KSNM60 in Non-thyroidal Radionuclide Therapy: Leaping into the Future

Abstract

This year, the Korean Society of Nuclear Medicine (KSNM) is celebrating its 60th anniversary. Treatment, as well as diagnosis, has played a very important role in the development of nuclear medicine. Since I-131 was used for thyroid therapy in 1959, other radionuclide therapy is still being used, and attempts to use new radionuclide are increasing. In this review, we briefly summarize and introduce the therapies such as radioimmunotherapy, transarterial radioembolization, radionuclide therapy for neuroendocrine tumors, peptide receptor radionuclide therapy, control of metastatic bone pain, radiation synovectomy, radionuclide brachytherapy, alpha particle therapy, and boron neutron capture therapy, which has been being attempted so far in the field of nuclear medicine.

Introduction

Radionuclide therapy is a process by which beta- and alpha-emitting radioisotopes are sent to a target organ to achieve a therapeutic effect. The clinical use of radioiodine to treat thyroid dysfunction and thyroid cancer is today a well-established component of radionuclide therapy. Today, efforts are ongoing to use radionuclide therapy as a treatment for various debilitating and life-threatening conditions, and a number of new therapeutic radioisotopes have accordingly been produced and assessed for their remedial potential.

In commemoration of the 60^th anniversary of the establishment of the Korean Society of Nuclear Medicine (KSNM), we would like to share some of the research that has opened up new avenues for radionuclide therapies in Korea.

Academic Achievements of Nuclear Therapy in Korea

Radioimmunotherapy

Radioimmunotherapy combines a monoclonal antibody with a radioisotope to increase the therapeutic effect of the former by ensuring that it only acts against tumors, thereby reducing toxicity to normal cells. Among malignant tumors, lymphoma is the most responsive to radiation. Radioimmunotherapy is particularly efficacious at targeting B-cell lymphoma, and the effects of monoclonal antibodies targeting the CD20 antigen are well-established.

The first radioimmunotherapy clinical trials began in Korea in November 2004 with the approval of the Korea Food and Drug Administration (KFDA). This 2004 study targeted patients suffering from several subtypes of refractory malignant B-cell lymphoma that expressed the CD20 antigen. I-131 rituximab, a radioimmunotherapy drug, was prepared by selecting the I-131isotope.

Single-Time Radioimmunotherapy Study

The first report concerning the effectiveness of radioimmunotherapy treatment trials conducted in Korea was published in 2011 [1]. In 24 patients with refractory or relapsed CD20 positive B-cell lymphoma, radioimmunotherapy provided a 29% overall response rate (three patients with complete remission (CR) and four patients with partial response (PR)). Statistically significant differences in response rates across histological subtypes were also observed; of 13 patients with low-grade lymphoma, three patients went into CR and three patients went into PR (a response rate of 46%), and in of 11 patients with diffuse large B-cell lymphoma, only one PR case was observed (a 9% response rate).

Although this single-dose radioimmunotherapy study confirmed I-131-rituximab’s efficacy and stability, it had short response maintenance period, so the researchers determined that additional research was needed to achieve an increased response rate and improvements in the progression-free survival period through repeated administration. In another study of these patients, the researchers analyzed the SUV max of the tumor and the sum of the products of the longest perpendicular dimensions (SPD) on the contrast CT of F-18 FDG PET/CT at the time points of 5 days, 1 month, and 3 months after a single I-131-rituximab treatment [2]. In the case of low-grade lymphoma, the overall treatment response was improved over time after administration of I-131-rituximab, but in the case of high-grade lymphoma, the rate of CR and PR decreased over time. In other words, the effects of treatment with I-131-rituximab were quick to disappear in the face of high-grade lymphoma’s rapid proliferation rate. It was clear that a strategy to reduce treatment intervals was needed.

Repeated Radioimmunotherapy Study

From November 2006, the protocol was changed to repeated radioimmunotherapy, and I-131-rituximab was repeatedly administered at least 1-month intervals (maximum 6 times) if the disease did not progress after the first radioimmunotherapy. The results of the repeated treatment protocol were reported in 2013 [3]. In 31 patients, 87 radioimmunotherapies were performed. The overall response rate was 68%, and the median duration of response was 8.6 months. There was no difference in response rates between low- and high-grade lymphomas according to histological subtypes, and in patients with high-grade lymphomas, the response rate from repeated administration was significantly higher than the previously reported 9% in a single treatment. The progression-free survival period of all patients was 9.8 months, the survival period was 48.2 months, and the 5-year survival rate was 42% (Fig. 1). No significant difference in survival rates was observed between the low- and high-grade lymphoma groups. In other words, it means that the response rate and survival period of high-grade lymphoma improved through repeated treatment.

