Iodine-125 seed implantation in the treatment of malignant tumors

Abstract

Malignant tumors are major causes of morbidity and mortality in China. Despite advances in surgical, radiological, chemotherapeutic, molecular targeting, and immunotherapeutic treatments, patients with malignant tumors still have poor prognoses. Low-dose-rate brachytherapy, specifically ¹²⁵I seed implantation, is beneficial because of its high local delivery dose and minimal damage to surrounding tissues. Consequently, it has gained increasing acceptance as a treatment modality for various malignant tumors. In this study, we explored the fundamental principles, clinical applications, and new technologies associated with ¹²⁵I radioactive seed implantation.

1. Introduction

Radioactive seed implantation therapy (RSIT) is a type of brachytherapy in which radionuclide-containing seeds are delivered to a tumor site under imaging guidance or during surgery.¹ The radiation released from these seeds destroys tumor cells, making RSIT a less invasive and highly targeted approach for treating solid tumors.2, 3, 4 Various radionuclides, such as ²²⁶Ra, ¹⁹¹Ir, ⁶⁰Co, ¹²⁵I, ¹⁰³Pd, and ¹⁹⁸Au are used, with ¹²⁵I being the most popular. Brachytherapy was introduced in China in the 1920s. The development of ¹²⁵I seeds in 2001 provided the impetus for Chinese scholars to complete the first ultrasound-guided transperineal ¹²⁵I seed prostate cancer implantation.⁵ RSIT is now a well-established treatment in China, with over 700 medical units and 3000 physicians involved in the procedure. Approximately 15,000 radioactive seed implantation procedures are performed, and approximately 2 million radioactive seeds are used yearly; these numbers are still growing.⁶ However, the cumbersome radiation protection process and lack of knowledge regarding radionuclides pose significant challenges to the widespread adoption of RSIT. This study explored the basic principles and applications of ¹²⁵I seed implantation therapy in treating malignant tumors.

2. Basics and principles of ¹²⁵I seed implantation therapy

2.1. Physicochemical properties of ¹²⁵I nuclides and ¹²⁵I seeds

¹²⁵I is an artificial radioactive iodine isotope with a half-life of 59.4 days. It emits X-rays and γ-rays with an energy of 27.4–31.5 ​KeV and decays to ¹²⁵Te through electron capture. In China, ¹²⁵I is primarily produced using the intermittent cycle loop method, which involves irradiation inside a nuclear reactor followed by decay outside the reactor.^{7 125}I is obtained by β⁺ decay from ¹²⁵Xe. However, despite the mature production of ¹²⁵I in China, mass-production institutions for radionuclides are lacking, leading to increased reliance on imports. Consequently, the demand for ¹²⁵I seeds in China continues to exceed the domestic supply.

Owing to its incompatibility with human tissue, ¹²⁵I radionuclide is plated on a silver wire measuring Φ0.5 mm ​× ​3 ​mm and wrapped with a titanium tube to form ¹²⁵I seeds, which have a conventional diameter of 0.8 ​mm and a length of 4.5 ​mm. The titanium shell has a thickness of 0.05 ​mm, and the seed has a tissue half-value layer of 1.7 ​cm and lead half-value layer of 0.025 ​mm.^8,9 Radiation from ¹²⁵I seeds is continuous and has a low-dose rate, with an approximate rate of 2.77 ​cGy/h.¹⁰ The amount of radioactivity used in clinical practice ranges from 0.1 to 1 ​mCi and can be adjusted based on the tumor's sensitivity to radiation. With the development of automated technology, ¹²⁵I seeds are now primarily sorted, filled, welded, and collected using an automated production process.¹¹ This not only improves the efficiency of ¹²⁵I seed preparation but also reduces radiation exposure to staff and supports the mass production of ¹²⁵I seeds.

