Therapeutic Bronchoscopic Intratumoral Injection in Lung Cancer: Current Advances, Challenges, and Opportunities for Resource-Limited Settings

Abstract

Lung cancer remains the leading cause of cancer-related deaths globally, with a high burden in Southeast Asia, including Indonesia. Conventional treatments, including surgery, radiotherapy, and systemic chemotherapy, are often limited by patient factors such as multifocal disease, poor pulmonary reserve, or central airway obstruction. This review explores bronchoscopic intratumoral injection as a novel, localized therapeutic strategy and assesses its feasibility in resource-limited settings. We conducted a narrative synthesis of recent literature on bronchoscopic intratumoral injection techniques, therapeutic agents, clinical outcomes, and implementation challenges. Additional focus was placed on the Indonesian healthcare context, particularly the infrastructure in West Sumatra. Bronchoscopic intratumoral injection delivers chemotherapeutic, immunologic, or gene-based agents directly into tumors using flexible bronchoscopy, including transbronchial needle injection, endobronchial ultrasound-guided injection, and cone-beam computed tomography. This approach achieves high local drug concentrations with minimal systemic toxicity, shifting the paradigm toward immune modulation and durable tumor control. Clinical outcomes include improved airway patency, lung function, symptom relief, and survival in patients ineligible for standard therapies. Feasibility in Indonesia is supported by existing clinical resources and agent availability. Despite challenges, such as limited access to advanced imaging, specialized equipment, and skilled personnel, bronchoscopic intratumoral injection may represent a promising investigational strategy in selected cases. Further research is warranted before routine clinical implementation can be contemplated. Strategies such as structured training and regional collaboration can bridge implementation gaps, aligning innovation with equitable lung cancer care in developing countries.

Resumen

El cáncer de pulmón sigue siendo la principal causa de mortalidad relacionada con el cáncer en el mundo, con una carga muy elevada en el Sureste Asiático, en particular en Indonesia. Los tratamientos convencionales—como la cirugía, la radioterapia y la quimioterapia sistémica—suelen verse limitados por factores asociados al paciente, como la enfermedad multifocal, la escasa reserva pulmonar o la obstrucción de las vías respiratorias centrales. En esta revisión se analiza la inyección intratumoral broncoscópica como una estrategia novedosa de tratamiento localizado y se evalúa su viabilidad en los entornos con recursos limitados. Se llevó a cabo una síntesis narrativa de la bibliografía reciente sobre las técnicas de inyección intratumoral broncoscópica, los fármacos, los resultados clínicos y las dificultades de aplicación. Se prestó especial atención al contexto sanitario indonesio, sobre todo a las infraestructuras de Sumatra Occidental. Con las inyecciones intratumorales broncoscópicas se administran antineoplásicos, inmunomoduladores o genofármacos directamente en los tumores mediante técnicas de broncoscopia flexible, como la inyección transbronquial con aguja, la inyección guiada por ecografía endobronquial y el TAC de haz cónico. De esta forma se consiguen concentraciones locales elevadas del fármaco con una toxicidad sistémica mínima, lo que supone un cambio de paradigma y permite la modulación inmunitaria y el control duradero del tumor. Los principales resultados clínicos son el aumento de la permeabilidad de las vías respiratorias, la mejora de la función pulmonar, el alivio de los síntomas y la supervivencia de pacientes que no cumplen los criterios para recibir los tratamientos habituales. La viabilidad de esta técnica en Indonesia se justifica por los recursos clínicos existentes y la disponibilidad de medicamentos. Pese a las dificultades, como el acceso limitado a las técnicas avanzadas de imagen, a los equipos especializados y al personal cualificado, la inyección intratumoral broncoscópica puede ser una estrategia experimental prometedora para casos seleccionados. Antes de proceder a su aplicación clínica sistemática es necesario realizar más estudios. Las dificultades de aplicación pueden mitigarse adoptando estrategias como la formación estructurada y la colaboración regional, para que la innovación redunde en un tratamiento del cáncer de pulmón más equitativo en los países en desarrollo.

