title: Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.
abstract: OBJECTIVE
  Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient?
  
  
  METHODS
  Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation.
  
  
  RESULTS
  The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3-5 gantry centers operating 14-16 h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy.
  
  
  CONCLUSIONS
  Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. hsuit@partners.org
authors.forename: Herman
authors.initials: H
authors.lastname: Suit
authors.forename: Hanne
authors.initials: H
authors.lastname: Kooy
authors.forename: Alexei
authors.initials: A
authors.lastname: Trofimov
authors.forename: Jonathan
authors.initials: J
authors.lastname: Farr
authors.forename: John
authors.initials: J
authors.lastname: Munzenrider
authors.forename: Thomas
authors.initials: T
authors.lastname: DeLaney
authors.forename: Jay
authors.initials: J
authors.lastname: Loeffler
authors.forename: Benjamin
authors.initials: B
authors.lastname: Clasie
authors.forename: Sairos
authors.initials: S
authors.lastname: Safai
authors.forename: Harald
authors.initials: H
authors.lastname: Paganetti
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D009369:Neoplasms / Q000532:radiotherapy*; D017785:Photons / Q000627:therapeutic use*; D061766:Proton Therapy; D011832:Radiation Injuries / Q000517:prevention & control; D018787:Radiation Oncology / Q000191:economics / Q000379:methods*; D011879:Radiotherapy Dosage; D011522:Protons
chemical_list: D011522:Protons