2.2. Radiobiological aspects of ¹²⁵I seed implantation therapy

Unlike external radiotherapy, ¹²⁵I seed radiation is continuous and has a low-dose rate. Studies comparing low-dose rate X/γ radiation from ¹²⁵I seeds to external radiotherapy X-rays or high-dose-rate ⁶⁰Co γ-rays have found that the biological effects are generally similar; however, some slight differences exist.^{10,12,13 125}I seeds cause DNA damage in tumor cells mainly by releasing large amounts of X-rays and γ-rays, leading to G2/M arrest, mitotic inhibition, and apoptosis induction, significantly decreasing tumor cell proliferation, invasion, and metastasis.14, 15, 16 Reactive oxygen species induced by ¹²⁵I radiation can also trigger apoptosis, autophagy, and parapoptosis in human esophageal squamous cell carcinoma.¹⁷ In addition, ¹²⁵I seeds can inhibit angiogenesis in lung cancer xenograft tumors by reducing hypoxia-inducible and vascular endothelial growth factors.^{18 125}I irradiation may induce apoptosis in tumor cells at the epigenetic level (such as during DNA methylation)¹⁹ and affect the metabolism of tumor cells by inhibiting the Warburg effect.²⁰ By exploring the biological mechanisms of radioactive seed implantation therapy, identifying the pathways of ¹²⁵I seeds for tumor treatment, discovering new targets, and translating these findings into clinical applications, the radiosensitivity of tumor cells in RSIT may be improved.

2.3. Radiophysical aspects of ¹²⁵I seed implantation therapy

The effectiveness of ¹²⁵I seed implantation therapy depends on accurate dose distribution, conformal dose delivery, and precise delineation of the target area. The gross tumor volume (GTV) refers to the tumor area indicated by imaging, while the clinical target volume (CTV) includes the extension of the GTV that encompasses subclinical lesions and the possible invasion range of the tumor. As positioning errors and organ movements have minimal impact on ¹²⁵I seed implantation therapy, the planning target volume range is consistent with the CTV. Dose distribution is commonly evaluated using D_x and V_x, which represent the minimum relative or absolute dose of the prescribed dose (PD) delivered to x% of the organ and the percentage of organ volume receiving at least x% of the PD, respectively.²¹ Other dosimetric parameters, such as the conformal index (COIN), coverage index (CI), and homogeneity index (HI) have also been compared in some studies. The recommended dosimetry values for ¹²⁵I seed implantation therapy, according to the American Brachytherapy Society (ABS) and the American Association of Physicists in Medicine, include D₉₀ >100%, V₁₀₀ ​> ​90–95%, and V₁₅₀ ​< ​50–60%.²² Major et al. examined the efficacy and side effects of low-dose-rate (LDR) and high-dose-rate (HDR) brachytherapies as monotherapies for treating early, organ-confined prostate cancer. Their results revealed that LDR had superior target volume coverage, while HDR showed better homogeneity and conformability, as evidenced by V₁₀₀, V₁₅₀, D₉₀, HI, and COIN.²³ To achieve improved dose distribution, novel technologies, such as 3D printing of individual templates based on computed tomography (CT) and magnetic resonance imaging (MRI) fusion images, have been explored and provided guidance for accurate positioning and dose distribution during radioactive ¹²⁵I seed implantation for the treatment of recurrent high-grade gliomas.²⁴ Additionally, intraoperative planning methods were more effective than pre-planning methods for treating lung tumors, as demonstrated by comparing V₁₀₀, V₁₅₀, V₂₀₀, CI, COIN, plan quality index, and HI.²⁵ However, comparing ¹²⁵I seed implantation therapy and external radiotherapy is challenging because it is difficult to accurately convert the absorbed dose of brachytherapy into that of external radiotherapy.

2.4. LDR brachytherapy vs. HDR radiotherapy

Radiotherapy can be categorized into various types based on the rate of radiation delivery: HDR (>12 ​Gy/h), medium-dose-rate (2–12 ​Gy/h), LDR (0.4–2 ​Gy/h), and extremely LDR radiotherapy (<0.4 ​Gy/h) are the commonly used types.²⁶ External radiotherapy (120 ​Gy/h) and ¹⁹²Ir intracavitary-interstitial brachytherapy (100 ​Gy/h) are HDR irradiation, while ¹²⁵I seed implantation therapy (0.7 ​cGy/h) is extremely LDR irradiation. Previous studies compared the biological effects of low- and high-dose radiation, including cell survival curves and cell cycle redistribution. Their results showed that the radiosensitivity of human tumor cells to both LDR and HDR irradiation was genotype-dependent.^27,28 Specifically, continuous LDR radiation of ¹²⁵I seeds significantly induced apoptosis and decreased the survival fraction of human pancreatic cancer cells compared with irradiation at identical doses of ⁶⁰Co γ-ray.²⁹ Furthermore, compared with HDR X-rays, ¹²⁵I seed LDR radiation more effectively increased the apoptosis rate and induced G2/M cell cycle arrest in colorectal cancer cells.³⁰ Many scholars have attributed these phenomena to low-dose hyper-radiosensitivity, which is independent of DNA-dependent protein kinase activity.^31,32 Although several studies have suggested that HDR brachytherapy is equivalent to LDR brachytherapy,^33,34 prospective studies comparing these two modalities in various diseases are necessary in the future.

