Research ArticleSupplement

Landscape of Nuclear Medicine in China and Its Progress on Theranostics

Weidong Yang, Fei Kang, Yue Chen, Zhaohui Zhu, Feng Wang, Chunxia Qin, Jin Du, Xiaoli Lan and Jing Wang
Journal of Nuclear Medicine May 2024, 65 (Supplement 1) 29S-37S; DOI: https://doi.org/10.2967/jnumed.123.266968

Abstract

Nuclear medicine in China started in 1956 and, with the rapid development of the economy and continuous breakthroughs in precision medicine, has made significant progress in recent years. Almost 13,000 staff members in nearly 1,200 hospitals serve more than 3.9 million patients each year. Over the past decade, the radiopharmaceutical industry has developed rapidly, with the initial formation of a complete industrial chain of production of various radiopharmaceuticals for both clinical use and basic research. Advanced equipment such as PET/CT scanners is being manufactured domestically and even installed abroad. Recently, research into screening and synthesizing new target probes and their translation into the clinic has gained more attention, with various new tracers with potential clinical value being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled tumor-targeted probes and others have been implemented for theranostics in an increasing number of hospitals and would be helped by approval from the National Medical Products Administration. Over the next 10–20 y, with the launch of the Mid- and Long-Term Development Plan for Medical Isotopes (2021–2035) by the Chinese government, there is great potential for nuclear medicine in China. With the rise in independent innovation in manufacturing, the shortage of radiopharmaceuticals will be effectively curtailed. We anticipate that the scale of nuclear medicine will at least double by 2035, covering all high-grade hospitals and leading to the aim of “one county, one department” in China.

With nearly 70 years of development, nuclear medicine in China has significantly progressed. A relatively complete nuclear medical system has formed, which plays a critical role in both clinical medicine and medical research. With the development of theranostics, nuclear medicine in China will go into a new era and keep moving forward rapidly.

MILESTONES OF NUCLEAR MEDICINE IN CHINA

In 1956, the first training course for isotope usage in Xi’an, Shaanxi Province, marked the beginning of nuclear medicine in China. Since then, nuclear medicine has started to enter clinical practice and serve patients. In the 1980s, its growth accelerated with the implementation of China’s reform and opening-up policy. The Nuclear Medicine Branch of the Chinese Medical Association (Chinese Society of Nuclear Medicine) was established in 1980, and the following year, the Chinese Journal of Nuclear Medicine was published. It was renamed the Chinese Journal of Nuclear Medicine and Molecular Imaging in 2012 and has been published monthly since 2017. The first SPECT machine was introduced in 1983, and the first clinical PET machine was installed in 1995. By the 21st century, nuclear medicine had developed tremendously in China. PET/CT scanning was introduced to clinical practice in 2002, and PET/MRI started to operate in 2012. PET/CT equipment manufactured by United Imaging Healthcare was installed at Fujita University, Japan, in 2017, marking the internationalization of nuclear medicine instruments manufactured in China. In 2021, the National Atomic Energy Agency, together with 7 other departments, including the Ministry of Science and Technology and the Ministry of Public Security, officially released the Mid- and Long-Term Development Plan for Medical Isotopes (2021–2035), which aims to rapidly promote the further development of nuclear medicine in China.

STATUS OF CURRENT NUCLEAR MEDICINE

During the past decade, the state of nuclear medicine has greatly improved in China. Detailed information is available from the Chinese Society of Nuclear Medicine, which conducts a national survey of the nuclear medicine industry every 2 y. Unfortunately, because of the coronavirus disease 2019 pandemic, the survey scheduled for 2022 was not conducted as planned. According to the most recent survey, in 2020, there were 1,148 departments in China engaged in nuclear medicine–related work, with 273 new departments (a 31.2% increase) since 2010 (1,2). Nuclear medicine professional staffing increased by 83.9% (12,578 in 2020 vs. 6,838 in 2010), as shown in Figure 1A. An increase of more than twice that in the number of nuclear medicine departments clearly indicates the scale of expansion of nuclear medicine. The main growth has been in SPECT/CT scanners, which have increased from 555 in 2010 to 903 in 2020; PET/CT scanners have more than doubled over 10 y (133 PET or PET/CT machines in 2010 vs. 427 in 2020; Fig. 1B). Surprisingly, numbers have doubled again in the past 3 y, with more than 800 PET/CT machines and almost 100 PET/MRI scanners in daily use. According to the 14th Five-Year Plan, by the end of 2025, the number will be doubled once more, with PET/CT scanners increasing to more than 1,600 and PET/MRI scanners increasing to more than 200.

FIGURE 1.
FIGURE 1.

State of nuclear medicine in China. (A) Growth in number of departments and staff in nuclear medicine. (B) Number of SPECT/CT scanners and PET/CT scanners. (C–F) Applications of PET/CT (C), PET/MRI (D), SPECT/CT (E), and radionuclide therapy (F) in 2020. 99Tc-MDP = 99mTc-methylene diphosphonate.

