Proton Beam Therapy for Hepatocellular Carcinoma Patients with Severe Cirrhosis

Masaharu Hata 1 2 Koichi Tokuuye 1 2 Shinji Sugahara 1 Nobuyoshi Fukumitsu 1 2 Takayuki Hashimoto 1 2 Kayoko Ohnishi 1 Keiko Nemoto 1 Kiyoshi Ohara 1 Yasushi Matsuzaki 0 Yasuyuki Akine 1 2 0 Department of Gastroenterology and Hepatology, University of Tsukuba , Tsukuba, Ibaraki, Japan 1 Department of Radiation Oncology, University of Tsukuba , Tsukuba, Ibaraki, Japan 2 Proton Medical Research Center, University of Tsukuba , Tsukuba, Ibaraki, Japan Background and Purpose: Hepatocellular carcinoma (HCC) patients with severe cirrhosis are usually treated with supportive care because of their poor prognosis. However, the survival of severe cirrhotic patients has recently improved due to advanced treatments. The aim of this study was to define the role of proton beam therapy for HCC patients with severe cirrhosis. Patients and Methods: 19 HCC patients with Child-Pugh class C cirrhosis received proton beam therapy. The hepatic tumors were solitary in 14 patients and multiple in five, and the tumor size was 25-80 mm (median 40 mm) in maximum diameter. No patient had regional lymph node or distant metastasis. Total doses of 50-84 Gy (median 72 Gy) in ten to 24 fractions (median 16) were delivered to the tumors. Results: Of the 19 patients, six, eight and four died of cancer, liver failure and intercurrent diseases, respectively, during the follow-up period of 3-63 months (median 17 months) after treatment. A remaining patient was alive with no evidence of disease 33 months after treatment. All but one of irradiated tumors were controlled during the follow-up period. Ten patients had new intrahepatic tumors outside the irradiated volume. The overall and progression-free survival rates were 53% and 47% at 1 year, respectively, and 42% each at 2 years. Performance status and Child-Pugh score were significant prognostic factors for survival. Therapy-related toxicity of grade 3 or more was not observed. Conclusion: Proton beam therapy for HCC patients with severe cirrhosis was tolerable. It may improve survival for patients with relatively good general condition and liver function. - Introduction Currently, hepatocellular carcinoma (HCC) patients can be effectively treated with various modalities, i.e., surgical resection, transcatheter arterial embolization (TAE) and infusion chemotherapy (TAI), percutaneous ethanol injection (PEI) and microwave coagulation (PMC), and radiofrequency ablation (RFA) [16]. However, these treatment modalities are often unsuitable for patients with severe cirrhosis because of the potential risk of liver failure or bleeding; furthermore, their prognosis is poor due to severe cirrhosis [8]. Therefore, HCC patients with severe cirrhosis are usually treated with palliative or supportive care [3]. At our institute, University of Tsukuba, Japan, proton beams have been employed in treatment for a variety of malignancies including HCC since 1983 [4, 11, 19, 30]. Proton beam irradiation yields theoretically excellent dose localization to the target due to sharp distal fall-off of the Bragg peak compared with photon irradiation, and consequently can reduce the irradiated volume and dose given to the hepatic parenchyma and digestive tract for HCC patients, while increasing the dose to the tumor [12, 21, 26, 28]. Tabelle 1. Patienten- und Tumorcharakteristika. HBV: Hepatitis-BVirus; HCV: Hepatitis-C-Virus; AFP: -Fetoprotein. We present herein the treatment results of proton beam therapy for HCC patients with severe cirrhosis. Patients and Methods Patients Between November 1990 and January 2000, 197 HCC patients received proton beam therapy. Of these patients, 19 had severe cirrhosis categorized as Child-Pugh class C at the initiation of proton beam therapy [25]. All patients were inoperable, and TAE and TAI were contraindicated due to the potential risk of liver failure. PEI, PMC and RFA were unfeasible because of bleeding tendency, large-sized tumors, or unfavorable tumor location. There were no other available treatment modalities for these patients. Exclusion criteria for proton beam therapy included extrahepatic metastasis, diffusely infiltrated tumor, and poor general condition of the Eastern Cooperative Oncology Group (ECOG) performance status 3 [23]. HCCs were diagnosed histopathologically by biopsy in eight patients, and clinically by medical imaging; contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), and elevated serum -fetoprotein (AFP) values in eleven patients. None had regional lymph node enlargement or distant metastasis. 14 and five patients were diagnosed clinically as stage I (T1 N0 M0) and stage II (T2 N0 M0), respectively, based on the TNM classification defined by the International Union Against Cancer (UICC), at the time of proton beam irradiation [27]. Patient and tumor characteristics are summarized in Table 1. Written informed consent was obtained from all patients before initiation of proton beam therapy. Proton Beam Therapy Metallic fiducial markers for proton beam therapy were implanted percutaneously into the hepatic parenchyma beside the tumors. Treatment planning for proton beam therapy was based on CT images at 5-mm intervals in the treatment position. Clinical target volume (CTV) was defined as gross tumor volume plus 5-mm margin. Planning target volume, which included CTV with 5-mm margin, was homogeneously set at the 100% dose level by utilizing the spread-out Bragg peak (SOBP) of proton beams (Figure 1). Multiple hepatic tumors, which were observed in five patients, were entirely included within the target volume. Proton beams generated by a booster synchrotron of the High Energy Accelerator Research Organization were degraded to 250 MeV for clinical use. The beams synchronized with respiration were delivered through the horizontal or vertical port for treatment. Respiratory gating was controlled by means of a strain gauge (Kyowa Electronic Instruments, Tokyo, Japan) attached to the abdominal surface of the patients, so that proton beams were delivered to the tumors in expiratory phase when the tumor position was considered to be most stable and reproducible [13, 22]. For each treatment Figure 1. Isodose distribution with the anterior and right lateral proton beams in a hepatocellular carcinoma patient with severe cirrhosis. Each isodose line corresponds to 90%, 50%, 30%, and 10% dose levels from the inside out, respectively. The critical organs such as the spinal cord and the digestive tracts are located entirely outside the irradiated volume due to sharp distal fall-off of the Bragg peak of proton beams. Abbildung 1. Isodosenverteilung bei anteriorem und lateralem Protonenstrahl bei einem Patienten mit Leberzellkarzinom und schwerer Zirrhose. Jede Isodosenlinie von innen nach auen entspricht jeweils 90%, 50%, 30% und 10%. Die kritischen Organe wie das Rckenmark und der Verdauungstrakt liegen wegen des scharfen distalen Abfalls der Bragg-Spitze des Protonenstrahls vollstndig auerhal (...truncated)