title: Optimizing the radiation therapy dose prescription for pediatric medulloblastoma: minimizing the life years lost attributable to failure to control the disease and late complication risk.
abstract: BACKGROUND
  A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale.
  
  
  METHODS
  Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling the primary disease. We compared the estimated LYL for three different treatments in 10 patients: 1) standard 3D conformal RT; 2) proton therapy; 3) risk-adaptive photon treatment lowering the dose to part of the craniospinal (CS) target volume situated close to critical risk organs.
  
  
  RESULTS
  Late toxicity is important, with 0.75 LYL (95% CI 0.60-7.2 years) for standard uniform 24 Gy CS irradiation. However, recurrence risk dominates the total LYL with 14.2 years (95% CI 13.4-16.6 years). Compared to standard treatment, a risk-adapted strategy prescribing 12 Gy to the spinal volume encompassing the 1st-10th thoracic vertebrae (Th1-Th10), and 36 Gy to the remaining CS volume, estimated a LYL reduction of 0.90 years (95% CI -0.18-2.41 years). Proton therapy with 36 Gy to the whole CS volume was associated with significantly fewer LYL compared to the risk-adapted photon strategies, with a mean LYL difference of 0.50 years (95% CI 0.25-2.60 years).
  
  
  CONCLUSIONS
  Optimization of RT prescription strategies considering both late complications and the risk of recurrence, an all-cause mortality dose painting approach, was demonstrated. The risk-adapted techniques compared favorably to the standard, and although in this context, the gain is small compared to estimated uncertainty, this study demonstrates a framework for all-cause mortality risk estimation, rather than evaluates direct clinical applicability of risk-adapted strategies.
authors.affiliation: Department of Radiation Oncology, Radiation Medicine Research Center, Rigshospitalet , Copenhagen , Denmark.
authors.forename: N Patrik
authors.initials: NP
authors.lastname: Brodin
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Vogelius
authors.forename: Thomas
authors.initials: T
authors.lastname: Björk-Eriksson
authors.forename: Per
authors.initials: P
authors.lastname: Munck Af Rosenschöld
authors.forename: Maja V
authors.initials: MV
authors.lastname: Maraldo
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Aznar
authors.forename: Lena
authors.initials: L
authors.lastname: Specht
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002528:Cerebellar Neoplasms / Q000401:mortality / Q000517:prevention & control / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D061888:Craniospinal Irradiation / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000401:mortality / Q000517:prevention & control / Q000532:radiotherapy*; D008875:Middle Aged; D008962:Models, Theoretical; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000401:mortality; D017785:Photons / Q000009:adverse effects; D011379:Prognosis; D061766:Proton Therapy / Q000009:adverse effects; D011832:Radiation Injuries / Q000209:etiology*; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted / Q000009:adverse effects; D020266:Radiotherapy, Conformal / Q000009:adverse effects; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult