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Local radiotherapy for patients with unresectable hepatocellular carcinoma
Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 4, pp. 1143–1150, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.08.028
CLINICAL INVESTIGATION
Liver
LOCAL RADIOTHERAPY FOR PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA WON PARK, M.D.,* DO HOON LIM, M.D.,* SEUNG WOON PAIK, M.D.,† KWANG CHEOL KOH, M.D.,† MOON SEOK CHOI, M.D.,† CHEOL KEUN PARK, M.D.,‡ BYUNG CHUL YOO, M.D.,† JEONG EUN LEE, M.D.,* MIN KYU KANG, M.D.,* YOUNG JE PARK, M.D.,* HEE RIM NAM, M.D.,* YONG CHAN AHN, M.D.,* AND SEUNG JAE HUH, M.D.* Departments of *Radiation Oncology, †Medicine, and ‡Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Purpose: To evaluate the response to local radiotherapy (RT) for unresectable hepatocellular carcinoma (HCC) and to analyze the dose–response relationship and the treatment-related morbidities. Methods and Materials: Between 1998 and 2002, 59 patients who were treated with localized RT were evaluated. RT was delivered with a curative intent, and the radiation dose was 30 –55 Gy (biologic effective dose of 39.0 –70.2 Gy10 using the ␣/ ratio of 10 Gy) with 2–3 Gy as a daily dose. The tumor response was evaluated by the change in maximum tumor size on serial CT scans, and the morbidity was evaluated by the Common Terminology Criteria for Adverse Events v3.0. Results: An objective tumor response was achieved in 39 of 59 patients (66.1%) with complete response (CR) in 5 patients and partial response (PR) in 34 patients. More than 50 Gy10 had a significant response; CR or PR was 72.8% with >50 Gy10 and 46.7% with <50 Gy10 (p ⴝ 0.0299). The 2-year overall survival rate after RT was 27.4% (median survival time: 10 months), and this was affected by the tumor response (p ⴝ 0.0640); the 2-year overall survival rate after RT was 50.0% for CR and 21.8% for PR. There was no Grade 3 or 4 acute toxicity, and 3 patients (5.1%) developed gastric or duodenal ulcer. Conclusions: Radiotherapy for unresectable HCC resulted in 66.1% of tumor response with acceptable toxicity, and the radiation dose seems to be a significant prognostic factor in RT response for HCC. © 2005 Elsevier Inc. Hepatocellular carcinoma, Radiotherapy, Dose–response relationship.
Primary hepatocellular carcinoma (HCC) is one of the most common malignancies in both Asia and Africa (1). It has a poor prognosis because of its rapid infiltrating growth and the complicating liver cirrhosis. The most effective curative treatment for patients with HCC is surgery. However, only small proportions of patients are suitable for surgical resection, because of lesion multifocality, vascular thrombosis or invasion, and poor hepatic function (2– 4). For these reasons, regional interventional therapies such as transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection therapy (PEIT), and radiofrequency ablation (RFA) have been tried (5). Several studies have shown an improved survival with TACE in unresectable HCC (6, 7). However, the benefits of this therapy for survival have not been substantiated in randomized trials (8, 9). PEIT has been accepted as a safe and effective treatment for small HCC (10, 11), but its applications are not suitable for those cases with irregular tumor margins, hemorrhagic tenden-
cies, and situations where there is no safe route for PEIT. RFA provides for a predictable necrosis with a low complication rate, and the preliminary data indicate that RFA was superior to PEIT for tumor ablation (12, 13). Early attempts at radiotherapy (RT) for the treatment of HCC have had unsatisfactory results (14 –16). Because of the low tolerance of the liver to irradiation as compared to the tumoricidal dose, the delivery of a sufficient radiation dose was not possible. Recently, local RT on the liver has had promising responses for patients with localized HCC. Several reports have shown that high-dose irradiation to a portion of the liver could be safely delivered either alone or in combination with other interventional modalities, and this has been shown to be an effective treatment (17–20). However, until now there have been questions about the optimal radiation dose regarding tumor response and the acute or late patient morbidity. In this study, we have retrospectively evaluated the treatment responses, and we have analyzed the dose–response relationship and the treatment-related morbidities for pa-
Reprint requests to: Do Hoon Lim, M.D., Samsung Medical Center, Department of Radiation Oncology, Ilwon-Dong 50, Kangnam-Ku, Seoul, South Korea. Tel: (⫹82) 2-3410-2603; Fax:
(⫹82) 2-3410-2619; E-mail: [email protected] Received Mar 8, 2004, and in revised form Aug 3, 2004. Accepted for publication Aug 6, 2004.
INTRODUCTION
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tients with unresectable HCC that were treated with local RT.
METHODS AND MATERIALS Patients Between January 1998 and December 2002, 59 patients with unresectable HCC treated with localized RT at Samsung Medical Center were evaluated. HCC was diagnosed by one of the following criteria: (1) a pathologic confirmation; (2) a serum ␣-fetoprotein (AFP) value exceeding 400 IU/mL, hypervascular tumor observed on at least 1 of the CT/MRI/angiograms, and the presence of risk factors including hepatitis B or C virus or liver cirrhosis; (3) the AFP value less than 400 IU/mL, hypervascular tumor on at least 2 of CT/MRI/angiograms, and the presence of risk factors including hepatitis B or C virus or liver cirrhosis. There were no patients enrolled in our study with AFP increased over normal levels combined with other malignant tumors, pregnancy, or disease. Fourteen patients had a histologic confirmation of the primary hepatic tumor. The characteristics of the 59 patients at the time of radiation treatment are summarized in Table 1. The ages ranged from 36 to 78 years with a median age of 59. None of the patients had extrahepatic metastasis. The maximum diameter of tumor was on average 9.6 ⫾ 4.2 cm (range, 1.0 –21.5 cm). Portal vein thrombosis was present in 33 patients, and CT scan or angiogram confirmed the portal vein thrombosis. Forty-nine patients had a recurrent or residual tumor in the liver regardless of the different kinds of treatment: TACE in 48, PEIT in 10, RFA in 2, and surgery in 2. They received RT as the salvage treatment. Ten patients received RT as the primary treatment, because of the lack of indications for other local treatment modalities.