Introduction

Lung cancer remains the leading cause of cancer-related death worldwide, accounting for approximately 2.48 million new cases and 1.82 million deaths annually, with a disproportionate burden in Asia.¹ In Southeast Asia, it is the most common cancer among men and the top cause of cancer mortality in several countries, including Indonesia, Malaysia, the Philippines, and Singapore.² In Indonesia, more than 80% of newly diagnosed lung cancer cases present at an advanced stage, often precluding curative options such as surgery or radiotherapy. This is largely due to the absence of a government-funded screening program and the limited accessibility of diagnostic tools such as computed tomography (CT) and positron emission tomography-CT in many provinces.³ In West Sumatra, a recent study found that only one-third of patients with advanced non-small cell lung cancer (NSCLC) achieved 1-year survival despite receiving standard chemotherapy, underscoring the urgent need for more effective, locally deliverable therapies to improve outcomes in this setting.⁴

For many patients, particularly those with early-stage, multifocal disease or compromised pulmonary function, standard surgical resection or systemic therapy may be unsuitable. As a result, there is increasing emphasis on parenchymal-sparing, locally delivered treatments such as stereotactic body radiation therapy, thermal ablation, and bronchoscopic interventions.⁵ Among these, bronchoscopic intratumoral injection has emerged as a novel and promising technique.

Bronchoscopic intratumoral injection enables the direct delivery of therapeutic agents, chemotherapeutic, immunomodulatory, or gene-based agents, into endobronchial tumors using flexible or guided bronchoscopy.^6,7 This localized approach offers several theoretical advantages: maximizing drug concentration within the tumor microenvironment, minimizing systemic exposure, and overcoming immune evasion mechanisms. Recent work suggests that bronchoscopic intratumoral injection may shift treatment paradigms from tumor debulking toward immune modulation and long-term control.⁷ The therapeutic role of endobronchial interventions continues to expand, not only as palliative tools but increasingly as components of individualized, multimodal treatment regimens.⁸ As bronchoscopic intratumoral injection gains traction across preclinical and clinical settings, particularly in Asia, where the burden of lung cancer is highest, its refinement and integration into standard care protocols warrant further investigation.

This narrative review explores the clinical rationale, current applications, procedural techniques, therapeutic agents, clinical outcomes, and future perspectives of bronchoscopic intratumoral injection in lung cancer.

Methods

A narrative review was conducted by searching PubMed and Google Scholar up to March 2025 using the keywords: “bronchoscopic intratumoral injection”, “endobronchial injection”, “intratumoral chemotherapy”, “lung cancer”, and “interventional pulmonology”. Articles were included if they were published in English and involved human or relevant preclinical studies focusing on bronchoscopic intratumoral injection in primary or metastatic lung cancer. Study types included case reports, cohort studies, clinical trials, and narrative reviews. Studies unrelated to lung malignancies or employing non-bronchoscopic techniques were excluded. The synthesis focused on key information covering clinical reasons for treatment, how procedures were performed, therapeutic agents used, patient outcomes, and recommendations for future research directions.

Overview of interventional bronchoscopy in lung cancer

Interventional bronchoscopy has become an essential therapeutic modality in managing airway tumors, particularly in patients with central airway obstruction. Established techniques such as electrocautery, argon plasma coagulation (APC), Nd: YAG laser, cryotherapy, photodynamic therapy (PDT), and stent placement are primarily aimed at debulking tumors and restoring airway patency to relieve symptoms.⁸ These mechanical or ablative methods typically offer rapid, if temporary, relief.

In recent years, the scope of interventional bronchoscopy has evolved with the emergence of precision-guided therapies. Navigation bronchoscopy, cone-beam CT, radial probe endobronchial ultrasound, and robotic platforms have enabled access to peripheral and complex lesions, facilitating not only diagnosis but also targeted intratumoral therapies.^9,10

Among recent innovations, bronchoscopic intratumoral injection signifies a clear evolution from purely palliative methods to pharmacological therapies. Compared to ablative procedures, this approach allows medications to be administered directly into the tumor, maximizing local drug concentration while minimizing systemic side effects.¹¹ A study from West Sumatra comparing fiberoptic bronchoscopy under general versus local anesthesia found that the majority of therapeutic bronchoscopic procedures, including forceps biopsy and cryobiopsy, are increasingly performed in high-risk patients with central lesions, reinforcing the clinical relevance and safety considerations of bronchoscopic therapeutic approaches in developing settings.¹²

Multiple narrative reviews have emphasized the growing role of bronchoscopic intratumoral injection in both central and peripheral tumors, especially as a complement to systemic therapy or thermal ablation.^5,6,13 The evolution of endobronchial injection from early chemotherapeutic trials to ongoing gene and immunotherapy protocols reflects the broader transformation of bronchoscopy from a purely mechanical tool into a platform for targeted and biologically active interventions.