3. Clinical application of ¹²⁵I seed implantation therapy in malignant tumors

3.1. ¹²⁵I seed implantation method

The implantation of ¹²⁵I seeds into tumor tissues can be achieved using various guidance methods, including imaging guidance (such as ultrasound, CT, and MRI), open-view delivery during surgical procedures,³⁵ and transendoscopic-guided implantation. The latter is gaining popularity owing to its benefits, including accurate positioning, minimal invasion, and short puncture distance.^36,37 Percutaneous puncture is the most common image-guided technique. However, each method has advantages and disadvantages. Ultrasound-guided implantation is economical, radiation-free, and allows real-time observation; however, it is unsuitable for cavity organs and lung seed implantation and has low resolution.³⁸ CT-guided puncture has a high resolution and tomographic display; however, it involves radiation and cannot be observed in real-time. Additionally, metallic artifacts from the puncture needle and ¹²⁵I seeds can affect intraoperative observation.³⁹ MR has high spatial and density resolution, allows for 3D reconstruction, and is radiation-free. However, its clinical application is limited by its high cost, susceptibility to interference from vascular pulsations, and the need for MR-specific surgical instruments.⁴⁰ In open-view delivery during surgical procedures, ¹²⁵I seeds are delivered via a needle to a designated site. This method is typically used as an adjuvant treatment in patients with positive incision margins or a high expected recurrence rate after surgical resection. Overall, the choice of guidance method for ¹²⁵I seed implantation should be based on the specific characteristics of the tumor, patient's condition, and expertise and equipment available to the physician.

3.2. General indications and contraindications

¹²⁵I seed implantation therapy has become increasingly popular among physicians from various departments, such as intervention radiotherapy, imaging, nuclear medicine, surgery, ultrasound, and medical oncology. However, owing to their different professional backgrounds, significant differences in patient selection, planning, and therapy operation exist. To address this issue, an Expert Consensus on CT-guided Permanent Interstitial ¹²⁵I Seed Implantation for Tumor Treatment was reached in 2017 by experts from various medical associations and collaborative groups.⁴¹ This consensus provided detailed indications, contraindications, reference doses, and activities of radioactive seeds for several solid tumors, including head and neck squamous carcinoma, lung cancer, pancreatic cancer, rectal cancer, cervical cancer, and soft-tissue tumors. The general indications for ¹²⁵I seed implantation therapy include recurrence after surgery or external radiotherapy, refusal of surgery or external radiotherapy, tumor diameter ≤7 ​cm, clear pathological diagnosis, a suitable puncture route, no bleeding tendency or hypercoagulable state, good physical condition (KPS>70 scores), tolerance of radioactive seed implantation, and expected survival time > 3 months. The general contraindications include severe bleeding, tumor rupture, severe diabetes, no suitable puncture route, and a preplanned target dose that was less than the prescribed dose. Relative contraindications include extensive metastases and expected survival ≤ 3 months, severe comorbidities, infections, immunocompromised and renal insufficiency, and allergy to iodine contrast agents. To ensure that physicians, physicists, nurses, technicians, and therapists can complete seed implantation therapy in a more standardized manner, domestic experts and scholars have launched a series of consensus and guidelines covering technical specifications, quality control indicators, radiation protection, 3D printing template technology, and other aspects.42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 The guidelines are listed in Table 1. Overall, expert consensus and guidelines provide standards and criteria for physicians who perform radioactive ¹²⁵I seed implantation therapy to maximize patient benefits.

Table 1.

Consensus of experts on radioactive seed implantation therapy.