Fig. 1.

The MIP images of ¹⁸F-FDG PET/CT of a 64-year-old male patient with marginal zone B-cell lymphoma. At enrollment, the patient had disease in the bilateral cervical, axillary, mediastinal, retroperitoneal, and inguinal lymph nodes, and spleen (a). He received a total 5 cycles of ¹³¹I-rituximab radioimmunotherapy and ¹⁸F-FDG PET/CT were taken after each radioimmunotherapy (b–f). Finally, he achieved complete remission

A Trial for Consolidation Therapy

From July 2012, radioimmunotherapy was studied as a potential consolidation therapy to be provided after standard chemotherapy to newly diagnosed patients with advanced diffuse large B-cell lymphoma. The results of this protocol were published in 2016 [4]. Although the enrolled patients were a small number of sixteen, the 2-year progression-free survival rate was 88%, and the 5-year progression-free survival rate was 81%, confirming the utility of I-131-rituximab as a consolidation therapy in lymphoma cases.

Transarterial Radioembolization

According to the National Cancer Information Center, in 2018, liver cancer was the sixth most common type of cancer and the second-highest cause of death in Korea. The therapeutic option selected to treat hepatocellular carcinoma is determined after considering the progression of the cancer and the liver function. One of non-surgical treatments is transarterial chemoembolization (TACE). Lipiodol has been commonly used for TACE until now. Korean studies into the effectiveness of I-131 lipiodol and Re-188 lipiodol as a means of increasing the effectiveness of treatment have been approved [5]. However, clinical use has not yet been carried out due to a manufacturing problem, the issues of permission and securing radioactive isotopes, and the lack of good treatment performance in previous studies. The Ho-166 Chitosan Complex (Milican), registered as a new drug in Korea, offered a new approach to the treatment of liver cancer. In small hepatocellular carcinomas (3 cm or less), the response rate was 77.5% through percutaneous injection, and 78% were reported through transarterial administration in single, large hepatocellular carcinoma [6–8].

While the particles used in Transarterial Chemoembolization (TACE) are known to cause embolism in arteries outside the cancerous liver tissue, two types of products labeled with Y-90 have been commercialized in other countries and their sizes are known to average 30 μm. The procedure performed using these particles is called “transarterial radioembolization (TARE).” The particles are located into liver cancer tissues and exert primarily with radiation therapy effects and some embolization. TARE is now used as a treatment worldwide, and in Korea, clinical data for TARE’s use has been accumulated [9–11]. One of the key factors in implementing TARE is determining dose. The important factor in clinical use is the appropriate dose of TARE to administer. An appropriate dose will achieve the desired therapeutic effect upon reaching the tumor but should not exceed an allowable amount in non-targeted organs such as the normal liver and lungs. A study using images of Tc-99 m macroaggregated albumin (MAA) on target to non-target ratio has been reported by Korean researchers [12]. Imaging studies have been performed using gamma image by Bremsstrahlung effect and F-18 fluorodeoxyglucose PET/CT to evaluate the distribution of particles and treatment effects of tumors by TARE [13, 14]. The Y-90 based TARE has not been used widely because it relies on imports, and has disadvantages such as having to perform Tc-99 m MAA scan to calculate the shunt of lungs before treatment, and high medical costs. To overcome these disadvantages of commercialized Y-90-based TARE, Korean investigators have developed chitosan hydrogel and I-131 based TARE agent, the so-called CHI. This therapeutic is currently undergoing clinical trials, and the results of which will be closely watched.

