First published online October 12, 2006
British Journal of Radiology (2007) 80, 194-201
© 2007 British Institute of Radiology
doi: 10.1259/bjr/33521596
Combined therapy of transcatheter arterial chemoembolisation and three-dimensional conformal radiotherapy for hepatocellular carcinoma
Z-H Zhou, MD
1
L-M Liu, MD
1
W-W Chen, MD
1
Z-Q Men, MD
1
J-H Lin, MD
1
Z Chen, MD
1
X-J Zhang, MD
2 and
G-L Jiang, MD
2
1 Department of Integrative Chinese and Western Medicine, 2 Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai 200032, China
Correspondence: Guo-Liang Jiang, Department of Radiation Oncology, Fudan University Cancer Hospital, 270 Dong An Road, Shanghai 200032, China E-mail: jianggl{at}21cn.com
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Abstract
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To evaluate the toxicity and efficacy of combined therapy of three-dimensional conformal radiotherapy (3DCRT) and transcatheter arterial chemoembolisation (TACE) for hepatocellular carcinoma (HCC). 50 HCC patients treated by combined TACE and 3DCRT were selected from a patient database. Sequence of treatments was that TACE was performed first, followed by 3DCRT with an interval of about 4 weeks between. TACE was administered by 5-Fu 500–600 mg m-2, cis-platinum 30–40 mg m-2, epi-adriamycin 40–60 mg m-2 mixed with iodized oil and Gelfoam embolisation. A median of two courses of TACE was given. 3DCRT was delivered by 4–6 coplanar or non-coplanar fields. The mean tumour dose was 43.0±6.3 Gy by conventional fractionation (2 Gy per fraction, five fractions a week), and mean dose to normal liver, 19.1±6.3 Gy. Acute hepatic toxicities were notable in five patients (10%) with Common Toxicity Criteria (CTC) grade 1 in two cases and grade 3 in three patients, but all recovered eventually. Two patients developed radiation-induced liver disease (RILD) and died soon after the onset of RILD. Four patients had Radiation Therapy Oncology Group (RTOG) grade 1 acute gastrointestinal complication and one patient had acute gastrointestinal bleeding. Five patients experienced RTOG Grade 1 leukopenia and Grade 2 in five cases. Nine patients achieved have partial response, and 37 patients were in stable disease. Four patients were observed to have progressive disease. The overall survival rates at 1 year, 2 years and 3 years were 60%, 38% and 28%, respectively, with a median survival period of 17 months. Irradiation dose, T-stage and hepatic cirrhosis were identified as independent predictors for overall survival by Cox proportional regression analysis. The 1 year, 2 years and 3 years local progression-free rates were 74%, 57% and 38%, and the 1 year, 2 years and 3 years distant metastasis rates were 15%, 21% and 40%, respectively. The combined modality of TACE and 3DCRT was tolerable for the majority of HCC patients, resulted in good outcome and warrants for further prospective trial.
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Introduction
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Hepatocellular carcinoma (HCC) is one of the most common human malignancies in China with an incidence of 39.86 per 100 000 and 19.45 per 100 000 for males and females, respectively in 2002 in Shanghai, which ranked in 4th and 5th in the epidemiological survey [1]. HCC is also one of the most ominous cancers [1]. Since 1990, HCC has been the second leading cause of cancer-related death in China with an annual mortality of 21.2 per 100 000 in the year 2000 [2]. Surgical resection is considered the treatment of choice for long-term tumour-free survival. However, surgical resection can be performed in patients who have small tumours located away from major vessels and without extrahepatic metastasis. Patients must also have good liver function in order to withstand a major operation. However, resectable patients only account for 20–25% of HCC patients in China. For the majority of patients, non-surgical treatment is the only alternative [3]. Transcatheter arterial chemoembolisation (TACE) has been actively performed in the treatment of technically unresectable or medically inoperable HCC. However, TACE alone has achieved very limited success [4, 5]. Conventional external irradiation was not effective, either [6]. It has been assumed that more than 507Gy would be necessary to sterilize HCC, but the conventional approach, in which the whole liver or large fields were exposed, would cause radiation-induced liver disease (RILD) and even hepatic failure. With new elegant three-dimensional conformal radiotherapy (3DCRT), it would be possible to minimize liver injury and increase irradiation dose to HCC [7]. We did a retrospective study on the combined therapy of TACE and 3DCRT in HCC. The aim of the present study was to investigate the toxicity and efficiency of the combined modality.
