I-125 brachytherapy for early-stage non-small cell lung cancer

Edited by: Peifang Wei

Lung cancer is the most frequent cause of cancer-related death worldwide,¹ with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases.² However, despite continuous advances in surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, the overall 5-year survival rate remains at approximately 19% and decreases significantly with disease progression.³ Most patients are diagnosed at advanced stage, though early detection significantly improves survival outcomes.^4,5 Lobectomy remains the standard treatment for early-stage NSCLC but may cause postoperative complications.⁶ Chemotherapy and radiotherapy serve as cornerstone therapies but are constrained by toxicity profiles, resistance development, and dose-limiting challenges.⁷ These limitations underscore the urgent need to identify safer and more effective treatment strategies for early-stage NSCLC.

Brachytherapy (BT) is a key radiation treatment that involves placing radioactive sources directly into the patient's body, either within a lumen or in the tissue itself. This technique delivers a high dose of radiation precisely to the target area while minimizing damage to surrounding healthy tissues, which is not achievable with external beam radiotherapy or stereotactic body radiotherapy. Iodine-125 (I-125), a radioactive isotope with a short half-life and low-energy emissions, is commonly used as the radiation source in BT. The I-125 seeds are approximately 4.5 ± 0.5 mm in mean length, with a palladium core encapsulated by I-125 and a titanium alloy shell sealed by laser technology. I-125 decays via electron capture, releasing both electrons and photons. The titanium shell absorbs the electrons, while the photons primarily emit X-rays (27.4 keV, 31.4 keV) and gamma-rays (35.5 keV). The gamma-rays have a low dose rate and limited tissue penetration (17 mm) with an effective lethal radius of 10–15 mm. The half-life of I-125 is 59.4 days. This enables targeted radiation therapy that effectively destroys tumor cells, with I-125 remaining within the tumor for an extended period and continuously emitting radiation, thereby minimizing the impact on surrounding healthy tissues, unlike traditional radiotherapy.

The mechanisms by which radiation affects cells can be summarized as follows. The first mechanism is DNA damage, whereby I-125 radiation impacts the DNA of tumor cells through both direct and indirect pathways. With direct damage, X-rays and gamma-rays directly target DNA, leading to strand breaks, particularly double-strand breaks. This disrupts the cell’s ability to divide and repair itself, resulting in G2/M phase arrest, inhibition of mitosis, and triggering of apoptosis, which significantly hampers growth, invasion, and metastasis of tumor cells. Indirect damage occurs through reactive oxygen species (ROS) or reactive nitrogen species, which produce highly reactive radicals, including hydroxyl radicals, nitro radicals, superoxide radicals, peroxynitrite, and hydrogen peroxide. These can cause single-strand and double-strand breaks, alter deoxyribose rings and bases, and create crosslinks between DNA and proteins, harming essential cell components like DNA, proteins, and membranes. If cells fail to repair this damage or do so incorrectly, detrimental changes can occur. Radiation-induced ROS can also trigger alterations in cells through non-nuclear pathways, damaging mitochondria,⁸ releasing damage-associated molecular pattern proteins and the signaling molecule adenosine,⁹ activating ROS-responsive protein kinases, triggering “cytokine-induced cell death” via members of the tumor necrosis factor superfamily, and activating inflammasomes. These processes create a self-reinforcing cycle that fosters a pro-inflammatory tumor microenvironment, has bystander effects, and leads to negative radiation-related outcomes. The second mechanism via which radiation exerts a cytotoxic effect is programmed tumor cell death, whereby radiation from I-125 seeds causes double-strand breaks in DNA, which activate apoptosis pathways within the cell, leading to tumor cell death. Key mechanisms include p53-mediated cell cycle arrest, activation of G1/S and G2/M checkpoints, and apoptosis, autophagy, and paraptosis driven by ROS.¹⁰ I-125 radiation also inhibits growth of tumor cells by suppressing the Warburg effect,¹¹ inducing DNA methylation,¹² upregulating apoptosis-related genes (e.g., B-cell lymphoma 2 [BCL2]/adenovirus E1B 19kDa interacting protein 3 [BNIP3] and Wnt family member 9A [WNT9A]), and activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway.¹³

While the radiotherapeutic effects of I-125 seeds are mainly targeted to tumor cells, they also affect non-tumor elements within the tumor microenvironment. The radiation reduces the expression of hypoxia-inducible factor and vascular endothelial growth factor, which in turn inhibits tumor angiogenesis, disrupts abnormal blood vessel networks, and decreases the blood supply, leading to increased tumor hypoxia. This hypoxia heightens the sensitivity of tumors to radiation and enhances the effectiveness of treatment by ROS-induced cell damage. Furthermore, radiation modifies the immunogenicity of tumors, making them more vulnerable to immune detection and elimination. After exposure to radiation, both tumor and endothelial cells show increased expression of “neoantigens” (such as major histocompatibility complex class I molecules, CD80, and Fas) and foster a pro-inflammatory,¹⁴ oxidative microenvironment through damage-associated molecular patterns and interactions involving ROS and reactive nitrogen species. These alterations ultimately promote death of tumor cells and improve the overall efficacy of the treatment (Fig. 1).

Fig. 1.

Changes in the tumor microenvironment induced by radiation. This figure depicts how ionizing radiation impacts the tumor microenvironment. Radiation suppresses tumor angiogenesis by lowering the levels of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF); radiation causes direct harm to tumor cells; radiation influences tumor cells via immune activation, modifying the tumor's immunogenic properties and enhancing its vulnerability to detection and elimination by the immune system. ATP: Adenosine triphosphate; CD80: Cluster of differentiation 80; HMGB1: High-mobility group Box 1; IL: Interleukin; MHC1: Major histocompatibility complex Class I; NF-κB: Nuclear factor Kappa-B; NLRP3: Nod-like receptor pyrin domain-containing 3; P2 × 7: Purinergic receptor P2 × 7; RNS: Reactive nitrogen species; ROS: Reactive oxygen species; TCR: T cell receptor; TLR2: Toll-like receptor 2.