In 2020, 849,942 PET/CT scans were performed, 5 times the number performed 10 y ago (158,000 scans in 2010). More than 96.3% (818,367) of the 2020 PET/CT scans were for tumor imaging, whereas 1.7% (14,753) were for neurologic investigation, 0.7% (4,846) were for cardiology, and all others were for a 68Ga- or 11C-labeled probe (Fig. 1C). In addition, 14,095 patients underwent PET/MRI in 2020: 81.9% (11,545) for tumors, 11.4% (1,607) for neurologic disease, 1.2% (175) for cardiologic disease, and all others for 68Ga- or 11C-labeled probes (Fig. 1D). In 2020, 2,514,142 SPECT scans were conducted, more than twice the 1,178,800 scans in 2010; of the 2020 scans, 63.1% (1,586,423) were for skeletal system imaging using 99mTc-methylene diphosphonate, 16% (402,262) were for endocrine system imaging, 12% (301,697) were for urinary system imaging, and 4% (100,565) were for circulatory system imaging (Fig. 1E). About 65% of the hospitals or medical institutions that used SPECT radiopharmaceuticals purchased 99mTc-labeled radiopharmaceuticals from centralized radiopharmacies; others purchased 99Mo/99mTc generators to prepare 99mTc-labeled radiopharmaceuticals themselves.

Recently, almost 528,480 radionuclide treatments have been conducted annually. The top 4 radionuclide types were 131I for thyroid disease, around 45% (235,202); 32P/90Sr/90Y for skin cancer, around 32% (169,603); 99Tc-methylene bisphosphonate (99Tc-methylene diphosphonate, or Yunke [Chengdu Yunke Pharmaceutical Co. Ltd.]), around 19% (98,355); and 125I particle implantation, around 2% (12,718; Fig. 1F) (1,2). In recent years, some medical institutions have begun to use 223Ra-dichloride for the treatment of castrated prostate cancer patients with bone metastases. Other therapeutic radiopharmaceuticals, such as 177Lu-DOTATATE and 177Lu-labeled prostate-specific membrane antigen (177Lu-PSMA), which have been approved in the United States but yet not by the National Medical Products Administration (NMPA), have also been prepared and investigated in clinical research for neuroendocrine tumors and prostate cancer. Once treated with radionuclides, patients should be followed up promptly to evaluate the treatment response, modify the treatment plan if necessary, and improve its effectiveness. The National Nuclear Medicine Quality Control Center has set specific follow-up goals for hospitalized patients such as those treated with 131I or patients with bone metastases undergoing radionuclide treatment. For example, as required by the National Nuclear Medicine Quality Control Center, hospitalized patients with bone metastases who underwent a SPECT/CT scan should be followed up in no less than 50% of cases.

Currently, the percentage of patients undergoing nuclear medicine examinations is still limited (0.28% of the population). One of the most important reasons is that the public is unfamiliar with nuclear medicine. The Chinese Society of Nuclear Medicine is devoted to the promotion of knowledge and popularization of nuclear medicine, and it has established an Information and Science Popularization Working Committee with these aims. Nuclear medicine experts have been organized periodically by the Chinese Society of Nuclear Medicine to record videos, write papers, and print pamphlets to introduce nuclear medicine to the public and even to clinicians; organize academic lectures for physicians or technicians; or dispatch experts to grassroots hospitals to assist in promoting nuclear medicine technology.

PRODUCTION OF MEDICAL RADIOISOTOPES

After decades of development, the radiopharmaceutical industry in China has made great progress, with a widespread supply of multiple radioisotopes for clinical use and for research. 99mTc is the most commonly used radioisotope for SPECT, accounting for more than 90% of all SPECT imaging, and most 99mTc still depends on international suppliers. The China Institute of Atomic Energy has developed fission 99Mo production with an emphasis on low-enriched-uranium targets (3–5) that is expected to improve 99mTc supply in the near future. 18F, the most commonly used radioisotope in PET scanning, has been used daily for more than 900 PET scanners all over the country. About 120 hospitals or medical institutions prepare their own 18F, and the rest purchase it from radiopharmacies. 131I is the main radioisotope used in therapy and is fully supplied domestically.

The rapid growth of the radiopharmaceutical industry has allowed the production or supply of other clinically used radioisotopes, including 125I, 198Au, 90Sr-90Y, 186Re, 153Sm, 161Tb, and 14C, and the promotion of nuclear medicine in China. However, some commonly used radioisotopes still cannot be produced domestically. For example, 68Ga, eluted from 68Ge/68Ga generators, is a popular PET radioisotope label for PSMA, TATE, etc., that is not yet available domestically. 68Ga/177Lu, a pair of radioisotopes used to label the same probe, is ideal for theranostics, but 177Lu has to be purchased from an international company such as Isotopen Technologien München. Recently and excitingly, the Mianyang Research Reactor of the China Academy of Engineering Physics has developed technology and production facilities for 177Lu, successfully producing no-carrier-added 177Lu (6). Small-batch production (at the curie level) was achieved, and the product has been used in clinical trials at some hospitals. Because there are 120 cyclotrons, Chinese researchers are focused on novel medical isotopes with established targets, which may help alleviate the shortage of radioisotope supplies.