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Follow-up The tumor response was based on the change in the maximum tumor size on serial CT scans 4 – 8 weeks after completion of RT, and then tumor response was checked at 2–3-month intervals. A complete disappearance of the tumor was defined as complete response (CR), a decrease of more than 50% of the tumor size as partial response (PR), a decrease of less than 50% of the tumor size or no change as stable disease (SD), and in-field progression with a tumor size increase of more than 25% as progressive disease (PD). Among the patients with abnormal AFP levels at the time of radiotherapy, the changes of AFP values after RT were evaluated, too. Acute morbidity was evaluated weekly during treatment and 1 month after the treatment. Late morbidity was defined as occurring after 3 months. Radiation-induced liver disease (RILD) was characterized by the presence of anicteric ascites and the elevation of alkaline phosphatase levels to at least a twofold increase over the pretreatment values in the absence of tumor progression (21). Adverse events in the liver function test after radiotherapy were graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).
Statistical methods Statistical significance was calculated at the 95% confidence interval (p value ⬍0.05) by the use of the chi-square test or Fisher’s exact test to compare the different groups. Survival was estimated from the date of diagnosis and from the date that radiotherapy began using the Kaplan-Meier method, and these data were compared using the log– rank test for some variables.
Table 1. Clinicopathologic characteristics for enrolled 59 patients Characteristics
Radiation therapy Computed tomography scans for RT planning were done with each patient in a supine position, with both arms raised above the head, which facilitated the use of lateral radiation ports. CT data were all transferred to a radiation treatment planning system, and the primary tumors in the liver parenchyma, normal liver, kidneys, spinal cord, and bowels were contoured. The radiation portals were designed to include the gross tumor (as was seen on CT scan), with 2–3-cm margins that were necessary when considering the movement of the liver. After May 2000, when using three-dimensional CT-based computerized treatment planning in 47 patients, the clinical target volume was determined with a 1–1.5-cm margin of the gross tumor volume, and the planning target volume had expanded by 0.5 cm of the clinical target volume. The extra margin (1–1.5 cm) in the craniocaudal direction was added to cover the respiratory liver motion. Two parallel opposing ports or 3 coplanar ports were used according to the tumor size and location. In some cases, noncoplanar ports were used to decrease the irradiated small-bowel volume in the treatment field. The treatment planning was designed under tentative guidelines, so that the normal liver volume irradiated with more than half of the prescription dose should not exceed 50% of the total liver volume. RT was delivered with a 6-MV or 10-MV linear accelerator, and the average tumor dose was 45.3 ⫾ 6.1 Gy (range, 30 –55 Gy, biologic effective dose (BED) ⫽ (total dose) ⫻ [1 ⫹ daily dose / (␣/)] assuming an ␣/ ratio of 10 Gy, 39.0 –70.2 Gy10) in a daily fraction of 2 to 3 Gy. During the treatment, verification films were routinely obtained, and liver function tests were monitored biweekly.
Gender Male Female ECOG performance status 0–1 2 Tumor stage (2002 AJCC) T1–2 T3–4 Tumor size (maximum diameter) ⬍5 cm 5 cm–10 cm ⬎10 cm Portal vein thrombosis Yes No ␣-fetoprotein (IU/mL) ⬍400 ⱖ400 Liver cirrhosis Yes No Child–Pugh class* A B Radiotherapy Primary Salvage * Only liver cirrhosis patients.
Number of patients (%) 46 (78.0) 13 (22.0) 51 (86.4) 8 (13.6) 9 (15.3) 50 (84.7) 9 (15.3) 24 (40.9) 26 (43.8) 33 (55.9) 26 (44.1) 26 (44.1) 33 (55.9) 41 (69.5) 18 (30.5) 38 (92.7) 3 (7.3) 10 (17.0) 49 (83.0)
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Fig. 1. Change in computed tomography images taken (a) before and (b) 5 months after radiotherapy. A 64-year-old man with 9 ⫻ 8 ⫻ 5-cm hepatocellular carcinoma (HCC) in right lobe was treated with radiotherapy (RT) after the failure of transcatheter arterial chemoembolization. This large tumor was given 45 Gy in 15 fractions. He is still alive with no evidence of disease at 42 months after RT.
RESULTS Tumor response The tumor response was evaluated in all 59 patients, and an objectively measured tumor response was achieved in 39 of 59 patients (66.1%), with a CR noted in 5 and PR noted in 34 (Fig. 1). SD was observed in 15 patients, and 5 patients had PD. There was a relationship between radiation
dose and tumor responsiveness. A dose of more than 50 Gy10 to tumor achieved a statistically significant response (Table 2); there was a complete or partial response rate of 72.8% for ⬎50 Gy10 and 46.7% for ⱕ50 Gy10 (p ⫽ 0.0299). However, this response rate was affected by the differences of the tumor size in each group. In the group of patients receiving more than 50 Gy10, 16 patients (36.4%) had a
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Table 2. Tumor response according to radiation dose Biologic effective dose (Gy10)
Complete response Partial response Stable disease Progressive disease Total
ⱕ50
⬎50
p value
0 (0%) 7 (46.7%) 4 (26.7%) 4 (26.7%) 15 (100%)
5 (11.4%) 27 (61.4%) 11 (25.0%) 1 (2.3%) 44 (100%)
0.0299*
* Fisher’s exact test.
tumor larger than 10 cm in size, but in the other group, 10 patients (66.7%) had a tumor larger than 10 cm. We analyzed the other parameters that predicted tumor response (Table 3). The only significant parameter affecting tumor response was tumor size. If the tumor was more than 10 cm (at maximum size), the response rate was 50.0%, but if the tumor was less than 10 cm, the response rate was 78.8% (p ⫽ 0.0109). We analyzed AFP response after RT. Among the 49 patients who had abnormally elevated AFP levels before RT, the AFP level was decreased in 35 patients (71.4%). In 30 patients (61.2%), the AFP level was decreased to less than 50% of the pretreatment level, and 4 patients (8.2%) achieved normal AFP levels. The AFP response had a tendency to relate with tumor response, but the relationship was not statistically significant (p ⫽ 0.1380). Table 3. Analysis of the parameters associated with tumor responsiveness Number of patients (%)
Parameter Gender Male Female Age ⬍60 ⬎60 Tumor stage (2002 AJCC) T1–2 T3–4 Tumor size (maximum diameter) ⬍5 cm 5 cm–10 cm ⬎10 cm Portal vein thrombosis Yes No Previous treatment Yes No
CR ⫹ PR
SD ⫹ PD
p value
31 (67.4) 8 (61.5)
15 (32.6) 5 (38.5)
0.7463
22 (62.9) 17 (70.8)
13 (37.1) 7 (29.2)
0.5852
5 (55.6) 34 (68.0)
4 (44.4) 16 (32.0)
0.4714
5 (55.6) 21 (87.5) 13 (50.0)
4 (44.4) 3 (12.5) 13 (50.0)
0.0109
21 (63.6) 18 (69.2)
12 (36.4) 8 (30.8)
0.7836
34 (69.4) 5 (50.0)
15 (30.6) 5 (50.0)
0.2833
Abbreviations: CR ⫽ complete response; PR ⫽ partial response; SD ⫽ stable disease; PD ⫽ progressive disease.
