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Japanese Journal of Clinical Oncology Advance Access published online on June 19, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym039
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© 2007 Foundation for Promotion of Cancer Research

First Attempt of Boron Neutron Capture Therapy (BNCT) for Hepatocellular Carcinoma

Minoru Suzuki1,, Yoshinori Sakurai2, Satoru Hagiwara3, Shinichiro Masunaga1, Yuko Kinashi1, Kenji Nagata1, Akira Maruhashi2, Masatoshi Kudo3 and Koji Ono1

1 Particle Oncology Research Center
2 Division of Medical Physics, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka
3 Department of Gastroenterology and Hepatology, Kinki University, School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan

For reprints and all correspondence: Minoru Suzuki, Particle Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. E-mail: msuzuki{at}rri.kyoto-u.ac.jp

Received October 18, 2006; accepted December 18, 2006


   Abstract
TOP
 Abstract
INTRODUCTION
 CASE REPORT
 DISCUSSION
 Conflict of interest statement
 References
 
A 60-year-old man with multiple hepatocellular carcinomas (HCCs) was enrolled as the first patient in a pilot study for treating multiple liver tumors with boron neutron capture therapy (BNCT). Because of compromised liver function, the multiple tumors in the right liver lobe were treated with BNCT and those in the left lobe with hepatic arterial chemoembolization. The feasibility and clinical outcome of this first case was assessed. During the treatment and follow-up period, no adverse effect as a result of BNCT was observed except for temporary temperature elevation to 38.3°C, and the AST and ALT being higher than 200 IU/l. For 1 month, the tumors treated with BNCT remained stable in size. The BNCT-treated tumors showed regrowth 3.5 months after BNCT and the patient died of liver dysfunction caused by progression of HCC 10 months after BNCT. The feasibility of BNCT for HCC is confirmed in this first case.

Key Words: boron neutron capture therapy • hepatocellular carcinoma • liver tumors


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
CASE REPORT
 DISCUSSION
 Conflict of interest statement
 References
 
Various therapeutic options including hepatic arterial infusion (HAI) chemotherapy and chemoembolization, radiofrequency ablation, percutaneous ethanol injection, external radiation therapy using photons, charged particle radiotherapy and combinations of these treatments have been applied to inoperable liver tumors (1–7). Recently, radiotherapy has played a major role in treating solitary or tumors less than four. Recent technical advances in external radiation therapy using photons, including three-dimensional (3D) conformal radiotherapy or intensity-modulated radiotherapy (IMRT), have enabled delivery of curative doses of >60 Gy to liver tumors, while keeping the radiation dose to the normal liver and adjacent organs below tolerable levels (8–11). These clinical studies have revealed dose–response relationships in treating liver tumors and have demonstrated the success of radiotherapy for liver tumors by selective delivery of curative doses.

In theory, boron neutron capture therapy (BNCT) provides a way to deliver curative doses to the tumors while sparing normal liver tissues (12,13). BNCT is based on the following nuclear reaction: non-radioactive isotope 10B atoms that have absorbed low energy (<0.5 eV) neutrons disintegrate into alpha (4He) particles and recoiled lithium nuclei (7Li), [10B(n,{alpha})7Li]. These particles deposit large amounts of energy along their very short path (<10 µm). For BNCT to be successful, a sufficient number of 10B atoms must accumulate in the tumors, and the concentration gradient of 10B atoms between the tumors and surrounding normal tissues must be large. One of the obstacles for applying BNCT to deep-seated tumors such as those in the liver is steep attenuation of the thermal neutron fluence within the body. To overcome this problem, there needs to be a large, highly selective accumulation of 10B atoms in the liver tumors. We have reported that intra-arterial delivery of a boron compound with a vessel embolizing agent (e.g. iodinated oil or lipiodol) enables such highly selective accumulation of large amounts of boron compounds in rat liver tumors (14). We evaluated the dose distribution of BNCT using computed tomography (CT) images of patients with multiple liver tumors and revealed that BNCT enables delivery of curative doses to the liver tumors while keeping the dose to the normal liver below a tolerable level (15).

