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The Phoenix Definition of Biochemical Failure Predicts for Overall Survival in Patients With Prostate Cancer Matthew C. Abramowitz, MD1 Tiaynu Li, MA2 Mark K. Buyyounouski, MD1 Eric Ross, PhD2 Robert G. Uzzo, MD3 Alan Pollack, MD, PhD1 Eric M. Horwitz, MD1
BACKGROUND. The American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure (BF) incorporates backdating, resulting in an artificial flattening of Kaplan-Meier curves and overly favorable estimates when follow-up is short. The nadir 1 2 ng/mL (Nadir 1 2; Phoenix) definition reduces these artifacts. The objective of the current study was to compare ASTRO and Phoenix BF estimates as determinants of distant metastasis (DM), cause-specific mortality (CSM), and overall mortality (OM).
METHODS. A total of 1831 patients with T1-4N0M0 prostate cancer were treated Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
with external beam radiotherapy (RT) using conventional or three-dimensional
2
months and the median RT dose was 72 Gy (range, 60–79 Gy). Cox regression
1
Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 3
Department of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
conformal methods to at least 60 grays (Gy). The median follow-up was 71 models incorporating BF as a time-dependent covariate were used for both univariate and multivariate analyses. Other covariates included in the analyses were T classification, Gleason score, neoadjuvant/adjuvant androgen deprivation, age, RT dose, and pretreatment prostate-specific antigen.
RESULTS. BF was observed in 389 men (21%) using the Phoenix definition and 460 men (25%) using the ASTRO definition. DM was observed in 84 patients (5%), 48 patients (3%) patients died of prostate cancer, and 404 patients (22%) died of any cause. The Phoenix definition of BF was found to be a significant predictor of DM, CSM, and OM, after controlling for other significant covariates. The ASTRO definition was found to be associated with CSM and DM, but not OM.
CONCLUSIONS. The Phoenix definition of BF is a more robust determinant of Supported in part by Grants CA-006927 and CA101984-01 from the National Cancer Institute and a grant from Varian Medical Systems, Palo Alto, California. We thank Dr. Gerald Hanks for his leadership in the establishment of the Fox Chase Cancer Center database for the treatment of prostate cancer reported herein and Ruth Peter for her dedication to its maintenance. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or Varian Medical Systems. Address for reprints: Eric M. Horwitz, MD, Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497; Fax: (215) 214-1629; E-mail: eric.
[email protected] Received June 20, 2007; revision received July 30, 2007; accepted August 2, 2007.
ª 2007 American Cancer Society
patient outcome compared with the ASTRO definition. The correlation with mortality, including OM, and the independence of this correlation from the use of neoadjuvant/adjuvant androgen deprivation, supports the use of Nadir 1 2 in prostate cancer clinical trials of RT with or without androgen deprivation. Cancer 2008;112:55–60. 2007 American Cancer Society.
KEYWORDS: prostate cancer, biochemical failure, definition, survival, radiotherapy.
I
n the late 1990s, the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus guidelines provided a starting point for a uniform definition of biochemical failure (BF) after treatment with radiotherapy alone.1 However, with greater patient numbers and longer follow-up, several weaknesses have become clear. First, the ASTRO definition backdates BF, causing an artificial early drop and late flattening of Kaplan-Meier curves. These effects contribute to a pronounced dependency on the length of follow-up.2,3 Second, the ASTRO definition was not, at the time of its recommendation, associated with clinical outcomes. In fact, after its incorporation as an endpoint, evidence of the prediction of overall mortality (OM) remained elusive.4–8 It was not until 2004 that the
DOI 10.1002/cncr.23139 Published online 29 October 2007 in Wiley InterScience (www.interscience.wiley.com).
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ASTRO definition, used as a time-dependant variable, was shown to be correlated with OM.9 Third, ASTRO BF was originally designed as an endpoint for patients treated with external beam radiotherapy alone. Because there is a natural elevation of the prostate-specific antigen (PSA) level after the withdrawal of androgen deprivation (AD), the ASTRO definition will overestimate BF in these patients.10 It also fails in many cases to account for the PSA bounce phenomenon, which has been well described11–13; patients treated with brachytherapy have a greater risk of PSA bounce and are more apt to be misclassified using the ASTRO definition. There are other BF definitions that are more accurate predictors of clinical outcome.14 Recently, many of these were compared in a pooled analysis.15 The results showed that when BF was described as a 2-ng/mL rise in PSA over the PSA nadir with BF designated as the time the event occurred (at call), the results were more sensitive and specific for clinical failure than the ASTRO definition and avoided its pitfalls. This analysis did not evaluate the correlations between the ASTRO and nadir 1 2 ng/mL definitions with cause-specific mortality (CSM) or OM. Although the appeal of the nadir 1 2 ng/mL (Nadir 1 2) definition was acknowledged at a consensus conference in 2006,16 to our knowledge, there is little evidence that this definition is a stronger predictor of mortality.4–7 Although both the Nadir 1 2 and ASTRO definitions have been shown to predict for overall survival, these studies did not compare the 2 definitions, were based on patients treated with low doses of radiotherapy (71 years. The average initial pretreatment PSA (iPSA) level was 7.1 ng/mL (range, 0–371 ng/mL). There were 716 patients (41%) with T1 disease, 857 patients (49%) with T2 disease, and 171 patients (10%) with T3/T4 disease. Neoadjuvant, concurrent, and/or adjuvant hormone therapy was used in 291 patients (16%). The median length of AD was 7.69 months (range, 0– 107.6 months). The Gleason score was 2 to 6 in 1244 patients (68%), 7 in 442 patients (24%), and 8 to 10 in 145 patients (8%). The median follow-up was 71 months (range, 1–204 months).
MATERIALS AND METHODS Patient Characteristics A total of 1831 patients with pathologically diagnosed prostate cancer who were treated at Fox Chase Cancer Center between 1987 and 2001 were included in our analysis. Postprostatectomy patients as well as those with lymph node-positive disease or evidence of metastasis at the time of presentation were excluded. Patient characteristics are shown in Table 1. The median age of the patients was 69 years (range, 43–89 years); 231 patients (13%) were aged 60 years, 773 patients (42%) were ages 61 to 70
Radiotherapy Techniques Patients were treated with conventional (81 patients) and 3-dimensional conformal radiotherapy (1750 patients) to a minimum dose of 60 Gy (range, 60–79 Gy). These methods have been reported previously.17 The International Commission on Radiation Units and Measurements reference point doses were used.18 Briefly, patients were simulated and treated in a supine position in a a-cradle cast for immobilization. In general, patients with T1-2AB disease and a Gleason score