COMMERCIAL RADIOPHARMACEUTICALS

The radiopharmaceuticals commonly used in clinical practice, such as 131I-sodium iodide oral solution, capsules for diagnostic or therapeutic use (131I-sodium iodide), 125I as a brachytherapy source, 99mTc-labeled radiopharmaceuticals (99mTc-methylene diphosphonate, 99mTc-methoxyisobutylisonitrile, and 99mTc-diethylenetriaminepentaacetic acid), 89Sr-chloride injection, 223Ra-dichloride injection, and 90Y-resin microspheres, are commercially available in China (data from https://www.nmpa.gov.cn). The NMPA has approved 11 types of radionuclides, involving 33 radiopharmaceuticals. In addition to the companies producing radiopharmaceuticals, holders of usage of radiopharmaceutical permission license III can manufacture positron radiopharmaceuticals such as 18F-sodium fluoride, 18F-FDG, and 11C-acetate that are approved by the NMPA, and holders of license IV can synthesize or produce radiotracers not yet approved by the NMPA.

In the past few years, various novel targets have been explored worldwide as imaging or radionuclide therapy targets. Researchers in China have been involved in developing radiopharmaceuticals and in clinical translation for diagnosis and therapy. Tremendous progress has been achieved; many new radiopharmaceuticals have been thoroughly studied, and several are seen as potentially useful radiopharmaceuticals that deserve commercial development, as reviewed by Hu et al. (7) and Cui et al. (8). Eighty-eight pharmaceutical companies qualified to produce radiopharmaceuticals are engaged in translational development or commercialization of these potential probes. Clinical trials are ongoing for 47 radiopharmaceuticals. Of these, 15 are in stage I, 4 are in stage II, and 28 are in stage III; 21 are for PET/CT imaging, 4 are for SPECT/CT imaging, and all others are for radionuclide therapy. Most of them are focused on oncology (79.2%), followed by neurology (16.7%) and all others (about 4.1%; Fig. 2). Detailed information is presented for phase I and II clinical trials in Table 1 and phase III trials in Table 2.

FIGURE 2.
FIGURE 2.

Commercial radiopharmaceuticals under development. (A) Radiopharmaceuticals in different stages of clinic trial. (B) Indications for radiopharmaceuticals under investigation.

View this table:
TABLE 1.

Radiopharmaceuticals Under Commercial Clinical Development or in Market Approval Process in China

View this table:
TABLE 2.

Radiopharmaceuticals in Phase III of Commercial Clinical Development or Market Approval Process in China

DOMESTIC ADVANCED EQUIPMENT

PET represents the most sophisticated equipment in nuclear medicine, and its development in China can be traced back to the work of a team at the Institute of High Energy Physics of the Chinese Academy of Sciences. The first prototype was successfully developed in June 1986, and preclinical images of a monkey’s brain were obtained. Unfortunately, it was not used for clinical application or commercialization. The first domestic clinical PET system was developed by Neusoft Healthcare in 2009, and the first PET/CT scanner was developed by United Imaging Healthcare in 2014. The United Imaging Healthcare also produced the first domestic PET/MRI scanner, which was installed in 2018.

Companies such as United Imaging Healthcare have quickly developed PET/CT or PET/MRI machines. The quality and performance of PET equipment have rapidly improved. The world’s first total-body PET/CT machine (uEXPLORER; United Imaging Healthcare), which allows dynamic imaging, was launched in 2018. It can obtain information about blood circulation throughout the body, providing a tool for studying physiology, as well as pathologic processes in disease (9). The latest digital PET/CT machine, uMI Panorama (United Imaging Healthcare), with a 2.9-mm National Electrical Manufacturers Association PET resolution and sub–200-ps timing resolution, provides extremely high-quality images (10).

Apart from dynamic imaging, whole-body PET/CT can significantly reduce scan time and dosage injection. Zhang et al. (11) and Hu et al. (12) showed that a fast PET protocol, with a 30- to 45-s acquisition time in the total-body uEXPLORER PET/CT scanner, could provide image quality equivalent to that of conventional digital scans. Zhao et al. (13) explored the relationship of image quality, lesion detection rate, and acquisition time in routine clinical practice using different injection dosages and showed that optimal image quality could be achieved with a dose reduction to a one-10th administered dose (0.37 MBq/kg) for total-body PET/CT. Short-duration scanning may be helpful for patients who are unable to tolerate a long scan, for example, because of severe cancer pain, and reducing injection dosage is particularly beneficial in pediatric patients.

Medical cyclotrons producing positron radioisotopes for PET/CT or PET/MRI have also played a critical role in nuclear medicine development. A few years ago, cyclotrons in the Chinese market relied on international companies; recently, domestic manufacturers have begun to emerge. SiChuan Longevous Beamtech Co., Ltd., has the ability to expand to low-energy and high-energy accelerators, including ion sources, with multispecification targets, shields, and other components and unique technical advantages. In 2020, Longevous-11 (Longevous Beamtech Co. Ltd.) became the first commercial medical cyclotron produced in China.

RESEARCH AND FUNDING OF NUCLEAR MEDICINE

From 2013 to 2022, the total number of applications for projects in the field of nuclear medicine and molecular imaging reached 2,949 in China, and 899 grants were supported by the National Natural Science Foundation of China. The number of applications and successful grants has steadily increased. Overall funding increased from 20.9 million yuan (∼$2.9 million) in 2013 to 59.5 million yuan (∼$8.2 million) in 2022. Of the 899 approved grants, 608 (69.3%) were for tumor studies and 269 (30.6%) were for nontumor studies. Most research has focused on the development of tumor-targeted molecular probes for precise imaging and radionuclide therapy (14).

