# Radiation Oncology/Protons

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Proton Therapy

## Clinical Chapters

* General CNS
** Acoustic neuroma
** Pituitary adenoma
** Craniopharyngioma
** Medulloblastoma
** Germinoma
** Pediatric low grade glioma
** Anaplastic glioma
** Glioblastoma
* Retinoblastoma
* Head & Neck
* Breast
* Esophagus
* Cholangiocarcinoma
* Hepatocellular carcinoma
* NSCLC
* Non-Hodgkin's Lymphoma
* Pancreas
* Prostate
* Cervix
* Chordoma
* Cancer pain

## Facilities and Vendors

* Please see the facilities and vendors page

## General Information

* Michigan; 2011 -- ASCO Post -- "We Can Conduct Clinical Trials of Protons" (Lawrence TS, ASCO Post, September 15, 2011, Volume 2, Issue 14)
** Conclusion: "In my opinion, proton facilities should not be permitted to continue to produce results that cannot be distinguished—except by the far greater price—from those produced by IMRT photons. Our patients deserve true improvements in outcome, rather than the hype and added expense that currently dominates the field."
* Independent Journalist; 2010 PMID 20339139 -- "The proton beam debate: are facilities outstripping the evidence?" (Goozner M, J Natl Cancer Inst. 2010 Apr 7;102(7):450-3. Epub 2010 Mar 25.)
** Comment
* Tufts; 2009 PMID 19755348 -- "Systematic Review: Charged-Particle Radiation Therapy for Cancer." (Terasawa T, Ann Intern Med. 2009 Sep 14. [Epub ahead of print])
** Literature review. 243 articles, 185 single-institution retrospective, 9 nonrandomized trials, 8 randomized trials
** Outcome: No statistically significant or important difference in overall, cancer-specific survival or total serious adverse events
** Conclusion: Evidence is needed
* Royal Marsden
** 2009 PMID 19672149 -- "Current clinical evidence for proton therapy." (Brada M, Cancer J. 2009 Jul-Aug;15(4):319-24.)
*** Updated review
** 2007 PMID 17350945 -- "Proton therapy in clinical practice: current clinical evidence." (Brada M, J Clin Oncol. 2007 Mar 10;25(8):965-70.)
*** Review
* Columbia; 2009 PMID 19185838 -- "Protons for radiotherapy: a 1946 proposal." (Hall E, Lancet Oncol. 2009 Feb;10(2):196.)
** Historical perspective
* Louisville; 2009 PMID 19111269 -- "Randomized prospective trials of innovative radiotherapy technology are necessary." (Halperin EC, J Am Coll Radiol. 2009 Jan;6(1):33-7.)
** Most important clinical problem facing radiation oncology is whether randomized prospective trials are necessary to assess innovative technologies. It is possible to identify innovations that should be required to meet the standard of proof of a benefit in a randomized prospective clinical trial before being introduced into widespread clinical practice.
* Yale; 2008 PMID 19028271 -- "Should proton-beam therapy be widely adopted?" (Schulz RJ, Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1307-9; discussion 1309–10.)
** Editorial (Schulz RJ): Clinical outcomes of PT generally indistinguishable from photons. Issues of capital and operating costs, and cost-effectiveness should be revisited
** Response (Suit H): Significantly less integral dose. Answers to comparative Phase III requests are readily answerable by treatment plan comparisons. Need to work on questions that are of unarguable importance, such as hypofractionation, organ tolerance, concurrent chemotherapy protocols, etc.
* 21st Century Oncology; 2008 PMID 18954812 -- "A changing paradigm in the study and adoption of emerging health care technologies: coverage with evidence development." (Wallner PE, J Am Coll Radiol. 2008 Nov;5(11):1125-9.)
** Evaluation of drivers for health care. Increased interest to generate more appropriate and usefule "evidence" of benefit.
** Recommendation that "coverage with evidence development" could be used for proton therapy
* Harvard; 2008 PMID 18262083 -- "Magical protons?" (Goitein M, Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):654-6.)
** Editorial. Few notes of caution about dangers of proton therapy
** Comment (Withers HR, UCLA) PMID 18954723
** Response (Goitein M, Harvard) PMID 20159368
* Harvard; 2008 PMID 18237800 -- "Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No." (Suit H, Radiother Oncol. 2008 Feb;86(2):148-53. Epub 2008 Jan 30.)
** Distribution of biological dose superior for proton therapy in most situations. There is no medical rationale for clinical trials of protons, since they deliver lower biological dose to non-target tissues
** Conclusion: Talent, effort and funds for phase III trials should be better spent to investigate real problems
* Harvard/MD Anderson; 2008 PMID 18182658 -- "Should randomized clinical trials be required for proton radiotherapy?" (Goitein M and Cox JD, J Clin Oncol. 2008 Jan 10;26(2):175-6.)
** Editorial. Argument for protons: 1 better dose-distribution due to physical depth dose characteristics, 2) virtually no difference in tissue response per unit dose, 3) radiation delivered to normal tissues damages them. Argument against protons: 1) no randomized evidence. Editorial conclusion: Burden of proof on conventional x-ray therapy to justify that cost savings of photons are not accompanied by undesirable additional morbidity
** Patient comment (PMID 18443348): RCT in this instance do not meet equipoise; there will be lawsuits for offering inferior treatment
** Comment (Glatstein E, University of Pennsylvania) PMID 18443345: RCT should be done because there is an uncertainty about clinical benefits of protons
** Comment (Tepper JE, University of North Carolina) PMID 18443346: Need some evidence of benefit, and expensive technology should have higher standards than technology with minimal cost. At minimum, need high quality Phase II trials, which we don't have yet
** Comment (Lewis BE, UNDMJ) PMID 18443346: Financial concerns cloud the judgment of physician and hospital, both of whom stand to benefit from increased use of new expensive technologies. We must have the courage to generate high quality, disinterested, and unbiased data
** Comment (Macbeth FR, NCC Cardiff) PMID 18443346: Only evidence for superiority is base of skull cordomas and ocular tumors, but both are retrospective, and not proven. Payors (patient, insurance, HMO, taxpayers) deserve to know how much better the treatment is, given the significant expense
** Comment (Brada M, Royal Marsden) PMID 18443346: Information thus far originates from proponents of protons, with frequent commercial interest in the new equipment. Having some evidence of clinical benefit is not too much to ask
** Rebuttal (Goitein & Cox,) PMID 18443346: We need to move beyond fixation on RCT and get on with the business of designing, funding, and conducting large-scale clinical studies using ethically defensible methodologies that would have the broad acceptance of our patients
* Uppsala; 2007 PMID 17499373 -- "Proton beam therapy - do we need the randomised trials and can we do them?" (Glimelius B, Radiother Oncol. 2007 May;83(2):105-9. Epub 2007 May 11.)
** Editorial for issue containing Lodge and Olsen studies below
* Cochrane Review; 2007 PMID 17502116 -- "A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer." (Lodge M, Radiother Oncol. 2007 May;83(2):110-22. Epub 2007 May 14.)
** Conclusion: Existing data do not suggest that rapid expansion of hadron therapy is appropriate
* Oslo; 2007 PMID 17499374 -- "Proton therapy - a systematic review of clinical effectiveness." (Olsen DR, Radiother Oncol. 2007 May;83(2):123-32. Epub 2007 May 11.)
** Review: 4 RCTs, 5 comparative studies, 44 cases series
** Conclusion: Only low-level evidence available to support proton use
* NCI; 2006 PMID 17148768 -- "Research groups promoting proton therapy "lite"." (Hede K, J Natl Cancer Inst. 2006 Dec 6;98(23):1682-4.)
** News brief
* Heidelberg; 2006 PMID 17010908 -- "Radiation therapy with charged particles." (Schulz-Ertner D, Semin Radiat Oncol. 2006 Oct;16(4):249-59.)
** Review of protons experience, then focus on carbon ions
* Duke; 2006 PMID 16887485 -- "Particle therapy and treatment of cancer." (Halperin EC, Lancet Oncol. 2006 Aug;7(8):676-85.)
** Historical perspective
* MGH/PSI; 2005 PMID 16332585 -- "Swedish protons." (Goitein M, Acta Oncol. 2005;44(8):793-7.)
** Editorial for an issue of Acta Oncologica dedicated to protons
* CNAO Italy; 2004 PMID 15971303 -- "Medical aspects of the National Center For Oncological Hadrontherapy (CNAO-Centro Nazionale Adroterapia Oncologica) in Italy." (Krengli M, Radiother Oncol. 2004 Dec;73 Suppl 2:S21-3.)
** Review of Centro Nazionale Adroterapia Oncologica (CNAO) rationale
* Milan
** 2004 PMID 15276173 -- "Clinical and research validity of hadrontherapy with ion beams." (Orecchia R, Crit Rev Oncol Hematol. 2004 Aug;51(2):81-90.)
*** Review of ion therapy literature
** 1998 PMID 9713294 -- "Particle beam therapy (hadrontherapy): basis for interest and clinical experience." (Orecchia R, Eur J Cancer. 1998 Mar;34(4):459-68.)
*** Review of indications for hadrontherapy
* Harvard; 1992 PMID 1311773 -- "Proton beams in radiation therapy." (Suit H, J Natl Cancer Inst. 1992 Feb 5;84(3):155-64.)
** Overview of proton therapy. 11,763 patients treated. 46% small intracranial lesions, 32% tumors of eye.
** Formation of PROG to evaluate efficacy of proton therapy