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Survival The median follow-up time was 23.0 months after diagnosis and 12.9 months after RT. There were 16 patients who remained alive. Twenty-eight patients had new development of intrahepatic metastasis, and 14 patients had extrahepatic metastasis, including 12 patients with lung metastasis and 2 with abdominal lymph node metastasis. The 2-year overall survival rate after the time of diagnosis was 47.1% (The median survival time was 18 months), and it was 27.4% after the beginning of RT (The median survival time was 10 months) (Fig. 2). The overall survival involved with RT was affected by tumor response, but this was only marginally significant (p ⫽ 0.0640); 50.0% of patients had a 2-year survival in the CR group, 21.8% of patients had a 2-year survival in the PR group, 12.7% in SD, and 20.0% in PD. During follow-up, 14 patients had disease progression in the irradiated liver, including 7 patients who gained a PR after RT. The 2-year in-field progression-free survival rate was 61.1% (median survival, 10 months). The in-field progression-free survival was significantly affected by tumor response (p ⬍ 0.0001): 100.0% in CR, 57.1% in PR, 61.1% in SD, and 0% in PD. Among the 5 patients who achieved CR, there was no in-field progression; however, 1 patient died of hepatic failure due to intrahepatic metastasis. Infield failure was significantly correlated with the irradiated dose (p ⫽ 0.031); the in-field failure rate was 46.7% in the groups irradiated with ⱕ50 Gy10, but it was 16.9% in the groups irradiated with ⬎50 Gy10.
Toxicity During the treatment, acute morbidity such as nausea or vomiting developed in 37 patients (62.7%); the acute morbidity was Grade 1 in 25 patients and Grade 2 in 12 patients. These toxicities were transient, and most of the patients recovered with medication. The incidence of acute morbidity was affected by which lobe was irradiated, and the difference was statistically significant (p ⫽ 0.0223). Among the 47 patients irradiated on the right lobe only, 26 patients (55.3%) developed acute morbidity, but 11 patients (91.7%) of the 12 that were irradiated to the left lobe developed acute morbidity. The subacute or late morbidity developed in 8 patients (13.6%): 3 patients had RILD, 2 had gastritis, and 3 had a gastric or duodenal ulcer. There were no fatal complications. Forty-one patients (69.5%) showed abnormal liver functions without evidence of tumor progression. However, according to CTCAE v3.0, most of these were Grade 1 or 2 adverse effects. There were no Grade 4 adverse effects, and only 3 patients (2 elevated transaminases and 2 hyperbilirubinemia) had Grade 3 adverse effects. Abnormal liver functions developed 1–2 months after the completion of RT, but the liver functions were recovered or stabilized into at least the upper limit of normal function or of the pretreatment level within 3– 6 months. Anicteric ascites without elevation of alkaline phosphatase levels developed in 12
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Fig. 2. Overall survival of 59 patients from the beginning of radiotherapy.
patients, and the ascites successfully resolved with or without diuretics. DISCUSSION Radiotherapy has not played a significant role in treating HCC, because of the low radiation tolerance of the whole liver and the lack of knowledge about the tolerated dose of the partial liver to high-dose radiation. A whole liver RT dose up to 30 Gy with the conventional external beam irradiation is generally accepted, but this dose level is much less than a tumor control dose (14, 22). There are several trials to increase the tumor dose for improvement of tumor control. Order et al. (23) reported that the response rate after 21 Gy whole liver RT alone was 23%, but it was 48% after 21 Gy whole liver RT after 131I antiferritin therapy, including 7% CR. Lawrence et al. (24) showed that patients who received boost treatment (30 Gy whole liver irradiation plus a 15 Gy or 30 Gy boost) tended to have a higher response rate (64%) than those patients who received only whole liver treatment (39%). They suggested that the intrahepatic malignancies could be treated by the concept of a dose– volume histogram analysis of the normal liver to allow the safe administration of doses that were potentially tumoricidal and were well tolerable for the liver. We summarized several reports about the treatment experiences of local liver RT (Table 4). Most studies were combined with nonsurgical therapies, because RT was considered as a supportive or alternative modality for other therapies in unresectable HCC. Robertson et al. (25) showed excellent tumor response (90.9%) in patients treated with local RT and hepatic artery fluorodeoxyuridine for primary hepatobiliary cancers. They delivered high RT dose (up to 72.6 Gy) to a portion of the
liver, and 7 patients had subacute or long-term toxicity, including 5 gastrointestinal bleedings and 1 case of nonfatal radiation hepatitis. Seong et al. (26) treated 30 patients with HCC using TACE followed by local RT. The objective response was observed in 63.3% with a median survival of 17 months. They concluded that this regimen would be a new promising modality in unresectable HCC. Cheng et al. (27) carried out local RT with or without TACE for 13 patients with HCC. Partial response was observed in 58% of patients, and the authors concluded that HCC is more radiosensitive than was traditionally expected. Recently, Guo et al. (28) retrospectively investigated the efficacy of TACE plus RT for unresectable HCC. The clinical features between the TACE plus RT group and the TACE-alone group were comparable. The authors demonstrated that the objective response rate in the TACE plus RT group was significantly higher than that in the TACE-alone group (47.4% vs. 28.1%). They concluded TACE combined with RT was a more promising treatment for unresectable HCC than TACE alone. But the response rate of TACE plus RT was lower than the response rates of the other treatment results, maybe because irradiation of only up to 50 Gy to the partial liver was given. Seong et al. (29) and Park et al. (30) reported the irradiated results of radical RT as the primary treatment or salvage aim after the failure of other nonsurgical modalities. The response rate of their studies was about 60%, and the median survival time was more than 10 months after RT. In our data, the response rate and median survival after the time of RT were comparable to these results. The present study and previous reports suggest that HCC is a comparatively radioresponsive tumor, and the radiation dose is a significant factor for increasing the objective tumor response and the survival rate when treating HCC. However, the surrounding structures such as stomach, small