Clinical indications for bronchoscopic intratumoral injection

Standard therapy for lung cancer includes surgical resection, radiation therapy, and systemic therapy with chemotherapy, targeted agents, or immunotherapy, depending on stage and molecular profile. These treatments may serve curative (definitive) or palliative purposes.¹⁴ While bronchoscopic interventions, such as stenting and thermal ablation, are widely used for symptomatic relief, bronchoscopic intratumoral injection has emerged as a promising adjunct or alternative approach in selected cases. By delivering therapeutic agents directly into tumor tissue under bronchoscopic guidance, this technique offers the potential for localized drug delivery, reduced systemic toxicity, and modulation of the tumor microenvironment. Although it is not yet part of standard therapy, its use has expanded across various clinical contexts.⁶ Based on a synthesis of published literature, the therapeutic applications of bronchoscopic intratumoral injection can be grouped into 4 categories: adjunct to standard therapy; alternative to standard therapy; investigational or translational applications; and other clinical scenarios.

Adjunct to standard therapy

Malignant central airway obstruction (CAO) is a life-threatening condition that requires immediate intervention to restore airway patency and improve clinical outcomes. Jiang et al. demonstrated that bronchoscopic intratumoral injections of cisplatin and recombinant human endostatin (Endostar®) effectively alleviated symptoms of dyspnea in patients with unresectable NSCLC, with all patients showing improvement in airway patency following the procedure and systemic chemotherapy.¹⁵ Similarly, Ji et al. showed that the combination of Endostar® and cisplatin administered intratumorally improved both short- and long-term therapeutic efficacy in patients with unresectable lung squamous cell carcinoma when used as an adjunct to chemoradiotherapy, without causing significant adverse effects.¹⁶ These findings support the use of bronchoscopic intratumoral injection as a bridging or adjunctive approach in patients with malignant CAO who are not candidates for immediate curative treatment.

Bronchoscopic intratumoral injection may serve as an initial local intervention to optimize subsequent standard therapy in selected patients with central airway tumors. Celikoglu et al. reported that endobronchial chemotherapy enabled downstaging of inoperable T3/T4 polypoid tumors near the carina, allowing reclassification to resectable T1 lesions.¹⁷ The authors further noted that asymptomatic lesions with <50% narrowing benefited from debulking, improving surgical margins and postoperative outcomes.¹¹ In another clinical scenario, Li et al. demonstrated that local treatment using endobronchial ultrasound (EBUS)-guided cisplatin injection, APC, and cryotherapy in a patient with severe chronic obstructive pulmonary disease improved functional status and airway patency, ultimately allowing the administration of low-dose systemic chemotherapy.¹⁸ These cases collectively support the strategic role of intratumoral injection in facilitating the transition to standard oncologic therapy.

In patients experiencing locoregional recurrence of lung cancer following systemic therapy or radiotherapy, bronchoscopic intratumoral injection has emerged as a viable salvage strategy. Kinsey et al. treated 38 patients with recurrent disease post-radiotherapy using EBUS-transbronchial needle injection (TBNI) cisplatin injection, aiming for local tumor control and avoidance of further systemic treatment.¹⁹ The intervention provided palliation and was supported by radiomics-based analysis. Similarly, Mehta & Jantz employed EBUS-guided cisplatin injections in cases of isolated mediastinal or hilar recurrence of NSCLC or small cell lung cancer after external beam radiation therapy in patients who mostly lacked additional local treatment options.²⁰ Multidisciplinary consensus guided the decision for this intervention, underscoring its role as a personalized adjunctive approach in challenging clinical scenarios.