Radionuclide Therapy for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors characterized by their ability to uptake neuroamine. These tumors have specific receptors, such as somatostatin receptors that are important roles to their localization and treatment. I-131 metaiodobenzylguanidine (MIBG) and beta-emitter labeled somatostatin analogs are well-established radionuclide therapy modalities for NETs. In Korea, I-131 MIBG therapy has been a part of clinical practice since the 1990s. The experience of patients with malignant pheochromocytoma and medullary thyroid carcinoma receiving I-131 MIBG therapy experience have been reported [15, 16]. I-131 MIBG therapy is increasingly used as a single or combined agent for the treatment of neuroblastoma. Recent studies have highlighted the effectiveness of combined treatment with I-131 MIBG, chemotherapy, and autologous stem cell transplantation at treating high-risk neuroblastoma [17–20].

Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) has emerged as a promising therapeutic option for patients with locally advanced and/or metastatic disease refractory to standard care treatment. The landmark international phase III NETTER-1 trial led to the approval of Lu-177 DOTATATE (Lutathera) for the treatment of somatostatin receptor (SST) positive gastroenteropancreatic NETs. Lutathera was approved for domestic use in July 2020, 2 years after it was approved by the US Federal Drug Administration (FDA). Recently, a research on SST expression level in 32 cancer types and a broad range of SST2 expression across diverse cancer subtypes were reported and this extended our knowledge base to diversify the indications for PRRT and SST imaging [21]. If the clinical experience of PRRT in Korea is accumulated, it is expected to contribute to the development of precision medicine as a good example of molecular theranostics.

Another promising application of PRRT is prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy for metastasized castration-resistant prostate cancer. PSMA is an attractive target for diagnosis and therapy because, as it is highly expressed in the vast majority of prostate cancers. In recent years, domestic researchers have focused on developing radiotracers for PSMA-targeted imaging [22–26]. Moreover, several PRRTs targeting PSMA have been developed and are undergoing clinical trials in Korea.

Palliation of Metastatic Bone Pain with Radiolabeled Phosphonates

Bone metastases are most common in the advanced stages of cancer. They may induce intractable bone pain and are not amenable to conventional treatment. Radionuclide therapy using bone-targeting radiopharmaceuticals has been found to benefit diffuse bone pain caused by metastases to multiple sites. This therapy is particularly appropriate where patients have responded poorly to other therapies or when there is concern about overuse of analgesics. In Korea, there was an effort of increase of labeling efficiency, stability, bone uptake, and image quality of Re-188 hydroxyethylidene diphosphonate (HEDP) as a bone pain treatment by adding carrier perrhenate [27]. In mouse models, Re-188 HEDP showed a higher uptake rate in the metastatic bone than in normal bone, and demonstrated a high analgesic effect when administered to patients with metastatic bone disease.

Radiation Synovectomy

Radiation synovectomy is local treatment for chronic inflammatory joint diseases in the context of medical and orthopedic efforts. In this treatment, radioactive agents are locally administered as an alternative to surgical synovectomy to influence the synovial process. Korean investigators compared the effectiveness of Re-188 tin colloid and Re-188 sulfur colloid as radionuclide therapeutic agents, concluding that Re-188 tin colloid offers higher labeling efficiency, better control over particle size, and lower residual activity in the injection syringes [28].

Radionuclide Brachytherapy

The traditional treatments for skin cancer are local destruction, surgery, and external radiation therapy. External radiation therapy is effective, but generally requires 5–6 weeks of treatment to deliver an optimal radiation dose to the tumors. In 1997, a study was published detailing the results of treatment with topically applied beta-emitting radionuclides, specifically a skin patch containing Ho-166 applied to sites of superficial skin lesions and Bowen’s disease [29]. In this clinical study, a 7.4–27.0 mCi Ho-166 patch was applied to the affected area for between 30 min to 1 h, and tissue biopsies were performed 8 weeks later. The subsequent biopsies revealed that all tumors disappeared. Side effects such as desquamation, erythema, or ulceration disappeared within 1 month, and no recurrence was observed for 8–20 months.

Percutaneous coronary intervention (PCI) is an effective therapeutic modality for coronary artery disease, but the relatively high rate of restenosis after PCI remains a major drawback to the procedure. While drug-eluting stents are now the mainstream treatment for coronary stent restenosis, several domestic studies reported on the utility of radionuclide brachytherapy. One study reported that beta-radiation using a Ho-166 coated balloon effectively inhibited neointimal hyperplasia within the stented porcine coronary artery with no side effects [30]. Another reported that local delivery of Tc-99 m hexamethylpropylene amine oxime (HMPAO) shortly after PCI had an inhibitory effect on neointimal hyperplasia in a porcine model [31]

Self-expendable metallic stents covered with Ho-166 were developed and studied in canine esophagus and canine common bile duct to reduce tissue hyperplasia [32, 33]. Both research teams expected that intraluminal brachytherapy would be used as an alternative therapeutic modality for malignant esophageal and biliary strictures. Re-188 mercaptoacetyltriglycine (MAG₃)-filled balloon dilatation has been studied to reduce tissue hyperplasia in a canine urethral model [34].