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Methods and materials
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Patient selection criteria
Patients were collected by the following selection criteria: (1) HCC confirmed by cytology or histology; (2) medically inoperable due to liver cirrhosis or cardiovascular diseases, or technically unresectable because of bulky tumour; (3) good general condition with Karnofsky performance status (KPS) of 
70; (4) liver cirrhosis of Child–Pugh A or B; (5) have been treated by TACE followed by 3DCRT, and dose to HCC more than 30 Gy; (6) follow up data available.
Patients
From August 2000 to March 2005, 50 HCC patients were collected from our hospital patient database. There were 42 men and 8 women. The median age was 53.5 years (range 29–78). The median KPS was 70 (range 70–90). The number of patients with Child–Pugh Grade A and Grade B of liver cirrhosis were 48 and 2, respectively. According to UICC staging (1997), the number of patients in Stage IIIa, IIIb, IVa and IVb were 27, 1, 19 and 3, respectively. Portal vein thrombosis (PVT) was detected in 11 patients by CAT/MRI. Serum hepatitis B virus (HBV) antigen markers were positive in 47 patients (94%) and negative in three patients (6%). A high serum alpha-fetoprotein (AFP) level of more than 400 IU ml-1 was found in 22 patients, 20 less than AFP less than 400 IU ml-1 in 10 and AFP less than 20 IU ml-1 in 18. The median gross tumour volume (GTV) was 144 cm3 (range 31–792 cm3), which was measured from treatment planning CT after TACE.
Treatment
TACE
TACE was performed using the Seldinger technique. The injection emulsion was composed of 5-Fu 500–600 mg m-2, cis-platinum 30–40 mg m-2, epi-adriamycin 40–60 mg m-2 and iodized oil, followed by Gelfoam embolisation. For the entire group, a median of two courses (range 1 to 3) was administered with the median interval of 5.4 weeks (range 1.3–12.8) between courses of TACE.
3DCRT
3DCRT was delivered after TACE with a median interval period of 4.3 weeks (range 1–31 weeks) between TACE and 3DCRT.
The technique of 3DCRT was as follows. After TACE, a CT scan for treatment planning would be performed again. Patients were immobilized using a vacuum-lock cradle, and were trained to breathe as shallowly as possible. For HCC with the margin not clear on plain CT, a plain CT would be taken first, and then, contrast CT scan to make the lesion margin clear. For patients whose contrast CT could not show clearly GTV margin either, MRI would be done, and its image would be fused with CT imaging. By combined diagnostic CT, MRI and idiom deposit, GTV could be delineated correctly. A treatment-planning CT scan was performed that included a portion of the inferior chest and the entire abdomen. 3DCRT plan was designed by CAD plan 6.0.8. Organs at risk (OAR) contoured included liver, kidneys, stomach, duodenum and spinal cord. GTV was delineated on CT scan aided by iodine injected by TACE, and the margin of GTV was about 0.5 cm beyond the iodine deposit. For patients whose lesion margin was not clear on CAT, and meanwhile, iodine deposit was poor, a fusing of CT and MRI was carried out to make the delineation of GTV more accurate. Planning target volume (PTV) is determined by adding 1.0–1.5 cm to GTV. The tumour motion due to respiration should be taken into account when PTV is decided. With the help of beam's eye view, 4–6 coplanar or non-coplanar fields were designed. Each treatment plan was evaluated with a cumulative dose–volume histogram (DVH). Optimization of 3DCRT plan included: (1) PTV was covered by 90% of isodose curves; (2) inhomogeneity of PTV ranged from 90% to 105%; (3) doses to OAR were limited in their tolerances; (4) mean dose to normal liver (MDTNL) was limited to 
30 Gy with the percentage volume of the normal liver receiving a dose exceeding 30 Gy (V30), the less, the better. Before the implementation of irradiation, the shape of fields was marked on the patient's skin surface, and then checked under fluoroscopy of simulator to confirm the coverage of lesions during patients' breathing. Irradiation was delivered by 6 MV X-ray.