Alternative to standard therapy

Bronchoscopic intratumoral injection has demonstrated potential as a non-systemic alternative in patients with malignant CAO who are ineligible for surgery, chemotherapy, or radiotherapy. Wang et al. described a case of tracheal papillary squamous cell carcinoma treated successfully with Endostar®-cisplatin injection after tumor debulking, resulting in 2 years of recurrence-free survival in a patient unfit for standard therapies due to poor performance status and tumor location.²¹ Supporting this, Celikoglu et al. conducted a case series of 65 patients, showing that intratumoral 5-FU achieved a 52.3% rate of >50% airway lumen restoration and symptom relief, particularly in patients without prior systemic therapy.²² Likewise, Mehta et al. reported that among 22 patients receiving endobronchial cisplatin, over 70% achieved a significant reduction in airway obstruction, with notable survival improvement in responders, even when used as monotherapy.²³ These findings collectively highlight that, beyond the adjunctive setting, intratumoral chemotherapy can serve as a feasible, effective standalone strategy for palliation and tumor control in highly selected patients lacking standard treatment options.

Residual tumor or symptomatic airway narrowing after conventional debulking in patients who are ineligible for standard systemic therapy may be managed with bronchoscopic intratumoral injection. In a multicenter pilot study, Yarmus et al. (2019) administered intratumoral paclitaxel following airway recanalization via rigid bronchoscopy, without any subsequent systemic therapy. All treated patients maintained airway patency during 12 weeks of follow-up without restenosis or additional intervention.²⁴ Similarly, Jantz et al. (2021) reported that alcohol injection following mechanical debulking or APC resulted in >50% improvement in airway diameter in most patients, despite the absence of chemotherapy or radiotherapy.²⁵ These findings support the use of intratumoral injection as a local consolidative strategy after initial mechanical intervention in patients unfit for standard oncological treatment.

Investigational or translational applications

Bronchoscopic intratumoral injection has been explored for translational and investigational purposes in NSCLC. Ishibashi et al. administered intratumoral injections of αGalCer-pulsed antigen-presenting cells as immunotherapy in 21 patients with advanced or recurrent NSCLC refractory to standard therapies, aiming to induce tumor-specific immune responses.²⁶ Swisher et al. evaluated Adp53 gene injections in 28 advanced NSCLC patients with p53 mutations after failure of conventional treatments, including 5 cases targeting endobronchial tumors via bronchoscopic delivery.²⁷ Ter Woerds et al. used bronchoscopic intratumoral injection to facilitate sentinel lymph node mapping in early-stage NSCLC patients prior to surgical resection, aiming for improved preoperative localization and individualized treatment planning.¹⁰ These studies illustrate the investigational use of bronchoscopic intratumoral injection as a promising strategy in immunotherapy, gene therapy, and diagnostic support.

Other clinical scenarios

Bronchoscopic intratumoral injection of tranexamic acid has demonstrated benefit in managing biopsy-induced bleeding in malignant CAO. Zamani et al. reported 2 cases where intratumoral injection of 250–500 mg of tranexamic acid via a 22G needle effectively stopped active bleeding, allowing multiple deep biopsies.²⁸ In a prospective series involving 57 patients, 35.1% experienced significant bleeding after the first biopsy attempt.²⁹ Intratumoral injection was used successfully in necrotic or hypervascular lesions, including patients on dual antiplatelet therapy, supporting its role as a bleeding control strategy during bronchoscopic procedures in malignant CAO (Table 1).

Table 1.

Summary clinical indications for bronchoscopic intratumoral injection.

