© 2006 Foundation for Promotion of Cancer Research
Results of Three-Dimensional Conformal Radiotherapy and Thalidomide for Advanced Hepatocellular Carcinoma
Departments of 1 Radiation Oncology, 2 Radiology, 3 Gastroenterology and 4 General Surgery, Cheng-Ching General Hospital, Taichung, 5 Department of Pharmacy, Buddhist Tzu-Chi General Hospital, Hualien and 6 Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
For reprint and all correspondence: Po-Ming Wang, Department of Radiation Oncology, Cheng-Ching General Hospital, Taichung, Taiwan, No. 118, Sec. 3, Chung-Kang Rd, Taichung, 407, Taiwan. E-mail: b753500{at}yahoo.com.tw
Received September 1, 2005; accepted November 29, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Purpose: To evaluate the effectiveness of three-dimensional conformal radiotherapy and thalidomide in the treatment of advanced hepatocellular carcinoma.
Methods: Between 1999 and 2003, 121 patients (mean age, 54.4 ± 12.4 years; range, 20–81 years) with advanced hepatocellular carcinoma received three-dimensional conformal radiotherapy and thalidomide. Radiation was delivered in 1.5 Gy fractions twice daily for 5 days a week, for a total dose of 45–75 Gy. Mean treatment volume was 429.52 ± 408.50 cm3 (range, 26.89–2284.82 cm3). Thalidomide was given concomitantly: 200 mg/day in 109 patients, 300 mg/day in 8 patients and 400 mg/day in 4 patients. Treatment responses, survival rates and factors affecting survival were analyzed.
Results: Treatment responses were observed in 61% of the patients. Liver cirrhosis (P = 0.001) and tumor size (P = 0.001) significantly affected the tumor responses. Overall survival at 6, 12 and 24 months was 84.8, 60.0 and 44.6%, respectively. On univariate analysis, liver cirrhosis (P = 0.003), Karnofsky performance status (P = 0.007), tumor size (P < 0.001), portal vein tumor thrombosis (P < 0.001) and alpha-fetoprotein level (P = 0.003) were shown to significantly affect survival. On multivariate analysis, only thrombosis (P = 0.039) and alpha-fetoprotein level (P = 0.006) were shown to be factors affecting survival.
Conclusions: Three-dimensional conformal radiotherapy with thalidomide seems to be effective in the treatment of advanced hepatocellular carcinoma.
Key Words: conformal radiotherapy • hepatocellular carcinoma • thalidomide
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INTRODUCTION |
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The prognosis for patients with untreated hepatocellular carcinoma (HCC) is poor, with an overall median survival time of 1.6 months (1). Surgical resection offers the best likelihood of a cure in HCC. However, only 10–20% of patients are suitable candidates for either tumor resection or liver transplantation (2–4). The remainder, who have extensive disease or poor hepatic function, receive various forms of therapy, including transarterial chemoembolization, percutaneous intratumoral injections of ethanol or radiofrequency tumor ablation, and radiotherapy (RT) (5–7). RT for hepatic malignancy has long been limited to palliative aims because of the low tolerance of the whole liver to radiation, with a limit of approximately 30–35 Gy (8,9). The introduction of an advanced computed tomography (CT)–assisted three-dimensional conformal RT (3D-CRT) treatment planning system allows the tumor to receive a higher dose and the normal liver to receive lower doses tolerable by patients with the non-diffuse disease (10–12).
Angiogenesis is an important factor in tumor growth and proliferation, as well as in conferring metastatic potential (13). Moreover, tumor angiogenesis is thought to be induced by a shift in the balance between angiogenic inducers and angiogenic inhibitors (14). These observations have led to the idea that angiogenic inhibitors can be used to treat neoplasms, especially vascularized tumors. Thalidomide is a sedative and an antiemetic agent once used in pregnant women, in whom it was associated with severe fetal malformations. This drug has also been shown to have antiangiogenic activity. Thalidomide is effective in the treatment of refractory multiple myeloma (15). In addition, studies have demonstrated that thalidomide is useful in the treatment of several types of solid tumors, including gliomas and breast, renal, ovarian and prostate cancers (1617). Preliminary data also suggest a beneficial effect of thalidomide in the treatment of advanced HCC (18, 20). Therefore, the purpose of this study was to evaluate the safety and effectiveness of 3D-CRT combined with thalidomide for the treatment of advanced HCC.