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Table 4. Treatment results after local radiotherapy for primary hepatocellular carcinoma
Study (year) Robertson et al. (1997) Seong et al. (1999) Cheng et al. (1999) Guo et al. (2003)
Seong et al. (2000) Park et al. (2002) This study
RT dose/fractions (BED, Gy10)
Response rate (%)
Median survival from the day of treatment (months)
90.9*
16
4 year: 20.0
TACE ⫹ RT
48–72.6 Gy/32–44 (55.2–84.6) 44.0 ⫾ 9.3 Gy† (51.9 ⫾ 11.0)
63.3
17
40–60 Gy/20–30 (48.0–72.0) 30–50 Gy/15–25 (36.0–60.0)
58.0
7
76
RT alone: 9 TACE ⫹ RT: 4 TACE ⫹ RT
1-year: 67.0 2-year: 33.3 3-year: 22.2 NA
47.4
19
89
TACE alone
28.1
10
27
Salvage RT
39.6–60 Gy/22–33 (46.7–70.1)
66.7
14
158
Primary RT: 107 Salvage RT: 51 Primary RT: 10 Salvage RT: 49
25.2–59.4 Gy/14–33 (29.7–70.1) 30.0–55 Gy/10–22 (39.0–70.2)
67.1
10
66.1
10
No. of patients
Treatment
22
RT ⫹ HA FdUrd
30 13
59
Survival rate from the day of treatment (%)
1-year: 3-year: 5-year: 1-year: 3-year: 5-year: 1-year: 2-year: 3-year: 1-year: 2-year: 1-year: 2-year: 3-year:
64.0 28.6 19.3 39.9 9.5 7.2 55.9 35.7 21.4 41.8 19.9 51.0 27.4 14.6
Late morbidities 5 gastrointestinal 1 RILD NA 3 gastrointestinal NA NA 5 gastrointestinal 17 gastrointestinal 11 RILD 5 gastrointestinal 3 RILD
Abbreviations: RT ⫽ radiotherapy; BED ⫽ biologic effective dose; HA FdUrd ⫽ hepatic artery fluorodeoxyuridine; RILD ⫽ radiation-induced liver disease; TACE ⫽ transcatheter arterial chemoembolization; NA ⫽ not available. * Assessed in 11 patients, including 10 hepatocellular carcinoma and 1 cholangiocarcinoma. † Average tumor dose, daily 1.8 Gy per fraction.
bowel, kidney, colon, and lung are radiation dose–limiting organs, and the liver itself is the most important factor to determine the radiation dose. Therefore, the optimal radiation dose in local RT for HCC is still unclear. To determine the irradiation dose, we must be concerned about the parenchymal disease status of the liver and the volume of the irradiated normal liver. In clinical practices, we excluded the patients with Eastern Cooperative Oncology Group performance status of more than 3 or with liver cirrhosis of Child-Pugh class C. The prescribed dose was determined under the tentative guideline that the irradiated normal liver volume with more than half of the prescription dose should not exceed 50% of the total liver volume. Recently, conformal radiotherapy has been applied for the treatment of HCC, and a dose–volume analysis was done by some researchers to quantify the tolerance of the liver. Dawson et al. (31, 32) estimated that the liver doses associated with a 5% risk of RILD for uniform irradiation of one-third, two-thirds, and the whole liver were 90 Gy, 47 Gy, and 31 Gy, respectively. The authors reported good response rates, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more. The response rate for 25 assessable patients was 68%. Patients treated with more than 70 Gy had a significantly improved median survival compared with those patients treated with less than 70 Gy (p ⫽ 0.0003). On the
other hand, Cheng et al. (27) suggested that a radiation dose ⱖ40 Gy was capable of achieving tumor regression. Park et al. (30) showed the dose–response relationship of local RT for HCC. The response rates with doses ⬍40 Gy, 40 –50 Gy, and ⬎50 Gy were 29.2%, 68.6%, and 77.1%, respectively. In our study, the irradiation dose was correlated with tumor response and in-field failure. Because the fraction size in this study variably ranged from 2 Gy to 3 Gy, we used the BED concept to analyze the radiation dose– response relationship. The BED 50 Gy10, which was a criterion of the radiation dose in this study, biologically corresponded with a radiation dose 42 Gy in a daily fraction of 1.8 to 2.0 Gy. The patients treated with radiation dose ⬎50 Gy10 were irradiated with more than 50 Gy in a daily fraction of 2 Gy or 45 Gy in a daily fraction of 3 Gy. The objective responses were 46.7% in ⱕ50 Gy10 and 72.8% in ⬎50 Gy10. In-field failure was 46.7% in the groups irradiated with ⱕ50 Gy10, but it was 16.9% in patients treated with ⬎50 Gy10. However, the radiation dose escalation could lead to increased radiation-related morbidities. According to Park et al. (30), the rates of RILD and gastrointestinal (GI) complications were increased with doses ⬍40 Gy, 40 –50 Gy, and ⬎50 Gy (RILD: 4.2%, 5.9%, 8.4%; GI: 4.2%, 9.9%, 13.2%, respectively). In this study, RILD and GI complications developed in 3 and 5 patients, respec-
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tively, but there was no relationship between the radiation dose and late complications.
CONCLUSION In conclusion, we show that local RT for unresectable HCC resulted in a tumor response of 66.1% with acceptable toxicity, and the radiation dose and tumor size seem to be significant prognostic factors in RT response for HCC. Tumor responsiveness affects the survival time after RT. However, the optimal radiation dose for HCC is
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not yet conclusive, because the patients in other published reports were heterogenous for their clinical features and treatment modalities, and there have been no randomized controlled studies. The radiation dose escalation may improve treatment results, but complications may also be increased. Therefore, randomized experimental and clinical research is required to define the indication and role of RT combined with nonsurgical modalities for treating unresectable HCC. Also, threedimensional conformal radiotherapy should be applied to escalate the radiation dose and to protect the remaining liver and adjacent organs in local RT for HCC.
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unresectable hepatocellular carcinoma patients who failed with transcatheter arterial chemoembolization. Int J Radiat Oncol Biol Phys 2000;47:1331–1335. 30. Park HC, Seong J, Han KH, et al. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002;54:150 –155.