Adjunct to standard therapy

• Life threatening malignant central airway obstruction.^15,16 • Central airway tumor with poor performance status, where local control may enable systemic therapy.^18 • Asymptomatic airway lesions with <50% narrowing, to improve resectability and postoperative outcomes.^11,17 • Locoregional recurrence after systemic therapy or radiotherapy.^19,20

Alternative to standard therapy

• Central airway tumors in patients who are medically inoperable or ineligible for standard systemic therapy due to tumor invasion, comorbidities, or poor performance status.^21–23,30 • Residual tumor or symptomatic airway narrowing after conventional debulking in patients who are ineligible for standard systemic therapy.^24,25

Investigational or translational applications

• Advanced/recurrent Lung Cancer with prior failure of standard treatment: Experimental immunotherapy or gene therapy.^26,27 • Early-stage resectable lung cancer: Tracer injection for sentinel lymph node mapping.^10

Other clinical scenarios

• Bleeding-prone tumors that interfere with safe biopsy or airway visualization.^28,29

Bronchoscopic intratumoral injection: agents, techniques, and outcome

Bronchoscopic intratumoral injection has emerged as a promising local therapy for lung cancer, enabling direct delivery of high-concentration agents into tumor tissue with reduced systemic toxicity. The method offers a pharmacologically active alternative or adjunct to standard therapies, particularly for centrally located NSCLC with endobronchial involvement. Agents studied range from conventional cytotoxics, such as cisplatin and mitomycin-C, to immunotherapies and anti-angiogenic drugs.¹¹ The approach is technically feasible via flexible or rigid bronchoscopy using TBNI or direct intraluminal injection, and has demonstrated rapid effects in tumor debulking, airway recanalization, and symptom relief.^7,9,13

Recent narrative reviews and interventional reports have highlighted the diversity of injected agents and the evolution of bronchoscopic techniques. In addition to conventional TBNI, several studies report the use of advanced guidance methods such as EBUS, cone-beam CT for real-time targeting, and even customized or modified injection needles to enhance tissue penetration and drug distribution.^7,11,13 These innovations improve procedural accuracy and expand the applicability of intratumoral injection to tumors in challenging anatomical locations. In many reports, injection is combined with other modalities such as cryotherapy or APC to optimize airway patency and treatment response.⁹

In addition, a recent case report demonstrated that dual debulking with para toluenesulfonamide (CLEAR-DUAL-PTS) restored airway patency with sustained clinical improvement in central airway obstruction.³³

Table 2 summarizes selected original studies and case reports that employed bronchoscopic intratumoral injection as part of lung cancer management. The table focuses on agents used, delivery techniques, and reported clinical outcomes to illustrate the diversity and evolving role of this interventional modality in thoracic oncology.

Table 2.

Summary of Bronchoscopic Intratumoral Injection Agents, Techniques, and Clinical Outcomes in Lung Cancer.

