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Title: Use of Individual Fraction Size Data from 3756 Patients to Directly Determine the {alpha}/{beta} Ratio of Prostate Cancer

Abstract

Purpose: To examine the effect of fraction size and total dose of radiation on recurrence of localized prostate cancer. Methods and Materials: A total of 3756 patients treated with radiation monotherapy at three institutions were analyzed, including 185 high-dose-rate brachytherapy (HDRB) boost patients. The 5th to 95th centiles of external beam radiotherapy (EBRT) fraction sizes and doses were 1.8 to 2.86 Gy, and 57.4 to 77.4 Gy, respectively, and HDRB fractional doses were between 5.5 and 12 Gy, totaling 147 unique fractionation schedules. Failure was defined by one biochemical (nadir + 2 ng/ml) and two advanced disease endpoints. The {alpha}/{beta} ratios were estimated via a proportional hazards model stratified by risk severity and institution. Results: The {alpha}/{beta} ratio using biochemical recurrence was 3.7 Gy (95% confidence interval [95% CI], 1.1, {infinity} Gy) for EBRT-only cases and 2.6 Gy (95% CI, 0.9, 4.8 Gy) after the addition of HDRB data. This estimate was highly dependent on an HDRB homogeneity correction factor (120% HDRB dose increase; {alpha}/{beta} ratio 4.5 Gy, 95% CI 1.6, 8.7 Gy). A 5-Gy increase in total dose reduced the hazard of failure by 16% (95% CI 11, 21%, p < 0.0001), and had more impact as follow-up maturedmore » (p < 0.0003). The clinically advanced endpoints concurred with the biochemical failure results, albeit with less precision. Conclusions: This study supports the concept that the {alpha}/{beta} ratio of prostate cancer is low, although considerable uncertainty remains in the estimated value. Outcome data from EBRT studies using substantially higher doses per fraction are needed to show increased precision in these estimates.« less

Authors:
 [1];  [2];  [3];  [2];  [4];  [5];  [6];  [6];  [7];  [8]
  1. Division of Radiation Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria (Australia). E-mail: scott.williams@petermac.org
  2. Department of Biostatistics, University of Michigan, Ann Arbor, MI (United States)
  3. (United States)
  4. Department of Mathematics and Statistics, Rochester Institute of Technology, Rochester, NY (United States)
  5. Division of Radiation Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria (Australia)
  6. Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States)
  7. Division of Radiation Oncology, Royal Brisbane Hospital, Brisbane, Queensland (Australia)
  8. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI (United States)
Publication Date:
OSTI Identifier:
20951611
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 68; Journal Issue: 1; Other Information: DOI: 10.1016/j.ijrobp.2006.12.036; PII: S0360-3016(06)03670-4; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ACCURACY; BETA RATIO; BRACHYTHERAPY; CARCINOMAS; CORRECTIONS; DOSE RATES; FAILURES; HAZARDS; PATIENTS; PROSTATE; RADIATION DOSES; RADIOBIOLOGY