I-125 seeds are a highly effective local treatment for early-stage NSCLC and have minimal adverse effects. Ji et al¹⁵ found that I-125 BT achieved a local control rate of 89.1% at one year, 77.5% at 3 years, and 75.7% at 5 years in 99 patients with early-stage NSCLC. The overall survival rates were 96.7% at 1 year, 70.1% at 3 years, and 54.4% at 5 years, and progression-free survival rates at 1, 3, and 5 years were significantly higher in their I-125 group than in their microwave ablation group (P = 0.011). Furthermore, Wu et al¹⁶ found that overall survival and disease-free survival rates were better in patients who received I-125 therapy than in those who underwent thermal ablation for early-stage NSCLC. Li et al³ assessed the impact of I-125 BT in patients with inoperable T1-3N0M0 NSCLC and concluded that it was a safe and effective treatment option for those who cannot undergo surgery. Moreover, a study that included seven patients with early-stage NSCLC who were unable to undergo surgical resection for medical reasons showed that computed tomography (CT)-guided percutaneous implantation of Pd-103 or I-125 seeds resulted in no local or regional failures after a median follow-up of 13 months.¹⁷ Overall, I-125 seeds serve as a potent local treatment with a low frequency of adverse effects, making them a viable option for patients with early-stage NSCLC, particularly those for whom the surgical risk is high.

The American Brachytherapy Society and the American Association of Physicists in Medicine outline dose guidelines for I-125 seed therapy in the TG-43 report, which include D90 >100%, V100 >90%–95%, and V150 <50%–60%.¹⁸ Ensuring accurate dose delivery is crucial for effective treatment of early-stage NSCLC, given that the radiation dose diminishes with the square of the distance from the source. A treatment planning system utilizes the source activity, decay properties, patient anatomy, and treatment area to model distribution of the seeds and allow dose reduction. The tumor should receive a dose of 100–150 Gy, while exposure to surrounding healthy tissues should be kept to a minimum. Recent advances in image-guided radiotherapy and tailored treatment planning have improved dose accuracy, enhancing tumor coverage while reducing damage to normal tissues.

Common implantation methods include percutaneous and tracheal techniques, which are chosen based on the location and size of the tumor, the patient’s condition, and technical factors. Percutaneous implantation, guided by CT or ultrasound, is ideal for superficial tumors, offering accuracy and direct visualization and allowing local anesthesia, but it is unsuitable for deep tumors or those near critical organs. Tracheal implantation, performed via bronchoscopy, is particularly suitable for tumors located near the airways, especially in early-stage NSCLC. This technique is minimally invasive and offers advantages for treating tumors adjacent to vital organs.

Common complications associated with I-125 implantation in patients with NSCLC include pneumothorax (19%), bleeding (14%), and radiation pneumonia (6%).¹⁹ Pneumothorax can vary in severity from mild cases that resolve spontaneously to severe cases that need chest drainage for lung re-expansion. The risk of bleeding is greater for tumors located near blood-rich areas, and severe bleeding can lead to hemothorax, hypotension, and respiratory distress, which may require hemostatic agents or surgical intervention. Radiation pneumonia can develop weeks to months after treatment, presenting with symptoms such as cough, chest pain, and difficulty breathing. The severity of this condition is influenced by the radiation dose, the volume of lung tissue irradiated, and the patient’s lung function; mild cases can be managed conservatively, while severe cases may need corticosteroids or immunosuppressants. A rare complication is dislodgement of the seeds, which may require image-guided repositioning. Furthermore, disposal of I-125 waste must adhere to the regulations, with low-level waste being treated through decay and disposed of as medical waste and high-level waste necessitating specialized disposal methods or burial.

I-125 BT delivers a sustained and localized high radiation dose that not only induces direct DNA damage in tumor cells but also modulates the tumor microenvironment, enhancing both antitumor immune responses and radiosensitivity. These characteristics position I-125 BT as a promising therapeutic modality for patients with early-stage NSCLC, particularly those who are medically inoperable and those who decline surgical intervention. Nevertheless, several technical challenges remain, including the need for precise seed implantation, maintenance of a homogeneous radiation dose distribution, and management of tumor motion relative to adjacent critical structures. In recent years, ground-glass nodules, which are radiologically characterized by low attenuation, slow growth, and variable malignant potential, have been attracting increasing clinical attention. Their indolent nature and diagnostic uncertainty pose unique challenges for clinical decision-making. As a minimally invasive, image-guided treatment modality, I-125 BT offers a potential alternative for local control of suspicious malignant ground-glass nodules, particularly in patients who are unsuitable for surgery or those requiring treatment in the absence of definitive histopathological confirmation. With ongoing advances in image-guided percutaneous technologies, artificial intelligence-assisted treatment planning, and radiobiological modeling, the accuracy, safety, and efficacy of I-125 seed implantation are expected to improve significantly. These innovations will likely expand the clinical indications for I-125 BT, reinforcing its role as a viable component in the multidisciplinary management of early-stage NSCLC and high-risk ground-glass nodules.

Funding

This work was supported by grants from National Natural Science Foundation of China (No. W2411068 to J.F.) and the Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-008A to J.F.).

CRediT authorship contribution statement

Leilei Shi: Writing – original draft, Writing – review & editing. Nansheng Wan: Writing – review & editing. Guangsheng Li: Writing – review & editing. Yubao Wang: Writing – review & editing. Jing Feng: Writing – review & editing, Resources, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare there is no conflict of interests.