Author (year)	No. of patients	Agents (volume)	Techniques	Outcome
Swisher et al.^27 (1999)	28	Adp53(1 × 10^2 PFU to 1 × 10^11 PFU)	Ad-p53 was administered by intratumoral injection either percutaneously under CT guidance or via bronchoscopy, repeated monthly for up to six sessions	Among 25 evaluable patients with advanced NSCLC, 2 (8%) showed partial response and 16 (64%) had stable disease lasting up to 14 months, with minimal vector-related toxicity and evidence of p53 transgene expression and increased tumor apoptosis in posttreatment biopsies.
Weill et al.^31 (2000)	12	Adp53(1 × 10^6 PFU to 1 × 10^11 PFU)	Adp53 was injected directly into endobronchial tumors via bronchoscopy using a fine needle, repeated every 28 days for up to six cycles, with injection volume adjusted by tumor size (3–10 mL)	Among 12 patients with advanced NSCLC, 3 achieved partial response and 4 had stable disease, while 6 patients experienced significant relief of airway obstruction with minimal vector-related toxicity
Khan et al.^32 (2024)	3	Cisplatin (20 mg)	A single dose of cisplatin was injected intratumorally using a 19 G EBUS needle during the same bronchoscopy session as diagnostic tissue acquisition, with real-time EBUS and cone-beam CT guidance to ensure accurate needle placement	No dose limiting toxicities were observed among the three patients, and the procedure was deemed safe and feasible as a neoadjuvant approach for stage IV NSCLC
Ji et al.^16 (2023)	20	Cisplatin (20 mg) and Endostar (15 mg)	Under sedation and propofol–remifentanil anesthesia, endostar and cisplatin were injected alternately (0.5 mL per dose, depth 3–4 mm) into 4–6 sites at the center and periphery of residual tumors via flexible bronchoscope on days 3 and 10 of each chemotherapy cycle, following bronchoscopic ablation	Among 20 patients receiving the injections, the treatment group showed significantly higher complete and significant remission rates (CRR 90%, CBR 100%) and improved median progression-free survival (8.0 vs. 4.8 months) compared to conventional chemoradiotherapy alone, without a notable increase in adverse events
Jiang et al.^15 (2022)	10	Cisplatin (20 mg) and Endostar (15 mg)	Following bronchoscopic tumor debulking, cisplatin and Endostar were injected into 4–6 intratumoral sites (0.5 mL each, 3–4 mm depth) using a bronchoscope-specific injection needle, with 4 total sessions per patient: the first on the day of debulking, and subsequent doses on days 2, 6, and 10 post systemic chemotherapy	All 10 patients showed significant and sustained airway reopening, improved FEV1/FVC ratio, increased KPS scores, and reduced dyspnea at 3 months post-treatment, with a 90% clinical remission rate and no serious adverse effects
Wang et al.^21 (2021)	1	Cisplatin (20 mg) and Endostar (15 mg)	Cisplatin and Endostar were injected into six submucosal sites every 21 days for four cycles. Procedures included APC, cryotherapy, and snare excision.	The tumor was completely eliminated after four sessions of bronchoscopic intratumoral injection with Endostar and cisplatin combined with electrotomy, APC, and cryotherapy. No recurrence was observed during the 2-year follow-up period, and the patient remained in good condition with stable renal and liver function
Li et al.^18 (2017)	1	Cisplatin (4 mg/mL)	Combined intraluminal injection via NM-200L needle and extraluminal delivery via EBUS-TBNI using a 21-gauge NA-201SX-4021 needle were performed, guided by Doppler to ensure avascularity. A total of four EBUS-TBNI sessions were completed within 6 weeks, alongside adjunctive argon plasma coagulation and cryotherapy.	The patient's FEV1 improved from 1.24 L (43% predicted) to 1.56 L, FEV1/FVC ratio increased to 51.9%, and MVV reached 64.0 L/min. CT at week 16 showed >50% tumor shrinkage with fully re-established patency of the left upper lobe bronchus and no evidence of progression
Mehta & Jantz^20 (2017)	35	Cisplatin (maximum 40 mg)	Under conscious sedation, cisplatin was injected via EBUS-guided transbronchial approach using a 22 G needle into 1–2 lesions per session (10 mg per puncture, 4 punctures per lesion), repeated weekly for 4 session	Among 35 evaluable patients, 69% had complete or partial response, and responders had significantly longer median survival (10 vs 6 months, p = 0.029) with no severe toxicity reported
Mehta et al.^23 (2015)	22	Cisplatin (maximum 40 mg)	Cisplatin was injected via flexible bronchoscope using a 19G Wang needle into visible endobronchial tumors (1–4 injections per lesion in a fanning pattern), with up to 4 weekly sessions; pre-injection debulking using forceps or APC was performed when necessary, and residual drug was suctioned after the procedure	Of 21 evaluable patients, 71.4% achieved ≥50% reduction in airway obstruction, 11 of 16 with atelectasis had improved aeration, and no significant adverse events or airway complications were reported
