The Research / Development and Medical Applications of Isotope and Radiation Technology in Taiwan Lie-Hang Shen , Mei-Hsiu Liao , Ying-Kai Fu Institute of Nuclear Energy Research, Atomic Energy Council, Taiwan, ROC
With the installation of H-/D - cyclotron in 1993, the Institute of Nuclear Energy Research (INER) has successfully developed radioisotopes such as 67
18
Ga, and
123
I,
201
Tl,
F. Up to now, 12 radiopharmaceuticals
13
including C-urea for breath test of Helicobacter pylori infection produced by INER have been licensed by the Department of Health for commercial production and distribution in Taiwan. The INER’s cyclotron and radiopharmaceutical facilities are operated according to ISO9001 and cGMP.
201
Tl-TlCl and 18F-FDG, etc., are sup-
plied by INER to local hospitals. Some radiopharmaceuticals are produced for preclinical and clinical trials, such as
123
I-ADAM,
123
I-IBZM,
123
I-MIBG and
111
In-DTPA-
Octreotide, etc. INER also supplies several cold kits to the domestic market for cals.
60
99m
Tc-labeled radiopharmaceuti-
Co irradiation is applied in several fields in
Taiwan, including medicine, agriculture, and industries. Another application of irradiation is in fine arts and sciences treasured by the nation. Recently, the 60Co facility obtained ISO-9001 certification. In conclusion, the prospects of isotope and radiation application in Taiwan are promising, and will continuously benefit the people and the society in our country. Key words: medical isotopes, radiopharmaceuticals, cyclotron, 60Co irradiation, radiation oncology
Ann Nucl Med Sci 2004;17:93-104
Received 12/17/2003; revised 2/5/2004; accepted 2/10/2004. For correspondence or reprints contact: Lie-Hang Shen, Ph.D., Isotope Application Division, Institute of Nuclear Energy Research, 1000 Wen-Hua Road, Cha-An Village, Lung-Tan, Taoyuan 325, Taiwan, ROC. Tel: (886)3-4711400 ext. 7010, Fax: (886)3-4711416, E-mail: lhshen@iner.gov.tw
Introduction In Taiwan, the Institute of Nuclear Energy Research (INER) has been working together with research groups in medical centers for a long time, and those in other institutes, studying in the fields of isotope and production technique and their applications [1-15]. Through 1973 to 1988, INER had developed isotope laboratories for the production of isotopes with the 40 MW Taiwan Research Reactor (TRR), such as the production of 99Mo from fission products. In 1987, a production license for 99Mo /99mTc generator was approved by the Department of Health (DOH) [2,3]. The shut down of the TRR in 1988 forced the local users to import radioactive products to meet the growing demand for the hospitals and the industry. Table 1 shows the top four imported nuclear medicine radioisotopes which are 99mTc, 131I, 201Tl and 67Ga. Malignant neoplasm, cerebrovascular disease and heart disease are the three leading causes of death in Taiwan. To improve the quality of health care for those patients, more and more nuclear medicine department and PET centers have been set up in local hospitals. Table 2 shows that, more than 92 SPECT and 15 PET scanners have been installed in 49 local hospitals, and 230,000 examinations had been performed in 2002. To meet with the increasing demand from nuclear medicine community for short-lived radiopharmaceuticals, such as 201Tl-thallous chloride, 67Ga-gallium citrate, 123Isodium iodide and 18F-fluorodeoxyglucose (FDG), INER installed a dual-beam compact cyclotron (H-: 15-30 MeV; D-: 8-15 MeV) with high beam current (500 ÂľA) in 1993 [3]. Figure 1 shows the statistics of cyclotrons and PET facilities in Taiwan by the end of 2003. In 1965, the first local 60Co irradiation plant was set up at the Industrial Technology Institute, Hsinchu, and was the beginning of radiation application research and development
Քϲ႔ ඈ Shen LH et al
Table 1. Statistics of major medical radioistope application in nuclear medicine from 1995~2002* Radioistopes 1995 1996 1997 1998 (Activity Ci) 99m Tc 1,474 1,812 2,116 2,622 131 I 142 143 180 203 201 Tl 30 37 60 64 67 Ga 33 35 53 64 * Data from the Department of Radiation Protection, AEC, Taiwan, 2003.
