External Beam Radiation Therapy For Unresectable Hepatocellular Carcinoma: An International Multicenter Phase I Trial, Sakk 77/07

To assess the feasibility and safety of conventionally fractionated radiation therapy (cfRT) in patients with hepatocellular carcinoma (HCC). This is a phase I multicenter clinical trial for patients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh score (CP) A or B disease. Metastatic HCC was allowed if ≥90% of total tumor volume was located within the liver. Patients were to be enrolled onto five dose-escalation levels (from 54-70Gy in 2Gy fractions) based on a modified 3 + 3 design. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and 9 laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1-3, and ≤10% in dose levels 4-5. Best objective response of target liver lesions and adverse events were assessed as secondary endpoints. The trial was terminated early due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary endpoint and 18 for the secondary endpoints. Median age was 69 years (range 45-82y). Twelve patients had CP A and three patients CP B disease. A total of 15 lesions were treated. Median size was 70mm (range 18-186 mm). Median follow-up was 11.8 months. The maximum tolerated dose was not reached, due to early trial termination. One of 6 patients in dose level 1 and 1 of 6 patients in dose level 2 experienced DLTs (lipase > 5xULN and neutrophils <500/μL). Both, dose level 1 and 2 each, had a DLT among the first 3 patients, requiring additional 3 patients at the same dose level as per protocol. However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients. Overall, 56% of patients had a partial response and 28% showed stable disease of the treated liver lesions according to RECIST criteria. No patient experienced > grade 2 acute or late gastrointestinal toxicity. No signs of radiation induced liver disease (RILD) occurred. Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact. The maximum tolerated dose could not be determined. Conventionally fractionated RT of at least 62Gy can be considered as safe for patients with HCC. Higher dose levels need investigation. External beam RT within multimodal treatment concepts merits controlled trials.