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First published online September 13, 2006
British Journal of Radiology (2007) 80, 38-42
© 2007 British Institute of Radiology
doi: 10.1259/bjr/55395102
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Full paper

Three-dimensional conformal radiotherapy for the treatment of arteriovenous shunting in patients with hepatocellular carcinoma

H C Hsu, MD 1,4 T Y Chen, MD 2 K W Chiu, MD 3 E Y Huang, MD 1,5 S W Leung, MD 6 Y J Huang, MD 1 and C Y Wang, MD 1

Department of 1Radiation Oncology 2Radiology and 3Hepato-Gastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, 4 School of Medicine, Chang Gung University College of Medicine, Kaohsiung, 5 School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Kaohsiung, 6 Department of Radiation Oncology, Yuan's General Hospital, Kaohsiung, Taiwan

Correspondence: Dr Hsuan-Chih Hsu, Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsung Medical Center, 123, Ta-Pei Road, Niao Sung Hsian, Kaohsiung 807, Taiwan. E-mail: hsuan5{at}ms65.hinet.net


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
The objective of this study is to evaluate the efficacy of radiotherapy for the treatment of arteriovenous shunting (AVS) in patients with hepatocellular carcinoma (HCC). Between November 1997 and April 2005, 20 HCC patients with AVS were referred to our department for radiotherapy. The radiation was delivered with 10–15 MV X-ray given 5 days per week at 2~2.5 Gy per fraction. Total doses ranged from 45 to 64 Gy (median dose 60 Gy). The patients were followed up with color Doppler sonography. When non-invasive imaging suggested obliteration, X-ray angiography was performed to verify the results. Four of the 20 AVS proved to be completely obliterated at X-ray angiography in 1.9, 2.8, 1.8 and 2.9 months after radiotherapy. One of the remaining 16 showed obvious regression on Doppler sonography 0.5 months after radiotherapy, but X-ray angiography was not performed to verify the result. Radiation-related hepatic failure did not occur during the follow-up period. In conclusion, radiotherapy is a treatment alternative for AVS in HCC patients and gives patients with poor prognosis the chance to receive further transcatheter arterial embolization.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Arteriovenous shunting (AVS) has been frequently reported in hepatocellular carcinoma (HCC). Ngan et al [1] observed 292 Chinese patients presenting with HCC, and hepatic angiograms demonstrated AVS in 91 cases (31.2%); shunting into the portal vein (arterioportal shunting, APS) was observed in 84 (28.8%) and shunting into the hepatic vein (arterio-hepatic vein shunting, AHS) in seven (2.4%). APS markedly elevates portal venous pressure, which may result in potentially fatal complications such as rupture of gastroesophageal varices and further deterioration of hepatic function [2–7]. Additionally, transcatheter arterial chemoembolisation (TACE) is generally recognized to be contraindicated when AVS is noted, except when of a minor degree, occurring into either branches of the portal vein or the hepatic vein [8]. Therefore, severe AVS needs to be treated. Reviewing the literature, Gelfoam and steel coil were the most commonly used embolic materials [9–11]. Intra-arterially delivered ethanol embolisation for severe APS in HCC patients was also tried by Huang et al [12]. However, radiotherapy for the treatment of shunting in hepatoma has never been reported before. In this study, we attempt to evaluate the obliteration effect of shunting and the survival benefit by using radiotherapy for the treatment of AVS in HCC patients.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
Patient characteristics
Between November 1997 and April 2005, 28 HCC patients with AVS were referred to our department for radiotherapy. Exclusion criteria included the presence of extrahepatic metastasis, patients with Child class C disease, or if the radiation dose was below 40 Gy. Therefore, this retrospective study was composed of 20 patients treated with definite irradiation. There were 14 men and 6 women. The age ranged from 40 years to 78 years (mean±SD, 61.4±11.3 years). Viral antigenemia was present in 17 patients, 7 patients with type B virus (HBV), 8 patients with type C virus (HCV) and 2 patients with both type B and C virus. The clinical characteristics of these patients are illustrated in Table 1Go.


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  		Table 1. Patient characteristics(n = 20)

 
Previous treatment before AVS was noted
Of 20 patients, seven did not receive any treatment for HCC before AVS was found. Transcatheter arterial embolisation (TAE), percutaneous ethanol injection (PEI) or operation (OP) were performed in the other 13 patients (1–14 times of TAE in 10, TAEx2+PEIx1 in 1, OP+TAEx5 in 1, PEIx1 in 1). In our hospital, TAE was performed with a mixture of iodized oil/ethanol (99.5%) in a ratio of 2:1, infused selectively into the supplying artery. Gelfoam cubes were also injected for the patients without tumour thrombus in the portal vein.

Angiography for diagnosis of AVS
All 20 patients with AVS were identified by angiography; shunting into the portal vein was observed in 18 patients (90%) and shunting into the hepatic vein in 2 patients (10%). During the course of performing the angiography, 10 patients received Gelfoam cube injection for embolisation of AVS and had temporary obliteration of the shunt. The other 10 patients did not receive any treatment for it. There was no consensus on the injection of Gelfoam cube for AVS at our hospital. It depended on the decision of different radiologists. Gelatin sponge particles (size, 1 mm3) were mixed with contrast media (Optiray 350, Mallinckrodt Medical Inc., Australia) and injected under fluoroscopic monitoring until a slow flow or stasis of AVS was demonstrated. Thirteen of 20 patients had a portal vein tumour thrombus (PVTT).

