The proponents of this novel therapy argue that this feature of proton Beam radiotherapy justifies its use. However, there are other ways to spare normal tissue, including: Three-dimensional conformal radiation therapy (3D-CRT. Intensity modulated radiation therapy (IMRT), Conformal proton beam radiation therapy, Stereotactic radiosurgery/stereotactic radiotherapy and  Brachytherapy (internal radiotherapy). In addition, the claim that safety alone is the reason to adopt proton beam for routine use should not be made in the absence of studies that confirm better outcomes.  Because proton beam technology is available on only a number of US facilities and because craniospinal radiation  is not performed very frequently, studies to support the assertion that proton beam radiotherapy is superior have not been done and the treatment should still be considered investigational.

Proton beam therapy systems are approved by the FDA 510(k) process as a “medical device designed to produce and deliver a proton beam for the treatment of patients with localized tumors and other conditions susceptible to treatment by radiation” (FDA, 2006). Examples of such systems are the Optivus Proton Beam Therapy System (Optivus Technology Inc., Loma Linda, CA) and the IBA Proton Therapy System-Proteus 235 (Ion Beam Applications S.A., Philadelphia, PA).

The Agency for Healthcare Research and Quality published a 2009 technology report on particle beam radiation therapies for the treatment of cancers including skull base and brain tumors. They noted that there is a proposed advantage of using particle beam therapy, including PBT, where precise radiation targeting is critical in tumors of the skull base and tumors adjacent to the brain and brain stem. The report concluded that studies on charged particle therapy “do not document the circumstances in contemporary treatment strategies in which radiotherapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible) are needed to document the theoretical advantages of charged particle radiotherapy to specific clinical situations”.

In a technology assessment on the use of PBT for the treatment of cancer, the Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies. It is not clear how this may relate to cranio-spinal radiation.

Y. Lievens, W. den BogaertProton beam therapy: Too expensive to become true?. Radiotherapy and Oncology, Volume 75, Issue 2, Pages 131-133 2005

Yock TI, Tarbell NJ.Technology insight: Proton beam radiotherapy for treatment in pediatric brain tumors. Nat Clin Pract Oncol. 2004 Dec;1(2):97-103;

Semenova J.Proton beam radiation therapy in the treatment of pediatric central nervous system malignancies: a review of the literature. J Pediatr Oncol Nurs. 2009 May-Jun;26(3):142-9. Epub 2009 May 21.

A recent review concluded: “While there is growing enthusiasm for the use of protons in the treatment of prostate cancer, a review of the literature suggests that there is so far no clear evidence to show that proton therapy would be superior to highly conformal photon treatments. As the use of protons in prostate cancer will no doubt become more widespread in the coming years, there is urgent need for a randomized trial of IMRT vs protons to provide us with concrete clinical data about the relative merits and potential risks of each type of therapy. The possibility of launching such a trial is currently being explored by the RTOG.” 2

Until results from such a trial are available, we continue to view protons in prostate cancer as a modality with tremendous promise. As it comes with a relatively high price tag, however, proton therapy must remain under scrutiny until it has proven itself against the best possible alternative.”

Proton beam therapy systems are approved by the FDA 510(k) process as a “medical device designed to produce and deliver a proton beam for the treatment of patients with localized tumors and other conditions susceptible to treatment by radiation” (FDA, 2006). Examples of such systems are the Optivus Proton Beam Therapy System (Optivus Technology Inc., Loma Linda, CA) and the IBA Proton Therapy System-Proteus 235 (Ion Beam Applications S.A., Philadelphia, PA).

The Agency for Healthcare Research and Quality published a 2009 technology report on particle beam radiation therapies for the treatment of cancers including skull base and brain tumors. They noted that there is a proposed advantage of using particle beam therapy, including PBT, where precise radiation targeting is critical in tumors of the skull base and tumors adjacent to the brain and brain stem. The report concluded that studies on charged particle therapy “do not document the circumstances in contemporary treatment strategies in which radiotherapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible) are needed to document the theoretical advantages of charged particle radiotherapy to specific clinical situations”.

In a technology assessment on the use of PBT for the treatment of cancer, the Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.

Y. Lievens, W. den BogaertProton beam therapy: Too expensive to become true?. Radiotherapy and Oncology, Volume 75, Issue 2, Pages 131-133 2005

Yock TI, Tarbell NJ.Technology insight: Proton beam radiotherapy for treatment in pediatric brain tumors. Nat Clin Pract Oncol. 2004 Dec;1(2):97-103;

Semenova J.Proton beam radiation therapy in the treatment of pediatric central nervous system malignancies: a review of the literature. J Pediatr Oncol Nurs. 2009 May-Jun;26(3):142-9. Epub 2009 May 21.

Tian X, Liu K, Hou Y, Cheng J, Zhang J. The evolution of proton beam therapy:Current and future status. Mol Clin Oncol. 2018 Jan;8(1):15-21.

