Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma.
ABSTRACT Hepatocellular carcinoma (HCC) is increasing in incidence and the majority of patients are not candidates for radical therapies. Therefore, interest in minimally invasive therapies in growing.
A Phase I dose escalation trial was conducted at Indiana University to determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary HCC. Eligible patients had Child-Turcotte-Pugh's Class (CTP) A or B, were not candidates for resection, had 1-3 lesions and cumulative tumour diameter less than or equal to 6 cm. Dose escalation started at 36 Gy in 3 fractions (12 Gy/fraction) with a subsequent planned escalation of 2 Gy/ fraction/level. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater toxicity.
Seventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10-42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively.
SBRT is a non-invasive feasible and well tolerated therapy in adequately selected patients with HCC. The preliminary local control and survival are encouraging. A confirmatory Phase II trial is currently open to accrual.
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is on the rise. The primary therapy is resection or liver transplant, but only a minority of patients present with resectable disease. Historically, radiotherapy has not played a significant role in the treatment of liver malignancies because of the low tolerance of the whole liver to radiation. With improvements in 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy, higher doses of radiation can be delivered to target lesions with low doses to the noninvolved liver; thus, experience in the use of radiation for the treatment of focal HCC has increased. At the same time, our understanding of the relationships between radiation dose and volume and the risk of classic radiation-induced liver disease and other toxicities more likely to occur in HCC patients has improved considerably. These developments have led to a body of evidence that now supports the careful use of radiotherapy for unresectable HCC. The rationale for studying radiotherapy in a randomized trial is strong.Seminars in radiation oncology 10/2011; 21(4):271-7. DOI:10.1016/j.semradonc.2011.05.002 · 3.77 Impact Factor
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ABSTRACT: Stereotactic body radiotherapy (SBRT) is a relatively new treatment for liver tumor. Outcomes of SBRT for liver tumors unsuitable for ablation or surgical resection were evaluated. A total of 79 patients treated with SBRT for primary hepatocellular carcinoma (HCC) between 2004 and 2012 in six Japanese institutions were studied retrospectively. Patients treated with SBRT preceded by trans-arterial chemoembolization were eligible. Their median age was 73 years, 76% were males, and their Child-Pugh scores were Grades A (85%) and B (11%) before SBRT. The median biologically effective dose (α/β = 10 Gy) was 96.3 Gy. The median follow-up time was 21.0 months for surviving patients. The 2-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival were 53%, 40% and 76%, respectively. Sex and serum PIVKA-II values were significant predictive factors for OS. Hypovascular or hypervascular types of HCC, sex and clinical stage were significant predictive factors for PFS. The 2-year PFS was 66% in Stage I vs 18% in Stages II-III. Multivariate analysis indicated that clinical stage was the only significant predictive factor for PFS. No Grade 3 laboratory toxicities in the acute, sub-acute, and chronic phases were observed. PFS after SBRT for liver tumor was satisfactory, especially for Stage I HCC, even though these patients were unsuitable for resection and ablation. SBRT is safe and might be an alternative to resection and ablation. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.Journal of Radiation Research 02/2015; 56(3). DOI:10.1093/jrr/rru130 · 1.69 Impact Factor
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ABSTRACT: Objective Individualized dose prescription for liver stereotactic body radiotherapy (SBRT) requires effective volume calculation and biological modeling to estimate the risk of liver injury. This study determined dose-volumetric (DV) parameters associated with low risk for radiation-induced liver disease (RILD) derived from normal tissue complication probability (NTCP) modeling with three-fraction and five-fraction SBRT for hepatocellular carcinomas (HCCs) > 5 cm. Methods Prescription dose was 24–36 Gy in three fractions and 40–45 Gy in five fractions. Effective volume was determined for 20 liver SBRT plans using the linear-quadratic (LQ) equation. Lyman-Kutcher-Burman NTCP model estimated the risk of liver toxicity. Mean dose to normal liver (MLD) was tabulated from plans associated with < 6 % toxicity prediction. Sensitivity analysis of model parameters and DV relationships to critical volume constraints was performed. Results Median normal liver volume was 1144 cm3 (710–2916 cm3) and the median planning target volume (PTV) was 633 cm3 (186–2388 cm3). MLD predicting low hepatic toxicity for three-fraction SBRT plans was 13.8 ± 0.6 Gy, while MLD from five-fraction SBRT plans was 16.1 ± 1.0 Gy. Lower n, α/β, and D 50 parameters and a higher m parameter increased %RILD, and vice versa. An estimated 1200 cm3 of normal liver was needed in 7 of 10 three-fraction plans for very large tumors to functionally preserve 700 cm3and 800 cm3 to ≤ 15 and ≤ 18 Gy, respectively. Conclusions MLD values derived for three-fraction and five-fraction SBRT by the NTCP method were consistent with established SBRT liver dose constraints. However, SBRT for large hepatocellular carcinomas may be limited by critical volume dose objectives.04/2015; 4(2):177-184. DOI:10.1007/s13566-015-0195-6