title: Modeling freedom from progression for standard-risk medulloblastoma: a mathematical tumor control model with multiple modes of failure.
abstract: OBJECTIVE
  As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data.
  
  
  METHODS
  Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data.
  
  
  RESULTS
  The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range.
  
  
  CONCLUSIONS
  Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available.
authors.affiliation: Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen, Denmark. nils.patrik.brodin@rh.dk
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: Søren M
authors.initials: SM
authors.lastname: Bentzen
mesh_terms: D000465:Algorithms; D002528:Cerebellar Neoplasms / Q000532:radiotherapy*; D002648:Child; D018572:Disease-Free Survival; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008527:Medulloblastoma / Q000532:radiotherapy*; D008954:Models, Biological; D009010:Monte Carlo Method; D009364:Neoplasm Recurrence, Local; D035583:Rare Diseases / Q000532:radiotherapy*; D017211:Treatment Failure; D035501:Uncertainty