Hepatocellular carcinomas (HCC) are highly lethal. In 2011 an estimated 26,190 new cases and 19,590 tumour related deaths occurred in the USA . Increased incidences are mostly related to liver cirrhosis , viral hepatitis (B,C) [83,84] and mycotoxin aflatoxin . Next to tumour stage, serum protein AFP, performance status, liver function and the presence of cirrhosis influence the prognosis. For medical operable patients with localized disease, surgery is the treatment of choice . An analysis of more than 400 preselected patients who received partial hepatectomy revealed an actuarial 5-year survival of 30 – 40% . Alternatively performed liver transplantation  did not improve outcome, yielding a 5-y OS of 20-30% for selected patients . Also several other methods are under investigation, among them radiofrequency ablation, chemoembolization (TACE), cryosurgery, percutaneous ethanol injection and targeted therapy [89-94].
Treatment strategy of conventional radiotherapy
HCC is a radiosensitive tumour , but liver as well as adjacent organs at risk have also a low radiation tolerance and therefore the conventionally applicable X-ray dose is limited [9,37]. RT is used for palliation or in curative intent for medically inoperable patients. High conformal radiation techniques like stereotactic body radiotherapy (SBRT) with gating/breath holding improved the delivery of tumoricidal doses to patients with unresectable hepatocellular carcinoma for primary treatment intent or to bridge time interval to liver transplantation [96-98]. For larger unresectable tumours (5cm or more) a combination of TACE and conformal radiotherapy showed promising results [99-101]. Treatment planning is performed on axial CT datasets. Image fusion with diagnostic MRI of the liver in treatment position can be performed to enhance tumour definition. Implantation of fiducial markers may be used for gating to increase visibility of organ motions in order to reduce internal target volume (ITV). Target volume encompasses gross tumour volume. Margins vary institutionally depending on the delivery precision of the available technique. Treatment dose protocols are under investigation [102,103]. To keep the rate of severe radiation induced liver disease (RILD) below 5%, the whole liver mean dose should be below 30-32 Gy when treated with 3D-CRT and >700cc of healthy liver tissue should have a maximum dose below 15 Gy for hypofractionated SBRT .
Treatment outcome of conventional radiotherapy
For tumours below 6cm diameter SBRT was well tolerated, yielding positive response rates of 90-100% (SD, PR, and CR) and a 2-year OS of 60-67% [102,104,105]. Patients with liver-confined disease who were treated with conformal RT or image guided RT with or without TACE achieved local control response rates from 40% to 90%. Median survival ranged from 10 to 25 months (mos). For patients with HCC who had portal vein thrombosis, the median survival after RT with or without TACE ranged from 5.3 to 9.7 mos . Pain reduction was observed in approximately 75% of patients with bone metastases from HCC who received palliative RT .
Therapeutical gap between conventional radiotherapy and ion beam therapy
Since tolerance of liver and adjacent organs to radiation is known to be poor [9,37], the ability of PBT to deliver highly conformal radiation has early been recognized as potential benefit. In 1994 a Japanese trial surveyed 32 patients with unresectable HCC treated with a median dose of 76.6 Gy alone or in combination with chemotherapy. Positive tumour response was seen in 92% and 100% of patients, respectively. Treatment was considered well tolerated . Another series of Japanese studies observed patients with poor performance status, multiple co-morbidities and unresectable HCC. Tumour was treated with either 24 Gy radiosurgery or 63-84 Gy in 3 fractions. Positive response was seen in up to 80% and progression free survival was up to 2.3 years. Patients eligible to receive repeated PBT in case of relapse reached a median survival of 5.2 years [107-109]. In 2011 the Kobe group published long term results comparing proton beam and carbon ion therapy of HCC. 343 patients who received 52.0 to 84.0 GyE of either one modality were surveyed. Results for protons and carbon ions were equivalent. 5-year control rate for proton and carbon therapy was 90.2% and 93%, respectively and the 5-year overall survival rates were 38% and 36.3%. Multivariate analysis identified tumour size as the only independent risk factor for local recurrence and Child-Pugh classification as the only independent risk factor for overall survival. No patient died of treatment-related toxicities . Next to cirrhosis and large tumour size, other publications considered portal vein thrombosis and adjacency of HCC location to the alimentary tract as negative predictive factors for treatment outcome and tolerance [111-113]. SBRT and PBT have both been tolerated well. 5-year overall survival after PBT pars with results of operation, even though most of the patients were medically inoperable or tumour was unresectable. Repeated salvage PBT for eligible patients yielded a median survival of 5.2 years, while only 20-30% of transplanted patients survived 5 years or more. SBRT achieved good results according to response rate and local control after 2 years, but experience is still young and long term results are under evaluation. Even though preliminary results are promising, optimal treatment dose remains to be defined and validation of clinical experience sets the need for prospective studies.
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