPC 652 nm 0.15 mg/kg 90–110 h 1–2 weeks 10–20 J/cm2 100–150 mW/cm2 
NPe6 664 nm 2.5–3.5 mg/kg 4 h 2–3 weeks 100 J/cm2 150 mW/cm2 
HPPH 665 nm 2.5–6 mg/m2 body surfaces area 24–48 h 2 weeks 125 J/cm2 300–400 mW/cm2 

DHE, dihematoporphyrin-ether; HPD, hematoporphyrin derivative; HPPH, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-alpha; mTHPC, meta-tetrahydroxyphenylchlorin; NPe6, mono-L-aspartyl chlorin e6; PS, photosensitizer; 1st, the first generation; 2nd, the second generation.

Fig. 1.

Mechanisms of action for PDT on tumors. There are three generations of PS and three illumination modalities. PS can be activated from a ground state to an excited state by the specific wavelength of light and oxygen to set off type I and type II reactions and then produce ROS to kill tumor cells. ALA, aminolevulinic acid; DHE, dihaematoporphyrin ether; HPD, hematoporphyrin derivative; HPPH, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; NIR, near-infrared; PDT, photodynamic therapy; PS, photosensitizer.

Fig. 1.

Mechanisms of action for PDT on tumors. There are three generations of PS and three illumination modalities. PS can be activated from a ground state to an excited state by the specific wavelength of light and oxygen to set off type I and type II reactions and then produce ROS to kill tumor cells. ALA, aminolevulinic acid; DHE, dihaematoporphyrin ether; HPD, hematoporphyrin derivative; HPPH, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; NIR, near-infrared; PDT, photodynamic therapy; PS, photosensitizer.

Close modal

There are three main illumination modalities [8‒10] (shown in Fig. 1): (1) superficial PDT: a treatment with a lower penetration depth used to treat small or superficial lesions; (2) interstitial PDT: a technique to treat large tumors or tumors far from the surface with the assistance of needles or catheters to insert the laser fibers directly into the tumor, thus maximizing treatment precision and minimizing damage to normal tissue. Fiber insertion generally does not cause tumor rupture or hemorrhage; (3) Deep PDT: a method for overcoming the limitations of low light penetration that is based on near-infrared light, ionizing radiation, self-illuminated compound systems, and emerging implants.

Light dosimetry is adjustable and crucial for treatment success, including light fluence (light power emitted on a cross-sectional area per second), light dose (the radiant energy on the irradiated spot), and exposure time [11, 12]. Ideal dosimetry should not only offer maximum tumor ablation but also minimize adverse effects [13]. Hyperthermia and PDT may act synergistically, while overheating (over 300 or 400 mW/cm2 irradiation) may lead to fibrosis, bleeding, perforation, and tissue deformation [8, 9, 14, 15]. However, it is difficult to determine the proper dosimetry because of complicated and unmeasurable factors, such as individual variability, the optical property of the tissue, etc. [14]. Thus, we summarize the common dose for clinical use (Table 1). Further studies are urgently needed.

Early Central Lung Cancer

Early central lung cancer (ECLC) is defined as carcinoma in situ (CIS) or cancer with limited invasion and malignancies measuring less than 2 cm in diameter, considered roentgenographically occult, biomicroscopically visible, located no further than the subsegmental bronchi, and without lymph node or distant metastases [16, 17]. ECLC can range from CIS to invasive tumor with exophytic behavior, and its morphology and extent decide treatment plan choice. This definition does not always comply with the TNM classification system since it does not specify lesion size, number, or distribution in the airway [18]. Surgery is commonly considered the initial treatment but can reduce lung function [19]. Chemotherapy and radiotherapy can be used for unresectable lesions but may have substantial toxicities and concomitant complications. PDT is a sort of flexible, safe, and tissue-sparing therapy [17]. It has been recommended for treating bronchial precancerous lesions and early malignant lesions [20]. In this section, we explore factors that influence PDT efficacy for ECLC.

Is the Depth of the Lesion worth Considering?

