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Japanese Journal of Clinical Oncology Advance Access originally published online on May 21, 2008
Japanese Journal of Clinical Oncology 2008 38(6):438-444; doi:10.1093/jjco/hyn038
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© The Author (2008). Published by Oxford University Press. All rights reserved

Three-dimensional Conformal Radiotherapy for Hepatocellular Carcinoma with Inferior Vena Cava Invasion

Hiroshi Igaki1, Keiichi Nakagawa1, Kenshiro Shiraishi1, Shuichiro Shiina2, Norihiro Kokudo3, Atsuro Terahara1, Hideomi Yamashita1, Nakashi Sasano1, Masao Omata2 and Kuni Ohtomo1

1 Departments of Radiology
2 Gastroenterology
3 Hepato-Biliary-Pancreatic Surgery, The University of Tokyo Hospital, Tokyo, Japan

For reprints and all correspondence: Hiroshi Igaki, Department of Radiology, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: igaki-tky{at}umin.ac.jp

Received February 25, 2008; accepted April 24, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 References
 
Background: Hepatocellular carcinoma with inferior vena cava invasion is a rare but fatal condition of disease progression. The aim of this study was to analyze the results of treatment for hepatocellular carcinoma with inferior vena cava invasion by three-dimensional conformal radiation therapy.

Methods: From 1990 to 2006, 18 histopathologically confirmed hepatocellular carcinoma patients with inferior vena cava invasion who were unsuitable for surgery were treated by three-dimensional conformal radiation therapy at our hospital with two to four static or dynamic conformal arc fields.

Results: A median total tumor dose of 50 Gy (range 30–60 Gy) was delivered. The progression-free rate was 91.6% among the patients in whom follow-up computed tomography was obtained. Actuarial survival at 1 year was 33.3%, and the median survival period was 5.6 months.

Conclusions: Three-dimensional conformal radiation therapy might offer a chance of long survival for a part of the hepatocellular carcinoma patients with inferior vena cava invasion, since a third of such patients survived more than a year. Additional treatments should be considered to prevent distant metastases and hepatic functional deterioration after three-dimensional conformal radiation therapy.

Key Words: hepatocellular carcinoma • inferior vena cava • three-dimensional conformal radiation therapy • hepatic functional reserve • liver cirrhosis


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 References
 
Hepatocellular carcinoma (HCC) is the eighth major cause of cancer death in the United States and the third in Japan (1,2). Local ablative therapies such as hepatectomy, radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) should be administered, if possible, to patients with limited extension of HCC. But when the tumor invades the inferior vena cava (IVC), these treatments are indicated only for very few patients. In some reports, a part of these patients can survive long by hepatic resection combined with IVC resection (3–5). But such aggressive surgeries are not suitable for most patients, and other treatment modalities are also restricted not only by poor hepatic function, but also frequently by extensive disease progression. Transcatheter arterial chemoembolization (TACE) is often tried in HCC patients with IVC invasion for whom ablative treatment is unsuitable. However, TACE rarely achieves local tumor control to prolong survival periods sufficiently in such a critical condition, although the efficacy of this treatment has been proven in meta-analyses (6,7).

A few decades ago, liver was assumed to be a highly radiosensitive organ that was unsuitable for high-dose radiotherapy. But recent progress in radiation oncology has enabled us to concentrate high-dose radiation on liver tumors while preserving hepatic function after treatment (8–15). In addition, some institutions apply stereotactic radiotherapy to solitary small liver tumors. Consequently, radiotherapy has come to play an important role in multidisciplinary treatment of HCC.

At our institution, three-dimensional conformal radiation therapy (3D-CRT) has been the primary treatment strategy for HCC with portal vein invasion, and has achieved good clinical results (9). As with the treatment of HCC patients with portal vein invasion, radiotherapy is considered for HCC patients with IVC invasion at our institution if they are unsuitable for surgery. But there are few reports on radiotherapy for such patients (16), and the natural course of such conditions is not well known. In the present study, we retrospectively reviewed the medical records of HCC patients with IVC invasion and analyzed the efficacy of radiotherapy in these patients.


   METHODS
TOP
 Abstract
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 References
 
From 1990 to 2006, 18 HCC patients with IVC invasion were treated by radiotherapy at our hospital. Their clinical courses and treatment results were retrospectively reviewed. HCC was diagnosed by using ultrasonography, computed tomography (CT), angiography and liver biopsy. In each patient, the diagnosis was confirmed histopathologically. IVC invasion was defined by a low-attenuation mass that protruded into the intraluminal space of IVC on enhanced CT and/or detection of pulsatile flow in IVC thrombi by Doppler ultrasonography. The patients' characteristics are shown in Table 1.