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MATERIALS AND METHODS |
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PATIENTS
Between October 1999 and December 2003, 121 patients with advanced HCC were enrolled in this study. Before patients' entry into this study, complete medical histories were taken and patients underwent physical examination, chest radiography, routine blood tests, biochemical liver function tests, serum alpha-fetoprotein (AFP) assay, abdominal sonography, bone scanning and CT. Eligibility criteria included the following: tumors not amenable to surgical resection and/or transarterial embolization, absence of uncontrollable ascites, no distant metastasis, leukocyte count >3000/µL, platelet count >80 000/µL, serum total bilirubin level
3.0 mg/dL, alanine aminotransferase level 100 kU, aspartate aminotransferase level 100 kU and no prior RT to the liver. The patients included 92 men and 29 women aged 20–81 years, with a mean age of 54.4 ± 12.4 years. Patients had a follow-up period from 1.1 to 51.5 months (mean ± standard deviation, 11.5 ± 10.7 months). The disease staging was determined using the TNM system of the American Joint Committee of Cancer (21) and the Okuda system for HCC (22). Table 1 shows the characteristics of the patients.
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The study was approved by the Ethics Committee of the Cheng-Ching General Hospital, Taichung, Taiwan. All patients provided written informed consent.
TREATMENT MODALITY
Patients were treated in the supine position with both arms placed overhead and were immobilized with an individualized vacuum cushion on the patient tray. A real-time infrared tracking device (ExacTrac; BrainLab AG, Heimstetten, Germany) was used for patient immobilization and reposition during the CT scan and treatment. In each patient, abdominal CT scan (X-vision, version 5.70; Toshiba, Tokyo, Japan) was performed with an immobilized and individualized vacuum cushion on the patient tray. During the CT scan, five reflective CT markers were attached to the patient's skin. We chose to position these markers on relatively immobile parts of the body (usually on the sternum and subcostal area) and also made sure that at least a few markers were around the target area. These skin markers helped in finding the correct marker position for further fractions. The CT images (5 mm slice thickness) were transferred to the planning system software (BrainSCAN, version 4.0; BrainLab AG, Heimstetten, Germany and THERAPLAN Plus version 3.5; Theratronics Ltd., Kanata, Ontario, Canada) via DICOM. The gross tumor volume was defined as the radiographic primary tumor plus abnormal portal areas revealed on CT images. The clinical target volume was defined as the gross tumor volume plus a 1 cm margin for subclinical disease. The planning target volume (PTV) was defined as the clinical target volume plus 0.5 cm in the axial dimension for daily patient setup variation and 1–2.5 cm in the cranial–caudal dimension to account for liver motion owing to respiration.
The use of three-dimensional conformal therapy was involved as the radiation techniques. The distance from the source to the isocenter (SAD) was 100 cm. Coplanar beams for 94 patients and non-coplanar beams for 27 patients were used. All treatment plans were normalized to the isocenter (dose reference point). The radiation oncologists selected and specified the treated volume, which was defined as the volume enclosed by an isodose surface (usually 85–90% in our study). The conformity index (C) was defined as C = 1 + (VNormal/VPTV), where VNormal is the volume of the normal tissue and VPTV is the volume of the PTV receiving the indicated dose. In other words, the conformity index C described the relation between the volume of normal tissue receiving the indicated dose and the volume of the PTV receiving the same dose. The conformity index at dose reference point ranged from 1.06 to 2.24, and the mean value was 1.33 ± 0.19. All treatments were delivered by means of a linear accelerator using 6 or 10 MV photons. Radiotherapy was given 5 days a week at 1.5 Gy per fraction twice per day, with fractions separated by 6 hours. The radiation dose to the target volume ranged from 45 to 75 Gy (65.52 ± 7.53 Gy), depending on the tolerance of the patients, their disease status and the functional reserve of the liver. The numbers of patients who received <60, 60–70 and >70 Gy were 3, 73 and 45, respectively. The treatment volume was 26.89–2284.82 cm3, with a mean value of 429.52 ± 408.50 cm3. Treatment portals ranged from two to eight, with a mean of 3.9 ± 1.1. The tolerance of other dose-limiting structures was taken into account, which included the spinal cord (38.4 Gy), the stomach (limited to 60 Gy outside of the target volume) and the duodenum (60 Gy). If >90% of one kidney was to receive >20 Gy, then <10% of the other kidney could receive 
18 Gy. Patients were monitored by physical examination, complete blood count determinations and liver function tests, performed weekly during RT and monthly after RT.