Radiotherapy
Radiotherapy commenced 6–21 days following angiography. For each patient, the computerized treatment planning system (Pinnacle, ADAC Laboratory, Milpitas, CA) was utilized to determine radiation fields. The clinical target volume (CTV) was defined as the AVS area by the radiologist, but PVTT was also included in 13 patients with PVTT. The planning target volume (PTV) included the CTV plus a 1–2 cm margin for daily set-up variation in the cranio caudal dimension to account for the ventilatory motion of the liver. Three-dimensional conformal radiotherapy planning was designed under tentative guidelines so that the non-target liver volume irradiated with more than one-half of the prescription dose should not be > 50% of the total non-target liver volume. Twenty cases were treated with 10–15 MV X-ray using a linear accelerator. The radiation dose ranged from 45 Gy to 64 Gy, 2–2.5 Gy per fraction, with a median dose of 60 Gy.

Follow-up
During treatment, patients were monitored weekly with liver function tests. Acute toxicity was scored by Common Toxicity Criteria version 2.0 [13]. Regular imaging follow-up examinations were performed non-invasively after radiotherapy using colour Doppler sonography by the same radiologist. When findings on these noninvasive examinations suggested obliteration of the AVS, X-ray angiography was performed to verify the results. Results were classified as follows: 1) complete obliteration, meaning that X-ray angiography verified complete occlusion of the AVS; 2) partial obliteration, indicating that obviously decreased AVS was observed on Doppler sonography, but that the X-ray angiography was still pending. All patients had at least 6 months of follow-up, except those deceased.

Statistics
The cumulative proportional survival rates were determined using the Kaplan-Meier method and the statistical significance of different groups was tested by log rank test. The difference in response rates of AVS between the combined treatment group (Gelfoam cube injection prior to radiation therapy) and radiotherapy alone group was calculated using the Fisher exact test.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
Response
Four of the 20 AVS proved to be completely obliterated at X-ray angiography at 1.9 months, 2.8 months, 1.8 months and 2.9 months after radiotherapy. TAE was performed in these four patients. One of the remaining 16 patients showed obvious regression on Doppler sonography 0.5 months after radiotherapy, but X-ray angiography was not performed to prove this because the patient had multiple medical problems. This result was classified as partial obliteration. Therefore, total response of the shunt (including complete and partial obliteration) was obtained in 5 of 20 patients (25%). Figure 1Go shows a HCC patient with shunting between the hepatic artery and hepatic vein who received radiotherapy. Complete resolution of the shunt was obtained.


Figure 1
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  		Figure 1. (a) Before radiotherapy, angiography showed arteriovenous shunting (->) between hepatic artery and vein. (b) Complete resolution of the shunt was noted 2.9 months after radiotherapy.

 
The response rate of AVS in 10 patients receiving injected Gelfoam cubes prior to radiation therapy was 20% (complete obliteration in 2) and that of the other 10 patients receiving radiotherapy alone was 30% (complete obliteration in 2 and partial obliteration in 1) (p = 1.00).

Survival
Survival rates were evaluated in all 20 patients from both the time of initial treatment and the time of completion of radiotherapy. From the time of initial treatment, survival rates at 6, 12 and 24 months were 90%, 58.7% and 37.3%, respectively, with a median survival of 14.1 months. From the time of completion of radiotherapy, survival rates at 6 months, 12 months and 24 months were 70%, 12.2% and 12.2%, respectively, with a median survival of 7.2 months (Figure 2Go). At the time of reporting, 4 patients are still alive; 16 patients are deceased.


Figure 2
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  		Figure 2. Overall survival rate of 20 hepatocellular carcinome(HCC) patients. Survivals from the date of initial treatment (—) and from the date of completion of radiotherapy (---) are shown.

 
Survival rates were also evaluated in responders and non-responders to AVS. From the time of completion of radiotherapy, the median survival duration and the 6-month survival rates in the four complete responders were 9.2 months and 100%, respectively; they were 6.3 months and 62.5%, respectively, in the other 16 patients (p = 0.2808).

Toxicity
During the period of radiotherapy, alteration of liver function test was seen in all patients. Elevation in alkaline phosphatase was seen in 11 patients (grade 1), transaminase (either alanine transaminase, or aspartate transaminase) in 9 (grade 1:6, grade 2:3), bilirubin in 5 (grade 1:2, grade 2:3), and albumin in 7 (grade 1:4, grade 2:3). No grade 3 or 4 toxicity was noted. For gastrointestinal complications, three patients developed gastroduodenal ulcer. There was no treatment-related death.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
Several embolic materials have been used to try to treat AVS in HCC patients [9–12, 14–19]. However, a safe and effective therapeutic method has not yet been established. Furuse et al [11] reported that the survival rate of 10 patients with HCC and APS after steel coil embolization was 45% at 6 months, 12% at 12 months and 6% at 24 months. Steel coil embolization for APS was contraindicated if the portal vein trunk was completely occluded with tumour thrombus, or if tumour thrombus was in both the right and left portal veins. In these patients, hepatic blood supply is completely disrupted with embolization of APS, and development of severe hepatic failure is possible.