1999
2000
2001
2002
3,512 216 79 66
3,790 231 97 69
4,787 280 120 74
5,946 355 158 83
Table 2. Statistics of nuclear medicine application in Taiwan, ROC. Year Items 1. Hospital & clinics 2. SPECT facilities 3. No. of examinations 4. PET Facilities 5. Compact cyclotron 6. Baby Cyclotron 7.No. of tests with PET facilities 8. No. of in-vitro tests 9. No. of therapy 10.Physicians
1997
1998
1999
2000
2001
2002
35 65 148,000 2 1 1
39 69 155,000 2 1 1
44 78 171,000 5 1 2
47 85 184,680 6 1 2
48 87 199,000 8 1 3
49 92 230,000 15 1 5
1,440
1,572
2,000
3,200
6,150
10,935
9,370,000 3,545 82
7,370,000 3,910 88
7,400,000 4,153 98
7,410,000 4,485 101
7,425,000 4,850 101
7,535,000 5,132 103
*Data from the Society of Nuclear Medicine, Taiwan, ROC (2003).
Chang-Gung Memorial Hospital (PET:1,2000.09)
Taipei Veterans General Hospital (baby cyclotron: 1, PET:2,1st. 1992.11; 2nd: 2001.09) Shin Kong Wu Ho-Su Memorial Hospital (baby cyclotron: 1, PET: 2, 1st: 2001.02,2nd: 2002.04) National Taiwan University Hospital (baby cyclotron: 1*, PET:1, 1995.07) Tri-Service General Hospital (baby cyclotron: 1, PET:1,2002.12) Sun Yat-Sen Cancer Center (PET:1, 2002.05) Taipei Medical University Hospital (PET :1,2002.05)
Institute of Nuclear Energy Research (compact cyclotron: 1,1993.08) Chung Shan Medical University Hospital (baby cyclotron: 1, PET:3, 1998.04) China Medical College Hospital (PET:1, 2002.06) Taichung Veterans General Hospital (PET:1,2002.09) Talin Medical Center, Buddhist Tzu Chi General Hospital (PET:1) I-shou University (baby cyclotron 1*, PET:1*)
Hualien Medical Center, Buddhist Tzu Chi General Hospital (baby cyclotron:1, PET:1)
* In progress
Figure 1. Distribution of cyclotron and PET facilities in Taiwan
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in Taiwan. INER built its own MCi air-type 60Co irradiation plant in June 1981. Since then, INER has already got a very significant progress in this field. In 1994, the first private commercial 60Co irradiation plant began to operate. This milestone will boost the radiation application to a much more promising future. There is always a multiple direction work in the radiation application studies in Taiwan. All the researches have actively promoted the use of radiation in medicine, agriculture and industry. In the past years, INER has achieved very a notable result which significantly promotes the peaceful use of nuclear energy in Taiwan.