Citation Formats

Williams, Scott G., Taylor, Jeremy M.G., Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, Liu Ning, Tra, Yolande, Duchesne, Gillian M., Kestin, Larry L., Martinez, Alvaro, Pratt, Gary R., and Sandler, Howard. Use of Individual Fraction Size Data from 3756 Patients to Directly Determine the {alpha}/{beta} Ratio of Prostate Cancer. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.12.036.
Williams, Scott G., Taylor, Jeremy M.G., Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, Liu Ning, Tra, Yolande, Duchesne, Gillian M., Kestin, Larry L., Martinez, Alvaro, Pratt, Gary R., & Sandler, Howard. Use of Individual Fraction Size Data from 3756 Patients to Directly Determine the {alpha}/{beta} Ratio of Prostate Cancer. United States. doi:10.1016/j.ijrobp.2006.12.036.
Williams, Scott G., Taylor, Jeremy M.G., Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, Liu Ning, Tra, Yolande, Duchesne, Gillian M., Kestin, Larry L., Martinez, Alvaro, Pratt, Gary R., and Sandler, Howard. Tue . "Use of Individual Fraction Size Data from 3756 Patients to Directly Determine the {alpha}/{beta} Ratio of Prostate Cancer". United States. doi:10.1016/j.ijrobp.2006.12.036.
@article{osti_20951611,
title = {Use of Individual Fraction Size Data from 3756 Patients to Directly Determine the {alpha}/{beta} Ratio of Prostate Cancer},
author = {Williams, Scott G. and Taylor, Jeremy M.G. and Department of Radiation Oncology, University of Michigan, Ann Arbor, MI and Liu Ning and Tra, Yolande and Duchesne, Gillian M. and Kestin, Larry L. and Martinez, Alvaro and Pratt, Gary R. and Sandler, Howard},
abstractNote = {Purpose: To examine the effect of fraction size and total dose of radiation on recurrence of localized prostate cancer. Methods and Materials: A total of 3756 patients treated with radiation monotherapy at three institutions were analyzed, including 185 high-dose-rate brachytherapy (HDRB) boost patients. The 5th to 95th centiles of external beam radiotherapy (EBRT) fraction sizes and doses were 1.8 to 2.86 Gy, and 57.4 to 77.4 Gy, respectively, and HDRB fractional doses were between 5.5 and 12 Gy, totaling 147 unique fractionation schedules. Failure was defined by one biochemical (nadir + 2 ng/ml) and two advanced disease endpoints. The {alpha}/{beta} ratios were estimated via a proportional hazards model stratified by risk severity and institution. Results: The {alpha}/{beta} ratio using biochemical recurrence was 3.7 Gy (95% confidence interval [95% CI], 1.1, {infinity} Gy) for EBRT-only cases and 2.6 Gy (95% CI, 0.9, 4.8 Gy) after the addition of HDRB data. This estimate was highly dependent on an HDRB homogeneity correction factor (120% HDRB dose increase; {alpha}/{beta} ratio 4.5 Gy, 95% CI 1.6, 8.7 Gy). A 5-Gy increase in total dose reduced the hazard of failure by 16% (95% CI 11, 21%, p < 0.0001), and had more impact as follow-up matured (p < 0.0003). The clinically advanced endpoints concurred with the biochemical failure results, albeit with less precision. Conclusions: This study supports the concept that the {alpha}/{beta} ratio of prostate cancer is low, although considerable uncertainty remains in the estimated value. Outcome data from EBRT studies using substantially higher doses per fraction are needed to show increased precision in these estimates.},
doi = {10.1016/j.ijrobp.2006.12.036},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 68,
place = {United States},
year = {Tue May 01 00:00:00 EDT 2007},
month = {Tue May 01 00:00:00 EDT 2007}
}
  • Purpose: There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. Methods and Materials: Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was usedmore » for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), {alpha} (dose-response slope using very low doses per fraction), and the ratio {alpha}/{beta} that characterizes dose-fractionation sensitivity. Results: There was no significant difference between the {alpha}/{beta} value for the three risk groups, and the value of {alpha}/{beta} for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the {alpha}/{beta} value. Conclusions: The overall {alpha}/{beta} value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.« less
  • Purpose: To estimate the α/β ratio for which the dose-dependent lung perfusion reductions for stereotactic body radiation therapy (SBRT) and conventionally fractionated radiation therapy (CFRT) are biologically equivalent. Methods and Materials: The relations between local dose and perfusion reduction 4 months after treatment in lung cancer patients treated with SBRT and CFRT were scaled according to the linear-quadratic model using α/β ratios from 0 Gy to ∞ Gy. To test for which α/β ratio both treatments have equal biological effect, a 5-parameter logistic model was optimized for both dose–effect relationships simultaneously. Beside the α/β ratio, the other 4 parameters weremore » d{sub 50}, the steepness parameter k, and 2 parameters (M{sub SBRT} and M{sub CFRT}) representing the maximal perfusion reduction at high doses for SBRT and CFRT, respectively. Results: The optimal fitted model resulted in an α/β ratio of 1.3 Gy (0.5-2.1 Gy), M{sub SBRT} = 42.6% (40.4%-44.9%), M{sub CFRT} = 66.9% (61.6%-72.1%), d{sub 50} = 35.4 Gy (31.5-9.2 Gy), and k = 2.0 (1.7-2.3). Conclusions: An equal reduction of lung perfusion in lung cancer was observed in SBRT and CFRT if local doses were converted by the linear-quadratic model with an α/β ratio equal to 1.3 Gy (0.5-2.1 Gy)« less
