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Monday, March 4, 2019

Proton Beam Therapy Outcomes for Localized Unresectable Hepatocellular Carcinoma

Clinical question 
What is the safety and efficacy of PBT for the treatment localized and unresectable HCC?

Take away point
PBT appears to show acceptable local control (81%) and overall survival (62%) at 2 years, with improved outcomes when the effective dose is over 90 GyE.

Study design
Retrospective review of 46 patients

Funding Source
MD Anderson Cancer Center Support grant, John E. and Dorothy J. Harris Endowed Professorship.

MD Anderson Cancer Center

Click here for abstract

Chadha AS, Gunther JR, Hsieh CE, et al. Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma. Radiotherapy and Oncology, 2019, 133, 54-61.


The authors evaluated the safety and efficacy of Proton Beam therapy (PBT) in localized HCC patients that were not surgical candidates. Patients included in this study had either 1 or up to 3 tumors without extrahepatic disease, were CP class A or B, ECOG 0-2 and had no prior radiation. PBT offers advantages over conventional X-ray by sparing surrounding tissues that is often diseased in cirrhotic patients. The tumor also has to be located greater than 1cm away from the gastrointestinal tract.

46 patients were included, the majority were CP A and ECOG 0-1. Eleven patients had undergone TACE, 6 patients TACE and sorafenib and 4 patients sorafenib only. Median tumor size was 6 cm (1.5-21 cm range), 22% had multiple tumors, and 28% had vascular invasion. Median dose was 67 GyE that was delivered over 21 days.

Median follow up was 14.5 months, median OS was 30.7 months (95% CI, 12.6-48.9 months), 1 year and 2 year PFS rates were 74% and 57% respectively. Local control rate at 1 and 2 years were 95% and 81%, respectively. Patients with tumors larger than 5 cm had a lower 2 year LC rate (62% vs 100%). 70% of patients had no progression at the time of last follow up. 14 patients developed recurrence, 6 of which outside of the treated field but within the liver. Thirteen patients had vascular invasion with 1 and 2 year OS rate of 58% and 44%, respectively. The authors found that patients that received biologically effective doses greater than 90GyE had better OS (49.9% vs 15.8 months. Multivariate analysis found higher BED as a predictor of improved OS. Grade 1 toxicities observed included fatigue (33%), erythema (24%), anorexia (11%) and vomiting (13%) . Thirteen percent of patients suffered acute grade 3 toxicities, including 9% ascites, 4% hyperbilirubinemia, and 2% with diarrhea and upper GI hemorrhage. CP score worsening was seen in 13% of patients. No grade >3 CTCAE toxicities were recorded.

The authors highlight that PBR offers dose deposition in a short distance which allows to cover large targets and minimize damage to surrounding structures. Their results also found that in 13 patients with tumor vascular thrombosis the 1 and 2 year OS rates were 58% and 44%, respectively, which the authors mention that is higher than historical outcomes using transcatheter infusion chemotherapy. PBT has it limitations compared to SBRT and include tumor distance greater than 1 cm from bowel, high cost, susceptibility to motion. The authors mention that the theoretical advantages, have not been proven and therefore need to be confirmed with further studies. Compared to SBRT, PBT has a lower risk of worsening CP score.

The study is limited by the retrospective nature of the study, the small sample size and the lack of control group. The authors conclude that PBT should be considered in the treatment algorithm for unresectable HCC, and that further studies are needed to evaluate the efficacy and cost compared to photon radiotherapy, TACE and sorafenib.

Figure 1- 85 year old patient with a 9.5 cm HCC treated with PBT. Pre-procedure Arterial and delayed images (a), Planning images (b), and subsequent follow up images show no residual tumor out to 2.5 years. Post radiation calcification and tumor shrinkage was seen on the last images.


This study provides important data supporting the use of PBT in the treatment of unresectable HCC in patients with good CP score and good functional status. PBT offers the theoretical advantage for delivering high dose in a concentrated area without damaging surrounding liver, which is detrimental in cirrhotic patients. The authors use the term tumor vascular thrombosis, which appears to be different from portal vein tumor thrombosis, since they are separated on table 3. It is unclear what it is meant by that term, which the authors use to support the use of PBT when compared to transcatheter infusion therapy. The authors reference 2 articles to support this statement, however the articles were published on 2005 and 2002, which is likely outdated. In addition, the lack of a similar control group makes it difficult to interpret the results. It is likely that PBT has a role in the treatment of unresectable HCC however it is unclear at this point where PBT falls in the algorithm of treatment, and as the authors mentioned the theoretical benefits need to be validated by head to head comparison with proton radiation therapy .

Post Author: 
Carlos J. Guevara, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Sciences, Houston



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