American Society For Therapeutic Radiology And Oncology Definition Research Articles

MP74-09 P2PSA AND DERIVATIVES (%P2PSA AND PHI) ACCURATELY PREDICT PROSTATE CANCER IN OBESE MEN FROM A MULTICENTER PROSPECTIVE EUROPEAN STUDY

be a more robust determinant of patient outcome compared with the American Society for Therapeutic Radiology and Oncology (ASTRO) definition (three consecutive increases of PSA). However, the Phoenix definition is not suitable for comparing BF of BT and that of radical prostatectomy (RP) because BF after RP is diagnosed when PSA >0.2ng/mL and a large portion of the patients undergo salvage therapy before PSA reaches 2.0 ng/mL. The objective of this study is to compare a new definition of BF, PSA>0.2ng/mL with three consecutive increases (NTMC definition), with the Phoenix definition and the ASTRO definition. METHODS: A total of 1442 patients with clinically localized PCa were treated with BT between September 2003 and October 2010 at our institution, and followed at least 36 months (22 to 118, median 70.0 months). The patients were treated with seed implantation using I-125 with or without EBRT combination. The patients may have neoadjuvant androgen deprivation therapy (ADT), but ADT after BT was not performed in any of the cases before the diagnosis of disease recurrence. Sesitivity and specificity of each definition are calculated and compared. True failure is confirmed by clinical failure. Possible failure (PF) is defined as rising PSA toward the end of observation without clear evidence of clinical recurrence. There were 46 PF cases and they were excluded from the study. RESULTS: Sensitivity and specificity of the Phoenix, the ASTRO, and our definition are shown in a table. NTMC definition showed much higher sensitivity and slightly lower specificity compared to the Phoenix definition. NTMC definition had similar sensitivity and higher specificity to the ASTRO definition. Neoadjuvant ADT lowered sensitivity of the Phoenix definition, and raised specificity of the Phoenix and our definition. CONCLUSIONS: NTMC definition of BF after BT such as PSA>0.2ng/mL with three consecutive increases showed sufficiently high sensitivity and specificity. The definition is useful especially the cases with neoadjuvant ADT, or when comparing therapeutic effect of BT and RP.

Equivalent Biochemical Control and Improved Prostate-Specific Antigen Nadir After Permanent Prostate Seed Implant Brachytherapy Versus High-Dose Three-Dimensional Conformal Radiotherapy and High-Dose Conformal Proton Beam Radiotherapy Boost

Permanent prostate implant brachytherapy (PPI), three-dimensional conformal radiotherapy (3D-CRT), and conformal proton beam radiotherapy (CPBRT) are used in the treatment of localized prostate cancer, although no head-to-head trials have compared these modalities. We studied the biochemical control (biochemical no evidence of disease [bNED]) and prostate-specific antigen (PSA) nadir achieved with contemporary PPI, and evaluated it against 3D-CRT and CPBRT. A total of 249 patients were treated with PPI at the University of California, San Francisco, and the outcomes were compared with those from a 3D-CRT cohort and the published results of a high-dose CPBRT boost (CPBRTB) trial. For each comparison, subsets of the PPI cohort were selected with patient and disease criteria similar to those of the reference group. With a median follow-up of 5.3 years, the bNED rate at 5 and 7 years achieved with PPI was 92% and 86%, respectively, using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, and 93% using the PSA nadir plus 2 ng/mL definition. Using the ASTRO definition, a 5-year bNED rate of 78% was achieved for the 3D-CRT patients compared with 94% for a comparable PPI subset and 93% vs. 92%, respectively, using the PSA nadir plus 2 ng/mL definition. The median PSA nadir for patients treated with PPI and 3D-CRT was 0.10 and 0.40 ng/mL, respectively (p < .0001). For the CPBRT comparison, the 5-year bNED rate after a CPBRTB was 91% using the ASTRO definition vs. 93% for a similar group of PPI patients. A greater proportion of PPI patients achieved a lower PSA nadir compared with those achieved in the CPBRTB trial (PSA nadir < or =0.5 ng/mL, 91% vs. 59%, respectively). We have demonstrated excellent outcomes in low- to intermediate-risk patients treated with PPI, suggesting at least equivalent 5-year bNED rates and a greater proportion of men achieving lower PSA nadirs compared with 3D-CRT or CPBRTB.

Recognizing False Biochemical Failure Calls After Radiation With or Without Neo-Adjuvant Androgen Deprivation for Prostate Cancer