Tumour dose was prescribed to isocentre with inhomogeneity correction. Conventional fractionation was used, i.e., 2 Gy/fraction and five fractions per week. The total tumour dose the patient would receive was decided by the physicians' own judgements according to the comprehensive consideration of patients' general conditions, hepatic function and tumour size. For the entire group, the mean tumour dose was 43.0±6.3 Gy (range 30–54 Gy). MDTNL was 19.1±6.3 Gy (range 10.5–29.6 Gy) and V30, 23%±11%.
Adjuvant therapy
During the treatment, adjuvant therapy was combined to relieve side effects and toxicity of treatment, which consisted of vitamins and Chinese herbs.
Patient evaluation
Patients were assessed by physical examination, blood chemistry analysis and a CT scan performed approximately 1 month after completion of therapy. Responses were categorised by WHO criteria: (1) complete response (CR): disappearance of all measurable disease; (2) partial response (PR): decrease of greater than 50% in all measurable lesions; (3) stable disease (SD): a decrease of less than 25% in any measured lesion, with no lesion increasing by more than 25%; (4) progressive disease (PD): an increase of greater than 25% or appearance of new lesions. Irradiation toxicities were scored by Radiation Therapy Oncology Group (RTOG) criteria, including acute (within the first 90 days of treatment) and late (more than 90 days post-treatment). Acute liver toxicity was graded according to common toxicity criteria (CTC), National Cancer Institute. Late toxicity was focused on RILD, as proposed by Lawrence et al [8]. RILD manifested by anicteric elevation of alkaline phosphatase (AKP) level of at least twofold and non-malignant ascities and hepatomegaly in the absence of documented progressive disease, or elevated transaminases of at least fivefold the upper limit of normal or of pretreatment level.
Statistics
Survival, local progression-free rate and distant metastasis rate were estimated from the date of initiation of treatment by Kaplan–Meier method. Local progression-free rate was defined as the tumour remained CR, PR or SD after treatment. Once a tumour reappeared, or enlarged in size on CT/MRI or clinical examination compared with the status right after 3DCRT, it was counted as local progression. Univariate and multivariate analyses by Cox proportional regression model were performed to identify the prognostic factors for survival.
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Results
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Follow up
All the patients had been followed up at the last follow up time. The last follow up was performed in July 2005 with a median follow up time of 16 months (range 3–57 months) for the entire group. At the last follow up visit, 17 patients remained alive with no evidence of disease in one patient, who received surgical resection after 3DCRT, with stable disease in 13 patients, with local tumour progression and no distance metastasis in two patients, and with both lung metastasis and local tumour progression in one patient. 33 patients had died at last follow up. The causes of death were disease progressions in 27 cases, which included distant disease in six cases (lung metastasis in three, bone metastasis in two, and abdominal metastasis in one) and local failure in 21 cases. The other four patients were associated with stable disease, but succumbed to gastrointestinal bleeding in two and RILD in two. For the remaining two patients, one died of hepatic failure immediately after surgery for HCC, and one of suicide with stable disease.
Tolerance and toxicities
Three patients were not able to tolerate treatments due to acute hepatic toxicity in one case, and general condition worsened in two cases during irradiation. Their irradiation dose to tumour was 30 Gy.