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31. Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat Oncol 2001;11:240 –246. 32. Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000;18:2210 –2218.
doi:10.1016/j.ijrobp.2004.08.028
CLINICAL INVESTIGATION
Liver
LOCAL RADIOTHERAPY FOR PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA WON PARK, M.D.,* DO HOON LIM, M.D.,* SEUNG WOON PAIK, M.D.,† KWANG CHEOL KOH, M.D.,† MOON SEOK CHOI, M.D.,† CHEOL KEUN PARK, M.D.,‡ BYUNG CHUL YOO, M.D.,† JEONG EUN LEE, M.D.,* MIN KYU KANG, M.D.,* YOUNG JE PARK, M.D.,* HEE RIM NAM, M.D.,* YONG CHAN AHN, M.D.,* AND SEUNG JAE HUH, M.D.* Departments of *Radiation Oncology, †Medicine, and ‡Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Purpose: To evaluate the response to local radiotherapy (RT) for unresectable hepatocellular carcinoma (HCC) and to analyze the dose–response relationship and the treatment-related morbidities. Methods and Materials: Between 1998 and 2002, 59 patients who were treated with localized RT were evaluated. RT was delivered with a curative intent, and the radiation dose was 30 –55 Gy (biologic effective dose of 39.0 –70.2 Gy10 using the ␣/ ratio of 10 Gy) with 2–3 Gy as a daily dose. The tumor response was evaluated by the change in maximum tumor size on serial CT scans, and the morbidity was evaluated by the Common Terminology Criteria for Adverse Events v3.0. Results: An objective tumor response was achieved in 39 of 59 patients (66.1%) with complete response (CR) in 5 patients and partial response (PR) in 34 patients. More than 50 Gy10 had a significant response; CR or PR was 72.8% with >50 Gy10 and 46.7% with <50 Gy10 (p ⴝ 0.0299). The 2-year overall survival rate after RT was 27.4% (median survival time: 10 months), and this was affected by the tumor response (p ⴝ 0.0640); the 2-year overall survival rate after RT was 50.0% for CR and 21.8% for PR. There was no Grade 3 or 4 acute toxicity, and 3 patients (5.1%) developed gastric or duodenal ulcer. Conclusions: Radiotherapy for unresectable HCC resulted in 66.1% of tumor response with acceptable toxicity, and the radiation dose seems to be a significant prognostic factor in RT response for HCC. © 2005 Elsevier Inc. Hepatocellular carcinoma, Radiotherapy, Dose–response relationship.
Primary hepatocellular carcinoma (HCC) is one of the most common malignancies in both Asia and Africa (1). It has a poor prognosis because of its rapid infiltrating growth and the complicating liver cirrhosis. The most effective curative treatment for patients with HCC is surgery. However, only small proportions of patients are suitable for surgical resection, because of lesion multifocality, vascular thrombosis or invasion, and poor hepatic function (2– 4). For these reasons, regional interventional therapies such as transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection therapy (PEIT), and radiofrequency ablation (RFA) have been tried (5). Several studies have shown an improved survival with TACE in unresectable HCC (6, 7). However, the benefits of this therapy for survival have not been substantiated in randomized trials (8, 9). PEIT has been accepted as a safe and effective treatment for small HCC (10, 11), but its applications are not suitable for those cases with irregular tumor margins, hemorrhagic tenden-
cies, and situations where there is no safe route for PEIT. RFA provides for a predictable necrosis with a low complication rate, and the preliminary data indicate that RFA was superior to PEIT for tumor ablation (12, 13). Early attempts at radiotherapy (RT) for the treatment of HCC have had unsatisfactory results (14 –16). Because of the low tolerance of the liver to irradiation as compared to the tumoricidal dose, the delivery of a sufficient radiation dose was not possible. Recently, local RT on the liver has had promising responses for patients with localized HCC. Several reports have shown that high-dose irradiation to a portion of the liver could be safely delivered either alone or in combination with other interventional modalities, and this has been shown to be an effective treatment (17–20). However, until now there have been questions about the optimal radiation dose regarding tumor response and the acute or late patient morbidity. In this study, we have retrospectively evaluated the treatment responses, and we have analyzed the dose–response relationship and the treatment-related morbidities for pa-
Reprint requests to: Do Hoon Lim, M.D., Samsung Medical Center, Department of Radiation Oncology, Ilwon-Dong 50, Kangnam-Ku, Seoul, South Korea. Tel: (⫹82) 2-3410-2603; Fax:
(⫹82) 2-3410-2619; E-mail: [email protected] Received Mar 8, 2004, and in revised form Aug 3, 2004. Accepted for publication Aug 6, 2004.
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tients with unresectable HCC that were treated with local RT.
METHODS AND MATERIALS Patients Between January 1998 and December 2002, 59 patients with unresectable HCC treated with localized RT at Samsung Medical Center were evaluated. HCC was diagnosed by one of the following criteria: (1) a pathologic confirmation; (2) a serum ␣-fetoprotein (AFP) value exceeding 400 IU/mL, hypervascular tumor observed on at least 1 of the CT/MRI/angiograms, and the presence of risk factors including hepatitis B or C virus or liver cirrhosis; (3) the AFP value less than 400 IU/mL, hypervascular tumor on at least 2 of CT/MRI/angiograms, and the presence of risk factors including hepatitis B or C virus or liver cirrhosis. There were no patients enrolled in our study with AFP increased over normal levels combined with other malignant tumors, pregnancy, or disease. Fourteen patients had a histologic confirmation of the primary hepatic tumor. The characteristics of the 59 patients at the time of radiation treatment are summarized in Table 1. The ages ranged from 36 to 78 years with a median age of 59. None of the patients had extrahepatic metastasis. The maximum diameter of tumor was on average 9.6 ⫾ 4.2 cm (range, 1.0 –21.5 cm). Portal vein thrombosis was present in 33 patients, and CT scan or angiogram confirmed the portal vein thrombosis. Forty-nine patients had a recurrent or residual tumor in the liver regardless of the different kinds of treatment: TACE in 48, PEIT in 10, RFA in 2, and surgery in 2. They received RT as the salvage treatment. Ten patients received RT as the primary treatment, because of the lack of indications for other local treatment modalities.