Based on these previous findings, we started a pilot study to treat inoperable liver tumors with BNCT using a newly developed boron delivery system, intra-arterial administration of a boron compound with a vessel embolizing agent, lipiodol. In this article, we describe the treatment procedure, feasibility and clinical results of the first patient with multiple hepatocellular carcinomas (HCCs) treated with BNCT.


   CASE REPORT
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
DISCUSSION
 Conflict of interest statement
 References
 
Human Subject Protection
This pilot study was reviewed and approved by the Institutional Review Board, Kinki University School of Medicine, Japan. In addition, the Institutional Review Board, Kyoto University Research Reactor Institute (KURRI), Japan, judged the eligibility of each patient for this pilot study.

Case Presentation
A 60-year-old man underwent resection of two HCCs in the caudate lobe in June 2004. In November 2004, recurrent multiple HCCs in both liver lobes were detected by abdominal CT. The tumors were treated with transcatheter arterial chemoembolization (TAE). In December 2004, new multiple liver tumors were detected by the abdominal CT. Because the interval between the TAE and development of new multiple HCCs was very short, new lesions were judged to be refractory to further TAE treatment. The patient was referred to our center for further treatment by BNCT and was informed about this pilot study. In this conversation with the patient, the study procedure, presumable effects and risks, other treatment options, voluntary participation in this study and data management were clarified. He gave a written informed consent to whole activities performed at the two institutions, Kinki University School of Medicine and Kyoto University Research Reactor Institute, and voluntarily agreed to participate in this trial.

Laboratory studies at 4 days before BNCT demonstrated total bilirubin 0.6 mg/dl, serum albumin 4.4 g/dl, aspartate aminotransferase (AST) 46 IU/l, alanine aminotransferase (ALT) 50 IU/l, serum creatinine 0.74 mg/dl, blood urea nitrogen (BUN) 20 mg/dl and serum {alpha}-fetoprotein (AFP) 11 ng/ml. The patient had Child–Pugh grade B cirrhosis. He was positive for hepatitis C virus antibody.

BNCT Procedure
On 22 February 2005, the patient underwent BNCT. Because the patient had Child–Pugh grade B cirrhosis, the irradiation was confined to the right liver lobe. In this case, boronophenylalanine (BPA) and borocaptate sodium (BSH), which have been available in on-going clinical BNCT trials, were used as 10B carriers (12). In the preparation for administration of these compounds, BPA (16 g, 250 mg/kg) was dissolved in 660 ml 5.4% fructose solution (BPA-f) and BSH (1 g/body) in 20 ml 50% physiological saline. In the morning, at the angiographic facility, the patient received intra-arterial administration of BPA-f and BSH through the catheter lodged in the right hepatic artery. BPA-f was administered over 60 min and was followed by injection of BSH. Because the embolizing effect of lipiodol requires a BSH solution/lipiodol mixture ratio of between 1 : 1 and 1 : 2, 15 ml BSH solution without lipiodol was administered, followed by injection of mixed BSH/lipiodol emulsion (5 ml BSH and 5 ml lipiodol). Selective accumulation of lipiodol in the multiple tumors was observed by fluoroscopy and confirmed by CT performed 2 days after BNCT (Fig. 1). For the treatment of the multiple HCCs in the left lobe, 20 mg epirubicin hydrochloride and 2 ml lipiodol was administered selectively via a catheter lodged in the left hepatic artery. No additional embolization of the right and left hepatic arteries by gelatin sponge particles was performed. Blood samples were taken at 0, 1 and 3 h after the end of infusion of the BSH/lipiodol emulsion, and before and after irradiation, for the measurement of 10B concentration. During injection of the BSH/lipiodol emulsion, the patient complained of mild upper abdominal pain, which needed no medication and disappeared after the injection.


Figure 1
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  		Figure 1. Abdominal CT performed 2 days after BNCT. Accumulation of lipiodol in the HCCs was confirmed.