Huang et al [12] compared long-term effects between intra-arterially delivered ethanol (64 patients) and Gelfoam (33 patients) for the treatment of severe APS in patients with HCC. The occlusion rate of APS after initial treatment in the ethanol group was 70.3% (45/64) and re-canalization rate of 1 month after embolization was 17.8% (8/45). Those in the Gelfoam group were 63.6% (21/33) and 85.7% (18/21). The survival rates in the ethanol group were 78% at 6 months, 49% at 12 months and 25% at 24 months, whereas those in the Gelfoam group were 58% at 6 months, 23% at 12 months and 15% at 24 months. The ethanol group showed significantly better survival than the Gelfoam group (p<0.05). Overall survival was calculated from the day of initial treatment until the day of death.

In our study, 10 of the 20 patients with AVS also received injected Gelfoam cubes for embolisation of AVS prior to radiation. Although Gelfoam is a temporary embolic material and will be absorbed two to four weeks after embolisation [12], we were still concerned whether this pre-treatment would confound the final result of radiation treatment. However, the difference in response rates of AVS between the combined treatment group (injection of Gelfoam cubes prior to radiation therapy) and radiotherapy alone group was not statistically significant (20% vs 30%, p = 1.00).

Radiotherapy for the treatment of cerebral arteriovenous malformations (AVMs) [20–22] or dural arteriovenous fistulas of the cavernous sinus (DAVFs) [23] has been reported. However, the treatment of AVS in HCC patients using radiotherapy is seldom mentioned. The probable mechanism of using radiotherapy to treat AVMs is that irradiation can lead to intimal proliferation and vascular occlusion, which was recognized by Harvey Cushing in 1928 [24]. Radiobiologically, AVMs fall under the category of late-responding tissue, have a low {alpha}/beta ratio, suggesting there would be little advantage in fractionating radiation compared to using a single large fraction in terms of AVM ablation [25]. The clinical results were comparable to the radiobiological theory. The complete obliteration rates within two years of using radiosurgery to treat cerebral AVMs and DAVFs were 71–89% [20–22] and 80% [23], respectively. However, the complete response rate using conventional fractionated irradiation (doses of 40 Gy to 55 Gy in fractions of 1.8 Gy to 3.5 Gy) to treat AVMs was only 21% (11 of 48 evaluable cases) [26–29].

In our study, total response of the shunt (including complete and partial obliteration) was obtained in 5 of 20 patients (25%). From the time of initial treatment, survival rates at 6 months, 12 months and 24 months were 90%, 58.7% and 37.3%, respectively. The survival rates of our study seemed better than when using other embolic methods (described as above), but we could not make any conclusions about it because the patient characteristics were different in every series. The obliteration rates of radiotherapy for AVS in HCC patients were worse than for AVMs or DAVFs in the brain. The probable reasons for poor response rates are as follows: 1) Follow-up time: It will take a long time to achieve the resolution of shunts, but the life span of HCC patients is so short. 2) Fraction size: We only used 2–2.5 Gy per fraction due to the possible treatment of toxicity of liver.

At our present level of knowledge, the exact mechanism of the AVS formation remains uncertain. Ngan et al [1] reported that most AVS occurred through the tumour or within a tumour thrombus in the main portal vein by the transvasal route [30]. Therefore, the cause of AVS in HCC patients may be partially associated with the tumour and is different from that of cerebral DAVFs or AVM. If the tumour can be controlled with radiotherapy, the AVS also has the chance to be obliterated. Maybe this is the reason why the time to achieve complete obliteration of AVS in our study (complete resolution was obtained 1.9 months, 2.8 months, 1.8 months and 2.9 months after radiotherapy) is shorter than with cerebral DAVFs or AVM.

Overall, we still think radiotherapy is a treatment alternative for AVS in HCC patients because it brings patients with poor prognosis the chance to receive further TAE. In our study, the 6-month survival rates of the four complete responders who reached complete obliteration of AVS at X-ray angiography and received further TAE were higher than the other 16 patients (100% vs 62.5%), although the difference was not statistically significant (p = 0.2808). Further investigation is needed on how to achieve better obliteration rates of AVS and improve the survival rates in HCC patients by using stereotactic body radiotherapy (large fraction size and hypofractionated).


   Conclusion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
Although the response rate using conventional fractionated irradiation (doses of 45 Gy to 64 Gy in fractions of 2 Gy to 2.5 Gy) to treat AVS in HCC patients is only 25%, we still think radiotherapy is a treatment alternative because it brings patients with poor prognosis the chance to receive further TAE. In the future, stereotactic body radiotherapy (large fraction size and hypofractionated) should be investigated further.

Received for publication April 3, 2006. Revision received May 25, 2006. Accepted for publication July 13, 2006.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

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This Article
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