Thalidomide was given together with the course of RT. Oral thalidomide was started at a dosage of 200 mg/day in two divided doses. The dosage was increased to 300 mg/day if progressive disease was observed at 1 month and increased again to 400 mg/day if the disease was still progressing at 2 months. (Tumor progression was defined by the findings on abdominal sonography and by AFP level.) The dosage of thalidomide was 200 mg/day in 109 patients, 300 mg/day in 8 patients and 400 mg/day in 4 patients.
EVALUATION OF TREATMENT RESPONSE AND TOXICITY
After RT was completed, routine physical examinations and laboratory tests were performed at 1 to 2 month intervals or when clinically indicated. A minimum of one set of CT scans was obtained at least 2–3 months after the completion of RT to scale the tumor response. CT scans were obtained at 2 to 3 month intervals for at least 2 years and at 6 month intervals thereafter. CT images were reviewed, and the response was defined as the change in tumor size in the treatment volume. In this study, the World Health Organization Response Evaluation Criteria in Solid Tumors were used (23). Complete response was defined as the disappearance of all measurable tumors. Partial response was defined as a 30% decrease in the sum of the longest diameters of all treated lesions compared with the baseline. Progressive disease was defined as a 20% increase in the sum of the longest diameters of all treated lesions. Stable disease was either shrinkage insufficient to be considered a partial response or an increase insufficient to be considered a progressive disease. Response rates were calculated for complete and partial responses, and stable and progressive disease was considered as no response.
Treatment-related toxicity was evaluated according to the Common Terminology Criteria of Adverse Events (CTCAE version 3.0; National Cancer Institute, Bethesda, MD, USA) (24).
STATISTICAL ANALYSIS
Statistical analyses were performed using SPSS version 10.0 (SPSS, Chicago, IL, USA). Survival was measured from the first day of treatment until the day of death or the last contact day with the patient. Survival curves were calculated using the Kaplan–Meier method, and comparisons were made using the log-rank test. Independent factors associated with the survival rate were assessed by means of Cox regression analysis, where significant variables from a univariate analysis were included in a multivariate analysis. The 
2 test was performed to analyze factors associated with tumor response. A P-value of <0.05 indicated significant difference.
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RESULTS |
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TUMOR LOCAL EFFECTS
In 104 patents, serial abdominal CT scans were obtained at the initiation of the treatment and at 3–6 months after RT. The images were assessed for tumor local effects. Of the remaining patients, 5 died, 11 discontinued the use of thalidomide (2 refused thalidomide, 1 had tumor rupture and 8 had treatment-related toxicity of grade 3 or above) and 1 was lost to follow-up after treatment, with no follow-up CT image obtained for evaluation.
Treatment local effects were observed in 63 (61%) of 104 patients, with 11 complete responses and 52 partial responses. A total of 27 patients had a stable disease, and 14 patients showed a progression. Table 2 lists tumor responses according to the patients' clinical characteristics.
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Age (P = 0.403), sex (P = 0.946), Karnofsky performance status (KPS) (P = 0.178) and hepatitis B or C (P = 0.245) did not significantly affect tumor response. In contrast, liver cirrhosis (P = 0.001) and tumor size (<5, 5–10, or >10 cm; P = 0.001) significantly influenced the tumor response. Portal vein tumor thrombosis (PVTT) (P = 0.094) and AFP level (P = 0.084) showed borderline significance.
SURVIVAL
Overall survival rates at 6, 12 and 24 months were 84.8, 60.0 and 44.6%, respectively. Mean and median survival times were 24.0 ± 2.2 and 18.5 ± 4.5 months, respectively.
The univariate analysis of parameters predictive of survival demonstrated that five parameters were statistically significant: liver cirrhosis (P = 0.003), PVTT (P < 0.001), AFP level (P = 0.003), KPS (P = 0.007) and tumor size (P < 0.001). On multivariate analysis with the Cox regression model, only PVTT (P = 0.039) and AFP level (P =0.006) were shown to affect the survival rates (Table 3).
