Status of Radiopharmaceutical Research, Therapy in Taiwan (Shyh-Jen Wang, Gann Ting)

The Status and Prospects of Radiopharmaceutical Research for Targeted Radiotherapy in Taiwan Shyh-Jen Wang1, Gann Ting2 1

Taichung Veterans General Hospital, Taichung, Taiwan Institute of Nuclear Energy Research, Lung-Tan, Taiwan

2

Therapeutic nuclear medicine has grown rapidly as a treatment modality in oncology in last decade. A variety of specific tumor-seeking radiopharmaceuticals have been commercialized for radiotherapy. However, most of these therapeutic radiopharmaceuticals are not applied to patients clinically in Taiwan because of difficulty in importing these drugs from other countries and their high expense. Therefore, the Institute of Nuclear

Introduction In last decade, therapeutic nuclear medicine has grown rapidly as a treatment modality in oncology. Many different specif ic tumor-seeking radiopharmaceuticals have been developed for treatment. However, the import of these radiopharmaceuticals is difficult and expensive. Certain therapeutic radiopharmaceuticals are being developed independently in Taiwan.

Energy Research (INER) in Taiwan has been putting their efforts on developing these therapeutic radiopharmaceuticals and several kinds of therapeutic radiopharmaceuticals have been developed successfully in the past few years.

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Y-lipiodol,

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Re-lipiodol and

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Re-

microsphere are developed for the therapy of hepatoma, 188

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Re-HEDP for metastatic bone pain and

Re-sulfur colloid for malignant ascites. Pre-clinical

studies of these radiopharmaceuticals are being carried out and clinical trials will be conducted soon.

Key words: radiotherapy, radiopharmaceutical, Lipiodol,

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Re-Lipiodol,

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Re-microsphere,

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Y-

Re-HEDP,

188

Re-sulfur colloid

Ann Nucl Med Sci 2002;15:195-200

Received 11/16/2001; accepted 6/2/2002.

For correspondence or reprints contact: Shyh-Jen Wang, M.D., Department of Nuclear Medicine, Taichung Veterans General Hospital, 160 Section 3, Taichung Harbor Road, Taichung 407, Taiwan, R.O.C., Tel: (886)4-23741349, Fax: (886)4-23741348, E-mail: sjwang@vghtc.vghtc.gov.tw

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Y-Lipiodol Hepatoma is one of the most common malignant tumors in the world, especially prevalent in southeastern Asia, Japan and sub-Saharan Africa. In Taiwan, hepatoma is the most common cancer in males, and the sixth most common in females. Hepatoma is often found at an advanced stage when surgery is difficult or impossible in most patients. Treatment of inoperable hepatoma with systemic cytotoxic chemotherapy has not been successful, with little or no improvement in the survival rate.

Carriers of therapeutic agents that treat hepatoma effectively, without damage to normal tissue, are currently under investigation. One such carrier is Lipiodol, an ethyl ester of poppy seed oil fatty acids. It has been found to be selectively retained in hepatoma [1]. In addition, Lipiodol is used to detect the existence of hepatoma [2], and is used as an embolic material in transhepatic arterial embolization [3,4].

131 I-Lipiodol has also been successfully developed and tested for the treatment of hepatoma [5,6]. Furthermore, some authors have suggested that 90Y is a better radiotherapeutic candidate than 131I. 90Y has several advantages over 131I, including a shorter half-life which is more suitable for therapy, lack of gamma ray emission, a longer beta energy range

Wang SJ et al

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Re has similar beta energy characteristics to 90Y, with

sufficient to kill cells, few shielding problems and little radiation dose to the surrounding normal tissue [7]. In 1994, the

many advantages such as generator production, a shorter

Institute of Nuclear Energy Research (INER) in Taiwan suc-

half-life than 90Y and the emission of 155 keV gamma rays

cessfully labeled Lipiodol with 90Y (Figure 1) [8]. In our pre-

for tumor imaging. In addition,

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188

Re may not have the same

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vious study, we analyzed the biodistribution of Y Lipiodol

bone uptake as Y due to differences in aqueous chemistry.

in rats with liver tumor [9]. We found the radioactivity in the

In 1995, INER labeled Lipiodol with

liver tumors was high at 1 and 24 h and then declined slowly,

analyzed its biodistribution in rats bearing hepatic tumors,

with a biological half-life of 84.1 h. The radioactivity in the

following hepatic arterial injection [10]. This study revealed

normal liver was also high at 1 h but was significantly lower

the radioactivity in the hepatic tumor was very high through-

than in the tumor with a biological half-life of 38.5 h. The

out this study, with a biological half-life of 122.9 h.

ratio of tissue concentration between the liver tumor and nor-

Radioactivity in the normal liver tissue was also high, but

mal liver tissue (T/N ratio) was 3.03 at 1 h and rose to 6.45 at

was significantly lower than the tumor. The biological half-

72 h. The radioactivity in the lung was almost as high as in

life in the normal liver tissue was 31.7 h. The T/N ratio was

the normal liver tissue and declined rapidly. A moderate con-

5.15 at 1 h and rose to 7.7 at 24 h. The level of radioactivity

centration of radioactivity was noted in the first 24 h. The

in the lung was high at 1 h, and declined rapidly over time.

concentration of radioactivity in skeletal muscle, spleen,

The radiation in muscle tissue, the spleen, the testes, bone

testes and whole blood was very low. This study concluded

and whole blood were insignificant. This study suggested

that trace uptake in liver tumors following hepatic arterial

that

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injection of Y-Lipiodol was high and the retention was long.

