Clinical Investigation
Stereotactic Body Radiotherapy for Patients With Unresectable Primary Hepatocellular Carcinoma: Dose-Volumetric Parameters Predicting the Hepatic Complication

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Purpose

To identify the parameters that predict hepatic toxicity and deterioration of hepatic function.

Materials and Methods

A total of 47 patients with small unresectable primary hepatocellular carcinoma received hypofractionated stereotactic body radiotherapy (SBRT) using the CyberKnife. Of those, 36 patients received no other local treatments that could influence hepatic toxicity at least for 3 months after the completion of SBRT. The gross tumor volume (GTV) was 18.3 ± 15.9 cm3 (range, 3.0–81.3 cm3), and the total dose administered was 30–39 Gy (median, 36 Gy). To assess the deterioration of hepatic function, we evaluated the presence or absence of the progression of Child-Pugh class (CP class). To identify the parameters of predicting the radiation-induced hepatic toxicity and deterioration of the hepatic function, several clinical and dose-volumetric parameters were evaluated.

Results

Of 36 patients, 12 (33%) developed Grade 2 or higher hepatic toxicity and 4 (11%) developed progression of CP class. The multivariate analysis showed that the only significant parameter associated with the progression of CP class was the total liver volume receiving a dose less than 18 Gy (<18 Gy).

Conclusions

The progression of CP class after SBRT limits other additional local treatments and also reflects the deterioration of hepatic function. Therefore, it would be important to note that the presence or absence of the progression of CP class is a dose-limiting factor. The total liver volume receiving <18 Gy should be greater than 800 cm3 to reduce the risk of the deterioration of hepatic function.

Introduction

Hepatocellular carcinoma (HCC), which is one of the most common malignant carcinomas worldwide, is a fatal disease that might cause death with severe complications if treated improperly 1, 2. The surgical resection has been considered as the choice of treatment for early-stage HCC. However, many patients are either inoperable or unresectable at the time of diagnosis. In the case of inoperable or unresectable HCC, external radiotherapy (RT), transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) have been used 3, 4, 5, 6, 7.

RT has not been widely used for the treatment of HCC because of the low tolerable dose of radiation for the entire liver, which was not effective for the tumor control 8, 9, 10. However, much literature has reported recently that partial volume irradiation of the liver was feasible and that it was a useful tool for the treatment of HCC within an acceptable range of hepatic toxicity 11, 12, 13, 14, 15. In addition, stereotactic body radiation therapy (SBRT) is now being extended to more patients and clinical targets, and, as a result, several reports have described clinical assessments of the response of HCC to SBRT 16, 17, 18, 19, 20.

Until now, radiation-induced liver disease (RILD) has been considered as a significant limiting factor in the use of RT. Several reports regarding the predicting parameters for RILD have been recently published 21, 22, 23, 24. However, these reports were based on the various definitions of RILD and the clinical data from conventional fractionation. In terms of hypofractionated SBRT, a few reports have been published showing that the normal tissue complication probability (NTCP) and the mean liver dose were predicting parameters 25, 26. Unfortunately, the NTCP and the value of mean dose are not supported by the CyberKnife planning system.

The purpose of our study is to evaluate the hepatic toxicity and deterioration of the hepatic function in patients with small-sized HCC, who were treated with hypofractionated SBRT, and also to identify the predicting parameters of hepatic toxicity and the deterioration of hepatic function.

Section snippets

Patient characteristics

Between April 2004 and May 2007, 47 patients with small unresectable primary HCC received SBRT using the CyberKnife (Accuray Inc, Sunnycale, CA) at the CyberKnife center, the Catholic University of Korea.

Most patients were treated with a combination therapy of SBRT, TACE, RFA, and PEI. To evaluate the hepatic toxicity and the presence or absence of the deterioration of hepatic function resulting from SBRT, we selected only patients who had not received any treatments influencing hepatic

Progression of hepatic toxicity within 6 month after the completion of SBRT

Of 36 patients analyzed, 7 patients (19%) already had Grade 2 hepatic toxicity before SBRT. Of those 7 patients, 4 (11%) had been treated with other local treatments, whereas other 3 (8%) had not been treated with any local treatments. After SBRT, 14 patients (39%) were noted to have Grade 2 or higher hepatic toxicity. Because we intended to evaluate the hepatic toxicity induced by SBRT, we considered a newly developed or progressed hepatic toxicity to a higher grade as significant adverse

Discussion

The classic RILD is defined as subacute hepatic toxicity presenting with anicteric ascites, hepatomegaly, and elevated alkaline phosphatase (10). Although it has been described to occur as early as 2 weeks and as late as 7 months, it typically occurs 4–8 weeks after the completion of RT (27). There has been no effective treatment for RILD to date, except for conservative management using steroids or diuretics. RILD could cause a liver failure if not treated properly, so, it is most important to

Conclusion

We believe that the presence or absence of progression of CP class could be a dose-limiting factor and suggest that the total liver volume receiving a dose less than 18 Gy (rV18Gy) should be >800 cm3 to reduce the risk of the deterioration of hepatic function. The data of predicting parameters derived from the data from the conventional RT are not appropriate to use for patients treated with hypofractionated RT.

Acknowledgments

The statistical analyses performed in this article were advised by Catholic Medical Center Clinical Research Coordinating Center. We thank to Hyeon-Woo, Yim, M.D., Ph.D., and Seung-Hee, Jeong, M.Ph.

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      Citation Excerpt :

      However, sufficient data were available to analyze 2 toxicities: liver enzyme changes and gastrointestinal (GI) toxicity. A variety of endpoints have been used in studies, including progression of the Child-Pugh score (12-14, 20, 21), classic and nonclassic radiation-induced liver disease (RILD) (11, 19, 22), liver enzyme changes (defined as elevation in alanine aminotransaminase or aspartate aminotransaminase) (11-14, 20, 21, 23), and/or Common Terminology Criteria for Adverse Events (CTCAE) grade progression for hepatic, thrombocytopenic, or general GI toxicity. General GI toxicities included fatigue, nausea, diarrhea, gastritis, ulcers, GI area pain, and colitis (9-12, 14, 21-26).

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    Conflicts of interest: none.

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