Proton Therapy Improves Survival Over Photon Therapy in HCC

Nina Niu Sanford, MD, Assistant Professor, Department of Radiation Oncology, University of Texas Southwestern, Dallas, and Theodore Hong, MD, Professor, Department of Radiation Oncology, Massachusetts General Hospital, Boston (pictured: L-R), discuss the results of a single-institution study comparing clinical outcomes of proton- versus photon-based radiation therapy in patients with unresectable hepatocellular carcinoma (HCC).

What existing data led you and your co-investigators to conduct this research?

The incidence of HCC is rising. Surgery (resection or transplant) is the gold standard for treatment, but donor livers are scarce, and many patients are either technically or medically inoperable. Historically, delivering radiotherapy to the liver was both poorly tolerated and ineffective because of inaccurate target localization necessitating treatment fields and lower radiation doses.

Two advances have potentially changed the treatment landscape for HCC. The first is stereotactic ablative radiation therapy, which allows for the delivery of higher doses per fraction due to improved target precision and patient immobilization. The second, which we aimed to investigate in this retrospective study, is proton radiotherapy.

The more commonly available treatment modality for ablative radiotherapy is with photons, which continues to deposit dose along the exit beam path beyond the target volume, leading to unwanted dose to non-target liver and other normal tissues. In contrast, proton beam therapy utilizes charged particles which come to rest within the patient and have no exit dose beyond a pre-specified target range.

Prior series have demonstrated high local control rates for both protons and photons and small single arm studies had suggested improved survival with protons, perhaps due to decreased unwanted radiation dose to non-target liver. There had been no prior comparisons however of protons versus photons for unresectable HCC.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

We conducted a single-institution, retrospective study of 133 patients with unresectable HCC treated at Massachusetts General Hospital between 2008 and 2017, including 49 (37%) who were treated with protons. The main finding of the study was that proton radiotherapy was associated with improved overall survival – the median overall survival of patients treated with protons versus photons was 31 and 14 months, respectively. In addition, patients treated with protons had lower incidence of non-classic radiation induced liver disease, so we hypothesized that the lower rates of liver decompensation could have translated into a survival benefit.

We were surprised about the large survival benefit observed in our study. While protons have a clear dosimetric advantage over photons in many disease sites, a survival benefit is rarely observed, even in cases where toxicity rates with protons are lower. This may reflect the unique HCC patient population, who given their underlying liver disease, could potentially stand to benefit more from reduced unwanted radiation dose. However, this is a retrospective study subject to the caveats of this study design, most notably selection bias, so our results are hypothesis generating.

What are the possible real-world applications of these findings in clinical practice?

If our findings are confirmed in future studies, including randomized trials, then proton radiotherapy could have a greater role in the treatment of HCC, for patients with unresectable disease (such as those included in our study), and potentially in other settings, such as pre- or post-operatively, or even as an alternative to surgery. However, at this juncture, protons remain a limited and costly resource, so studies would be needed to optimize patient selection for protons.

Do you and your co-investigators intend to expand upon this research?

Yes; one of the co-investigators of this study, Clemens Grassberger, PhD, led a study examining in detail dosimetric properties of proton versus photon radiotherapy for liver cancer using the same patient cohort to shed further insight into the potential association between proton radiotherapy and reduced risk of liver decompensation.

Dr Hong, senior investigator of this study, is also leading a multi-center NRG randomized trial of photon versus proton radiotherapy for liver cancer with the goal of providing level 1 evidence on the question of radiation modality for this disease.