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  		Table 1. Patient characteristics

 
Patients with liver cirrhosis of Child–Pugh class C were not indicated for the treatment. CT-based radiotherapy treatment planning was made for all patients by the following treatment planning systems, RPS700U(3D) (Mitsubishi Electric Co., Tokyo, Japan) or Pinnacle3 (Philips/ADAC, Milpitas, CA, USA). Clinical target volume was contoured on serial CT images with a 0.5–1-cm margin around the gross tumor volume, covering IVC-protruding tumor as well as the primary tumor invading to the IVC. Other co-existing intrahepatic tumors which had no continuity to the IVC-invading tumor were not included in the clinical target volume, and managed by other treatment modalities. Planning target volume was determined by a 0.5–2.0-cm margin around the clinical target volume. A dynamic conformal arc or two to four static ports were used for irradiation. In earlier periods, dynamic conformal arc therapy or multi-port (mainly four ports) treatment plans were used, and we could not obtain dose-volume histograms in the treatment-planning machine. In recent years, treatment plans using two opposed fields have been preferred, because such treatment enables the maximization of the non-irradiated volume of the normal liver tissue. This treatment planning strategy is based on the fact that the normal liver tissue tolerance is lower in patients with viral hepatitis and liver cirrhosis than in healthy patients (8). The general principle of treatment planning was to keep V30, which was defined as the percent volume of the liver exceeding 30 Gy, lower than 30% of the whole liver volume minus tumor volume. We aimed for a total tumor dose of 50–60 Gy in conventional fractionation, but allowed smaller doses according to the dose-volume histogram of the normal liver at the physician's discretion. X-rays were delivered by linear accelerators ML15-MDX (Mitsubishi Electric Co., Tokyo, Japan) or CRS-6000 (Mitsubishi Electric Co., Tokyo, Japan). Written informed consent was obtained from the patients before treatment.

Follow-up and survival periods were calculated from the first day of radiation therapy. Actuarial survival rates were calculated by the Kaplan–Meier method. The statistical significance between groups was assessed with the log-rank test. Differences were considered statistically significant when P < 0.05.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 Funding
 References
 
All patients tolerated the treatment well. No severe complications were observed during the treatment period. The total tumor dose ranged from 30 to 60 Gy, with a median dose of 50 Gy (Table 2). All patients were followed until death except for the three patients who were alive at the time of analysis. Other treatment variables and results are summarized in Table 2.


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  		Table 2. Treatment-related variables and results

 
Treatment response was defined as the tumor status at the last follow-up CT (Table 2). The response rate (complete response + partial response) and progression-free rate (complete response + partial response + stable disease) were 33.3% (95% confidential interval: 6.7–60.0%) and 91.6% (95% confidential interval: 75.9–100%), respectively, among the 12 patients for whom follow-up CTs were obtained. Only one patient developed local progression of the IVC-invading tumor within 6 months after 3D-CRT, and this was determined to be a progressive disease. This patient started systemic chemotherapy with 5-fluorouracil and interferon after diagnosis of a progressive disease, and was alive at the time of this analysis with no further progression of the tumor after introduction of this chemotherapy, 26.2 months after treatment. In the remaining 11 patients, no tumor regrowth was observed within the irradiated volume at the last follow-up.

At the time of the last follow-up, three patients were alive and the others were dead. Actuarial survival rate was 33.3% at 1 year, with a median survival period of 5.6 months (Fig. 1). The causes of death are shown in Table 2. The Child–Pugh class A group tended to survive longer than the class B group, but the difference did not reach statistical significance level (7.8 months versus 3.3 months, P = 0.136, Fig. 2 and Table 3). The survival period did not differ between responders (complete response + partial response) and non-responders (stable disease + progressive disease) (Fig. 3 and Table 3). Older patients (70 years or older) and patients with hepatitis C virus tended to survive longer than the other patients, but the differences were also not statistically significant (Fig. 4). The median survival periods were 7.8 and 3.3 months for the groups 70 years or older and under 70 years, respectively (P = 0.064). The median survival periods of the patients with HCV carriers and other etiologies were 7.8 and 3.7 months, respectively (P = 0.111). A representative case is shown in Fig. 5.


Figure 1
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  		Figure 1. Overall survival of the whole group of 18 patients.