In the past decade, the National Natural Science Foundation of China has responded to national funding directives and steadily expanded funding for young researchers in nuclear medicine and molecular imaging. The number of related projects and the total funding have steadily increased, with diverse, often interdisciplinary, projects. However, it is still necessary to strengthen funding for major projects in this field. In recent years, the Chinese government has established several major scientific research projects to develop new, high-quality equipment in nuclear medicine, with total funding of 118 million yuan (∼$16 million).

POTENTIAL OF NUCLEAR MEDICINE IN CHINA

Although nuclear medicine in China has improved significantly in the past few years, the coverage of nuclear medicine remains low. There are only 0.305 PET/CT scanners and 0.645 SPECT/CT scanners for every 1 million Chinese people. Only 6.07 per 10,000 people have had a PET/CT scan, and just 3.79 per 10,000 people have received radionuclide therapy annually. This is lower than in the United States or European countries. However, Chinese nuclear medicine can remain at the forefront of international nuclear medicine through the installation of PET/CT and PET/MRI scanners, the application of new radiopharmaceuticals, etc. In tight cooperation with international colleagues, theranostics such as 68Ga/177Lu-PSMA and 68Ga/177Lu-fibroblast activation protein inhibitor (FAPI) are being rapidly developed and broadly explored in the clinic. Other theranostics are also under investigation, and innovative radiopharmaceuticals may be commercialized in the near future.

PROGRESS IN THERANOSTICS IN CHINA

As a promising clinical tool for personalized medicine, theranostics has received great attention in China over the past decade. Probes specifically targeted to lesions can be labeled with different radionuclides, including positron radionuclide labeling for PET imaging and β- or α-emitter radionuclide labeling for radiation therapy. With typical theranostics, lesions detected by PET could be suited to radionuclide therapy to effectively improve treatment. Serial clinical translational studies of novel theranostics, such as 68Ga-, 177Lu-, or 225Ac-labeled probes for neuroendocrine tumors and prostate cancer, have been conducted in an increasing number of hospitals.

68GA/177LU THERANOSTICS FOR NEUROENDOCRINE TUMOR

Using 68Ga-DOTATATE PET/CT imaging in patients with neuroendocrine tumors at baseline and/or after several cycles of treatment with 177Lu-DOTATATE has been widely explored in China. 177Lu-DOTATATE treatment of neuroendocrine tumors is undergoing phase III clinical trials. In addition to DOTATATE, Chinese researchers have designed new radiopharmaceuticals for clinical studies that optimize the pharmacokinetics of 177Lu-DOTATATE. 177Lu-DOTA-EB-TATE was designed by adding an Evans blue motif to 177Lu-DOTATATE. As expected, 177Lu-DOTA-EB-TATE achieved a 7.9-fold increase in tumor dose, whereas the increased doses to the kidneys and bone marrow were 3.2- and 18.2-fold, respectively (15). In patients given a single dose of 177Lu-DOTA-EB-TATE, as low as 0.66 ± 0.06 GBq (17.8 ± 1.7 mCi), 72.5% of 40 neuroendocrine tumors with a diameter of at least 2.0 cm showed a more than 15% decrease of SUVmax (16). Dose escalations up to approximately 3.7 GBq/cycle (100 mCi) for 3 cycles seemed to be well tolerated, achieving a response rate of 48.3% and a disease control rate of 86.2% (17–19). Moreover, the 177Lu-DOTA-EB-TATE treatment, without amino acid infusion, demonstrated a favorable safety profile in neuroendocrine tumor patients (20). In addition to 177Lu, an α-particle emitter such as 225Ac has been studied for labeling a somatostatin analog. A case report by Peng et al. (21) showed that 225Ac-DOTATATE could be used successfully for metastatic pheochromocytoma. Before treatment, 68Ga-DOTATATE PET/CT showed multiple lesions with elevated tracer uptake throughout the body; however, tracer uptake of almost all lesions was significantly reduced after 3 cycles of 225Ac-DOTATATE, with a dose of approximately 7.4 MBq (0.2 mCi) per injection.

68GA/177LU THERANOSTICS FOR PROSTATE CANCER

177Lu-PSMA treatment for prostate cancer has also undergone phase III clinical trials in 11 centers, and approval by the NMPA is expected in 2025. Bu et al. (22) conducted a single-center study evaluating the efficacy and safety of 177Lu-PSMA I&T in East Asian populations. Enrolled patients were selected by 68Ga-PSMA PET. After 2 or more cycles of 177Lu-PSMA I&T, 68Ga-PSMA PET/CT was repeated to evaluate response to treatment. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1–4 bone marrow dysfunction in this study. Changes in prostate-specific antigen were assessed after therapy, with partial response in 25 patients (62.5%), stable disease in 5 patients (12.5%), and progressive disease in 10 patients (25%). Quality of life, Karnofsky performance status, and pain were all significantly improved after treatment (P < 0.05). This study showed that 177Lu-PSMA I&T achieved favorable responses in East Asian populations.

177Lu-EB-PSMA-617 was developed to optimize the pharmacokinetics, prolong tumor retention, and improve the efficacy of treatment. A dosimetry study showed that in comparable bone metastases (SUVmax, 10.0–15.0), the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617 (23,24). Furthermore, approximately 2.0 GBq of 177Lu-EB-PSMA for up to 3 cycles achieved a prostate-specific antigen response, with hematologic toxicity comparable to that from 7.4-GBq doses of 177Lu-PSMA-617 for 4–6 cycles (Fig. 3) (25).