 
The patient was transported to KURRI for irradiation 6 h after injection of the boron compounds. In positioning the patient in the irradiation room, we referred to the two lines on the skin, which were marked by fluoroscopy the day before BNCT, indicating the upper and lower range of the liver movement due to respiration. The patient was treated with right and posterior neutron beams. A 20-cm circle collimator which encompassed the right lobe was used for both of the beams. In this pilot study, the dose constraint to determine the irradiation time was the dose delivered to normal liver. In this first case, irradiation time was determined so as to deliver a radiation dose of 2.0 Gy-Eq (Gy-Eq, photon-equivalent dose) to 50% of the right liver lobe. The compound biological effectiveness (CBE) factors were used as an alternative relative biological effectiveness (RBE) in evaluating the biologically photon equivalent absorbed dose (Gy-Eq) by the dose component of [10B(n,{alpha})7Li] in BNCT (13). Table 1 summarizes the RBE and CBE used in this pilot study. The irradiation time was adjusted using the 10B concentration in the liver and the epithermal neutron fluence rate monitored during the BNCT. The former was estimated by the prompt {gamma}-ray data emitted from the patient's liver which were collected through the {gamma}-ray telescope (16). In this case, 10B concentration in the liver was estimated to be 11.6 ppm. As shown in Fig. 2, the 10B concentration in the blood just before irradiation was 23.8 ppm, two times higher than that in the liver. The irradiation time of the right beam was 62 min and that of the posterior beam, 21 min. The right and posterior neutron beams were administered with the patient in the supine and right-decubitus positions, respectively, because the neutron beams were emitted from a fixed port installed in the irradiation room. No adverse effect was observed during and just after irradiation.


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  		Table 1. RBE and CBE factors for the liver used for conversion of physical dose (Gy) to photon-equivalent dose (Gy-Eq)

 

Figure 2
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  		Figure 2. 10B concentration in the blood as a function of time. The timing of irradiation and estimated 10B concentration in the liver during irradiation is shown.

 
Dose Distribution Analysis
Figure 3 shows the dose distribution resulting from the irradiation with right and posterior neutron beams. Peak and mean doses to the right lobe of the liver were 4.9 and 2.7 Gy-Eq, respectively.


Figure 3
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  		Figure 3. Isodose distributions in the right lobe resulting from irradiation with right and posterior epithermal neutron beams. In this case, the left lobe was outside the radiation field. The contour of the liver is shown as a solid white line.

 
Post-Treatment Course and Clinical Outcome
The changes in the AST, ALT, serum creatinine and BUN during 3.5 months after BNCT are illustrated in Fig. 4. Although there was a temporary temperature elevation to 38.3°C, and the AST and ALT were higher than 200 IU/l, all returned to normal within 1 week (Fig. 4). The serum creatinine, BUN and amylase levels remained within normal range. The patient did not complain of nausea or abdominal pain. The patient was discharged on the 10th day after BNCT. Response and progression were evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) committee (17).


Figure 4
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  		Figure 4. The changes in blood chemistry tests relating liver, renal and pancreatic functions. AST, aspartate aminotransferase; ALT, alanine aminotransferase; AMY, amylase; CRE, creatinine; BUN, blood urea nitrogen.

 
A follow-up abdominal CT at 1 month post-BNCT showed that multiple HCCs in the right lobe remained stable in size and were judged as stable disease (SD). Multiple HCCs in the left lobe treated with chemoembolization of 20 mg epirubicin hydrochloride and 2 ml lipiodol were enlarged in size and judged as progressive disease (PD) (Fig. 5). TAE was selected for the further treatment 2 months after BNCT, although repeating BNCT was discussed among the treatment team. Mitomycin C (10 mg) and emulsion of epirubicin hydrochloride (20 mg) and lipiodol (2 ml) were infused via right and left hepatic arteries. Additional embolization by gelatin sponge particles was performed to the left hepatic arteries, not to the right hepatic arteries. As shown in Fig. 4, the transient increases in the AST and ALT following TAE were greater compared with those following BNCT.


Figure 5
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  		Figure 5. (a) and (b) Pre-treatment CT images showing multiple HCCs in both liver lobes. (c) and (d) Follow-up CT after 1 month showing no growth of tumors in the right lobe treated with BNCT and enlargement of tumor size in the left lobe treated with chemoembolization.