Establishment of the Core Facilities and Core Technologies The TR-30/15 Compact Cyclotron, supplied by Ebco, was installed with four beam lines which are extended to the four target caves at INER in 1993. One of the target stations is equipped with Nordion’s 123I target and isotope production system. The other caves with three beam ports are now installed with a liquid target for 18F production, a gas target for the production of 81Rb/81mKr and 18F, and a solid target for the production of 67Ga and 111In. The third and fourth target caves are now designated for production of 201Tl and less activated experiment on new isotope study and material source, respectively. The cyclotron is at good reliability and has supported for R/D work and routine production for more than ten years at INER [9]. Figure 2 shows the cyclotron vault with four target caves, and major research activities. The R/D and routine supply of radiopharmacuticals at INER is in aseptic rooms. Each production is complied with GMP/cGMP regulations. A unique facility exists to support extended research in radiopharmaceuticals. It is INER’s radiopharmacological laboratory (as shown in Figure 3) with microPET, microSPECT/CT, SPECT and autoradiography machine which are used for preclinical study including biodistribution and MIRD dosimetry studies. The organic ligand synthesis and identification laboratory at INER also is important for new radiopharmaceutical development. Preventive maintenance (PM) with commercial PM software has become part of the routine work for INER’s TR 30/15 cyclotron operation. The institute has established oper-
८̄ᗁᄫ 2004;17:93-104
Figure 2. The major application and layout of the TR 30/15 cyclotron at INER
ation, maintenance and PM techniques for the cyclotron. The cyclotron has fully supported each research and production run from 1993 to 2001. Cyclotron targetry technology has been developed. Targets in liquid phase (18F-fluoride production), in gaseous phase (81Rb/81mKr generator and 18F-F2 productions), and in solid phase (201Tl, 67Ga and 68Ge/68Ga productions), have been developed by INER. The INER’s radiopharmaceutical center is a legal radiopharmaceutical plant and complies with GMP/cGMP regulations. INER is a member of international Measurement Assurance Program (MAP). The validation of aseptic production and quality control has also been accomplished. With the existing and a newly constructed radiopharmaceutical laboratories, the institute is now the center for preclinical and dosimetry studies for radiopharmaceuticals in Taiwan [16-22]. In 1996, while INER’s 18F-FDG was produced at the first time, INER’s physicists initiated the Animal PET Instrumentation Development project. 18F-FDG is already routinely commercial supply for local hospitals and microPET also has developed successfully. These technologies which INER has developed will continue to support further progress in the fields of medical isotopes, radiopharmaceutical R/D and production.
2004ѐ6͡ 17ס2ഇ
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ƓMicroPET
ƔMicroSPECT/CT Radiopharmacology Laboratory
Figure 3. Radiopharmacology laboratory and microPET
Major Radioisotope R/D and Production Activities R/D and Production of Radioisotopes with Cyclotron With TR 30/15 Compact cyclotron, target stations, and lead cells, INER has developed core facilities and technologies in the production of more than 10 short-lived radioisotopes. Most of these nuclides are transferred to "INER’s radiopharmaceutical Center" as raw materials for the production of radiopharmaceuticals, which are used in the application for SPECT, as well as PET imaging. Cyclotron and isotope production groups passed the criteria of ISO-9001 (2000) qualification and were certified by TÜV in October, 2001. Table 3 summarizes the types of nuclear reactions, applications and the present status for research and produc-
Ann Nucl Med Sci 2004;17:93-104
96
tion of some short-lived gamma-emitting radionuclides at INER [23-31]. Table 4 shows the short-lived positron-emitting radionuclides produced at INER. R/D and Production of Radioisotopes from Reactor-produced Isotopes The main reactor-produced radioisotopes which INER studies or produces currently are 99Mo/99mTc, 90Sr/90Y, and 188
W/188Re. The bulk radioisotopes are imported. The produc-