ECLCs develop through a series of increasing morphological abnormalities from basal cell metaplasia, dysplasia, CIS, microinvasive carcinoma (MIC), and then more invasive diseases [17]. CIS is characterized by intraepithelial invasion without infiltration of the basement membrane; MIC can disrupt the epithelium basement membrane within the confined cartilage layer [21‒24] (shown in Fig. 2). The cartilage layer is an essential structure [22]. Intracartilaginous lesions can benefit from PDT [22, 25, 26]. The majority of intracartilaginous cases show no nodal involvement and are likely to have a favorable outcome [6, 27]. Extracartilaginous cases are unlikely to receive any clinical benefit due to the limited penetration of light [28]. In this instance, debulking before irradiation may improve its effectiveness [16]. Invasion beyond the cartilage layer indicates a high risk of metastasis [21, 29]. Histological findings showed that lymph node metastases occurred in 22.2% of extracartilaginous or extrabronchial cases, and microscopic lymph vessel invasion occurred in 44.4% of cases [21]. Generally, consideration of the depth of tumor invasion into the bronchial wall is crucial when assessing appropriate PDT indications [28, 30].

Fig. 2.

Bronchial structure and the classification of invasion depth. Tumors develop from CIS within the epithelial layer to MIC within the cartilaginous layer and then to IC beyond the cartilaginous layer. CIS, carcinoma in situ; IC, invasive carcinoma; MIC, microinvasive carcinoma.

Fig. 2.

Bronchial structure and the classification of invasion depth. Tumors develop from CIS within the epithelial layer to MIC within the cartilaginous layer and then to IC beyond the cartilaginous layer. CIS, carcinoma in situ; IC, invasive carcinoma; MIC, microinvasive carcinoma.

Close modal

Lesion depth seems to be the most significant influential factor of PDT efficacy for ECLC among depth, length, and appearance. Since the penetration depth of PDT is limited about 0.5–1.0 cm [12]. Some superficial lesions with a diameter of <1.0 cm may invade the cartilaginous layer, and the outcome will be far below expectations [22]. However, the new generation of PSs will potentially overcome obstacles to achieve greater penetration depth [3].

Does the Length of the Lesions Affect the Results?

The major challenge in determining the ideal length of lesions is identifying the length of nonmetastatic tumors. Based on data from surgical specimens, more than 90.0% of tumors smaller than 2.0 cm could present with no lymph node involvement [29, 31]. In contrast, one-quarter or even one-third of tumors larger than 2.0 cm were found to have lymph node involvement [21, 31]. It is therefore reasonable to examine the effects of PDT on tumors within this range (shown in Fig. 3).

Fig. 3.

Relationship between tumor size and complete remission rates of PDT.

Fig. 3.

Relationship between tumor size and complete remission rates of PDT.

Close modal

A phase II study on Photofrin-PDT [32] demonstrated that the length of longitudinal tumor extent was the only independent predictor of CR after PDT. Numerous studies [32‒37] have reported a great disparity in CR rates among lesions ≤0.5 cm (93.1%–100%), lesions ≤1.0 cm (91.3%–97.8%) and lesions >1.0 cm (36.6%–65.5%) in diameter. A long-term follow-up of PDT showed 5- and 10-year OS rates of over 80% and 70% for lesions ≤1.0 cm, respectively [36]. However, survival outcome is perhaps more associated with the baseline performance status and other treatment strategies [35, 37].

NPe6-PDT may be more effective against large tumors measuring >1.0 cm in diameter than Photofrin-PDT. Studies of NPe6-PDT revealed little difference in CR rates between tumors ≤1.0 cm (93.9%–94.3%) and >1.0 cm (80.0%–90.4%) in diameter [16, 38]. However, it may be partially explained by the multiple imaging techniques to define tumor margin and thorough reduction of the intraluminal part of the tumor before NPe6-PDT.

These findings support the widely held opinion that the longitudinal extent of the tumor is critical to the success of PDT, emphasizing the importance of identifying the exact lengths of the lesions. Even so, some cases with large lesions can also achieve potential remission and long-term control through PDT. PDT should be given active consideration in patients with lesions >1.0 cm in diameter, especially if other approaches are not feasible.

Can Different Endoscopic Features Influence Efficacy?

There are three main groups of classifications depending on endoscopic appearances (shown in Fig. 4) [21, 23]:

  • Superficial type with irregular or thickened bronchial epithelium without obvious bulging (<2 mm).

  • Nodular type protruding in localized areas (>2 mm).

  • Polypoid type showing pedunculated lesions.

Fig. 4.

This schematic illustration shows the endoscopic features of lung cancer.

Fig. 4.

This schematic illustration shows the endoscopic features of lung cancer.