## Economic Issues

* Please see the Economics page

## Secondary Cancers

* Columbia University
** 2008 PMID 18192046 -- "Secondary neutrons in clinical proton radiotherapy: A charged issue." (Brenner DJ, Radiother Oncol. 2008 Feb;86(2):165-70. Epub 2008 Jan 14.)
** 2007 PMID 17668949 -- "The impact of protons on the incidence of second malignancies in radiotherapy." (Hall EJ, Technol Cancer Res Treat. 2007 Aug;6(4 Suppl):31-4.)
** 2006 PMID 16618572 -- "Intensity-modulated radiation therapy, protons, and the risk of second cancers." (Hall EJ, Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):1-7.)

## Randomized Evidence

* Please see the level I evidence in proton therapy page

## Image-Guided Proton Therapy (IGPT)

* Shelby A. Lane et al. Image-Guided Proton Therapy: A Comprehensive Review. Cancers (Basel). 2023 May; 15(9): 2555. (PMID: 37174022)

## Proton Boron Capture Therapy (PBCT)

* G A P Cirrone et al. Sci Rep. 2018. First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness (PMID: 29348437)

## Proton Boron Fusion therapy (PBFT)

* Joo-Young Jung et al. Oncotarget. 2017. Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a monte carlo study (PMID: 28427153)
* Farshid Tabbakh et al. Sci Rep. 2020. Enhancement of Radiation Effectiveness in Proton Therapy: Comparison Between Fusion and Fission Methods and Further Approaches (PMID: 32214140)