tion of 99Mo/99mTc generator has been approved by the DOH. 90
Sr/90Y, and
188
W/188Re generators are produced for research
and the development of therapeutic radiopharmaceuticals [32-36]. Tungstan-188 was supplied by ORNL under a cooperation project between USA and Taiwan. INER also rou-
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έ៉ТҜ৵ᗁጯᑕϡᄃᏬडԫఙ൴ण Isotope medical applications and radiation technology development in Taiwan
Table 3. Short-lived gamma-emitting radionuclides produced at INER Isotope
Product
123
Nuclear reaction
123
I 201 Tl 67 Ga 111 In 57 Co 95m Tc 81 Rb/ 81mKr
124
I-NaI 201 Tl-TlCl 67 Ga -GaCl3 111 In -InCl3 57 Co-CoCl2 95m Tc-HTcO4 81m Kr
Xe (p, 2n) 203 Tl (p, 3n) 68 Zn (p, 2n) 112 Cd (p, 2n) 58 Ni (p, 2p) 57Co 95 Mo (p, n) 95mTc 82 Kr (p, 2n) 81Rb
Separation/purification
Status
Adsorption Coppt/Ion exchange Cation-exchange Cation-exchange Cation-exchange Sublimation/ Adsorption Ion exchange
1 Ci/batch 2 Ci/batch 1 Ci/batch 0.6 Ci/batch 6 mCi/batch 10 mCi/batch 0.1 Ci/batch
Table 4. Short-lived positron-emitting radionuclides produced at INER Isotope
Product
18
18
F Zn/ 62Cu 68 Ge/ 68Ga 62
Nuclear reaction 18
F-NaF 62 Cu 68 Ga
Separation/purification
Status
Anion-exchange Anion-exchange Adsorption
2 Ci/batch 0.1 Ci/batch 30 mCi/batch
18
O (p, n) F Cu (p, 2n) 62Zn 69 Ga (p, 2n) 68Ge 63
Table 5. Reactor-produced radioisotopes at INER Radioisotope
Product
Application
Status
Sr/ Y
Generator (50mCi)
R/D for therapy
W/ 188Re
Generator (500mCi)
R/D for therapy
Mo/ 99mTc
Generator (500mCi)
Diagnosis
Sealed Source (100Ci)
Industry
Production for R/D Production for R/D and Clinical Trial Production & Supply (Licensed by DOH) Routine Supply
90
90
188
99
192
Ir
tinely produces sealed 192Ir sources for nondestructive testing
local market in this year. The demand of 18F-FDG for PET
in industry. Table 5 shows the reactor-produced radioisotopes
increases rapidly. INER routinely supplies 18F-FDG to local
at INER.
hospitals and PET centers five days a week in Taiwan. Several
Research and Production of Radiopharmaceuticals In the last 24 years, INER has developed their core facilities and core techniques in research and production of several radiopharmaceuticals. The institute also produces pharmaceuticals which are from stable isotopes.
123
I-labeled compounds, include
roblastoma imaging,
123
123
I-MIBG for neu-
I-IBZM for dopamine D2 receptor
imaging are under clinical trials. The institute has developed a kit formulation for rapid preparation of
111
In-DTPA-
Octreotide, a promising diagnostic tool for localizing primary tumors, staging, control and follow-up after therapy. Table 6 shows several cyclotron-produced radiopharmaceuticals developed at INER recently.
Radiopharmaceuticals
from
Cyclotron-produced
Radioisotopes
Radiopharmaceuticals
INER studies and produces several cyclotron-produced diagnostic radiopharmaceuticals [37-56]. INER’s injection solution,
123
201
Tl-TlCl
67
from
Reactor-produced
Radioisotopes INER has developed several
99m
Tc-labeled radiophar-
I-NaI oral solution, and Ga-citrate
maceuticals since 1980’s. Four cold kit formulations are rou-
injection solution are approved to supply to the hospitals
tinely supplied to domestic hospitals. They are HMPAO,
routinely. INER’s
201
Tl injection solution shares 75% of the
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DMS, MDP, and MAG3. 99mTc-MAG3 is similar to 131I-labeled
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Table 6. Cyclotron-produced radiopharmaceuticals developed and produced at INER Radiopharmaceutical
Application
Status
I-NaI Oral Solution 201 Tl-TlCl Injection 67 Ga-Ctrate Injection 81m Kr Gas and Ventilation Apparatus 18 F-FDG Injection 123 I-IBZM Injection
Thyroid Diagnosis Heart and Tumor Diagnosis Tumor Diagnosis
Approved by DOH and Routine Supply Approved by DOH and Routine Supply Approved by DOH and Routine Supply
Lung Diagnosis
Approved by DOH and Routine Supply
Whole body tumor Diagnosis Neuropsychiatric Diagnosis Pheochromocytoma and Neuroblastoma Diagnosis Neuroendocrine Tumor Diagnosis
Approved by DOH and Routine Supply Clinical Trial
123
123
111
I-MIBG Injection Solution
In-DTPA-Octreotide Injection
hippuran in the mechanism of renal extraction and will replace the applications of
131
I-OIH.