FIGURE 3.
FIGURE 3.

Metastatic castration-resistant prostate cancer patients with whole-body metastases treated with 177Lu-EB-PSMA at 1.85 GBq for each cycle, as shown with PSMA PET. (A–C) Patients treated with 1–3 cycles of 177Lu-EB-PSMA. After treatment, total-lesion PSMA (TLP), PSMA volume (PSMA-VOL), and prostate-specific antigen (PSA) were significantly decreased.

68GA/177LU THERANOSTICS BY TARGETING FAP

FAP is a type II transmembrane protein that is overexpressed in cancer-associated fibroblasts and therefore is a promising target for diagnosis and treatment of numerous malignant tumors. Radioisotope-labeled FAPI is under broad investigation in China. Baseline imaging by 68Ga-FAPI that demonstrates tumor FAP expression was used to select patients for radionuclide-targeted therapy. Fu et al. (26) showed that 177Lu-FAPI-46 was useful in metastatic nasopharyngeal carcinoma and could be used for treatment of advanced radioiodine-refractory differentiated thyroid cancer. Intense radiotracer uptake was observed in such metastatic lesions on a 68Ga-FAPI PET/CT scan before and after therapeutic scintigraphy. Follow-up examinations, after 4 cycles of 177Lu-FAPI-46 treatment, revealed stable metastatic lesions (26). Several structurally optimized FAPI probes are undergoing clinical research to further improve the effectiveness of radionuclide-labeled FAPI in the treatment of solid tumors. Fu et al. (27) further produced 177Lu-EB-FAPI (177Lu-LNC1004) and treated patients with metastatic radioiodine-refractory thyroid cancer, showing that 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated, with high-radiation-dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects. In addition to thyroid carcinoma, Rao reported that 177Lu-FAPI-2286 was effective in squamous cell lung cancer with systemic metastases (28). It may be anticipated that 68Ga/177Lu-FAPI theranostics will be extended to other solid carcinomas in an increasing number of hospitals.

THERANOSTICS FOR BONE METASTASIS

Bone is the most common site of distant metastasis of malignant tumors. Bisphosphonate, an antibone absorbent, has been widely used in cancer bone metastasis, but it has a limited inhibitory effect on cancer cells, and in clinical practice, high doses of bisphosphonates often cause jawbone necrosis. However, ibandronate, an imidazole derivative and third-generation bisphosphonate, can be used for treatment of bone metastasis. Wang et al. (29,30) independently designed and developed a targeted diagnosis- and treatment-integrated radiopharmaceutical, 68Ga/177Lu-DOTA-ibandronate. The results in 18 cases of bone metastases showed that baseline 68Ga-DOTA-ibandronate PET imaging had higher diagnostic efficacy for bone metastases than did 99mTc-methylene diphosphonate SPECT. Subsequent 177Lu-DOTA-ibandronate treatment showed that in 17 patients who experienced pain before treatment, 14 (82%) achieved relief of bone pain. An 8-wk follow-up 68Ga-DOTA-ibandronate PET/CT showed partial remission in 3 patients, disease progression in 1 patient, and stable disease in 14 patients (Fig. 4). More recently, 177Lu-DOTA-ibandronate–targeted therapy has been used for bone metastases from various tumors, including lung, breast, prostate, thyroid, colon, and kidney, as well as neuroendocrine tumors (31,32). Furthermore, ibandronate has been labeled with 225Ac, and the clinical translation of 225Ac-labeled DOTA-ibandronate has shown a potent response of bone metastases after 1 cycle of 225Ac-DOTA-ibandronate therapy (33). All studies indicated that 68Ga/177Lu/225Ac-DOTA-ibandronate provides a potential set of integrated radiopharmaceuticals with good prospects in the diagnosis and treatment of bone metastases (32,34).

FIGURE 4.
FIGURE 4.

66-y-old patient with prostate cancer and bone metastases who received 4 cycles of therapy with 370 MBq of 177Lu-DOTA-ibandronate. (A) 68Ga-DOTA-ibandronate PET/CT image before treatment. (B–E) 68Ga-DOTA-ibandronate PET/CT images after each cycle. After 4 cycles of treatment, uptake of 68Ga-DOTA-ibandronate was significantly decreased. Arrows refer to metastases at L4-5 vertebra, and arrowheads refer to metastases at 10th rib on right side.

OTHERS

Additional theranostic agents based on different probes for imaging and radionuclide therapy, such as 90Y-resin microspheres, have been used clinically. 90Y radioembolization is a promising approach for treating liver malignancies and received approval by the NMPA on January 30, 2022. To conduct 90Y-resin microsphere treatment, 99mTc-labeled macroaggregated albumin is first administered to simulate the deposition of the 90Y-resin microspheres in the patient and to calculate the required dose of 90Y. Angiography is then repeated after 1–2 wk to facilitate the administration of the calculated dose of 90Y, and after treatment, the patient undergoes a SPECT/CT or PET/CT scan for confirmation of the distribution of the 90Y-resin microspheres to assess the efficacy and safety profile. Feng et al. (35) and Li et al. (36) reported the first case treated with 90Y-resin microspheres in China, and since then, more than 100 patients have received 90Y-resin microsphere treatment.