Celikoglu et al.^17 (2006)	17	Cisplatin (up to 40 mg)	Seventeen patients underwent four weekly sessions of cisplatin injection via flexible bronchoscope using a 19–21G retractable needle, with multiple punctures per session in a fanning technique, combined with piecemeal tumor debridement using forceps	All patients experienced complete reopening of the collapsed lung and elimination of endobronchial tumor mass, allowing curative surgical resection without postoperative complications, with a 3-year survival rate of 65%
Kinsey et al.^19 (2020)	38	Cisplatin (up to 40 mg)	Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) of cisplatin was performed directly into recurrent lung tumors using a convex-probe EBUS, guided by prior CT-based tumor segmentation.	Among 38 treated lesions, 71% showed complete or partial radiographic response per RECIST criteria
Jantz et al.^25 (2021)	42	Dehydrated alcohol (3–5 ml)	Dehydrated alcohol was injected into endobronchial tumors using a 19–22 G Wang needle through a flexible bronchoscope in 1–2 passes per session, often after mechanical or thermal debulking, with repeat bronchoscopy performed within 2–7 days as needed	Among 34 evaluable patients, 82% achieved ≥50% airway patency, with alcohol-induced tissue necrosis facilitating tumor removal in follow-up procedures; no significant complications were directly attributed to alcohol injection
Yarmus et al.^24 (2019)	10	Paclitaxel (1.5 mg)	Following rigid bronchoscopy and mechanical recanalization, a 34-gauge microneedle balloon catheter was inserted through a flexible bronchoscope to deliver 3 to 4 circumferential submucosal injections of paclitaxel	No procedure-related adverse events occurred; airway stenosis significantly improved post-procedure (from 75–90% to 25–50%) and remained stable at 6 weeks, with no restenosis or need for stenting
Li et al.^30 (2016)	88	Para–toluenesulfonamide	Para-toluenesulfonamide (PTS) was injected intratumorally via flexible bronchoscopy using a 21-gauge retractable needle. The procedure involved multiple puncture sites (2–3) targeting the root of the tumor with fanning injection, guided by prior CT and bronchoscopy. Injections were performed weekly for 2–4 sessions, with cumulative volume based on tumor size.	Among 88 patients with severe malignant airway obstruction, the objective response rate was 59.1% by CT and 48.9% by bronchoscopy on day 7. FEV1 increased by a mean of 0.27 L. Atelectasis resolution occurred in 42.9% of cases. Median overall survival was 394 days. Improvements in FACT-LCS and BDI scores were observed. No major complications occurred, and treatment-related adverse events were mild and self-limiting.
Tan et al.^33	1	Para–toluenesulfonamide	Five session bronchoscopic dual debulking combining electrocautering snaring and intratumoral para-toluenesulfonamide (PTS) injection (4–5.25 mL/session) including EBUS-guided extraluminal injection. Cryoextraction and APC were used adjunctively.	Airway patency restored after the sessions with marked clinical and radiological improvement. Patient remained symptom-free without adverse events.
Tursz et al.^34 (1996)	6	rAd.RSVβ-gal(1 × 10^7 PFU to 1 × 10^8 PFU)	A single 2.1 mL intratumoral injection of rAd.RSVβ-gal was delivered via fiberoptic bronchoscopy using a 21-gauge needle, with the virus dispersed at deep, intermediate, and superficial layers of the endobronchial tumor	Among six patients with inoperable lung cancer, four showed objective tumor responses (two complete, two partial), and recombinant gene expression (β-gal) was detected in biopsy samples from three patients without serious toxicity
Zamani^29 (2014)	20	Tranexamic acid (250–500 mg in 2.5 mL)	In 20 patients with active bleeding from necrotic or hypervascular endobronchial tumors, intratumoral tranexamic acid was injected via a 22-gauge Wang cytology needle into 2–7 sites per lesion during bronchoscopy, followed by forceps biopsies after 2–3 minutes of hemostasis waiting time	All 20 patients underwent 3–10 forceps biopsies without active bleeding or complications, including two patients on continuous dual antiplatelet therapy
Ishibashi et al.^26 (2020)	21	α-Galactosylceramide-pulsed autologous APCs (1 × 10^8 to 1 × 10^9 cells/injection)	Bronchoscopic intratumoral or intranodal injection of autologous antigen presenting cells pulsed with α-galactosylceramide was performed once or twice under fluoroscopic or endobronchial ultrasound guidance	Of 19 evaluable patients, one showed partial response, eight had stable disease, and ten experienced progressive disease, with increased peripheral iNKT cell counts and IFN-γ production observed in subsets of responders