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Figure 1 shows the comparison of survival rates between patients with no PVTT, those with intrahepatic PVTT and those with extrahepatic PVTT (P = 0.0001). Survival was significantly better in the no-PVTT group than in either the intrahepatic PVTT (P = 0.0001) or the extrahepatic PVTT (P = 0.0002) group. Moreover, patients who were AFP positive had a poorer prognosis than the AFP-negative group (P = 0.0015, Figure 2).
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TREATMENT-RELATED TOXICITY
Adverse events were evaluated weekly during the treatment period and monthly after the treatment. Table 4 summarizes the adverse events related to 3D-CRT and thalidomide. The most common adverse events were constipation (48.8%), fatigue (39.7%) and skin pruritus or rash (34.7%). Eight patients with grade 3 treatment-related toxicity or higher discontinued thalidomide therapy; adverse effects included three cases of intense and severe skin reaction, three cases of hepatobiliary dysfunction (one case with elevation of serum glutamic pyruvic transaminase levels and two cases with elevation of total bilirubin levels), one case of leukopenia and one case of severe fatigue. Symptoms improved in six patients after symptomatic treatment and discontinuation of thalidomide. However, two patients with hepatobiliary dysfunction died from acute hepatic failure after the cessation of RT and thalidomide. The clinical features and treatments of the patients with grade 3 or higher treatment-related toxicity are listed in Table 5.
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DISCUSSION |
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The role of conventional RT in HCC was formerly limited because of the low dose tolerated by the entire liver. This dose is about 30 Gy in conventional fractionation (9,25) and lower than the curative dose for HCC (7,26,27). With advances in the three-dimensional treatment planning system, multiple portals allow for design from the perspective of the beam. Various angles and non-coplanar dimensions can be used to concentrate higher doses to tumor areas and to minimize doses to the surrounding normal tissue. Preliminary data suggest that targeting of the tumor alone and sparing of uninvolved liver can be accomplished simultaneously (6,7,10–12).
HCC cells have a doubling time of 
41 days (28). This rapid cell division suggests that hyperfractionated RT might add an advantage in achieving remission of HCC. However, a prospective trial by the Radiation Therapy Oncology Group using hyperfractionated hepatic irradiation demonstrated no improvement of the survival rate, and the incidence of acute adverse reaction increased (25). This finding may have been due to the treatment with a dose of 24 Gy, which is far lower than the curative dose for HCC. In addition, the radiation field included the whole liver. Robertson et al. (10,11) suggested that a dose–response relationship might exist for HCC, because tumor control in the target volume was encouraging in their group receiving focal high-dose radiation. In addition, they demonstrated that the reduction in hepatic lesion progression is 50% after 2 years following hyperfractionated RT. Seong et al. (27,29) reported a 63.3–67.1% response rate in unresectable HCC treated with local RT. In our study, the response rate was 60.6%, compatible with the results of the other studies and our previous studies (7,12,20,27,30). These results are in contrast to those of earlier reports on low-dose whole-liver RT, which achieved a response rate of 20% (26,31).
In this study, liver cirrhosis (P = 0.001) and tumor size (P = 0.001) significantly influenced the tumor response. Hepatic cirrhosis might result in poor functional reserve of the liver, and large tumors may tend to outgrow their blood supply, resulting in inadequate perfusion and poor oxygenation. These mechanisms might have accounted for the poor tumor responses. PVTT (P = 0.094) and AFP level (P = 0.084) exhibited borderline significance, and more evidence is required to prove their effect on tumor response.
The 1- and 2-year survival rates of unresectable HCC treated with local RT have been reported (26,27,29,30,32) as 54–68.2 and 30.5–41%, respectively. In this study, survival rates at 1 and 2 years were 60.0 and 44.6%, respectively. The 1-year survival rate was similar to previous data, whereas the 2-year survival rate seemed better than that previously reported. Because the patterns of failure after local RT are mainly multiple intrahepatic recurrences outside the field of irradiation or extrahepatic metastasis, we used 3D-CRT combined with thalidomide, differing from previous groups using RT alone or RT combined with transarterial chemoembolization.