Close modal

Previous studies have found a relationship between endoscopic features, invasion depth, and tumor size. Nakamura et al. [21] found that superficial tumors had larger dimensions than polypoid/nodular tumors. In contrast, Konaka et al. [23] analyzed pathologically resected specimens and found that polypoid/nodular tumors were more likely to extend past 1.0 cm in size and invade into/beyond the cartilaginous layer than superficial tumors. The inconsistent results may be due to the different populations studied and the lack of comprehensive comparative analysis of the above three parameters.

Akaogi et al. [39] indicated that superficial lesions <1.5 cm and polypoid/nodular lesions <1.0 cm were at low risk for cartilaginous invasion and metastasis, and over 90% of superficial tumors <1.0 cm in size were CIS. Generally, superficial tumors prefer to extend longitudinally along a greater distance of the bronchial wall, while polypoid/nodular tumors tend to grow deep to the depth of the bronchial layer, so the length of different endoscopic types reaching a certain depth is different.

Hayata et al. [28, 34] reported on 21 early stage cases and then enlarged the sample size to 168 cases and confirmed that PDT was more effective in the treatment of superficial lesions. They also reported CR rates of 93.1% in superficial lesions and 86.8% in nodular lesions when the diameters did not exceed 1.0 cm, but these rates were reduced to 44.1% for superficial and 14.3% for nodular lesions when the diameter exceeded 1.0 cm [34]. Although some polypoid or nodular lesions are likely to be large and extend beyond the cartilaginous layer, the resulting high remission rates when the neoplasm is reduced by ablation technologies look promising [16].

Can the Tumor Stage Predict the Outcome of PDT?

PDT efficacy has a great difference in tumor stage determination. Previous studies showed that the CR rates ranged from 73% to 100% for Tis lesions and from 69.2% to 79.5% for T1 tumors [32, 40]. Early detection and adequate treatment of these lesions are critical in improving survival. In a long-term study, overall survival rates at 5 years (5-year OS) for inoperable patients treated with PDT in stage Tis and T1 disease were 67.0% and 37.5%, respectively [40]. Thus, accurate staging of airway lesions could improve PDT efficacy, benefiting patients with ECLC.

How Can the Tumor Margin Be Confirmed More Accurately?

White light bronchoscopy (WLB) is the most commonly used to determine the tumor margin before performing PDT. The CR rate can reach 88.5%–91.6% for lesions with visible distal margins but is only 57.1%–71.4% for those without visible distal margins [32, 33, 37, 41]. A closer examination is necessary for superficial tumors as they extend further longitudinally than other tumor types [21]. Inadequate estimation of the peripheral tumor margin leads to partial illumination, and it may be responsible for local recurrences at the site near the margin following CR [16, 22, 28, 35, 38]. However, it is difficult to visualize preinvasive lesions solely by conventional WLB [42]. The development of numerous diagnostic and screening technologies is set to facilitate earlier and more accurate detection of tumor invasion.

Autofluorescence bronchoscopy (AFB) can capture tiny changes in the bronchial mucosa that are sometimes missed by WLB and are based on the principle of variations in the fluorescence and light absorption capabilities of the normal and diseased bronchial epithelium [43]. Overall, most studies showed that AFB plus WLB is more sensitive than WLB alone (43%–100% vs. 0%–85%) in detecting preinvasive lesions [20]. A meta-analysis found a pooled sensitivity of 85% for detecting preinvasive lesions with WLB and AFB, compared with 43% with WLB alone, with an overall relative sensitivity of 2.04 [25]. However, AFB may reveal false-positive lesions (e.g., inflammatory) weakening its specificity [44]. The estimated specificities of WLB plus AFB ranged from 4%–94% compared to 36%–94% for WLB alone [20, 45].

In practical clinical applications, however, abnormal lesions’ red color is difficult to distinguish from normal mucosa, which may lead to false negatives [38, 46]. Currently, several simultaneous-display endoscopy systems have been used to detect faint autofluorescence emitted from tumors, including autofluorescence endoscopy-3000® (SAFE-3000®, Pentax, Japan) and ELUXEO 7000® (ELUXEO, Fujifilm, Japan) [16, 17, 38, 46].