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Follow-up The tumor response was based on the change in the maximum tumor size on serial CT scans 4 – 8 weeks after completion of RT, and then tumor response was checked at 2–3-month intervals. A complete disappearance of the tumor was defined as complete response (CR), a decrease of more than 50% of the tumor size as partial response (PR), a decrease of less than 50% of the tumor size or no change as stable disease (SD), and in-field progression with a tumor size increase of more than 25% as progressive disease (PD). Among the patients with abnormal AFP levels at the time of radiotherapy, the changes of AFP values after RT were evaluated, too. Acute morbidity was evaluated weekly during treatment and 1 month after the treatment. Late morbidity was defined as occurring after 3 months. Radiation-induced liver disease (RILD) was characterized by the presence of anicteric ascites and the elevation of alkaline phosphatase levels to at least a twofold increase over the pretreatment values in the absence of tumor progression (21). Adverse events in the liver function test after radiotherapy were graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).
Statistical methods Statistical significance was calculated at the 95% confidence interval (p value ⬍0.05) by the use of the chi-square test or Fisher’s exact test to compare the different groups. Survival was estimated from the date of diagnosis and from the date that radiotherapy began using the Kaplan-Meier method, and these data were compared using the log– rank test for some variables.
Table 1. Clinicopathologic characteristics for enrolled 59 patients Characteristics
Radiation therapy Computed tomography scans for RT planning were done with each patient in a supine position, with both arms raised above the head, which facilitated the use of lateral radiation ports. CT data were all transferred to a radiation treatment planning system, and the primary tumors in the liver parenchyma, normal liver, kidneys, spinal cord, and bowels were contoured. The radiation portals were designed to include the gross tumor (as was seen on CT scan), with 2–3-cm margins that were necessary when considering the movement of the liver. After May 2000, when using three-dimensional CT-based computerized treatment planning in 47 patients, the clinical target volume was determined with a 1–1.5-cm margin of the gross tumor volume, and the planning target volume had expanded by 0.5 cm of the clinical target volume. The extra margin (1–1.5 cm) in the craniocaudal direction was added to cover the respiratory liver motion. Two parallel opposing ports or 3 coplanar ports were used according to the tumor size and location. In some cases, noncoplanar ports were used to decrease the irradiated small-bowel volume in the treatment field. The treatment planning was designed under tentative guidelines, so that the normal liver volume irradiated with more than half of the prescription dose should not exceed 50% of the total liver volume. RT was delivered with a 6-MV or 10-MV linear accelerator, and the average tumor dose was 45.3 ⫾ 6.1 Gy (range, 30 –55 Gy, biologic effective dose (BED) ⫽ (total dose) ⫻ [1 ⫹ daily dose / (␣/)] assuming an ␣/ ratio of 10 Gy, 39.0 –70.2 Gy10) in a daily fraction of 2 to 3 Gy. During the treatment, verification films were routinely obtained, and liver function tests were monitored biweekly.
Gender Male Female ECOG performance status 0–1 2 Tumor stage (2002 AJCC) T1–2 T3–4 Tumor size (maximum diameter) ⬍5 cm 5 cm–10 cm ⬎10 cm Portal vein thrombosis Yes No ␣-fetoprotein (IU/mL) ⬍400 ⱖ400 Liver cirrhosis Yes No Child–Pugh class* A B Radiotherapy Primary Salvage * Only liver cirrhosis patients.
Number of patients (%) 46 (78.0) 13 (22.0) 51 (86.4) 8 (13.6) 9 (15.3) 50 (84.7) 9 (15.3) 24 (40.9) 26 (43.8) 33 (55.9) 26 (44.1) 26 (44.1) 33 (55.9) 41 (69.5) 18 (30.5) 38 (92.7) 3 (7.3) 10 (17.0) 49 (83.0)
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Fig. 1. Change in computed tomography images taken (a) before and (b) 5 months after radiotherapy. A 64-year-old man with 9 ⫻ 8 ⫻ 5-cm hepatocellular carcinoma (HCC) in right lobe was treated with radiotherapy (RT) after the failure of transcatheter arterial chemoembolization. This large tumor was given 45 Gy in 15 fractions. He is still alive with no evidence of disease at 42 months after RT.
RESULTS Tumor response The tumor response was evaluated in all 59 patients, and an objectively measured tumor response was achieved in 39 of 59 patients (66.1%), with a CR noted in 5 and PR noted in 34 (Fig. 1). SD was observed in 15 patients, and 5 patients had PD. There was a relationship between radiation
dose and tumor responsiveness. A dose of more than 50 Gy10 to tumor achieved a statistically significant response (Table 2); there was a complete or partial response rate of 72.8% for ⬎50 Gy10 and 46.7% for ⱕ50 Gy10 (p ⫽ 0.0299). However, this response rate was affected by the differences of the tumor size in each group. In the group of patients receiving more than 50 Gy10, 16 patients (36.4%) had a
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Table 2. Tumor response according to radiation dose Biologic effective dose (Gy10)
Complete response Partial response Stable disease Progressive disease Total
ⱕ50
⬎50
p value
0 (0%) 7 (46.7%) 4 (26.7%) 4 (26.7%) 15 (100%)
5 (11.4%) 27 (61.4%) 11 (25.0%) 1 (2.3%) 44 (100%)
0.0299*
* Fisher’s exact test.
tumor larger than 10 cm in size, but in the other group, 10 patients (66.7%) had a tumor larger than 10 cm. We analyzed the other parameters that predicted tumor response (Table 3). The only significant parameter affecting tumor response was tumor size. If the tumor was more than 10 cm (at maximum size), the response rate was 50.0%, but if the tumor was less than 10 cm, the response rate was 78.8% (p ⫽ 0.0109). We analyzed AFP response after RT. Among the 49 patients who had abnormally elevated AFP levels before RT, the AFP level was decreased in 35 patients (71.4%). In 30 patients (61.2%), the AFP level was decreased to less than 50% of the pretreatment level, and 4 patients (8.2%) achieved normal AFP levels. The AFP response had a tendency to relate with tumor response, but the relationship was not statistically significant (p ⫽ 0.1380). Table 3. Analysis of the parameters associated with tumor responsiveness Number of patients (%)
Parameter Gender Male Female Age ⬍60 ⬎60 Tumor stage (2002 AJCC) T1–2 T3–4 Tumor size (maximum diameter) ⬍5 cm 5 cm–10 cm ⬎10 cm Portal vein thrombosis Yes No Previous treatment Yes No
CR ⫹ PR
SD ⫹ PD
p value
31 (67.4) 8 (61.5)
15 (32.6) 5 (38.5)
0.7463
22 (62.9) 17 (70.8)
13 (37.1) 7 (29.2)
0.5852
5 (55.6) 34 (68.0)
4 (44.4) 16 (32.0)
0.4714
5 (55.6) 21 (87.5) 13 (50.0)
4 (44.4) 3 (12.5) 13 (50.0)
0.0109
21 (63.6) 18 (69.2)
12 (36.4) 8 (30.8)
0.7836
34 (69.4) 5 (50.0)
15 (30.6) 5 (50.0)
0.2833
Abbreviations: CR ⫽ complete response; PR ⫽ partial response; SD ⫽ stable disease; PD ⫽ progressive disease.