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Re (Figure 2) and

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Re-Lipiodol is a potential radiopharmaceutical for the

hepatic arterial treatment of hepatic tumors.

As a result, large therapeutic radiation doses could be deliv-

Re-Lipiodol Although 90Y-Lipiodol is found to be localized and retained in the tumor, it could also accumulate in non-target organs especially in the skeletal system. The radiation burden to bone marrow, an organ highly sensitive to radiation, may limit the clinical use of 90Y-Lipiodol.

New Generation 188Re-Lipiodol Jacqueline Whang’Peng, Director of Division of Cancer Research, National Health Research Institute, Taiwan, appreciated the development of 188Re-lipiodol and would like to conduct a clinical trial using 188Re-Lipiodol to treat hepatoma. However, the toxicity of N,N,N',N'tetrakis(2-benzymidazolylmethyl)-1,2-ethanediamine (EDTB, used as a chelating agent) is not very clear. Thus, we

Figure 1. Preparation scheme for 90Y-EDTB-Lipiodol

Figure 2. Preparation scheme for 188Re-EDTB-Lipiodol

ered to the tumor.

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Re-Lipiodol

half-life of 170 h. Radioactivity in the lung was 1.78 % of

(without chelating agent), and test the stability, dosimetry

the injected dose at 1 h but declined rapidly over time. The

will try to develop a new second-generation and efficacy of this new

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Re-Lipiodol preparation for treat-

concentration in the urine was 6.14 % and declined rapidly thereafter. The radioactivity in other organs was quite low.

ing hepatic tumors.

The survival time of rats receiving intratumoral injection of 188

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Re-microspheres was significantly longer than the control

Re-Microspheres In previous reports of regional intra-arterial administration of radiolabeled 131I- or 90Y-microspheres, selective internal radiation as a single modality could deliver a tumoricidal dose of radiation to a hepatic tumor without jeopardizing nontumorous liver tissue [11]. Studies have shown that selective internal radiation is practical and feasible [12,13].

However, intra-arterial injection of radionuclide has some disadvantages: (1) the radionuclide reaches the tumor site by a non-specific route; (2) because of the nonspecific distribution, a large quantity of radionuclide must be used; (3) this technique requires extremely selective catheterization and is therefore, highly dependent on the skill of the operator and quality of equipment; (4) with the common existence of arteriovenous shunts in hepatoma, systemic leakage of radionuclide to the lung is very likely. Tian et al. directly injected 90 Y-microspheres into the tumor under real-time ultrasound guidance and obtained very encouraging results [14].

However, the preparation of 90Y glass microspheres is technically complicated and time consuming. In 1998, INER labeled microspheres with 188Re (Figure 3) and analyzed the biodistribution and survival time in rats with hepatoma after injection of this drug [15]. This study revealed radioactivtiy throughout the hepatoma was very high, with a biological

Re-HEDP Nearly 50 % of patients dying of cancer have bone metastases at the time of death. Bone metastases result in pain, hypercalcemia, loss of function following pathological fracture, and neurological symptoms from nerve compression. Although external radiation therapy provides significant palliation in approximately 80 % of patients with painful bone metastases, its application is not feasible in patients with multiple bony metastases. Due to the large number of lesions in many patients, the systemic administration of radiation therapy with radiopharmaceuticals may be preferable. 89Sr-SrCl2 and 153Sm-ethylenediaminetetramethylene phosphonate (EDTMP) were approved by the Food and Drug Administration (FDA) for palliative treatment of matastatic bone pain. Until now, only 89Sr is available but very expensive in Taiwan. In 1997, INER and National Tsing Hua University labeled hydroxyethylidene diphosphonate (HEDP) with 188Re for treatment of metastatic bone pain (Figure 4) [16]. This study revealed that the biological half-

Figure 3. Preparation scheme for 188Re-microspheres

Figure 4. Preparation scheme for 188Re-HEDP

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group. This study concluded that direct intratumoral injection of 188Re-microspheres is extremely attractive as a clinical therapeutic alternative in hepatoma patients.

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life in bone is 60.86 h. In contrast, the biological half-life in

maceuticals should allow the full potential of radionuclide

muscle is 2.99 h. The radioactivity in muscle, spleen, testes

therapy to be realized. During the last decade, many new

and stool was quite low. Most of the tracer was excreted by

radiopharmaceuticals have been developed in Taiwan. These

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Re-HEDP is

drugs are anticipated to have minimal toxicity and are envi-

a very good potential candidate for the treatment of metastat-

sioned to be effective. We sincerely wish that our develop-

ic bone pain.

ment of these new therapeutic radiopharmaceuticals would

the urinary system. This study concluded that

eventually contribute to the improvement of the health of our 188

Re-Sulfur Colloid Malignant ascites is usually ascribed to increased production of peritoneal fluid probably as a result of peritoneal irritation and to decreased removal rate resulting from lymphatic obstruction. The tumors chiefly responsible for malignant ascites are metastatic ovarian, renal, and gastrointestinal cancers and occasionally methothelioma and disseminated lymphoma. Radiocolloid therapy is administered in cases of recurrent malignant effusions when systemic therapy and repeated paracenteses fail to control ascites. 188Re-sulfur colloid has been developed by INER for palliating malignant ascites (Figure 5).

Figure 5. Preparation scheme for 188Re-sulfur colloid

Conclusion Therapeutic radiopharmaceuticals allow nuclear physicians to treat the disease by attacking only the affected cells.

A significant portion of the growth and future of nuclear medicine will depend on the development of new radionuclide therapies. The development of new and ideal radiophar-

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people.

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