Endobronchial ultrasound (EBUS), equipped with a 20- or 30-MHz frequency rotating transducer, is widely used to detect tumor depth and can provide imaging of the bronchial wall structure. It has greater insights into the depth of tumor invasion than computed tomography (CT) imaging [22]. The accuracy of EBUS was 80%–95.8% when compared with histopathologic findings [22, 30]. However, the presence of CIS may not be detectable by EBUS since the tumor is entirely contained within the marginal echo [22]. Radial-EBUS can be used to provide a shallower first marginal echo, thus allowing for a more precise diagnosis of CIS or tumor invasion within the airway’s basement membrane [22, 47].

Optical coherence tomography is an optical imaging technique using near-infrared light to provide 3 mm-resolution images of the bronchial epithelial layer and offer detailed information on intraepithelial lesions [24, 48]. In addition to AFB and EBUS in PDT trials, Optical coherence tomography greatly contributed to confirming whether there was an unevenly distributed area and breach of the layer structure [16, 38].

Advanced Obstructive or Inoperable Lung Cancer

Most of these patients have highly symptomatic diseases with delayed diagnoses that are not suitable for surgery. Chemotherapy, radiation, immunotherapy, and targeted therapy can be used in advanced and inoperable cases to prolong survival time [6]. However, these above therapies are always insufficient to alleviate the airway symptoms and complications of advanced diseases, such as airway obstruction and hemorrhage. The survival rate in patients with airway obstruction is significantly lower than that of those with patent airways [49]. Yi et al. [50] demonstrated a longer median OS (24.1 months vs. 14.9 months) and disease-free survival (DFS, 34.1 months vs. 7.5 months) in patients with a fully reopened bronchial lumen than in those with incomplete reopening after PDT. However, when it comes to severe airway stenosis, PDT alone may be insufficient due to its delayed effect and acute mucosal edema, and thus, combining PDT with other interventions (e.g., lasers, stents) is essential to relieve the obstruction [51]. In addition, PDT may enhance the efficacy of the above traditional antitumor therapies by reducing tumor volume, overcoming drug resistance, and improving response rate to achieve greater survival benefits [3]. Thus, endobronchial interventions are important palliative methods [6, 52], and PDT has become one of the most promising interventional treatments [53]. Noval PDT methods are also developing. A phase I/Il study using EBUS with transbronchial needle guided interstitial PDT in patients with malignant airway obstructions is recruiting (NCT03735095).

Does Tumor Morphology or Histopathology Affect the Therapeutic Effect?

Tumor size measurements have enabled the optimization of the PDT process. Advanced tumors tend to have multiple sites and long extensions [54]. An examination of the treated area and the distal airway is essential for successful treatment. Smaller tumors benefit more from PDT. Studies have demonstrated a significant disparity in local remission rates, with 64%–100% in lesions ≤1.0 cm2, 57%–100% in lesions ≤2.0 cm2, 46%–48% in lesions ≤3.0 cm2, and 0% in lesions >3.0 cm2 in surface area [55, 56].

Tumor depth is important to predict the long-term clinical response to PDT. Lam et al. [57] found a long-lasting positive impact on tumors limited to the mucosa, rather than submucosal/peribronchial lesions (the reduced mean degree of obstruction, 68% vs. 25%; a median duration, 5.5 months vs. 1.8 months). In addition, CT is a reliable tool for assessing the extent of airway distortion distal to a blockage and helps determine whether tumors are intraluminal or extraluminal [57]. However, distinguishing peribronchial tumor extension from the bronchial wall, peribronchial tissue, and atelectasis on CT is challenging [58]. Radionuclide quantitative ventilation-perfusion lung scans can be used in that case. Absent perfusion or a reduction in regional perfusion disproportional to ventilation is associated with poor PDT outcomes [57].

Tumor stage has been regarded as a critical factor affecting survival duration [50]. Sutedja et al. [59] conducted a small retrospective study of 26 patients with inoperable NSCLC and found that 90.9% of patients with stage I disease achieved remission after PDT, but none of the patients with stage III disease did. McCaughan et al. [60] reported data from their 14-year experience to evaluate the survival of 175 patients with inoperable stage I-IV tumors only treated with PDT and found that patients with stage I disease had a 93% 5-year survival rate without reaching the median survival, while those with stage II, IIIa, IIIb, and IV disease had median survivals of 22.5, 5.7, 5.5, and 5.0 months, respectively.

Tumor histology does not appear to correlate with PDT response. Both squamous cell cancer and adenocarcinoma can be successfully treated with PDT [60]. There is no evidence of differences in PDT efficacy among other types of NSCLC. Additionally, patients with SCLC may also benefit from PDT similarly to those with NSCLC, suggesting that these patients should not be excluded from PDT simply based on cancer type [53, 61].