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Survival The median follow-up time was 23.0 months after diagnosis and 12.9 months after RT. There were 16 patients who remained alive. Twenty-eight patients had new development of intrahepatic metastasis, and 14 patients had extrahepatic metastasis, including 12 patients with lung metastasis and 2 with abdominal lymph node metastasis. The 2-year overall survival rate after the time of diagnosis was 47.1% (The median survival time was 18 months), and it was 27.4% after the beginning of RT (The median survival time was 10 months) (Fig. 2). The overall survival involved with RT was affected by tumor response, but this was only marginally significant (p ⫽ 0.0640); 50.0% of patients had a 2-year survival in the CR group, 21.8% of patients had a 2-year survival in the PR group, 12.7% in SD, and 20.0% in PD. During follow-up, 14 patients had disease progression in the irradiated liver, including 7 patients who gained a PR after RT. The 2-year in-field progression-free survival rate was 61.1% (median survival, 10 months). The in-field progression-free survival was significantly affected by tumor response (p ⬍ 0.0001): 100.0% in CR, 57.1% in PR, 61.1% in SD, and 0% in PD. Among the 5 patients who achieved CR, there was no in-field progression; however, 1 patient died of hepatic failure due to intrahepatic metastasis. Infield failure was significantly correlated with the irradiated dose (p ⫽ 0.031); the in-field failure rate was 46.7% in the groups irradiated with ⱕ50 Gy10, but it was 16.9% in the groups irradiated with ⬎50 Gy10.
Toxicity During the treatment, acute morbidity such as nausea or vomiting developed in 37 patients (62.7%); the acute morbidity was Grade 1 in 25 patients and Grade 2 in 12 patients. These toxicities were transient, and most of the patients recovered with medication. The incidence of acute morbidity was affected by which lobe was irradiated, and the difference was statistically significant (p ⫽ 0.0223). Among the 47 patients irradiated on the right lobe only, 26 patients (55.3%) developed acute morbidity, but 11 patients (91.7%) of the 12 that were irradiated to the left lobe developed acute morbidity. The subacute or late morbidity developed in 8 patients (13.6%): 3 patients had RILD, 2 had gastritis, and 3 had a gastric or duodenal ulcer. There were no fatal complications. Forty-one patients (69.5%) showed abnormal liver functions without evidence of tumor progression. However, according to CTCAE v3.0, most of these were Grade 1 or 2 adverse effects. There were no Grade 4 adverse effects, and only 3 patients (2 elevated transaminases and 2 hyperbilirubinemia) had Grade 3 adverse effects. Abnormal liver functions developed 1–2 months after the completion of RT, but the liver functions were recovered or stabilized into at least the upper limit of normal function or of the pretreatment level within 3– 6 months. Anicteric ascites without elevation of alkaline phosphatase levels developed in 12
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Fig. 2. Overall survival of 59 patients from the beginning of radiotherapy.
patients, and the ascites successfully resolved with or without diuretics. DISCUSSION Radiotherapy has not played a significant role in treating HCC, because of the low radiation tolerance of the whole liver and the lack of knowledge about the tolerated dose of the partial liver to high-dose radiation. A whole liver RT dose up to 30 Gy with the conventional external beam irradiation is generally accepted, but this dose level is much less than a tumor control dose (14, 22). There are several trials to increase the tumor dose for improvement of tumor control. Order et al. (23) reported that the response rate after 21 Gy whole liver RT alone was 23%, but it was 48% after 21 Gy whole liver RT after 131I antiferritin therapy, including 7% CR. Lawrence et al. (24) showed that patients who received boost treatment (30 Gy whole liver irradiation plus a 15 Gy or 30 Gy boost) tended to have a higher response rate (64%) than those patients who received only whole liver treatment (39%). They suggested that the intrahepatic malignancies could be treated by the concept of a dose– volume histogram analysis of the normal liver to allow the safe administration of doses that were potentially tumoricidal and were well tolerable for the liver. We summarized several reports about the treatment experiences of local liver RT (Table 4). Most studies were combined with nonsurgical therapies, because RT was considered as a supportive or alternative modality for other therapies in unresectable HCC. Robertson et al. (25) showed excellent tumor response (90.9%) in patients treated with local RT and hepatic artery fluorodeoxyuridine for primary hepatobiliary cancers. They delivered high RT dose (up to 72.6 Gy) to a portion of the
liver, and 7 patients had subacute or long-term toxicity, including 5 gastrointestinal bleedings and 1 case of nonfatal radiation hepatitis. Seong et al. (26) treated 30 patients with HCC using TACE followed by local RT. The objective response was observed in 63.3% with a median survival of 17 months. They concluded that this regimen would be a new promising modality in unresectable HCC. Cheng et al. (27) carried out local RT with or without TACE for 13 patients with HCC. Partial response was observed in 58% of patients, and the authors concluded that HCC is more radiosensitive than was traditionally expected. Recently, Guo et al. (28) retrospectively investigated the efficacy of TACE plus RT for unresectable HCC. The clinical features between the TACE plus RT group and the TACE-alone group were comparable. The authors demonstrated that the objective response rate in the TACE plus RT group was significantly higher than that in the TACE-alone group (47.4% vs. 28.1%). They concluded TACE combined with RT was a more promising treatment for unresectable HCC than TACE alone. But the response rate of TACE plus RT was lower than the response rates of the other treatment results, maybe because irradiation of only up to 50 Gy to the partial liver was given. Seong et al. (29) and Park et al. (30) reported the irradiated results of radical RT as the primary treatment or salvage aim after the failure of other nonsurgical modalities. The response rate of their studies was about 60%, and the median survival time was more than 10 months after RT. In our data, the response rate and median survival after the time of RT were comparable to these results. The present study and previous reports suggest that HCC is a comparatively radioresponsive tumor, and the radiation dose is a significant factor for increasing the objective tumor response and the survival rate when treating HCC. However, the surrounding structures such as stomach, small