Treatment-related toxicities were assessable in all 50 patients. Acute hepatic toxicities were notable in five patients (10%) with CTC grade 1 in two cases and grade 3 in three patients, but all recovered eventually. Acute gastrointestinal complication of grade 1 occurred in four patients (8%) with acute gastrointestinal bleeding in one case. Leukopenia of grade one was seen in five patients (10%) and grade two in five cases (10%). RILD was observed in two patients (4%) over 3 months after completion of radiation treatment. Both RILD patients were positive for HBV and associated with cirrhosis of Child–Pugh A. Their MDTNL were 24.9 Gy and 23.3 Gy, and V30 were 32% and 17%, respectively. Despite treatment with both medications and Chinese herbs to retain their hepatic function, they died of hepatic failure soon after the onset of RILD.
Tumour response
Immediate tumour response was evaluated 1 month after 3DCRT for all patients. PR was seen in nine patients (18%) and SD in 37 patients (74%). PD was observed in four patients (8%), of whom one had local tumour progression without distance metastasis, one with lung metastasis and no local progression, one with bone metastasis and without local failure, and one with both local tumour progression and lung metastasis.
Survival, local progression-free rate and distant metastasis
The overall survival rates at 1 year, 2 years and 3 years were 60%, 38% and 28%, respectively, with the median survival period of 17 months (range 3–57 months) (Figure 1
). The 1 year, 2 years and 3 years local progression-free rates were 74%, 57% and 38%, respectively. The 1 year, 2 years and 3 years distant metastasis rates were 15%, 21% and 40%, respectively.
Prognostic factors affecting overall survival
Prognostic factors evaluated by univariate analysis consisted of gender, age, T stage, AFP, GTV, HBV, PVT, tumour dose and Child–Pugh grade. Analysis showed that gender, age, AFP, HBV, and GTV had no significant impact on the overall survival (all p>0.05). However, T3, no PVT, irradiation dose of 45 Gy and Child–Pugh grade A could predict a better overall survival (p = 0.000, 0.001, 0.020 and 0.000, respectively) (Table 1) (Figures 2– 5).
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Table 1. Univariate analysis of prognostic predictors for overall survival in 50 HCC patients treated by TACE and 3DCRT
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Figure 2. Overall survivals and presence of portal vein thrombosis(PVT) in 50 hepatocellular carcinoma patients treated by transcatheter arterial chemoembolisation and three-dimensional conformal radiation therapy.
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Figure 3. Overall survivals and irradiation doses in 50 hepatocellular carcinoma patients treated by transcatheter arterial chemoembolisation and three-dimensional conformal radiation therapy.
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Figure 4. Overall survivals and T stages in 50 hepatocellular carcinoma patients treated by transcatheter arterial chemoembolisation and three-dimensional conformal radiation therapy.
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Figure 5. Overall survivals and Child–Pugh grades in 50 hepatocellular carcinoma patients treated by transcatheter arterial chemoembolisation and three-dimensional conformal radiation therapy.
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From Cox proportional regression analysis, irradiation dose, T stage and hepatic cirrhosis were demonstrated as independent predictors for overall survival (p = 0.040, 0.044 and 0.002, respectively). Patients with irradiation dose of 45 Gy, T3 or Child–Pugh A survived longer than others (Table 2).
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Table 2. Multivariate analysis of prognostic parameters for overall survival in 50 HCC patients treated by TACE and 3DCRT
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Discussion
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HCC is a major malignant disease in China. Early diagnosis and curative surgical resection can achieve the best prognosis. Even though recent progress in imaging techniques has permitted detection of early lesions, the number of resected cases is still limited even for small tumours, due to the unique characteristics of this carcinoma, including multifocality, early vascular invasion, or concurrent hepatic parenchymal disease such as liver cirrhosis [9, 10]. For the majority of patients (approximately 80%), non-surgical treatment is the only alternative. TACE has long been used as a palliative treatment for patients with technically unresectable or medically inoperable HCC. However, the results of TACE are sometimes unsatisfactory, especially for patients with portal vein thrombosis or large infiltrative hepatic tumours. TACE alone frequently results in incomplete tumour necrosis. Moreover, no survival benefits have been observed in randomized trials of TACE [11]. Hence, TACE therapy alone is a sub-optimum treatment.