What Is the Impact of Functional Status?

The Eastern Cooperative Oncology Group performance status (ECOG-PS) and the Karnofsky Performance Scale (KPS) classify patients based on their functional status. These scoring systems can be used to compare the efficacy of different therapies and assess individual prognoses [53, 60]. Moghissi et al. [53] showed a significant difference in survival between patients with pretreatment ECOG-PS scores ≤2 and >2 (14 months vs. 4 months). McCaughan et al. [60] demonstrated that a KPS score ≥50 was a significant predictor of survival in patients with stage III and IV disease. Furthermore, they also found that patients with extensive and obstructive tumors could maintain a KPS of 90 for over 5 years with repeated PDT [60]. Thus, PDT can significantly improve the ECOG-PS and KPS scores in NSCLC patients with poor baseline conditions, providing an opportunity to initiate or continue systemic antitumor treatment [10, 53]. Equal opportunities for PDT should be given to patients rather than prioritizing chemo/radiotherapy before their condition worsens.

Peripheral Lung Cancer

Peripheral lung cancer has been detected more frequently because of lung cancer screening recommendations. It is usually diagnosed earlier in a potentially curable stage [62]. Surgical resection remains the primary treatment for peripheral tumors [63]. Stereotactic ablative radiation, a highly conformal external beam technique, is a reasonable choice for medically inoperative patients but is not suitable for those with underlying pulmonary diseases, prior radiation exposure, or tumors close to vital structures [64]. There is a strong rationale for using local ablative methods to treat peripheral lesions [65]. PDT is performed by inserting fibers into the tissue to produce limited irradiation without damaging the parietal pleura or adjacent healthy tissues [66]. The procedure is relatively safe and feasible and is increasingly used for peripheral malignancies.

Bronchoscopic PDT

The newly developed composite optical fiberscope and laser transmission could provide simultaneous imaging and improve the accuracy of targeting peripheral tumors in animal models [67]. This novel device for PDT was subsequently studied in a clinical trial to treat peripheral malignant lesions with a diameter of 1.0–2.0 cm, resulting in a 57.1% rate of complete ablation [63]. The use of electromagnetic navigational bronchoscopy for PDT when treating peripheral lung cancer in dogs was proven effective and safe [68]. This approach was then successfully used to target peripheral nodules 0.8–3.6 cm in diameter and achieve complete ablation in 3 patients [69]. Recently, robotic bronchoscopy has been developed to overcome the natural shortcomings of operators and their vision and stability, providing better prospects for peripheral PDT ablation. This method has been proven to be safe and feasible, with a success rate of 96% in localizing lesions, a diagnostic yield of 69–77% in patients, and a similar adverse event rate to conventional bronchoscopy [70, 71]. An open-label phase 1/1b Study of peripheral lung cancer using padeliporfin vascular targeted PDT assisting with robotic bronchoscopy and cone beam CT guidance is recruiting (NCT05918783).

Percutaneous PDT

Video-assisted thoracoscopic PDT can offer a three-dimensional view of the intrathoracic lesions. It has been used to safely treat advanced peripheral diseases in 3 patients [72]. CT guidance has been adopted for PDT in peripheral lung cancers measuring 1.2–8.0 cm in diameter, resulting in a partial remission rate of 77.8% in 9 patients [73]. However, fiber displacement and unstable fixation were significant obstacles to achieving complete ablation. The percutaneous approach may also result in complications such as pneumothorax, hemorrhage, catheter dislodging, and difficulty targeting the tumor after lung collapse [65].

The application of nanotechnology of PDT in lung cancer has been focused on because of its high selectivity and precise target. PLGA-lipid hybrid nanoparticles loaded with pTHPP have been reported to overcome drug-selected and metastasis-associated multidrug resistance [74].

Increasing evidence has highlighted the role of chemo-photodynamic combinatorial therapy in lung cancer and metastatic sites. PDT and chemotherapy can be delivered simultaneously with chlorin e6 and doxorubicin-loaded with mesoporous silica nanoparticles [75], and pemetrexed loaded with mesoporous polydopamine nanoparticles [76]. The chlorin e6 and cisplatin drugs modified with the mMnO2-coated UCNPs and tumor-targeting pentapeptide were successfully used to treat spinal metastasis of NSCLC [77]. Encapsulating gefitinib-loaded albumin nanoparticles inside cRGD-modified red blood cell membranes is a promising therapeutic formulation for the treatment of lung cancer without obvious systemic side effects [78]. EGFR-expressing NSCLC patients may benefit from near-infrared fluorescence imaging with the ICG-Osi [79].