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Table 4. Treatment results after local radiotherapy for primary hepatocellular carcinoma
Study (year) Robertson et al. (1997) Seong et al. (1999) Cheng et al. (1999) Guo et al. (2003)
Seong et al. (2000) Park et al. (2002) This study
RT dose/fractions (BED, Gy10)
Response rate (%)
Median survival from the day of treatment (months)
90.9*
16
4 year: 20.0
TACE ⫹ RT
48–72.6 Gy/32–44 (55.2–84.6) 44.0 ⫾ 9.3 Gy† (51.9 ⫾ 11.0)
63.3
17
40–60 Gy/20–30 (48.0–72.0) 30–50 Gy/15–25 (36.0–60.0)
58.0
7
76
RT alone: 9 TACE ⫹ RT: 4 TACE ⫹ RT
1-year: 67.0 2-year: 33.3 3-year: 22.2 NA
47.4
19
89
TACE alone
28.1
10
27
Salvage RT
39.6–60 Gy/22–33 (46.7–70.1)
66.7
14
158
Primary RT: 107 Salvage RT: 51 Primary RT: 10 Salvage RT: 49
25.2–59.4 Gy/14–33 (29.7–70.1) 30.0–55 Gy/10–22 (39.0–70.2)
67.1
10
66.1
10
No. of patients
Treatment
22
RT ⫹ HA FdUrd
30 13
59
Survival rate from the day of treatment (%)
1-year: 3-year: 5-year: 1-year: 3-year: 5-year: 1-year: 2-year: 3-year: 1-year: 2-year: 1-year: 2-year: 3-year:
64.0 28.6 19.3 39.9 9.5 7.2 55.9 35.7 21.4 41.8 19.9 51.0 27.4 14.6
Late morbidities 5 gastrointestinal 1 RILD NA 3 gastrointestinal NA NA 5 gastrointestinal 17 gastrointestinal 11 RILD 5 gastrointestinal 3 RILD
Abbreviations: RT ⫽ radiotherapy; BED ⫽ biologic effective dose; HA FdUrd ⫽ hepatic artery fluorodeoxyuridine; RILD ⫽ radiation-induced liver disease; TACE ⫽ transcatheter arterial chemoembolization; NA ⫽ not available. * Assessed in 11 patients, including 10 hepatocellular carcinoma and 1 cholangiocarcinoma. † Average tumor dose, daily 1.8 Gy per fraction.
bowel, kidney, colon, and lung are radiation dose–limiting organs, and the liver itself is the most important factor to determine the radiation dose. Therefore, the optimal radiation dose in local RT for HCC is still unclear. To determine the irradiation dose, we must be concerned about the parenchymal disease status of the liver and the volume of the irradiated normal liver. In clinical practices, we excluded the patients with Eastern Cooperative Oncology Group performance status of more than 3 or with liver cirrhosis of Child-Pugh class C. The prescribed dose was determined under the tentative guideline that the irradiated normal liver volume with more than half of the prescription dose should not exceed 50% of the total liver volume. Recently, conformal radiotherapy has been applied for the treatment of HCC, and a dose–volume analysis was done by some researchers to quantify the tolerance of the liver. Dawson et al. (31, 32) estimated that the liver doses associated with a 5% risk of RILD for uniform irradiation of one-third, two-thirds, and the whole liver were 90 Gy, 47 Gy, and 31 Gy, respectively. The authors reported good response rates, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more. The response rate for 25 assessable patients was 68%. Patients treated with more than 70 Gy had a significantly improved median survival compared with those patients treated with less than 70 Gy (p ⫽ 0.0003). On the
other hand, Cheng et al. (27) suggested that a radiation dose ⱖ40 Gy was capable of achieving tumor regression. Park et al. (30) showed the dose–response relationship of local RT for HCC. The response rates with doses ⬍40 Gy, 40 –50 Gy, and ⬎50 Gy were 29.2%, 68.6%, and 77.1%, respectively. In our study, the irradiation dose was correlated with tumor response and in-field failure. Because the fraction size in this study variably ranged from 2 Gy to 3 Gy, we used the BED concept to analyze the radiation dose– response relationship. The BED 50 Gy10, which was a criterion of the radiation dose in this study, biologically corresponded with a radiation dose 42 Gy in a daily fraction of 1.8 to 2.0 Gy. The patients treated with radiation dose ⬎50 Gy10 were irradiated with more than 50 Gy in a daily fraction of 2 Gy or 45 Gy in a daily fraction of 3 Gy. The objective responses were 46.7% in ⱕ50 Gy10 and 72.8% in ⬎50 Gy10. In-field failure was 46.7% in the groups irradiated with ⱕ50 Gy10, but it was 16.9% in patients treated with ⬎50 Gy10. However, the radiation dose escalation could lead to increased radiation-related morbidities. According to Park et al. (30), the rates of RILD and gastrointestinal (GI) complications were increased with doses ⬍40 Gy, 40 –50 Gy, and ⬎50 Gy (RILD: 4.2%, 5.9%, 8.4%; GI: 4.2%, 9.9%, 13.2%, respectively). In this study, RILD and GI complications developed in 3 and 5 patients, respec-
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tively, but there was no relationship between the radiation dose and late complications.
CONCLUSION In conclusion, we show that local RT for unresectable HCC resulted in a tumor response of 66.1% with acceptable toxicity, and the radiation dose and tumor size seem to be significant prognostic factors in RT response for HCC. Tumor responsiveness affects the survival time after RT. However, the optimal radiation dose for HCC is
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not yet conclusive, because the patients in other published reports were heterogenous for their clinical features and treatment modalities, and there have been no randomized controlled studies. The radiation dose escalation may improve treatment results, but complications may also be increased. Therefore, randomized experimental and clinical research is required to define the indication and role of RT combined with nonsurgical modalities for treating unresectable HCC. Also, threedimensional conformal radiotherapy should be applied to escalate the radiation dose and to protect the remaining liver and adjacent organs in local RT for HCC.
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