Similarly, authors of a recent cohort study of 727 patients with esophageal cancer who underwent either IMRT or proton beam therapy at the University of Texas MD Anderson Cancer Center in Houston reported that proton therapy was associated with less irradiation of the heart and cardiac substructures compared with IMRT in patients with mid- to distal esophageal tumors.5

Critics have voiced concern, however, that the significant cost of building proton radiotherapy centers will encourage overuse, unnecessarily increasing the cost of treatment for more common cancers for which the evidence base for proton therapy remains unclear.1,6

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Exploring Its Potential

Because it is a new and not yet widely used modality, the empirical evidence base for proton therapy has been slow to mature.3 Little is known about overall survival rates associated with proton therapy, for example. The relative biological effectiveness of proton therapy is still under study and factors such as beam angle, dose, and tissue type may affect results.7

The American Society for Radiation Oncology (ASTRO) recently issued a model policy on proton beam therapy, noting that proton beam therapy “may offer dosimetric advantages as well as added complexity over conventional radiotherapy, 3D conformal radiation therapy (3D CRT) or intensity modulated radiation therapy (IMRT)” under some circumstances. 

The model policy notes the need for continued development of the clinical evidence base and the need for comparative effectiveness analyses to determine when it is appropriate to use PBT for different cancer sites. “Before applying PBT techniques, a comprehensive understanding of the benefits and consequences is required,” the ASTRO model policy states.

A recent prospective cohort assessment of proton beam therapy, involving 204 evaluable men with intermediate- and high-risk prostate cancer at the Medipolis Proton Therapy and Research Center in Japan found similar proton beam therapy monotherapy can maintain quality of life, with only 3.9% of patients experiencing grade 2 gastrointestinal toxicities within 6 months of treatment.8 A separate single-institution analysis of outcomes among 81 patients with prostate cancer found that proton beam therapy (79.2 Gy) was associated with good urinary and gastrointestinal function and quality of life, regardless of prostate size.9 However, as with studies of proton therapy in breast cancer, well-designed, randomized head-to-head comparative trials are still needed to justify its use — and its significant excess cost — over traditional radiotherapy modalities such as IMRT.1,9

There are at least 122 ongoing clinical studies of proton beam radiotherapy, according to a recent review, 21% of which address gastrointestinal tract cancers; 15%, central nervous system (CNS) tumors; and 12%, prostate cancers.6 Five are randomized clinical trials (enrolling patients with cancers of the lung, esophagus, oropharynx, prostate, and breast) designed to compare proton therapy outcomes against traditional photon EBRT.6

Neutron Radiation Risks

One continuing theoretical concern with the technology is that tungsten-alloy multileaf collimators (MLCs) for dose-escalated delivery of proton therapy, an approach that is undergoing clinical study, could interact with proton beams to yield out-of-field secondary and residual neutron radiation exposures for radiotherapy staff and patients.10 Efforts are under way to develop detectors and tracking systems to study and monitor neutron scatter risks.11


1. Furlow B. Dosimetric promise versus cost: critics question proton therapy. Lancet Oncol. 2013;14(9):805-806.

2. Doyen J, Falk AT, Floquet V, Hérault J, Hannoun-Levi JM. Proton beams in cancer treatments: clinical outcomes and dosimetric comparisons with photon therapy. Cancer Treat Rev. 2016;43:104-112.

3. Mohan R, Grosshans D. Proton therapy — present and future. Adv Drug Deliv Rev. 2017;109:26-44.

4. Kammerer E, Le Guevelou J, Chaikh A, et al. Proton therapy for locally advanced breast cancer: a systematic review of the literature. Cancer Treat Rev. 2018;63:19-27.

5. Shiraishi Y, Xu C, Yang J, Komaki R, Lin SH. Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or intensity-modulated radiation therapy. Radiother Oncol. 2017;125(1):48-54.

6. Mishra MV, Aggarwal S, Bentzen SM, Knight N, Mehta MP, Regine WF. Establishing evidence-based indications for proton therapy: an overview of current clinical trials. Int J Radiat Oncol Biol Phys. 2016;97(2):228-235.

7. Lühr A, von Neubeck C, Krause M, Troost EGC. Relative biological effectiveness in proton beam therapy — current knowledge and future challenges. Clin Transl Radiat Oncol. 2018;9:35-41.

8. Arimura T, Kondo N, Matsukawa K, et al. The role of proton beam therapy for patients with intermediate- and high-risk prostate cancer. Poster presentation at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA. Abstract 97.

9. Goenka A, Newman NB, Fontanilla H, et al. Patient-reported quality of life after proton beam therapy for prostate cancer: the effect of prostate size. Clin Genitourin Cancer. 2017;15(6):704-710.

10. Stokkevåg CH, Schneider U, Muren LP, Newhauser W. Radiation-induced cancer risk predictions in proton and heavy ion radiotherapy. Phys Med. 2017;42:259-262.

11. Valle SM, Battistoni G, Patera V, et al. The MONDO project: a secondary neutron tracker detector for particle therapy. Nucl Instrum Methods Phys Res A. 2017;845:556-559.