  • Purpose/Objectives: The addition of whole pelvic (WP) compared with prostate-only (PO) radiation therapy (RT) for clinically node-negative prostate cancer remains controversial. The purpose of our study was to evaluate the survival benefit of adding WPRT versus PO-RT for high-risk, node-negative prostate cancer, using the National Cancer Data Base (NCDB). Methods and Materials: Patients with high-risk prostate cancer treated from 2004 to 2006, with available data for RT volume, coded as prostate and pelvis (WPRT) or prostate alone (PO-RT) were included. Multivariate analysis (MVA) and propensity-score matched analysis (PSM) were performed. Recursive partitioning analysis (RPA) based on overall survival (OS) usingmore » Gleason score (GS), T stage, and pretreatment prostate-specific antigen (PSA) was also conducted. Results: A total of 14,817 patients were included: 7606 (51.3%) received WPRT, and 7211 (48.7%) received PO-RT. The median follow-up time was 81 months (range, 2-122 months). Under MVA, the addition of WPRT for high-risk patients had no OS benefit compared with PO-RT (HR 1.05; P=.100). On subset analysis, patients receiving dose-escalated RT also did not benefit from WPRT (HR 1.01; P=.908). PSM confirmed no survival benefit with the addition of WPRT for high-risk patients (HR 1.05; P=.141). In addition, RPA was unable to demonstrate a survival benefit of WPRT for any subset. Other prognostic factors for inferior OS under MVA included older age (HR 1.25; P<.001), increasing comorbidity scores (HR 1.46; P<.001), higher T stage (HR 1.17; P<.001), PSA (HR 1.81; P<.001), and GS (HR 1.29; P<.001), and decreasing median county household income (HR 1.15; P=.011). Factors improving OS included the addition of androgen deprivation therapy (HR 0.92; P=.033), combination external beam RT plus brachytherapy boost (HR 0.71; P<.001), and treatment at an academic/research institution (HR 0.84; P=.002). Conclusion: In the largest reported analysis of WPRT for patients with high-risk prostate cancer treated in the dose-escalated era, the addition of WPRT demonstrated no survival advantage compared with PO-RT.« less
  • Purpose: To estimate the {alpha}/{beta} ratio of prostate cancer treated with external beam radiation only by use of a model of long-term prostate-specific antigen (PSA) dynamics. Methods and Materials: Repeated measures of PSA from 5,093 patients from 6 institutions treated for localized prostate cancer by external beam radiation therapy (EBRT) without planned androgen deprivation were analyzed. A biphasic linear mixed model described the post-treatment evolution of PSA, rather than a conventional model of time to biochemical recurrence. The model was adjusted for standard prognostic factors (T stage, initial PSA level, and Gleason score) and cohort-specific effects. The radiation dose fractionationmore » effect was estimated from the long-term rate of rise of PSA level. Results: Adjusted for other factors, total dose of EBRT and sum of squared doses per fraction were associated with long-term rate of change of PSA level (p = 0.0017 and p = 0.0003, respectively), an increase of each being associated with a lower rate of rise. The {alpha}/{beta} ratio was estimated at 1.55 Gy (95% confidence band, 0.46-4.52 Gy). This estimate was robust to adjustment of the linear mixed model. Conclusions: By analysis of a large EBRT-only cohort along with a method that uses all the repeated measures of PSA after the end of treatment, a low and precise {alpha}/{beta} was estimated. These data support the use of hypofractionation at fractional doses up to 2.8 Gy but cannot presently be assumed to accurately represent higher doses per fraction.« less
  • Purpose: To present a novel method for meta-analysis of the fractionation sensitivity of tumors as applied to prostate cancer in the presence of an overall time factor. Methods and Materials: A systematic search for radiation dose-fractionation trials in prostate cancer was performed using PubMed and by manual search. Published trials comparing standard fractionated external beam radiation therapy with alternative fractionation were eligible. For each trial the {alpha}/{beta} ratio and its 95% confidence interval (CI) were extracted, and the data were synthesized with each study weighted by the inverse variance. An overall time factor was included in the analysis, and itsmore » influence on {alpha}/{beta} was investigated. Results: Five studies involving 1965 patients were included in the meta-analysis of {alpha}/{beta}. The synthesized {alpha}/{beta} assuming no effect of overall treatment time was -0.07 Gy (95% CI -0.73-0.59), which was increased to 0.47 Gy (95% CI -0.55-1.50) if a single highly weighted study was excluded. In a separate analysis, 2 studies based on 10,808 patients in total allowed extraction of a synthesized estimate of a time factor of 0.31 Gy/d (95% CI 0.20-0.42). The time factor increased the {alpha}/{beta} estimate to 0.58 Gy (95% CI -0.53-1.69)/1.93 Gy (95% CI -0.27-4.14) with/without the heavily weighted study. An analysis of the uncertainty of the {alpha}/{beta} estimate showed a loss of information when the hypofractionated arm was underdosed compared with the normo-fractionated arm. Conclusions: The current external beam fractionation studies are consistent with a very low {alpha}/{beta} ratio for prostate cancer, although the CIs include {alpha}/{beta} ratios up to 4.14 Gy in the presence of a time factor. Details of the dose fractionation in the 2 trial arms have critical influence on the information that can be extracted from a study. Studies with unfortunate designs will supply little or no information about {alpha}/{beta} regardless of the number of subjects enrolled.« less