Long-term survival in patients with hepatocellular carcinoma initially treated with definitive proton beam therapy

Reporting Author: Abigail T. Berman, MD
Last Modified: June 10, 2013

Presenting Author: T. Okumura, MD
Presenting Author Affiliation: University of Tsukuba, Proton Medical Research Center, Tsukuba


  • Hepatocellular carcinoma (HCC) is the 5th most common solid organ cancer and the 3rd most common cause of cancer death with 600,000 deaths annually. The incidence in the United States is rising in parallel to the increasing incidence of Hepatitis C. HCC can arise in the setting of cirrhosis from alcohol, hepatitis, or other idiopathic causes.
  • The local therapies for HCC include surgery, transarterial chemoembolization, RFA, and liver transplantation.
  • Historically, external beam radiation therapy has not been widely used because of concern for radiation induced liver disease (RILD). Proton beam therapy, with its highly conformal SOBP is ideally suited to treatment of only the involved part of the liver.
  • The purpose of this study is to evaluate the efficacy of proton beam therapy as definitive treatment for localized hepatocellular carcinoma.

Materials and Methods

  • Between June 1992 and December 2005, one hundred and fourteen (114) patients with localized HCC were initially treated with proton beam therapy (PBT) alone.
  • All patients had localized HCC and were previously untreated. All lesions were included in the PTV.
  • There were 83 men and 31 women.
  • Ninety-six patients (84%) had hepatitis virus infection with 88 with Hepatitis C, 8 with Hepatitis B, 2 with AL, and 16 with NBNC.
  • The diameter of the tumor ranged from 10 to 135 mm (median: 41.2 mm).
  • The mean tumor number was 1.28 (1-4)
  • Nine patients had portal vein tumor thrombus (Vp2/ 3/ 4 = 3/ 2/ 4).
  • Median AFP was 29 ng/mL (1-115,591).
  • 82 patients were Childs-Pugh A, 24 B, and 8 C. The average was 6.18 (5-12).
  • There were 54 patients who refused other treatment and there were 60 patients who could not be treated by another modality
  • Treatment was given using the following:
    • Real-time tumor localization using fluoroscope
    • Fiducial markers implanted around the tumor
    • Respiratory-gated irradiation
  • Three general treatment protocols (66GyE in 10 fractions for peripheral tumors; 72.6GyE in 22 fractions for central tumors; 77 GyE in 35 fractions for tumors close to the GI system) were applied, depending on tumor location.


  • After median follow up period of 37.3 months (2.3 to 155.3 months), 61 patients were alive and 53 were dead.
  • Overall survival rate (OS) for all the patients was 75.9 % at 3 years and 48.5% at 5 years.
  • OS at 3 years by liver function were 82.7 %, 70.8 %, and 25 % for Child A, B, and C cases, respectively.
  • There was no significant difference in OS by number of tumors (single vs 2-4) or tumor size (< or > 5 cm).
  • Progression-free survival was 42.3% at 3 years for all the patients, although local progression was observed in 10.3 % of the treated tumor.
  • Treatment related morbidity was minimal.
    • No patient discontinued treatment due to acute reactions.
    • 3.2% of patients had grade 3 hematologic toxicity (plt <50,000)
    • Late toxicities included: 3 grade 3 GI toxicities (2.6%), 3 biliary stenosis/biloma (2.6%), and 3 rib fractures (2.6%)

Author's Conclusions

  • These results suggest proton beam therapy can play a role of definitive treatment of patients with localized HCC.
  • The advantage of proton beam therapy is:
    • applicability for patients who are not candidates for standard treatment
    • good local control regardless of numbers of tumor or tumor size

Clinical Implications

  • Historically, external beam radiation therapy has not been used to treat HCC, because of concern for toxicity; at whole liver doses of 28 Gy, the risk of radiation induced liver disease (RILD) increases.
  • However, proton beam therapy, with its highly conformal SOBP is ideally suited to treatment of only the involved part of the liver.
  • Bush, Slater et al. published their phase II study of the safety and efficacy of proton beam therapy for HCC. Patients received 63 Gy delivered over a 3-week period. Out of 67 patients, they found that median progression-free survival for the entire group was 36 months, with a 60% 3-year progression-free survival rate for patients within the Milan criteria. Eighteen patients then underwent liver transplantation; 6 (33%) had a complete pathological response and 7 (39%) showed only microscopic residual (Bush Cancer 2011).
  • This is a well-performed study which shows excellent local local control and a reasonable rate of long-term survival, although measurable risk of adverse events. The median follow up was almost 3 years, which is a reasonable amount of time to have seen disease progression. Although rare, it is important to be aware that thrombocytopenia and GI toxicity are possible. The 3 fractionation schemes employed appear to be reasonable. The authors specifically put emphasis on their motion management, which is critical in proton beam therapy. Additional information regarding which if any patients went on to liver transplantation would have been interesting.
  • Currently, RTOG 1112, a "Randomized Phase III Study of Sorafenib versus Stereotactic Body Radiation Therapy followed by Sorafenib in Hepatocellular Carcinoma" is looking to determine if SBRT improves overall survival in HCC patients treated with sorafenib. Eligible patients include those who are unsuitable for resection or transplant or radiofrequency ablation (RFA); unsuitable for TACE or refractory to TACE; Barcelona Clinic Liver Cancer Stage (BCLC) intermediate (B) or advanced (C).
  • Future directions in proton beam therapy for HCC will focus on:
    • Combination and timing with sorafenib and combination of radiotherapy other local therapies including TACE.
    • Motion management of liver tumors as the proton beam is very sensitive to any small changes due to respiratory motion.
    • Dosimetric studies highlighting which dosimetric parameters may predict for grade 3 GI or hematologic toxicity.


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