Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in NSCLC

Jacob G. Scott, Geoff Sedor, Jessica A. Scarborough, Michael W. Kattan, Jeffrey Peacock, G. Daniel Grass, Eric A. Mellon, Ram Thapa, Michael Schell, Anthony Waller, Sean Poppen, George Andl, Jamie K. Teer, Steven A. Eschrich, Thomas J. Dilling, William S. Dalton, Louis B. Harrison, Tim Fox, Javier F. Torres-Roca

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Introduction: Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation. Methods: We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics. Results: Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit. Conclusions: Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.

Original languageEnglish (US)
Pages (from-to)428-438
Number of pages11
JournalJournal of Thoracic Oncology
Volume16
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Mathematical modeling
  • Non–small cell lung cancer
  • Personalized medicine
  • Radiation oncology

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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