title: Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities.
abstract: Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities.
  
  
  
  We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed.
  
  
  
  Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P<0.05); but not with improvement of OS, DM, or CSM at either time point. BED escalation was not correlated with increased acute toxicities; it was correlated with increased late gastrointestinal toxicities in patients treated with 3D-CRT (1.5% increase over BED range, P<0.01). IMRT patients had significantly fewer late toxicities, despite being treated at higher BED.
  
  
  
  RT BED escalation has resulted in significantly improved PCa FFBF at up to 10 years; but not with improvement in OS, DM, or CSM. Thus, FFBF is a poor surrogate of overall patient outcomes for trials of RT. Late toxicities were less frequent with IMRT than with 3D-CRT, even at higher BED.
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Zaorsky
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Keith
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center.
authors.forename: Talha
authors.initials: T
authors.lastname: Shaikh
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Nguyen
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Horwitz
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
mesh_terms: D006801:Humans; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000401:mortality / Q000532:radiotherapy; D011832:Radiation Injuries / Q000209:etiology / Q000401:mortality; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000401:mortality; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects / Q000401:mortality; D015996:Survival Rate; D016032:Randomized Controlled Trials as Topic