Radiotherapy (RT) in HCC has been overlooked because the tolerance dose of the whole liver is no more than 30 Gy, which is far less than a sterilization dose [12]. In the 1970s, we used a moving strip technique to increase irradiation dose; the total dose delivered was approximately 30–35 Gy, which was still less than the tumouricidal dose [13]. With the advent of 3DCRT it has been possible to confidently localize intrahepatic disease and to quantify the amount of normal liver irradiated. This allows higher RT doses to be given safely with no severe complications. In the past decade, 3DCRT has been utilized for HCC in a series of trials resulting in encouraging outcomes, including increases in response rate, hepatic tumour control and survival. Robertson et al reported 22 unresectable primary hepatobiliary cancers treated by 3DCRT that achieved a median survival of 16 months [14]. Cheng et al treated HCC by RT with or without TACE, and obtained a promising result of 2 year survival rate of 41% and a median survival time of 19 months [15]. Liu et al revealed 3DCRT in 44 unresectable HCC with a median survival time of 15.2 months and 1 year, 2 years and 3 years survival of 60.5%, 40.3% and 32.0%, respectively [16]. Kim et al reported 59 cases of HCC with PVT treated by 3DCRT with a 45.8% objective response rate, and in responders, the median survival time was 10.7 months and the 1 year and 2 years overall survival rates were 40.7% and 20.7% respectively [17]. Liang et al recently reported 128 primary liver carcinomas that treated by hypofractionated 3DCRT with or without TACE that achieved a median survival of 20 months and the overall survival rates at 1 year, 2 years and 3 years were 65%, 43% and 33% [18].
The aim of the present study was to retrospectively investigate the toxicity and efficacy of 3DCRT combined with TACE in unresectable HCC and to explore a new modality for these patients.
The rationales for combined modality of TACE and 3DCRT were based on the following three considerations. First, biological behaviour of HCC showed the tendency of multifoci because of called "field cancerization". Therefore TACE would probably reduce or delay the occurrence of multiple hepatic lesions as HCC was supplied mainly by the hepatic artery. Second, the tumour margin of HCC on CT was not very sharp in many cases, which made delineation of GTV not very accurate. Because of iodized oil injection by TACE, the deposit of iodine would have made the GTV margin more clear, which made GTV delineation more accurate and RT plan verification easier, e.g. check of tumour coverage, and observation of patients set-up errors by portal film or electronic portal image device (EPID). Third, intrahepatic spreads were quite often seen in HCC, but CT scan usually could not detect them when the lesions were small. However, iodine would deposit there in the post-TACE CT scan. These areas with iodine would be considered as parts of GTV, or irradiation would be given up when they were too many. In 2005, Zeng et al had reported a better outcome for HCC treated by combined therapy of TACE and irradiation compared with that treated by TACE alone [19]. Nevertheless, there have been debates on negative impact of TACE on RT. As embolisation could decrease blood supply of HCC, a higher percentage of hypoxic tumour cells would result, and then the radiosensitivity of HCC would be worsened. However, we thought TACE had demonstrated its effect on inhibition of tumour growth from past clinical experience. Thus, after TACE, tumour burden became less and the number of tumour cells decreased, which would make RT easier to control tumours. Besides, RT began several weeks after TACE (interval of 4.3 weeks in our study), it had been postulated that blood supply to tumour had been partially restored, which would make probably tumour cells reoxygenized.
Delineation of GTV was the key step for success of irradiation. On plain CT, the margin of GTV was not very sharp, or even not clear for many HCC cases. Thus, CT with contrast and MRI would be necessary for correctly delineation of GTV in these patients. In addition, the deposited iodized oil in HCC lesions would be of great help to show GTV, even though iodized oil did not deposit very well in some cases. However, by combining all means mentioned above and the help from diagnostic radiologists we could delineate GTV confidently.
However, iodized oil has the characteristics to be retained in the HCC tissue. After TACE, the deposition of iodized oil revealed tiny intrahepatic lesions in the post-TACE CT scan, which is usually difficult to detect with a regular CT scan. It should be mentioned that the target delineation was not completely based on iodized oil, although iodized oil has the character to be retained in the HCC tissue for up to 1 year after TACE, but not the whole tumour. Some iodized oil would clear later. And some patients' tumours were also changed after TACE. So we usually do CT (bolus injection) after TACE and prior to 3DCRT to detect the tumour size correctly. Sometimes MRI was also used for target delineation.