 

Figure 2
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  		Figure 2. Overall survival by pre-treatment hepatic functional reserve.

 

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  		Table 3. Univariate analysis of potential prognostic factors

 

Figure 3
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  		Figure 3. Overall survival by treatment response.

 

Figure 4
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  		Figure 4. Overall survival by age (left panel) or etiology (right panel).

 

Figure 5
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  		Figure 5. A representative case of a 72-year-old male with Child–Pugh class A hepatic function (case 12 in the Tables 1 and 2). (a) Before radiotherapy, the tumor located in S7 extended to IVC and the intraluminal space was narrow in the CT images. The tumor was indicated by the red arrowhead. (b) Dose distribution of the treatment plan. A total tumor dose of 50 Gy was delivered in 25 fractions by a dynamic conformal arc with four static fields. (c) Three months after radiotherapy. S7 tumor disappeared and no enhancement defect was observed within IVC, and the treatment response was judged as a complete response. The patient died of hepatic failure 13.7 months after irradiation. The irradiated tumor had no sign of regrowth at the time of death. (A colour version of this figure is available as supplementary data at http://www.jjco.oxfordjournals.org.)

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 Funding
 References
 
HCC with IVC invasion is difficult to treat and associated with poor prognosis, because of its inherent nature of serious condition of the disease and the limited availability of treatment strategies. We have treated such patients by 3D-CRT, and here reviewed their treatment results retrospectively.

The literature offers no detailed data on the natural history of HCC with IVC invasion. But vascular invasion from HCC has been associated with miserable prognoses (16–18) and a limited life expectancy of 2–3 months, if untreated. However, Mizumoto et al. (19) reported good clinical results of proton beam therapy in patients with HCC invading to the IVC. All three of the patients they treated lived more than a year after this therapy.

The prognosis of patients with HCC is known to be dependent on the hepatic functional reserve (20,21). Our results are consistent with this knowledge, because the median survival of Child–Pugh class A patients was slightly longer than that of class B patients (Fig. 2). On the other hand, treatment response did not influence patients' survival periods (Fig. 3). But the treatment response after radiotherapy is predictive of survival in the curative treatment settings in many primary cancer sites (22–24). There are three possible explanations for this: (i) a relatively long period (typically several months) is required for tumor shrinkage after radiotherapy, considering the median survival periods of these patients; (ii) fatal deterioration of hepatic function can be seen, owing to the damage to normal liver tissue as a result of radiotherapy; (iii) it is sometimes difficult to distinguish the tumor thrombus from blood clots adhering to the IVC-invading tumor on follow-up CT images; and (iv) the group in this analysis was too small for statistical differences. Older age was a marginally significant prognostic factor in our results (Fig. 4). Age as a prognostic factor, however, is controversial in the literature, because older age might sometimes be a favorable prognostic factor in some conditions but an unfavorable one in others (25–27).

In our experience, six patients died of liver failure. Of these six, three were assumed to be owing to the intrahepatic tumor growth from their clinical courses, and the other three were brought by undetermined causes. We could not differentiate the natural course of cirrhosis from treatment-related liver failure exactly. In this respect, we could not exclude the possibility of the treatment-related morbidities in Cases 5, 8 and 10 in Tables 1 and 2 with liver failures, although there had been no case with clinically apparent radiation-induced liver disease (RILD). In addition, there is no denying that the rupture of esophageal varix and the pulmonary embolization have occurred irrelevant to 3D-CRT or other treatments in Cases 6 and 13. But after 3D-CRT, 33.3% of our patients survived more than a year. In this respect, our 3D-CRT appeared to offer a chance to survive more than a year for a third of the patients with such critical conditions, although the median survival period was not satisfactory. The reason for such unsatisfactory results included the high incidence of deaths due to metastatic disease or liver failure despite the good progression-free rate of 91.6% for the irradiated IVC-invading tumor.

To minimize the probability of radiotherapy-related liver failure, treatment strategies have been improved (28,29). Despite these efforts, RILD can sometimes occur typically 2 weeks to 4 months after hepatic irradiation, and the threshold for RILD is reported to be 31 Gy of mean liver dose (29). Moreover, 50–76% of the patients who developed RILD died of this complication (30,31). Considering these situations, 3D-CRT has a potential benefit over the conventional two-dimensional radiotherapy in the viewpoint of normal liver protection. This point, however, has not been demonstrated in the previous literature to the best of our knowledge.