99m
Animal Trial Clinical Trial
filled with liquid
188
Re (14 or 20Gy on 0.5mm depth from
Tc-TRODAT-l has
surface). Another thirty patients underwent PTCA, followed
been reported as the first 99mTc-labeled radiotracer for in-vivo
by perfusion balloon inflation without brachytherapy, served
imaging of central dopamine transporters (DATs) in humans.
as the control group. Final results were radiation safety for
The specific binding of this tracer to DAT in the basal gan-
30 days, angiography restenosis and no any major adverse
glia region of brain implies its potential uses for the diagno-
cardiac events were found in 6 months follow-up. Restenosis
sis of deficit of DATs in neuro-degenerative diseases, such as
with 20 Gy at 0.5mm depth was 21%, which was 60% lower
Parkinson’s disease (PD). Clinical trials with hundreds of
than with 14 Gy. Next stage, TRIPPER-II will be designed in
cases in Taiwan will be completed by the end of this year. On
cases with in stent restenosis underwent with IVUS guide,
the other hand, INER also involves in the studies of thera-
followed by 20 Gy irradiation.
peutic radiopharmaceuticals. Due to its high osseous affinity of strontium element and high beta energy (1.46 MeV) of 89
89
Sr, Sr-SrCl2 can function as bone pain palliative therapy
agent. The carrier effect of strontium in the agent has been studied with rats through cooperation with local hospital. The results showed that carrier effect on strontium accumulation of bone is negligible in the range from free to 0.6 mg Sr for 0.2 kg rat and indicated that bone has strong affinity to accumulate strontium while the other organs eliminate it rapidly. The clinical trials of 89Sr-SrCl2 has been finished under GCP guidelines by means of cooperation with local hospital. The clinical trial of rhenium-188 perrhenate for preventing restenosis after precutaneous transluminal coronary angiography (PTCA) has been carried out by a team organized by INER and a local medical center (Taiwan Radiation in Prevention of the Post-Pure Balloon Angioplasty Restenosis Trial, TRIPPER-1). Fifty-five patients underwent PTCA for de novo or restenotic (without stenting) lesions, followed by IVUS guide brachytherapy, perfusion balloon
Ann Nucl Med Sci 2004;17:93-104
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R/D and Production Diagnostic Pharmaceutical from Stable Isotope in Taiwan The Stable Isotope Laboratory at INER has focused its effort on the application of 13C, 15N and 18O [57-63]. The laboratory has developed the 13C-urea breath test (13C-UBT) which is a non-invasive method for detecting Helicobacter pylori. In recent years, Helicobacter pylori infection is proved as the major cause of most gastroduodenal diseases, such as chronic gastritis, peptic ulcer, and gastric cancers. In 1998, the production of INER’s 13C-urea was approved by DOH in Taiwan. The technique has been transferred to a domestic GMP pharmaceutical plant for large scale production in 2000 and the test has been reimbursed by National Health Insurance in Taiwan since 2001. The second generation MRI contrast agent, INER Gadodiamide Injection (Gd-DTPA-BMA), has been developed. The injection is the formulation of the gadolinium complex of diethylenetriaminepentaaceticacid bismethylamide, and is a nonionic extracellular contrast agent for MR
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έ៉ТҜ৵ᗁጯᑕϡᄃᏬडԫఙ൴ण Isotope medical applications and radiation technology development in Taiwan
Table 7. Current irradiation service items at INER’s irradiation plant Category
Item
Purpose
Industry
Polyswitch
Medical devices
Gloves, Petri-Dish, Surgical Gown, Antibiotics, Herbs, etc.