 
Abdominal CT at 3.5 months after BNCT showed regrowth of the liver tumors in the right lobe, which were judged as PD (Fig. 6a). On abdominal CT at 8 months after BNCT, no shrinkage was observed suggesting progression of liver cirrhosis at the right lobe treated with BNCT and, however, the liver tumors involved diffusely in the right lobe (Fig. 6b). On 14 December 2005, the patient died of hepatic failure as a result of progression of the liver tumors 10 months after BNCT.


Figure 6
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  		Figure 6. (a) Follow-up CT after 3.5 months showing tumor regrowth in the right lobe. (b) Follow-up CT after 8 months showing diffusely tumor involvement in the right lobe. Neither shrinkage nor progression of cirrhosis at the right lobe treated with BNCT was observed.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
Conflict of interest statement
 References
 
We presented in this report the first case of multiple HCCs to be treated with BNCT. The application of BNCT to liver tumors has already been reported by Pinelli et al. (18). They developed a novel method for delivering sufficient and homogenous thermal fluence to the whole liver. In their study, a patient suffering multiple liver metastases from colon cancer was treated with BNCT. The liver was surgically removed and transported to a reactor for irradiation with thermal neutrons. The irradiation facility was designed to irradiate the whole liver similarly in all directions. After irradiation, the liver was autotransplanted to the patient. This success with BNCT for multiple liver metastases justified its application to liver tumors. The drawback of the study by Pinelli et al. is that the treatment needs an invasive surgical procedure. Unfortunately, the number of candidates for aggressive surgery such as liver autotransplantation is limited due to advanced disease, advanced age and comorbidities. However, the intra-arterial administration of a boron compound with lipiodol is technically an application of chemoembolization, which has been widely used for the treatment of liver tumors and is a much less invasive procedure compared with surgery. Therefore, our pilot study provides the possibility to extend the application of BNCT to liver tumors that are judged to be inoperable or refractory to HAI chemotherapy or chemoembolization.

Many authors have reported promising results with the treatment of liver tumors with 3D conformal radiotherapy (1,6,8,10). BNCT has two advantages over external photon radiotherapy. First, BNCT can theoretically treat both apparent and undetectable liver tumors. 3D conformal radiotherapy can deliver curative doses to the tumors while sparing the normal liver or adjacent organs by multi-port irradiation with shaping the ports by the use of a multi-leaf collimator. With conformal external radiotherapy, only visible liver tumors which are delineated by the physician in the treatment planning can be treated. However, with BNCT, all the liver tumors in which the boron compound is accumulated can receive high linear energy transfer (LET) particle irradiation by thermal neutron irradiation of the whole liver (14). In addition, in our pilot study, we injected lipiodol with the BSH. Lipiodol is widely used for detecting occult liver tumors that cannot be detected by CT or magnetic resonance imaging (19,20). Liver tumors that have accumulated lipiodol can be expected to have a large amount of boron compound and to receive a large radiation dose (14). Second, the number of liver tumors that can be treated by 3D conformal radiotherapy is limited to one to three. When 3D conformal radiotherapy is applied to the treatment of multiple liver tumors, the multi-port irradiation that is generally used in this treatment delivers a radiation dose greater than that which is tolerable to normal liver, which may cause fatal liver failure.

In this pilot study, the irradiation dose delivered to the liver tumors cannot be estimated because of the lack of a system for measuring 10B concentrations in the tumors in real time. Although our {gamma}-ray telescope system is under development and cannot measure the 10B concentration in small volumes, such as liver tumors, it is available for monitoring 10B concentration in large volumes of normal liver during irradiation. Therefore, the irradiation dose delivered to the normal liver can be estimated in this pilot study. The dose–response relationship in hepatotoxicity caused by BNCT might be revealed by further phase I and II studies for treating multiple liver tumors with BNCT.