Regarding the RT fractionation, as in the literature, we used conventional fractionated RT, i.e. 2 Gy per fraction, five fractions a week, because liver was considered a late responding normal organ with a low ratio of 
/
, but we understood that the tumour sterilization of small fraction size also lessened. In China, hypofractionated RT has been quite often employed. In a recently published study, Liang et al [18] reported a 3 year overall survival of 33% for 128 cases of primary liver cancer treated by hypofractionated 3DCRT (4–5 Gy per fraction, three fractions a week) with a median total dose of 53.6 Gy. However, 15% RILD occurred (19/128), which could be attributed to large fraction size and high total RT dose. Therefore, the optimum fraction size as well as the total dose for HCC need further investigations.
Our study demonstrated the combined modality was tolerable for the majority of HCC. All acute treatment-related toxicities, including gastrointestinal, hepatic and haematopoietic were manageable without severe sequelae. The most serious late complication was RILD, which occurred in two cases (2/50), less than 5%, but both died of it. As in our previous experience, RILD was the most serious radiation-induced complication and almost fatal once it occurred. Thus, we have to pay much more attention to avoid it by limiting dose to normal liver to a safe level.
Beyond our expectation, the combined modality of TACE and 3DCRT resulted in improved outcome, with 1-year, 2-year and 3-year survival rates of 60%, 38% and 28%, respectively, and a median survival period of 17 months. The 1-year, 2-year and 3-year local progression-free rates were 74%, 57% and 38%. The 1-year, 2-year and 3-year distant metastasis rates were 15%, 21% and 40%, respectively. Of course, we have to confess that patients in this study were highly selected with good performance and without serious cirrhosis (96% of patients with Child–Pugh Grade A). Fortunately, our outcomes were quite similar to those reported recently. Therefore, we felt somewhat optimistic for 3DCRT to treat HCC. Reasons for improved outcome by irradiation for HCC were the modern technology of 3DCRT, which provided accurate localization of tumour and surrounding normal organs in 3-dimensions, optimized design of irradiation plan and accurate calculation of irradiation doses to tumour as well as to OARs. Dose to normal liver was critical because overdose induced RILD that was almost always fatal. 3DCRT planning system would help us to avoid it.
As to the prognostic predictors for HCC irradiation, tumour size, T stage, serum AFP level and PVT have been reported in the literature. Cheng et al [15] demonstrated the survival advantage in their patients with no PVT, Okuda Stage I, lower pretreatment AFP level and smaller tumour size. Park et al confirmed the significantly longer survival for patients with higher radiation dose [20]. In our study, from univariate analysis, T stage, PVT, irradiation dose and liver cirrhosis significantly impacted on overall survival (p = 0.000, 0.001, 0.020 and 0.000, respectively), in favour of T3 stage, no thrombosis in portal vein, irradiation dose of 45 Gy and Child–Pugh Grade A. From Coxregression analysis only irradiation dose, T stage and liver cirrhosis were shown to be independent prognostic factors (p = 0.040, 0.044 and 0.002). From our experience we proposed that the indication for the combined modality of TACE and 3DCRT would be HCC patients with good liver function (Child–Pugh Grade A), and irradiation dose to tumour should be over 45 Gy by conventional fractionation, but keep normal liver dose within a safe level. A further dose escalation study will be necessary to the clarify maximum tolerated dose. Moreover, the 3DCRT technique needs to be improved, including accurate delineation of GTV and tumour motion due to respiration.
In conclusion, the combined modality of TACE and 3DCRT used in our study was tolerable for the majority of HCC patients, resulted in good outcome and warrants further prospective trial.
Received for publication February 3, 2006.
Revision received May 5, 2006.
Accepted for publication July 28, 2006.
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Abstract
Introduction