Radiation-Induced Polymerization, Crosslinking Radiosterilization
Food
Garlic Feed for Experimental Animals Dehydrated Vegetables
Sprout Inhibition Radiosterilization Radiodisinfestation and Decontamination
Tulip, Lily Flower Cosmetics
Dwarfing Reducing Microorganism
Miscellanies
Table 8. Renewed regulation of irradiation processing for food in Taiwan (Sep. 1999) Maximum
Maximum
Source
Radiation Energy (MeV)
Radiation Dose (kGy)
Purpose of Irradiation
Electron Beam
10
X-ray or ə-ray
5
0.15
Sprout Inhibition
Papaya, Mango
Electron Beam X-ray or ə-ray
10 5
1.5
Shelf-life Extension; Disinfestation
Strawberry
Electron Beam X-ray or ə-ray
10 5
2.4
Shelf-life Extension
Bean
Electron Beam X-ray or ə-ray
10 5
1
Disinfestation
Fresh Vegetable
Electron Beam X-ray or ə-ray
10 5
1
Shelf-life Extension; Disinfestation
Electron Beam
10
X-ray or ə-ray
5
1
Disinfestation
Electron Beam
10 5
Shelf-life Extension; Disinfestation
Radiation Irradiation Food Potatoes, Sweet Potatoes, Scallion, Onion, Garlic, Ginger
Grains and its Hucked Products Frozen Poultry and Boneless Poultry Refrigersated Flesh
X-ray or ə-ray
5
Electron Beam X-ray or ə-ray
10 5
4.5
Shelf-life Extension
Electron Beam X-ray or ə-ray
10 5
7
Shelf-life Extension
Electron Beam
10
X-ray or ə-ray
5
30
Shelf-life Extension; Disinfestation
Pollen
Electron Beam X-ray or ə-ray
10 5
8
Shelf-life Extension
Animal Seasoning
Electron Beam X-ray or ə-ray
10 5
10
Shelf-life Extension
Frozen Flesh Dries or Dehydrated Seasoning
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imaging. The result of clinical trial of INER Gadodiamide
of national health care and people’s duality of life in Taiwan.
Injection is promising. It is concluded that INER Gadodiamide Injection is safe and well tolerated as a single dose contrast agent to provide as effective in the enhancement of CNS lesion delineation in MRI diagnosis as Magnevist, the marketed standard treatment. To produce quality radiopharmaceuticals with INER’s self-developed technology, the “INER’s Radiopharmaceutital Center” has been set up and was approved by the
Acknowledgments The authors would like to thank the support from AEC and INER in Taiwan, and staffs in Isotope Application Division, Chemistry Division, Physics Division, Health Physic Division and Engineering Division for their efforts in R/D and production activities. We also thank Dr. Zei-Tsan Tsai for his help in review of this article.
Department of Health in Taiwan in 1998. The performance of this pharmaceutical center has been audited and certificated with GMP/cGMP from the government. The operation of radioisotope production at this plant is certificated with ISO900l by TÜV Rheinland Aniagentechnik GmbH.
R/D and Applications of Radiation Processing Technology INER’s Co-60 Irradiation Plant has been operated for 23 years. It is one of the three largest irradiation plants in our country. They are "China Biotech Corporation" with designed capacity of 5 MCi (current 2900 kCi). (Industrial Technology Research Institute( with designed capacity of 0.3 MCi (current 2200 kCi), and (INER’s Irradiation Plant( with designed capacity of 1 MCi (current ~600 kCi). The irradiation plant at INER is operated with ISO9001 quality assurance system to offer best radiation service. Table 7 shows some of the current irradiation service items at INER’s irradiation plant. A renewed regulation for the irradiation processing of food was issued in September 1999. Fresh poultry, meat, fresh vegetable and fruit, grain, and pollen are included in the demended regulation. Table 8 shows the items which are allowed to irradiation processing in Taiwan. Conclusion and Future Prospects The research related to molecular and functional imaging, gene expression imaging and cell proliferation imaging, targeted radionuclide therapy would be carried out by research institute and medical centers in Taiwan. With the support of the government and private sectors, INER will work together with research institutes and hospitals to advance our isotope and radiation applications for improving
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ᙯᔣෟĈ
८̄ᗁᄫ2004;17:93-104
92ѐ12͡17͟צந 93ѐ2͡5࣒͟Լ 93ѐ2͡10͟ତצΏྶ ᓑඛˠĈՔϲ႔౾̀ ॿᎩᐷሔฏָщՅ̼͛ྮ1000ཱི ८ਕࡁտٙТҜ৵ᑕϡ ྖĈ(03)-4711400ᖼ7010 ็ৌĈ(03)-4711416 ̄ܫቐĈlhshen@iner.gov.tw
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