A single course of BNCT could not eradicate the HCCs in the present case. On the CT scan 1 month after treatment, tumors in the right lobe treated with BNCT remained unchanged in size and the tumors in the left robe treated with chemoembolization grew larger. Although effectiveness of BNCT cannot be concluded from this preliminary result, feasibility of this protocol was confirmed. To exploit the potential benefits of BNCT for patients suffering from multiple liver tumors that are inoperable or refractory to chemotherapy or chemoembolization, we have planned to expand this pilot study into phase I study determining tolerant dose of normal liver in BNCT. Further evaluation of the treatment in this pilot study is warranted with strict eligibility criteria and careful monitoring of complications.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 Conflict of interest statement
 References
 
1 Cheng JC, Chuang VP, Cheng SH, Huang AT, Lin YM, Cheng TI, et al. Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys (2000) 47:435–42.[CrossRef][ISI][Medline]

2 Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S, Chuganji Y, Kagei K, et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res (2005) 15:3799–805.

3 Curley SA, Izzo F. Radiofrequency ablation of primary and metastatic hepatic malignancies. Int J Clin Oncol (2002) 7:72–81.[Medline]

4 Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet (2003) 361:368–73.[CrossRef][ISI][Medline]

5 Meloni F, Lazzaroni S, Livraghi T. Percutaneous ethanol injection: single session treatment. Eur J Ultrasound (2001) 13:107–15.[CrossRef][Medline]

6 Seong J, Park HC, Han KH, Chon CY. Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: a retrospective study of 158 patients. Int J Radiat Oncol Biol Phys (2003) 55:329–36.[CrossRef][ISI][Medline]

7 Stuart K. Chemoembolization in the management of liver tumors. Oncologist (2003) 8:425–37.[Abstract/Free Full Text]

8 Kim DY, Park W, Lim DH, Lee JH, Yoo BC, Paik SW, et al. Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma. Cancer (2005) 103:2419–26.[CrossRef][ISI][Medline]

9 Park HC, Seong J, Han KH, Chon CY, Moon YM, Suh CO. Dose–response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys (2002) 54:150–5.[ISI][Medline]

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11 Thomas E, Chapet O, Kessler ML, Lawrence TS, Ten Haken RK. Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors. Int J Radiat Oncol Biol Phys (2005) 62:571–8.[CrossRef][ISI][Medline]

12 Barth RF, Coderre JA, Vicente MG, Blue TE. Boron neutron capture therapy of cancer: current status and future prospects. Clin Cancer Res (2005) 11:3987–4002.[Abstract/Free Full Text]

13 Coderre JA, Morris GM. The radiation biology of boron neutron capture therapy. Radiat Res (1999) 151:1–18.[ISI][Medline]

14 Suzuki M, Masunaga S, Kinashi Y, Nagata K, Sakurai Y, Nakamatsu K, et al. Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model. Int J Radiat Oncol Biol Phys (2004) 59:260–6.[CrossRef][ISI][Medline]

15 Suzuki M, Sakurai Y, Masunaga S, Kinashi Y, Nagata K, Ono K. Dosimetric study of boron neutron capture therapy with borocaptate sodium (BSH)/lipiodol emulsion (BSH/lipiodol-BNCT) for treatment of multiple liver tumors. Int J Radiat Oncol Biol Phys (2004) 58:892–6.[CrossRef][ISI][Medline]

16 Sakurai Y, Maruhashi A. The irradiation system and dose estimation joint-system for NCT wider application in Kyoto University. Appl Radiat Isot (2004) 61:829–33.[CrossRef][ISI][Medline]

17 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:215–6.

18 Pinelli T, Zonta A, Altieri S, Barni S, Braghieri A, Pedroni P, et al. TAOrMINA: from the first idea to the application to the human liver. In: Research and Development in Neutron Capture Therapy—Sauerwein MW, Moss R, Wittig A, eds. (2002) Bologna: Monduzzi Editore, International Proceedings Division. 1065–72.

19 Nakakuma K, Tashiro S, Hiraoka T, Ogata K, Ootsuka K. Hepatocellular carcinoma and metastatic cancer detected by iodized oil. Radiology (1985) 154:15–7.[Abstract/Free Full Text]

20 Yumoto Y, Jinno K, Tokuyama K, Araki Y, Ishimitsu T, Maeda H, et al. Hepatocellular carcinoma detected by iodized oil. Radiology (1985) 154:19–24.[Abstract/Free Full Text]


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