Although portal blood supply predominates at the early stage of hepatocarcinogenesis in HCC, arterial supply dominates as the tumors grow. Arterialization is generally associated with hypervascularity in HCC, especially in HCC >2 cm in diameter (2). During the process of arterialization, changes in the secretion of angiogenic factor occur. Thalidomide might have an additive effect to 3D-CRT for local tumor control by lessening tumor growth and distant metastasis. Whether thalidomide inhibits HCC tumor growth solely because of its antiangiogenic effect is not clear. Other mechanisms, such as immune modulation, suppression of tumor necrosis factor-
expression and activity, and sensitization of cancer cells to preapoptotic signals, might also contribute to the inhibition of cancer cell growth (19,33–35). Our results suggested that prolonged survival might be expected after the administration of RT combined with thalidomide. Criteria for selecting suitable candidates and for providing treatment with this combined regimen are not well established. Further research is required to clarify this issue.
The prognosis of patients with HCC is hard to predict because it is influenced by complex factors. The reported prognostic factors in HCC include tumor size, tumor type, tumor location, tumor stage, liver cirrhosis, AFP, PVTT, KPS, radiation dose and several serum parameters related to hepatic function (26,27,31,36). In the present study, variables associated significantly with survival in the univariate analysis were liver cirrhosis, PVTT, AFP, KPS and tumor size. However, PVTT (P = 0.039) and AFP (P = 0.006) were the only independent factors in the multivariate analysis. The 1-year survival rates for patients with no PVTT, those with intrahepatic PVTT and those with extrahepatic PVTT were 78.55, 34.7 and 25.6%, respectively. PVTT may lead not only to the wide dissemination of tumor throughout the liver but also to marked deterioration of hepatic function (32,36). Moreover, PVTT could increase portal pressure, resulting in esophageal variceal bleeding, especially in patients with liver cirrhosis. The 1-year survival rate for the patients who were AFP negative and AFP positive were 79.3 and 50.7%, respectively. This finding indicated that patients with a high AFP level had poorer survival (4,26,32); however, results of several series have raised doubts about this (12,27,36). Because of the variation in the sample size, the treatment modalities and the definition of AFP level, it is difficult to confirm whether AFP level is a prognostic factor in HCC.
In this study, the most common adverse events of 3D-CRT and thalidomide treatment were constipation (48.8%), fatigue (39.7%) and skin pruritus or rash (34.7%). Almost all toxicities were limited to grade 1 or 2 and improved after supportive treatment. Only eight patients had grade 3 treatment-related toxicity or higher. Only two treatment-related deaths occurred; these were due to radiation-induced liver disease. These two patients were chronic hepatitis B carriers with liver cirrhosis. They were treated with radiation doses of 58.5 and 60 Gy in combination with thalidomide 200 mg per day. Hsu et al. (19) reported that the adverse effects of thalidomide include skin reactions (45.5%), leukopenia (1.5%), anemia (5.9%), gastritis (16.2%), constipation (42.6%), hepatobiliary effects (2.9%), fatigue (38.2%) and neurosensory effects (11.8%). The adverse events in our study were similar, except for hepatobiliary effects and blood count toxicity. The poor hepatobiliary results might have been due to a portion of the liver and the hematopoietic organ being included in the RT field; therefore, RT combined with thalidomide led to greater hepatobiliary dysfunction than thalidomide alone. In Taiwan, HCC is usually associated with viral hepatitis B/C and pre-existing cirrhosis of the liver is present in the majority of patients (37). These two commonly observed conditions add to the complexity of management. Hepatic irradiation may render these patients more susceptible to hepatic failure (26). Moreover, tracing back these two patients' history, both of them had taken unknown herbal drugs after the treatment. Hence, the acute hepatic failure could be attributed to the interaction of acute exacerbation of chronic hepatitis, radiation-induced hepatitis and drug-induced hepatitis. Furthermore, bone marrow suppression might have occurred because part of the bone marrow was included in the RT field.
In conclusion, 3D-CRT combined with thalidomide is feasible and may be a useful and safe modality for treating unresectable HCC. Liver cirrhosis and tumor size were significantly associated with the tumor response. Compared with others, patients with PVTT and abnormal AFP levels had a significantly poor survival rate. More experience is required to clarify the role of 3D-CRT combined with thalidomide and to define its optimal timing and dose in the treatment of HCC.
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Acknowledgments |
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This study was supported by Cheng-Ching General Hospital Research Fund (grant number CH04000052).
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References |
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