Year	Title	Authors	References
English
2017	Expert consensus workshop report: Guideline for three-dimensional printing template-assisted computed tomography-guided 125I seeds interstitial implantation brachytherapy	Wang J, Zhang F, Guo J et al.	42
2017	Radioactive particles implantation treatment technology management specification interpretation and clinical application of quality control index	X K Hu, F J Zhang.	43
2018	Expert consensus statement on computed tomography-guided 125I radioactive seeds permanent interstitial brachytherapy	Wang J, Chai S, Zheng G et al.	44
2018	Chinese expert consensus on radioactive 125I seeds interstitial implantation brachytherapy for pancreatic cancer	Gai B, Zhang F.	45
2019	Expert consensus on computed tomography-assisted three-dimensional-printed coplanar template guidance for interstitial permanent radioactive 125I seed implantation therapy	Wang J, Chai S, Wang R et al.	46
Chinese
2017	Technical management specifications for radioactive particle implantation therapy (2017 edition)	Chinese Medical Doctor Association, China Anti-Cancer Association	47
2017	Quality control index of clinical application of radioactive seed implantation therapy technology (2017 edition)	Chinese Medical Doctor Association, China Anti-Cancer Association	48
2017	Expert consensus on radiation protection management standards for radioactive 125I seed ward	China Anti-Cancer Association	49
2017	Expert consensus on the technical process of 3D-printing non-coplanar template-assisted CT-guided radioactive 125I seed implantation and quality control	Chinese Medical Association, Chinese Medical Doctor Association	50
2018	Operation procedure of radioactive seed implantation for abdominal solid malignant tumors	Gai B, Guo J, Wang J, Zhang F.	51
2019	Expert consensus on standardization process of radioactive seed therapy for intracranial tumors	China Anti-Cancer Association, China Medical Education Association, Chinese Medical Doctor Association	52
2021	Expert consensus on CT combined with coplanar template-guided radioactive seed implantation for lung cancer (2021 edition)	Chinese Nuclear Society	53

3.3. ¹²⁵I seed implantation therapy in solid tumors

3.3.1. Individual applications

The use of ¹²⁵I seeds for medical treatments requires careful consideration because of their radioactive nature, which raises concerns regarding radiation protection. Therefore, this method is typically employed after surgery, external radiotherapy, or combined radiotherapy and chemotherapy, except for primary prostate cancer treatment. For over 50 years, ¹²⁵I seeds have been extensively used in the treatment of prostate cancer, and the 2021 European Society of Urology guidelines strongly recommend LDR brachytherapy for low- or intermediate-risk patients with good urinary function and a positive prognosis.⁵⁴ The National Comprehensive Cancer Network and American Brachytherapy Association also endorse ¹²⁵I seed implantation as the standard treatment for early prostate cancer.^55,56 In China, ¹²⁵I seed implantation therapy is gaining popularity for treating other solid tumors, such as lung, pancreatic, head and neck, soft tissue, liver, cervical, ovarian, rectal, bone, kidney, ureteral, breast, and abdominal wall cancers. However, owing to the lack of large-scale randomized clinical trials, the international promotion of ¹²⁵I seed implantation therapy for these tumors remains limited.

3.3.2. Combined applications with other treatments

Combining ¹²⁵I seed implantation therapy with other regional or systemic treatments has the potential to improve efficacy but may also increase adverse effects. Therefore, combining ¹²⁵I seeds with other therapies for solid tumors is currently an area of research. Zheng et al. compared surgery combined with ¹²⁵I seed implantation (n ​= ​34) to surgery alone (n ​= ​32) for pancreatic head cancer. The combined group showed better tumor remission, time to disease progression, overall survival, postoperative pain scores, and quality of life than the surgery-alone group, demonstrating the effectiveness of ¹²⁵I seed implantation therapy combined with surgery.⁵⁷ Zhang et al. compared ¹²⁵I seed implantation therapy combined with gemcitabine and cisplatin (GP) (n ​= ​24) with GP alone (n ​= ​29) for non-small cell lung cancer. The combined group showed a better objective response rate, median survival, and progression-free survival than the GP-alone group, with no serious complications except for a few adverse effects.⁵⁸ Lu et al. evaluated the feasibility, safety, and short-term efficacy of ¹²⁵I seed implantation therapy combined with microwave ablation (MWA) for recurrent retroperitoneal liposarcoma in a single-arm study. All 11 patients achieved a partial response 1 month after undergoing MWA, and six achieved a complete response within 12 months after additional ¹²⁵I seed implantation therapy.^{59 125}I seed implantation therapy combined with cryoablation, systemic therapy, endocrine therapy, and transcatheter arterial chemoembolization is also safe and effective.60, 61, 62, 63 However, prospective, global, and multicenter clinical trials are required to validate this evidence.