Doyen J, Bondiau PY, Bénézéry K, et al. Current situation and perspectives of proton
therapy. Cancer Radiother. 2015 May;19(3):211-9; quiz 231-2, 235.

Mishra MV, Aggarwal S, Bentzen SM, et. al Establishing Evidence-Based Indications for Proton Therapy: An Overview of Current Clinical Trials. Int J Radiat Oncol Biol Phys. 2017 Feb 1;97(2):228-235.

Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.7

A report by ASTRO’s Emerging Technologies Committee states that there is reason to be optimistic about the potential developments in proton beam therapy (PBT) and the prospective research that is ongoing at centers worldwide. Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, GI malignancies (with the exception of HCC) and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dosimetric benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical research is needed and should be encouraged (ASTRO, 2011).

ACR appropriateness criteria state that the physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. Results from larger, prospective, controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer (ACR, 2010).4

A Blue Cross Blue Shield technology assessment evaluated health outcomes following proton beam therapy (PBT) compared to stereotactic body radiotherapy (SBRT) for the management of Proton Beam Radiation Therapy: Medical Policy 12 non-small-cell lung cancer. The report concluded that, overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer. All PBT studies are case series, and there are no studies directly comparing proton beam therapy (PBT) and stereotactic body radiotherapy (SBRT). In the absence of randomized, controlled trials, the comparative effectiveness of PBT and SBRT is uncertain (BCBS, 2011).6

The only guideline that I found that offers a qualified support is NCCN. The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints 5

It is quite clear from limited studies that proton beam is not inferior to other radiotherapy techniques. What has not been proven is that it is superior and that its ability to spare the tissues translates to a better outcome. It makes sense that it should, but in science that would be called a hypothesis that needs to be proven. This si especially so for ehad and neck, where there is less consensus than in prostate cancer. Because PBT is only available in limited centers and is much more complex and expensive than other tissue sparing radiation therapy techniques, it should still be considered investigational.

ANal Cacner

ASTRO PBT July 2017 policy that supports Proton Beam in this situation, given the comparative dose distribution plan.The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints. The ability of precision therapy to reduce toxicity
was demonstrated in RTOG 0529 which prospectively implemented dose-painted intensity modulated radiation therapy (IMRT) in a phase II trial design. Additionally, some studies have suggested that long-term outcomes are associated with time to completion of therapy and radiation dose

1.Y. Lievens, W. den BogaertProton beam therapy: Too expensive to become true?. Radiotherapy and Oncology, Volume 75, Issue 2, Pages 131-133 2005

2.Agency for Healthcare Research and Quality (AHRQ). Technology Assessment. Comparative
evaluation of radiation treatments for clinically localized prostate cancer: an update. August
2010. Available at: http://www.cms.gov/coveragegeninfo/downloads/id69ta.pdf.

3.Agency for Healthcare Research and Quality (AHRQ). Trikalinos TA, Terasawa T, Ip S, Raman
G, Lau J. Particle Beam Radiation Therapies for Cancer. Technical Brief No. 1. (Prepared by
Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA-290-07-10055.)
Rockville, MD: AHRQ. Revised November 2009. Available at:
http://www.effectivehealthcare.ahrq.gov/ehc/products/58/173/particle%20beam%20mainreptrev1 1-09(r).pdf.

4.American College of Radiology (ACR). ACR Appropriateness Criteria. Nonsurgical treatment for non-small-cell lung cancer. 2010. Available at: http://www.acr.org/ac.

5.American Society for Radiation Oncology (ASTRO). Emerging Technologies Committee. An
evaluation of proton beam therapy. June 2011. Available at:

http://www.astro.org/HealthPolicy/EmergingTechnology/EvaluationProjects/documents/ProtonBea

mReport.pdf.

6.Blue Cross Blue Shield Association (BCBSA). Proton beam therapy for non-small-cell lung cancer. TEC Assessment, October 2010.

7.Purins A, Mundy L, Hiller J. Boron neutron capture therapy for cancer treatment. Horizon Scanning Prioritising Summary. Adelaide, SA: Adelaide Health Technology Assessment (AHTA); October 2007.

Semin Radiat Oncol. 2018 Apr;28(2):97-107.

Tian X, Liu K, Hou Y, Cheng J, Zhang J. The evolution of proton beam therapy: Current and future status. Mol Clin Oncol. 2017;8(1):15-21.

Anal Cancer

E.J. Vaios et al, Proton beam radiotherapy for anal and rectal cancers. J Gastrointest Oncol 2020;11(1):176-186

Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated
radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in
carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33.

Ghosn M, Kourie HR, Abdayem P, et al. Anal cancer treatment: Current status and future perspectives. World J
Gastroenterol 2015;21:2294-302.

Press, Robert H et al. “Clinical Review of Proton Therapy in the Treatment of Unilateral Head and Neck Cancers.” International journal of particle therapy vol. 8,1 248-260. 25 Jun. 2021, doi:10.14338/IJPT-D-20-00055.1