Some institutions adopt stereotactic body radiotherapy by multi-port irradiation technique. But the volume of low-dose-irradiated normal liver tissue is increased by the multi-port irradiation, especially when the clinical target volume is large. Radiation tolerance of the non-cancerous liver with chronic viral hepatitis or cirrhosis is known to be lower than that of healthy liver (29). We have a hypothesis that two opposed fields radiotherapy might be more protective than multiple-port radiotherapy for the cirrhotic liver. This is why we changed the 3D-CRT strategy from multiple-port irradiation to two opposed fields irradiation. We are now under investigation of the effect of treatment strategy on the survival or on the risk of RILD.

Follow-up CT could not be obtained for six patients. This might be attributable in part to early deterioration in performance status, since all six died within 8 months after treatment. It is possible that disease control was not achieved in these patients and that the progression-free rate of 91.6% was thus overestimated. In this respect, additional treatments should be considered as many patients developed distant metastases or hepatic functional deterioration shortly after 3D-CRT.


   CONCLUSIONS
TOP
 Abstract
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
Funding
 References
 
A part of the HCC patients with IVC invasion might have benefited from 3D-CRT and a third of such patients had had a chance of surviving more than a year; otherwise they could not have survived long with this progressive fatal disease. However, further treatment should be considered to prevent distant metastasis and to protect post-treatment hepatic function, because the majority of the patients died from metastatic diseases or liver failure in spite of good local tumor control by 3D-CRT.


   Funding
TOP
 Abstract
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
References
 
This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan (18790877 to H.I.).

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 References
 
1 Surveillance Epidemiology and End Results NCI, US National Institute of Health [homepage on the Internet]. Summary of changes in cancer mortality, 1950–2004 and 5-year relative survival rates, 1950–2003 [cited 2008 February 26]. Available format: http://seer.cancer.gov/csr/1975_2004/results_single/sect_01_table.03.pdf.

2 Center for Cancer Control and Information Services, National Cancer Center, Japan [homepage on the Internet]. Graph database, Cancer information service for medical staff [cited 2008 February 26]. Available at: http://ganjoho.ncc.go.jp/pro/statistics/en/graph_db_index.html.

3 Arii S, Teramoto K, Kawamura T, Takamatsu S, Sato E, Nakamura N, et al. Significance of hepatic resection combined with inferior vena cava resection and its reconstruction with expanded polytetrafluoroethylene for treatment of liver tumors. J Am Coll Surg (2003) 196:243–9.[CrossRef][Web of Science][Medline]

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5 Hemming AW, Reed AI, Langham MR Jr, Fujita S, Howard RJ. Combined resection of the liver and inferior vena cava for hepatic malignancy. Ann Surg (2004) 239:712–9. discussion 719–21.[CrossRef][Web of Science][Medline]

6 Cammà C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology (2002) 224:47–54.[Abstract/Free Full Text]

7 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology (2003) 37:429–42.[CrossRef][Web of Science][Medline]

8 Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol (2005) 15:279–83.[CrossRef][Web of Science][Medline]

9 Nakagawa K, Yamashita H, Shiraishi K, Nakamura N, Tago M, Igaki H, et al. Radiation therapy for portal venous invasion by hepatocellular carcinoma. World J Gastroenterol (2005) 11:7237–41.[Medline]

10 Huang CJ, Lian SL, Chen SC, Wu DK, Wei SY, Huang MY, et al. External beam radiation therapy for inoperable hepatocellular carcinoma with portal vein thrombosis. Kaohsiung J Med Sci (2001) 17:610–4.[Medline]

11 Tazawa J, Maeda M, Sakai Y, Yamane M, Ohbayashi H, Kakinuma S, et al. Radiation therapy in combination with transcatheter arterial chemoembolization for hepatocellular carcinoma with extensive portal vein involvement. J Gastroenterol Hepatol (2001) 16:660–5.[CrossRef][Web of Science][Medline]

12 Ishikura S, Ogino T, Furuse J, Satake M, Baba S, Kawashima M, et al. Radiotherapy after transcatheter arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Clin Oncol (2002) 25:189–93.[CrossRef][Web of Science][Medline]

13 Yamada K, Izaki K, Sugimoto K, Mayahara H, Morita Y, Yoden E, et al. Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys (2003) 57:113–9.[CrossRef][Web of Science][Medline]

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19 Mizumoto M, Tokuuye K, Sugahara S, Hata M, Fukumitsu N, Hashimoto T, et al. Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases. Jpn J Clin Oncol (2007) 37:459–62.[Abstract/Free Full Text]

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