The combination of PDT and immune checkpoint inhibitors is a promising approach in reducing lung cancer invasion. Radiolabeled 99mTc-PLA/PVA/Atezolizumab nanoparticles reached higher drug concentrations in tumor sites than the nonparticulate atezolizumab [80]. PDT mediated by porphyrin cholesterol conjugates nanoparticles could induce immunogenic cell death, making cancer cells more susceptible to immune checkpoint inhibitors [81].

Short-term complications: The tumor and surrounding normal tissue can slough, swell, and hemorrhage 24–48 h following treatment, leading to cough, hemoptysis, chest pain, and respiratory distress [74, 82]. Complications (e.g., respiratory failure, infection, and hemoptysis) are frequently occurring in advanced-stage patients due to the main airway obstruction and the inability to clear heavy secretions [83]. Therefore, caution is needed in the treatment of main airway obstruction. Debridement/clean-up bronchoscopy is often necessary within 1–3 days, and preparation for debridement should be performed at any time in the first week [83]. Perforation is rare due to the limited penetration depth of light. Pneumothorax may occur spontaneously during coughing episodes in patients with peripheral lesions who undergo percutaneous lung puncture and in those with severe COPD [54, 73]. Drug allergic reaction is usually ruled out by performing a skin test for PS prior to injection.

Long-term complications: Skin photosensitivity appears because of the aggregation of PSs in the skin. It is the major complication occurring in approximately 3–31% of PDT patients [26, 32, 84]. The development of PSs can reduce the incidence and duration. In photofrin-PDT, photosensitivity occurs in up to 4–6 weeks after injection and may result in skin hyperpigmentation [32, 84, 85]. In NPe6-PDT, the duration of photosensitivity is reduced to 15–18 days without hyperpigmentation [41]. In HPPH-PDT, protection against light exposure is only required for 7–10 days post-PDT [26]. Infection and fever are mild and transient [54]. Fistula formation is rare but may occur in patients undergoing multiple or multidisciplinary procedures [85]. Localized scarring and fibrosis may occur in the surrounding tissues [74].

Close observation is crucial after PDT. Microscopic residual tumor cells may be detected through histological examinations of specimens resected after PDT, even with apparent CR based on endoscopic and biopsy findings [28]. For recurrent lesions or residual lesions, repeat PDT can be performed over the next 3–5 days since the PSs are selectively retained in malignant tissue for a longer period than in normal mucosa [86].

We have presented an overview of the PDT modality of most clinical scenarios. The focus is set on influence factors on the efficacy of PDT. The influence of PDT on ECLC is highly dependent on the lesion length, depth, endoscopic appearances, tumor stage, and lesion margin sharpness. We identified that the main challenges or limitations of advanced or inoperative lung cancer are the tumor size, depth, stage, and functional status. We also noted the necessity to properly target the peripheral lesions using novel technologies for a better comparison between results. Each PDT modality offers specific treatment capabilities rather than a universal solution. It may find specific niches and be used in individualized management strategies. Obviously, the recognition of the multiplicity of factors influencing PDT effects is beneficial for lung cancer treatment, and emerging technologies break new ground for improving PDT.

We thank to all staff in respiratory department and specialists of bronchoscopic intervention.

The authors have no conflicts of interest to declare.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Wen Sun: conceptualization (lead), formal analysis (equal), investigation (equal), project administration (equal), resources (equal), writing – original draft (lead), and writing – review and editing (equal). Qi Zhang: project administration (equal), supervision (equal), visualization (equal), and writing – review and editing (equal). Xi Wang: conceptualization (equal), project administration (equal), supervision (equal), validation (equal), visualization (equal), writing – review and editing (equal). Zhou Jin: investigation (equal), project administration (equal), visualization (equal), and writing – review and editing (equal). Yuan Cheng: conceptualization (equal), investigation (equal), project administration (equal), supervision (equal), visualization (equal), and writing – review and editing (equal). Guangfa Wang: conceptualization (equal), methodology (equal), project administration (equal), supervision (equal), visualization (equal), writing – original draft (equal), and writing – review and editing (equal).

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