ASTRO 2021: The Present and Future of Proton Beam Therapy

( In an educational session at the American Society for Radiation Oncology (ASTRO) Annual Congress focused on the best treatment for early prostate cancer, Dr. Hoffman presented on the role of proton beam therapy including both the current utilization and potential future roles.

Dr. Hoffman began by highlighting that external beam radiotherapy (EBRT) is an excellent treatment option for patients with localized prostate cancer. Based on cited data from the ProtecT trial among patients with low and intermediate risk disease, EBRT provides comparable cancer control as radical prostatectomy. She further highlighted that the side effect profile of EBRT is distinct from prostatectomy, with better short-term sexual function and less incontinence but higher urinary obstruction and bowel symptoms in the ProtecT trial. Citing data from the CEASAR prospective cohort study, Dr. Hoffman emphasized that modern treatment approaches to EBRT may have improved treatment toxicity outcomes.

She further highlighted that there are different ways to deliver EBRT, including fractionation regimes (conventional fractionation, moderate hypofractionation, and ultrahypofractionation) as well as modalities (photon versus proton). She highlighted that protons and photons have physical properties that are distinct. While photon based radiotherapy delivers the highest dose initially (the entrance dose), proton based radiotherapy delivers the majority of the dose over a discrete area called the Bragg peak. These may be stacked or spread out across the target to deliver the desired dose. As a result, proton therapy can deliver less inadvertent radiation to non-target areas. However, the question is whether this is clinically relevant for patients with prostate cancer.

She further emphasized that proton beam therapy has evolved over time, including the introduction of pencil beam scanning which is more conformal and allows for intensity modulation, with sparing of the rectum in the cases of prostate cancer treatment. However, there are inherent proton radiation uncertainties including RBE uncertainty, range uncertainty, and the sensitivity to motion and positional changes. Robust optimization in treatment planning can help to account for these.

Dr. Hoffman highlighted that the potential benefit of proton based radiotherapy compared from a lower integral dose which may reduce the risk of radiation-induced secondary cancers (though the absolute rate is relatively low with traditional photon based EBRT). She deemed this a more theoretical benefit but it may be particularly meaningful for younger men. Additionally, proton therapy delivers less radiation dose to the testicles. Thus, while IMRT is associated with a decrease in testosterone levels after therapy, proton therapy is not. However, the clinical relevance of this is not clear.

In medical claims studies, while limited numbers of patients were treated with proton beam radiotherapy, there is a potential signal of increased late gastrointestinal toxicity.


She suggested that patient and physician reported outcomes studies may better reflect the toxicity of treatment. While numbers of patients are smaller here, late gastrointestinal toxicity appeared similar between patients who received proton and photon EBRT.


However, all of these studies utilized conventional fractionation and much of EBRT has transitioned towards hypofractionation. Dr. Hoffman suggested that hypofractionation might solve one of the pitfalls of proton beam therapy, given its higher cost. A number of phase II trials have examined hypofractionated proton therapy, with a recent pooled analysis suggesting that there may be higher rates of late grade 2+ GI toxicity among patients receiving moderately hypofractionated proton (as compared to photon) therapy. However, adjusting for patient and cancer characteristics as well as anticoagulant use made this no longer significant. Further, no difference in acute grade 2+ GI toxicity and acute or late grade 2+ GU toxicity was observed.

Citing a large case series from the University of Florida, Dr. Hoffman emphasized that proton radiation effectively controls prostate cancer with reasonable biochemical relapse rates.

She further highlighted that some patients have a strong preference for proton therapy, often based on what they have read and from direct to patient advertising. Prostate radiation is one of the most common disease sites advertised.

In contrast to the current dearth of comparative data, Dr. Hoffman emphasized that we will have randomized evidence comparing the relative toxicity of proton and IMRT radiotherapy, based on forthcoming work from Dr. Efstathiou and colleagues. This study is assessing the primary endpoint of patient-reported bowel function at 2-years.


Currently, 447 of a planned 450 patients have been enrolled. She emphasized that included patients are relatively representative of both disease characteristics and treatment approaches that are currently utilized.

The COMPARE study is a parallel cohort study of patients who are planned for either IMRT or proton therapy with planned comparisons of patient and physician reported bowel toxicity, as well as freedom from biochemical progression. Enrollment is expected to be complete as of fall 2022. Within this parallel cohort study, there is a nest randomization comparing 60 Gy in 3 Gy fractions (20 fractions) and 78 Gy in 2 Gy fractions (39 fractions).

Looking to the future, Dr. Hoffman is looking forward to evidence to guide when and how to use proton therapy in prostate cancer. There are currently many ongoing and maturing phase II and phase III trials that should help to better delineate the role of proton therapy.


Further, there have been recent improvements in on board imaging with a transition from orthogonal films for patient alignment to surface guidance and cone-beam CT integration and current investigations of MRI-guided proton therapy. Further, she considers it likely that proton radiation will be used for intraprostatic boost. However, identifying those patients who are most likely to benefit remains to be assessed.

In conclusion, she highlighted that proton radiation delivers a lower integral dose, compared to IMRT. It has an acceptable toxicity profile and effectively controls disease. However, there is no clear evidence supporting a benefit of proton therapy relative to IMRT. However, randomized data are forthcoming with the PARTIQoL trial.

Presented by: Karen Elizabeth Hoffman, M.D., M.H.Sc., M.P.H., Department of Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.