PROCEDURES AND CHALLENGES OF THERANOSTICS

Before novel theranostic radiopharmaceuticals can be used in the clinic, applicants must comply with the requirements of good clinical practice issued by the NMPA and must apply to the hospital ethics committee for approval. The ethics committee is responsible for conducting a comprehensive evaluation of the scientific rationale and procedures involved in the clinical trial, as well as the risks and benefits to patients. Trials will be approved only when the design and implementation of clinical trials comply with ethical regulations, protecting the safety, health, and other rights of patients. For radiopharmaceutical companies, a registration application needs to be submitted to the NMPA, which evaluates the value, safety, efficacy, production processes, and quality control of the radiopharmaceuticals. If the application is approved, the NMPA will issue a registration certificate, permitting commercialization and use in the clinic. Several radiopharmaceuticals have entered the approval process, clinical trials, or the marketing approval stage, and some of these are expected to be approved in the near future.

Interdisciplinary cooperation and collaboration between academia and industry is essential for theranostics. Multidisciplinary discussions by a combination of nuclear medicine physicians, oncologists, urologists, and other relevant specialists about patient selection, individual treatment plans, and response evaluation are required before theranostics. In the development of radiotracers for theranostics, multiple disciplines, such as biomedicine and radiochemistry, are required to work together to screen specific targets, synthesize high-affinity probes, label with radionuclides, and translate research into the clinic.

Researchers in hospitals or institutes and in commercial companies can all develop radiopharmaceuticals. Once radiotracers have shown definite diagnostic or therapeutic effects, researchers in hospitals or institutes can transfer their patents to companies for commercialization. For example, 177Lu-DOTA-ibandronate, mentioned earlier, has already had its patent transferred to the commercial company Kelun-Biotech for production. The patent for 18F-PFPN, developed by Lan et al. (37) in Union Hospital, Huazhong University of Science and Technology, for melanoma PET/CT imaging, was transferred to HighTech Atom Co., Ltd. Yang et al. at Peking University Cancer Hospital have successfully transferred several radiopharmaceutical patents to companies, and the latest PSMA-P137 was authorized to Yunnan Baiyao Group Co., Ltd., in August 2022 (38). In addition, researchers can commercialize radiotracers themselves. However, if commercial companies develop a potential radiotracer with good preclinical results, they can collaborate with researchers in hospitals for clinic trials for final NMPA approval.

The rapidly growing need for skilled professionals in nuclear medicine remains a major challenge. China has established a comprehensive system to cultivate nuclear medicine professionals, including undergraduate education and master’s and doctoral training. After graduating from medical colleges, students should receive systematic training for 3 y, in accordance with the standardized training content and standards for nuclear medicine resident physicians issued by the National Health Commission. However, because of great demand, the existing professional training system is still inadequate; therefore, doctors in other fields have been enrolled to work in nuclear medicine, and continuing education is essential for these specialists. As a new technology, theranostics requires special training and has been limited to a few specialist hospitals. Nuclear medicine physicians preparing to conduct theranostics can attend those specific hospitals for special training and advance their knowledge through various academic conferences or special lectures.

New technologies and radiopharmaceuticals for theranostics are still relatively expensive for most Chinese patients, because they are not yet covered by health care programs. For example, the 18F- or 68Ga-labeled probe for PET/CT usually costs more than 5,000 yuan (∼$691), and the 177Lu-labeled probe for radionuclide therapy will be more expensive than PET/CT imaging. However, we anticipate that with improvement of the technology and gradual expansion of clinical applications, radiopharmaceutical prices will be gradually reduced, becoming affordable for an increasing number of patients, and could be covered by health care programs in the near future. If so, these will greatly promote the development of theranostics.

THE FUTURE

Nuclear medicine in China has made tremendous progress in the past 70 y. Millions of patients benefit each year from the development of nuclear medicine; however, shortages of supplies of radioisotopes and lack of radiopharmaceuticals persist. Nevertheless, the potential scope for future nuclear medicine in China remains enormous; there are more than 3,000 tertiary hospitals, the highest-ranked hospitals in China, yet only one third of them provide nuclear medicine services at present. The issuing of Healthy China 2030 and the Mid- and Long-Term Development Plan for Medical Isotopes (2021–2035) by the Chinese government resulted in a bright blueprint for Chinese nuclear medicine. As planned, nuclear medicine will cover all tertiary hospitals and be launched in another 2,000 hospitals throughout the country to implement the “one county, one department” policy. We anticipate that by the end of 2035, the shortage of radioisotopes and radiopharmaceuticals will no longer exist. Independent innovation in radiopharmaceuticals will continuously emerge, and more advanced, high-quality equipment will be produced by local companies. The scale of nuclear medicine will be 3–4 times greater than it is today, serving more than 10 million patients each year in China.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

We thank Xiang Zhou, Jiajun Ye, Xiang Li, and Lin Qiu for technical assistance.