4. Novel techniques for ¹²⁵I seed implantation therapy

4.1. ¹²⁵I radioactive seed strand

The conventional method of ¹²⁵I seed implantation involves delivering individual seeds, which can result in uneven dose distribution owing to lesion characteristics and operator limitations. Additionally, the seeds may migrate into the veins during treatment, causing pulmonary embolism.⁶⁴ To address these issues, researchers have developed new techniques, such as loading seeds into catheters and fixing them into chains of uniformly spaced seeds for implantation.⁶⁵ Jiao et al. loaded ¹²⁵I seeds into a catheter and combined it with a self-expandable metallic stent (SEMS) to treat malignant obstructive jaundice, and showed that ¹²⁵I seed strands were effective in increasing the patency of the SEMS and that double strands were significantly more effective than single strands.⁶⁶ Biodegradable materials have also been used to connect seeds, allowing them to be collected in the tumor and avoiding damage to the surrounding tissues during treatment. Although polymers have been used previously, their long degradation times are unsatisfactory. A novel ¹²⁵I seed strand attached to a magnesium alloy (AZ31) has shown promise, with magnesium alloy tubes fragmenting 14 days after implantation and potentially having a further tumor-killing effect by producing Mg²⁺ and hydrogen.⁶⁷

4.2. ¹²⁵I radioactive seed stent

Stent placement is a common palliative treatment for unresectable cavity organ tumors, such as esophageal, bile duct, and uroepithelial cancers. These tumors often cause stenosis or cavity obstruction; however, stent restenosis remains a significant challenge because of tumor growth and granulation tissue proliferation. To address this issue, ¹²⁵I seeds are loaded into the stent to form a radioactive seed stent that can suppress tumors and relieve obstruction. Prof. Teng achieved a significant breakthrough in this field by completing the first ¹²⁵I radioactive seed stent esophageal implantation on January 9, 2003, breaking through the previously considered forbidden zone for radioactive seed implantation in cavity organs. A multicenter phase III clinical trial of ¹²⁵I seed esophageal stent implantation versus conventional stent implantation was reported in The Lancet Oncology in 2014.⁶⁸ The trial randomly assigned 160 patients with esophageal cancer to either the radiation stenting group (n ​= ​80) or the conventional stenting group (n ​= ​80). Their results showed that the median overall survival was significantly longer in the radiation stenting group than in the conventional stenting group (177 vs. 147 days). Despite these promising results, several challenges remain, including the development of materials, use and loading of nuclides, mismatch of stent-release systems, and difficulty in validating the spatial dose distribution.

4.3. Oxygen-carrying microbubbles can increase the radiosensitivity of tumors to ¹²⁵I seeds

Radiologists have summarized the dynamic changes that occur in tumor cells exposed to radiation as the "4R theory,” which includes Repair of radiation damage, Reoxygenation, Redistribution, and Repopulation. However, prolonged radiation exposure can cause tumor cells to become resistant to radiotherapy owing to the hypoxic microenvironment of solid tumors. This is where the oxygen effect occurs because oxygen plays a significant role in the radiosensitivity of tumors. Peng et al. developed ultrasound-activated oxygen-carrying microbubbles that delivered oxygen to tumor tissue, increasing the radiosensitivity of the tumor to ¹²⁵I seed implantation therapy.⁶⁹ This material is expected to have clinical applications as a radiosensitizer in ¹²⁵I seed implantation therapy. Additionally, loading small-molecule compounds, such as radiosensitized miRNA, circRNA, and proteins, into oxygen-carrying microbubbles can further enhance the sensitivity of tumor cells to ¹²⁵I seed implantation treatment. Although this study is still in the experimental stage, it shows promise for improving the effectiveness of radiotherapy in the treatment of solid tumors.

5. Conclusion

¹²⁵I seed implantation therapy has become increasingly popular for treating various solid tumors owing to its unique advantages. However, several drawbacks have emerged as this treatment continues to develop rapidly. First, dosimetric studies on ¹²⁵I seed implantation and its conversion to external radiotherapy remain ambiguous. Second, basic radiobiological research on ¹²⁵I brachytherapy is relatively limited. Third, standardized guidelines for ¹²⁵I seed implantation therapy for certain tumors are lacking. Finally, most medical units lack sufficient staff, especially radiation physicists, leading to the misuse of ¹²⁵I radioactive seeds. In conclusion, although ¹²⁵I seed implantation therapy presents opportunities and challenges, it plays a significant role in cancer treatment.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work.