APC: argon plasma coagulation; BDI: beck depression inventory; CT: computed tomography; CBR: clinical benefit rate; CRR: complete response rate; EBUS: endobronchial ultrasound; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; KPS: Karnofsky performance status; MVV: maximal voluntary ventilation; NSCLC: non-small cell lung cancer; PFU: plaque-forming unit; TBNI: transbronchial needle injection.

The future of bronchoscopic intratumoral injection in developing countries

While national guidelines in Indonesia recommend CT-based lung cancer screening for high-risk populations, such programs remain largely inaccessible due to cost, uneven infrastructure, and lack of insurance coverage. Therefore, therapeutic options that address late-stage presentation remain a public health priority.³ Bronchoscopic intratumoral injection is a highly promising therapeutic innovation, particularly suited for developing countries, where lung cancer remains a leading cause of morbidity and mortality, yet resources for advanced systemic therapies and surgical interventions are limited. The direct delivery of therapeutic agents into tumor tissues provides an opportunity to achieve high local drug concentrations, reduce systemic toxicity, and improve patient outcomes at lower costs than conventional systemic treatments. This approach could significantly enhance accessibility to effective patient treatment in resource-constrained settings.

However, the successful implementation of bronchoscopic intratumoral injection in developing countries faces several challenges, including limited availability of specialized bronchoscopic equipment and therapeutic agents such as advanced biologics or gene-based therapies. Additional barriers include inadequate infrastructure, shortage of trained interventional pulmonologists, and logistical challenges associated with drug storage and preparation. Addressing these limitations requires investment in capacity building, standardized training programs, and regional collaboration to facilitate technology transfer and local adaptation of this innovative treatment approach.

Indonesia, specifically West Sumatra, exemplifies both the challenges and opportunities associated with adopting bronchoscopic intratumoral injection. At our center in West Sumatra, several therapeutic agents discussed in this narrative review are already available, and the implementation of various techniques described herein is feasible. Given the notably low survival rates of lung cancer patients in this region, particularly those suffering from malignant CAO, there is a strong impetus to further develop and adopt bronchoscopic intratumoral injection as part of routine clinical care. We can substantially advance this technique through strategic investment in local training, infrastructure, and regional collaborations, ultimately enhancing patient outcomes and setting a replicable example for other resource-limited settings.

Bronchoscopic intratumoral injection holds investigational promise as a cost-effective and minimally invasive strategy for selected patients in developing countries. However, its integration into routine clinical care requires further validation. Collaborative trials, standardized protocols, and implementation studies are needed to assess its safety, efficacy, and feasibility. While early-phase reports are encouraging, current evidence is largely limited to phase I–II trials and small case series. Broader adoption will depend on stronger clinical data and real-world applicability.

Implementing bronchoscopic intratumoral injection in resource-limited settings poses significant logistical and financial challenges. The cost of injectable agents, including chemotherapeutics or immunomodulators, remains high, and these products are often unavailable through national formularies. Furthermore, the procedure requires trained personnel proficient in advanced bronchoscopic techniques or CT-guided interventions, which are concentrated in urban referral centers. Equipment such as flexible bronchoscopes with injection needles, fluoroscopy or radial EBUS guidance, and dedicated endoscopy units add to the complexity. These barriers necessitate a phased implementation strategy, focusing on pilot programs, skill-building initiatives, and context-specific clinical pathways to ensure safe and equitable deployment. Nonetheless, the optimal technique that balances precision, therapeutic effect, and cost-effectiveness remains under active investigation. Simplified protocols using standard flexible bronchoscopy and accessible injection tools may enable broader implementation in selected centers, particularly in settings with limited resources. This suggests that bronchoscopic intratumoral injection continues to hold significant promise as the field evolves.

Conclusion

Bronchoscopic intratumoral injection is an emerging investigational approach that may have future therapeutic value in lung cancer care, particularly for developing countries, by enabling high local drug concentrations, reducing systemic toxicity, and offering a cost-effective alternative or adjunct to standard therapies. Despite challenges such as limited resources, infrastructure, and trained personnel, its significant potential warrants further development, especially in regions with high lung cancer burdens like Southeast Asia, and Indonesia in particular.

Artificial intelligence involvement

Assistance from generative artificial intelligence tools was limited to language refinement and formatting suggestions. All content was critically reviewed and authored by the listed authors.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Dimas Bayu Firdaus contributed to the conceptualization, literature review, and manuscript writing. Oea Khairsyaf supervised the clinical aspects and provided critical revision.

Russilawati Russilawati guided the overall study design and final manuscript approval.

Conflict of interest

The authors declare that they have no conflicts of interest related to the content of this manuscript.