REFERENCES

  1. 1.↵
    Chinese Society of Nuclear Medicine. A brief report on the results of the national survey nuclear medicine in 2020. Chin J Nucl Med Mol Imaging. 2020;40:747–749.
    OpenUrl
  2. 2.↵
    Chinese Society of Nuclear Medicine. National survey of nuclear medicine status in 2010. Chin J Nucl Med Mol Imaging. 2010;30:428–429.
    OpenUrl
  3. 3.↵
    1. Liang J,
    2. Shen Y,
    3. Wu Y,
    4. et al
    . Development of simulated process for medical fission 99Mo production using electroplating UO2 target with low enriched uranium. J Isot. 2018;31:165–172.
    OpenUrl
  4. 4.
    1. Luo Z,
    2. Wu Y,
    3. Liang J
    . Methods for production of medical radioisotope 99Mo. J Isot. 2018;31:129–142.
    OpenUrl
  5. 5.↵
    1. Huang W,
    2. Liang J,
    3. Wu Y,
    4. et al
    . Investigation on separation of 99Mo from low enriched uranium target by Al2O3 chromatography. J Isot. 2021;34:54–60.
    OpenUrl
  6. 6.↵
    1. Peng S,
    2. Yang Y,
    3. Xie X,
    4. et al
    . Current status and prospects of reactor produced medical radioisotopes in China. Chin Sci Bull. 2020;65:3526–3537.
    OpenUrl
  7. 7.↵
    1. Hu J,
    2. Li H,
    3. Sui Y,
    4. et al
    . Current status and future perspective of radiopharmaceuticals in China. Eur J Nucl Med Mol Imaging. 2022;49:2514–2530.
    OpenUrl
  8. 8.↵
    1. Cui X,
    2. Liu Y,
    3. Wang C,
    4. et al
    . China’s radiopharmaceuticals on expressway: 2014–2021. Radiochim Acta. 2022;110:765–784.
    OpenUrl
  9. 9.↵
    1. Zhang X,
    2. Cherry SR,
    3. Xie Z,
    4. et al
    . Subsecond total-body imaging using ultrasensitive positron emission tomography. Proc Natl Acad Sci USA. 2020;117:2265–2267.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Li G,
    2. Ma W,
    3. Li X,
    4. et al
    . Performance evaluation of the uMI Panorama PET/CT system in accordance with the National Electrical Manufacturers Association NU 2-2018 standard. J Nucl Med. February 22, 2024 [Epub ahead of print].
  11. 11.↵
    1. Zhang YQ,
    2. Hu PC,
    3. Wu RZ,
    4. et al
    . The image quality, lesion detectability, and acquisition time of 18F-FDG total-body PET/CT in oncological patients. Eur J Nucl Med Mol Imaging. 2020;47:2507–2515.
    OpenUrl
  12. 12.↵
    1. Hu P,
    2. Zhang Y,
    3. Yu H,
    4. et al
    . Total-body 18F-FDG PET/CT scan in oncology patients: how fast could it be? Eur J Nucl Med Mol Imaging. 2021;48:2384–2394.
    OpenUrl
  13. 13.↵
    1. Zhao YM,
    2. Li YH,
    3. Chen T,
    4. et al
    . Image quality and lesion detectability in low-dose pediatric 18F-FDG scans using total-body PET/CT. Eur J Nucl Med Mol Imaging. 2021;48:3378–3385.
    OpenUrl
  14. 14.↵
    1. Zhang M,
    2. Guo W,
    3. Zhou Z,
    4. et al
    . Analysis of funding in nuclear medicine and molecular imaging research projects supported by National Natural Science Foundation of China from 2013 to 2022. Chin J Nucl Med Mol Imaging. 2023;43:554–558.
    OpenUrl
  15. 15.↵
    1. Zhang J,
    2. Wang H,
    3. Jacobson O,
    4. et al
    . Safety, pharmacokinetics and dosimetry of a long-acting radiolabeled somatostatin analogue 177Lu-DOTA-EB-TATE in patients with advanced metastatic neuroendocrine tumors. J Nucl Med. 2018;59:1699–1705.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Wang H,
    2. Cheng Y,
    3. Zhang J,
    4. et al
    . Response to single low-dose 177Lu-DOTA-EB-TATE treatment in patients with advanced neuroendocrine neoplasm: a prospective pilot study. Theranostics. 2018;8:3308–3316.
    OpenUrl
  17. 17.↵
    1. Liu Q,
    2. Cheng Y,
    3. Zang J,
    4. et al
    . Dose escalation of an Evans blue-modified radiolabeled somatostatin analog 177Lu-DOTA-EB-TATE in the treatment of metastatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2020;47:947–957.
    OpenUrlPubMed
  18. 18.
    1. Liu Q,
    2. Zang J,
    3. Sui H,
    4. et al
    . Peptide receptor radionuclide therapy of late-stage neuroendocrine tumor patients with multiple cycles of 177Lu-DOTA-EB-TATE. J Nucl Med. 2021;62:386–392.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Jiang Y,
    2. Liu Q,
    3. Wang G,
    4. et al
    . Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumors. Theranostics. 2022;12:6437–6445.
    OpenUrl
  20. 20.↵
    1. Jiang Y,
    2. Liu Q,
    3. Wang G,
    4. et al
    . Evaluation of safety, biodistribution, and dosimetry of a long-acting radiolabeled somatostatin analog 177Lu-DOTA-EB-TATE with and without amino acid infusion. Clin Nucl Med. 2023;48:e289–e293.
