title: The Quest for Evidence for Proton Therapy: Model-Based Approach and Precision Medicine.
abstract: OBJECTIVE
  Reducing dose to normal tissues is the advantage of protons versus photons. We aimed to describe a method for translating this reduction into a clinically relevant benefit.
  
  
  METHODS
  Dutch scientific and health care governance bodies have recently issued landmark reports regarding generation of relevant evidence for new technologies in health care including proton therapy. An approach based on normal tissue complication probability (NTCP) models has been adopted to select patients who are most likely to experience fewer (serious) adverse events achievable by state-of-the-art proton treatment.
  
  
  RESULTS
  By analogy with biologically targeted therapies, the technology needs to be tested in enriched cohorts of patients exhibiting the decisive predictive marker: difference in normal tissue dosimetric signatures between proton and photon treatment plans. Expected clinical benefit is then estimated by virtue of multifactorial NTCP models. In this sense, high-tech radiation therapy falls under precision medicine. As a consequence, randomizing nonenriched populations between photons and protons is predictably inefficient and likely to produce confusing results.
  
  
  CONCLUSIONS
  Validating NTCP models in appropriately composed cohorts treated with protons should be the primary research agenda leading to urgently needed evidence for proton therapy.
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.widder@umcg.nl.
authors.forename: Joachim
authors.initials: J
authors.lastname: Widder
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: van der Schaaf
authors.affiliation: Department of Radiation Oncology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Corrie A M
authors.initials: CAM
authors.lastname: Marijnen
authors.affiliation: Department of Radiation Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pignol
authors.affiliation: Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Coen R
authors.initials: CR
authors.lastname: Rasch
authors.affiliation: Department of Radiation Oncology, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Slotman
authors.affiliation: Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
mesh_terms: D015415:Biomarkers; D019317:Evidence-Based Medicine; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000532:radiotherapy; D009426:Netherlands; D059351:Organ Sparing Treatments / Q000379:methods; D058958:Organs at Risk / Q000528:radiation effects*; D018579:Patient Selection; D017785:Photons / Q000627:therapeutic use; D057285:Precision Medicine / Q000379:methods*; D011336:Probability; D061766:Proton Therapy / Q000009:adverse effects / Q000379:methods*; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control*; D020266:Radiotherapy, Conformal; D050397:Radiotherapy, Intensity-Modulated; D016032:Randomized Controlled Trials as Topic
chemical_list: D015415:Biomarkers