title: Efficacy of dose escalation on TCP, recurrence and second cancer risks: a mathematical study.
abstract: OBJECTIVE
  We investigated the effects of conventional and hypofractionation protocols by modelling tumour control probability (TCP) and tumour recurrence time, and examined their impact on second cancer risks. The main objectives of this study include the following: (a) incorporate tumour recurrence time and second cancer risks into the TCP framework and analyse the effects of variable doses and (b) investigate an efficient protocol to reduce the risk of a secondary malignancy while maximizing disease-free survival and tumour control.
  
  
  METHODS
  A generalized mathematical formalism was developed that incorporated recurrence and second cancer risk models into the TCP dynamics.
  
  
  RESULTS
  Our results suggest that TCP and relapse time are almost identical for conventional and hypofractionated regimens; however, second cancer risks resulting from hypofractionation were reduced by 22% when compared with the second cancer risk associated with a conventional protocol. The hypofractionated regimen appears to be sensitive to dose escalation and the corresponding impact on tumour recurrence time and reduction in second cancer risks. The reduction in second cancer risks is approximately 20% when the dose is increased from 60 to 72 Gy in a hypofractionated protocol.
  
  
  CONCLUSIONS
  Our results suggest that hypofractionation may be a more efficient regimen in the context of TCP, relapse time and second cancer risks. Overall, our study demonstrates the importance of including a second cancer risk model in designing an efficient radiation regimen.
  
  
  CONCLUSIONS
  The impact of various fractionation protocols on TCP and relapse in conjunction with second cancer risks is an important clinical question that is as yet unexplored.
authors.affiliation: 1 Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada.
authors.forename: V S K
authors.initials: VS
authors.lastname: Manem
authors.forename: A
authors.initials: A
authors.lastname: Dhawan
authors.forename: M
authors.initials: M
authors.lastname: Kohandel
authors.forename: S
authors.initials: S
authors.lastname: Sivaloganathan
mesh_terms: D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D006801:Humans; D008962:Models, Theoretical; D009364:Neoplasm Recurrence, Local / Q000532:radiotherapy*; D016609:Neoplasms, Second Primary / Q000532:radiotherapy*; D012307:Risk Factors