    OpenUrl
  21. 21.↵
    1. Peng D,
    2. Liu H,
    3. Huang L,
    4. et al
    . 225Ac-DOTATATE therapy in a case of metastatic pheochromocytoma. Eur J Nucl Med Mol Imaging. 2022;49:3596–3597.
    OpenUrl
  22. 22.↵
    1. Bu T,
    2. Zhang L,
    3. Yu F,
    4. et al
    . 177Lu-PSMA-I&T radioligand therapy for treating metastatic castration-resistant prostate cancer: a single-centre study in east Asians. Front Oncol. 2022;12:835956.
    OpenUrl
  23. 23.↵
    1. Wang J,
    2. Zang J,
    3. Wang H,
    4. et al
    . Pretherapeutic 68Ga-PSMA-617 PET may indicate the dosimetry of 177Lu-PSMA-617 and 177Lu-EB-PSMA-617 in main organs and tumor lesions. Clin Nucl Med. 2019;44:431–438.
    OpenUrl
  24. 24.↵
    1. Zang J,
    2. Fan X,
    3. Wang H,
    4. et al
    . First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46:148–158.
    OpenUrl
  25. 25.↵
    1. Wang G,
    2. Zang J,
    3. Jiang Y,
    4. et al
    . A single-arm, low-dose, prospective study of 177Lu-EB-PSMA radioligand therapy in patients with metastatic castration-resistant prostate cancer. J Nucl Med. 2023;64:611–617.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Fu K,
    2. Pang Y,
    3. Zhao L,
    4. et al
    . FAP-targeted radionuclide therapy with 177Lu-FAPI-46 in metastatic nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging. 2022;49:1767–1769.
    OpenUrl
  27. 27.↵
    1. Fu H,
    2. Huang J,
    3. Zhao T,
    4. et al
    . Fibroblast activation protein-targeted radioligand therapy with 177Lu-EB-FAPI for metastatic radioiodine refractory thyroid cancer: first-in-human, dose-escalation study. Clin Cancer Res. 2023;29:4740–4750.
    OpenUrl
  28. 28.↵
    1. Rao Z,
    2. Zhang Y,
    3. Liu L,
    4. Wang M,
    5. Zhang C
    . [177Lu]Lu-FAP-2286 therapy in a case of right lung squamous cell carcinoma with systemic metastases. Eur J Nucl Med Mol Imaging. 2023;50:1266–1267.
    OpenUrl
  29. 29.↵
    1. Wang Y,
    2. Wang Q,
    3. Chen Z,
    4. et al
    . Preparation, biological characterization and preliminary human imaging studies of 68Ga-DOTA-IBA. Front Oncol. 2022;12:1027792.
    OpenUrl
  30. 30.↵
    1. Wang Q,
    2. Yang J,
    3. Wang Y,
    4. et al
    . Lutetium177-labeled DOTA-ibandronate: a novel radiopharmaceutical for targeted treatment of bone metastases. Mol Pharm. 2023;20:1788–1795.
    OpenUrl
  31. 31.↵
    1. Li H,
    2. Xu T,
    3. Hua Q,
    4. et al
    . 177Lu-DOTA-IBA therapy in prostate cancer with bone metastases. Clin Nucl Med. 2023;48:740–742.
    OpenUrl
  32. 32.↵
    1. Qiu L,
    2. Wang Y,
    3. Liu H,
    4. et al
    . Safety and efficacy of 68Ga- or 177Lu-labeled DOTA-IBA as a novel theranostic radiopharmaceutical for bone metastases: a phase 0/I study. Clin Nucl Med. 2023;48:489–496.
    OpenUrl
  33. 33.↵
    1. Xu T,
    2. Qu G,
    3. Liu G,
    4. et al
    . A new radiopharmaceutical 225Ac-DOTA-IBA in the treatment of a case of bone metastases. Clin Nucl Med. 2023;48:650–652.
    OpenUrl
  34. 34.↵
    1. Yang J,
    2. Deng J,
    3. Fan D,
    4. et al
    . Biodistribution and internal dosimetry of 68Ga-DOTA-IBA PET imaging for patients with bone metastases. Clin Nucl Med. 2023;48:847–852.
    OpenUrl
  35. 35.↵
    1. Feng X,
    2. Zhang L,
    3. Niu H,
    4. et al
    . Selective internal radiation therapy with yttrium-90 resin microspheres followed by anatomical hepatectomy: a potential curative strategy in advanced hepatocellular carcinoma. Asia Pac J Clin Oncol. 2024;20:319–322.
    OpenUrl
  36. 36.↵
    1. Li X,
    2. Yue X,
    3. Zhang L,
    4. et al
    . Imaging evaluation following transarterial radioembolization with yttrium-90 microspheres downstaging hepatocellular carcinoma: the first case in China. Quant Imaging Med Surg. 2023;13:2744–2750.
    OpenUrl
  37. 37.↵
    1. Zhang X,
    2. Li M,
    3. Gai Y,
    4. et al
    . 18F-PFPN PET: a new and attractive imaging modality for patients with malignant melanoma. J Nucl Med. 2022;63:1537–1543.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Duan X,
    2. Cao Z,
    3. Zhu H,
    4. et al
    . 68Ga-labeled ODAP-urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent. Eur J Nucl Med Mol Imaging. 2022;49:1030–1040.
    OpenUrl
  • Received for publication October 30, 2023.
  • Revision received March 25, 2024.
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Bookmark this article

Jump to section

Keywords