Short-Course Carbon Ion Radiotherapy for Hepatocellular Carcinoma: Phase I/II and Phase II Clinical Trials

Purpose: To evaluate the toxicity and anti-tumor effect of short-course carbon ion radiotherapy for hepatocellular carcinoma (HCC).Patients and Methods: Eighty-two patients with 86 histologically proven HCCs with liver cirrhosis were enrolled onto the phase I/II study of short-course carbon ion radiotherapy from April 1997 to February 2001. Fifty-two lesions (60%) were recurrent tumors after other therapies. Thirty-eight (44%) were Stage II, 35 (41%) Stage IIIA and 13 (15%) Stage IVA. Child-Pugh grade was A in 69 (81%), B in 14 (16%) and not evaluable in 3. Median tumor size was 4.0 (1.2-12.0) cm in diameter. Thirty-four lesions were treated with 12 fractions / 3 weeks, 24 with 8 fractions / 2 weeks, 28 with 4 fractions / 1 week. A dose escalation study was carried out by fraction dose increments of 10 %. Total doses ranged from 54.0 to 69.6 GyE in 12 fractions, 48.0 to 58.0 GyE in 8 fractions and 48.0 to 52.8 GyE in 4 fractions. Forty-four patients with 47 lesions associated with chronic hepatitis or liver cirrhosis were enrolled onto the phase II study of 4-fraction carbon ion radiotherapy from April 2001 to February 2003. In this report, the subjects were 36 patients with 36 lesions whose follow-up periods were longer than 1 year. Fifteen (42%) had recurrent tumors. Seven (19%) were Stage II, 11 (31%) Stage IIIA and 18 (50%) Stage IVA. Child-Pugh grade was A in 28 (78%) and B in 8 (22%). Median tumor size was 3.9 (1.2-7.5) cm in diameter. A fraction dose was fixed at 13.2 GyE, and four fractions were given within 1 week. Common Toxicity Criteria, RTOG/EORTC criteria and Child-Pugh score were used for evaluation of toxicity. Anti-tumor effect was evaluated in terms of cumulative local control and survival rates.Results: In both studies, no severe adverse effects and no treatment-related deaths occurred during a median follow-up of 54 (30-75) months and 20 (12-27) months, respectively. Within 3 months after the start of therapy (early phase), no change or only a 1-point increase in the Child-Pugh score was observed in 95% and 91% of the subjects, respectively. Within 3 to 12 months after (late phase), similar observations were made in 78% and 83%, respectively. The score never increased by more than 2 points except for 3 patients (5%) in the late phase in the former study. In the former study, local control rates were 93% and 87% at 1 and 2 to 3 years, respectively. Overall survival rates were 89%, 70% and 47% at 1, 2 and 3 year, respectively. In the latter study, local control rates were 97% and 83% at 1 and 2 year, respectively. Overall survival rates were 92% and 85% at 1 and 2 year, respectively.Conclusion: Short-course carbon ion radiotherapy has preliminarily proved to be safe and effective for patients with HCC. However, further long-term observation will be needed to confirm its therapeutic efficacy.2004 Gastrointestinal Cancers Symposiu