Targeted α-Emitting Radionuclide Therapy

Radioisotopes emit alpha particles, which have energy around 5–8 MeV, which is 100–1000 times higher than beta radiation. Their short path length is 50–80 μm. Consequently, radioisotopes provide high linear energy transfer (LET), and alpha-particles can cause irreversible double-strand DNA breaks on tumors while avoiding unwanted damage to adjacent normal tissues. Targeted alpha therapy (TAT) using Ac-225, Bi-213, and Th-227 has shown impressive results against various cancers in clinical and preclinical studies. There have been some efforts by Korean researchers to secure these alpha emitting radionuclides. In 2014, the Korea Institute of Radiological and Medical Sciences (KIRAMS) produced At-211 using the MC-50 cyclotron [35]. More recently, KIRAMS successfully separated and purified At-211 using a domestically developed system, allowing for the production of this alpha-particle at quantities necessary to conduct preclinical research. Researchers evaluated the performance of a Compton single photon emission computed tomography (SPECT) imager at monitoring the position and distribution of Ac-225 radionuclide in in vivo TAT [36].

Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a binary radiotherapy based on the nuclear reactions that occur when B-10 is irradiated with neutrons and subsequently ejects high-energy alpha particles. To date, clinical and non-clinical trials of BNCT for the treatment of variable refractory cancer diseases have begun in the hopes of identifying clinical applications. BNCT systems have been actively developed by Korean investigators since the early 2000s [37–39]. Proton accelerator-based BNCT (A-BNCT) facilities have been installed successfully at Songdo in December 2017. Recently, Korean investigators have extended their research field in the radiation safety of BNCT, the boron carriers such as PEGylated liposomes, platinum complexes, imaging system of simultaneous PET, and single prompt photon images during BNCT [40–44].

Summary and Perspectives

Outside of Korea, radionuclide therapies were used as medical treatments since 1920, but the Nuclear Power Act, the legal basis for the use of radionuclide, enacted in Korea in March 1959. Later in 1959, I-131 was first applied to patients with hyperthyroidism. Since then, radionuclide therapy has increased significantly in the thyroid field. In the recent development of therapeutic radiopharmaceuticals, various attempts have been made to research the economically easy production method of radionuclide, build a production system of suitable bioactive substances to be labeled with it, and various treatments have been explored as above we introduced.

Radioimmunotherapy will be performed using Ac-225, an alpha-emitting radioisotope whose energy is far stronger than that of I-131 and has a shorter distance to which radiation affects. Through this, it is expected to increase the therapeutic response of radioimmunotherapy and to minimize side effects on vital organs such as bone marrow. In liver cancer treatment, nuclear medicine has been making efforts over the past few decades to strengthen existing treatments or develop new treatments using therapeutic radionuclide. These efforts will result in more options for liver cancer treatment. Korean investigators have reported good results by studying how to design the effective peptide and to combine binding moiety with bioactive substances such as small-sized albumins to increase target to non-target ratios, and to reduce residual radioactivity in the body, and various efforts are being made to commercialize them. KSNM’s past and present efforts in the supply of pharmaceuticals including therapeutic radionuclide and the development of a variety of target moieties will doubtless contribute to a future in which diseases are targeted with a new generation of effective and safe treatments.

Author Contribution

Byung Hyun Byun and Myoung Hyoun Kim: historical data collection and analyses and primary writing. Yeon-Hee Han: data review and curation and editing. Hwan-Jeong Jeong: data review and approval and critical manuscript revisions.

Data Availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethics Approval and Consent to Participate

This work does not contain any studies with human participants or animals performed by any of the authors.

Consent for Publication

Not applicable.

Competing Interests

Byung Hyun Byun, Myoung Hyoun Kim, Yeon-Hee Han, and Hwan-Jeong Jeong declare no competing interests.