We studied prostate-specific antigen (PSA) changes after radiation with or without neoadjuvant androgen deprivation to determine posttreatment PSA scenarios in which false-positive biochemical failures (FPBF) are most likely to occur. In the Trans-Tasman Radiation Oncology 96.01 Group trial, patients with T2b, 2c, 3, 4 N0 prostate cancer were randomized to 3 or 6 months goserelin and flutamide (STAD) before and during 66 Gy to the prostate and seminal vesicles (XRT) or to XRT alone. Piecewise longitudinal changes in PSA before relapse were characterized and quantified to determine which might cause FPBF calls. Between 1996 and 2000, 802 eligible patients were randomized. Of these, 492 met the criteria for American Society for Therapeutic Radiology and Oncology (ASTRO) failure and 467 for Phoenix failure. Seventy-seven ASTRO fails and 39 Phoenix fails were deemed false positives (FPs). The majority of FPBFs were associated with the "plateauing" in PSA values that follow posttreatment nadir. FPBFs were particularly common in men treated with STAD, in whom small, consecutive PSA rises before or during this phenomenon triggered 56 FP ASTRO fail calls. In these men, the Phoenix fail criteria triggered only 15 FPBF calls. However, the Phoenix criteria were more vulnerable than ASTRO to short-term isolated PSA rises during plateau, which resulted in 15 Phoenix fail calls but only 3 FP ASTRO fails. The Phoenix definition avoided 50% of FPBF calls that occurred with the ASTRO definition. Failures should be confirmed by further PSA rises before investigation and treatment is considered.

The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer

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 + 2 ng/mL (Nadir + 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). A total of 1831 patients with T1-4N0M0 prostate cancer were treated with external beam radiotherapy (RT) using conventional or three-dimensional conformal methods to at least 60 grays (Gy). The median follow-up was 71 months and the median RT dose was 72 Gy (range, 60-79 Gy). Cox regression 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. 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. The Phoenix definition of BF is a more robust determinant of 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 + 2 in prostate cancer clinical trials of RT with or without androgen deprivation.

What Dose of External-Beam Radiation is High Enough for Prostate Cancer?

To quantify the radiotherapy dose-response of prostate cancer, adjusted for prognostic factors in a mature cohort of men treated relatively uniformly at a single institution. The study cohort consisted of 1,530 men treated with three-dimensional conformal external-beam radiotherapy between 1989 and 2002. Patients were divided into four isocenter dose groups: <70 Gy (n = 43), 70-74.9 Gy (n = 552), 75-79.9 Gy (n = 568), and > or =80 Gy (n = 367). The primary endpoints were freedom from biochemical failure (FFBF), defined by American Society for Therapeutic Radiology and Oncology (ASTRO) and Phoenix (nadir + 2.0 ng/mL) criteria, and freedom from distant metastases (FFDM). Multivariate analyses were performed and adjusted Kaplan-Meier estimates were calculated. Logit regression dose-response functions were determined at 5 and 8 years for FFBF and at 5 and 10 years for FFDM. Radiotherapy dose was significant in multivariate analyses for FFBF (ASTRO and Phoenix) and FFDM. Adjusted 5-year estimates of ASTRO FFBF for the four dose groups were 60%, 68%, 76%, and 84%. Adjusted 5-year Phoenix FFBFs for the four dose groups were 70%, 81%, 83%, and 89%. Adjusted 5-year and 10-year estimates of FFDM for the four dose groups were 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%. Dose-response functions showed an increasing benefit for doses > or =80 Gy. Doses of > or =80 Gy are recommended for most men with prostate cancer. The ASTRO definition of biochemical failure does not accurately estimate the effects of radiotherapy at 5 years because of backdating, compared to the Phoenix definition, which is less sensitive to follow-up and more reproducible over time.

Intermediate-Risk Localized Prostate Cancer in the PSA Era: Radiotherapeutic Alternatives

To retrospectively compare the biochemical disease-free survival (BDFS) of patients treated with standard dose external beam radiotherapy (SD-EBRT), SD-EBRT plus androgen deprivation (AD), and brachytherapy-based treatment (brachytherapy with or without EBRT with or without AD). All 297 patients with intermediate-risk prostate cancer treated with these radiation-based treatments at our institution from August 1989 to June 2001 were included. Biochemical relapse was defined according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, a prostate-specific antigen level of 1.5 ng/mL or greater and rising on two consecutive occasions (the "Bolla" definition), and the current prostate-specific antigen nadir plus 2 ng/mL with failure dated "at call" (the "Houston/Phoenix" definition). The number of patients treated with SD-EBRT, SD-EBRT plus AD, and brachytherapy-based treatment was 141, 84, and 72, respectively. The year of treatment was analyzed as a prognostic factor. The median follow-up was 32.3, 34.7, and 41.5 months for the ASTRO, Bolla, and Houston/Phoenix definitions, respectively. The brachytherapy-based treatment resulted in improved BDFS compared with SD-EBRT (ASTRO definition, 5-year BDFS rate 88% +/- 5% versus 49% +/- 5%, P <0.01; Bolla definition, 88% +/- 8% versus 49% +/- 5%, P <0.01; Houston/Phoenix definition, 81% +/- 10% versus 64% +/- 5%, P = 0.01). SD-EBRT plus AD was superior to SD-EBRT alone using the Bolla definition (5-year BDFS 76% +/- 7% versus 49% +/- 5%, P <0.01) and the Houston/Phoenix definition (85% +/- 6% versus 64% +/- 5%, P = 0.01), but not using the ASTRO definition (P = 0.17). Multivariate analysis, including prostate-specific antigen, clinical stage, Gleason score, and year of treatment, demonstrated improved biochemical outcomes for brachytherapy-based treatment versus SD-EBRT (ASTRO, P <0.01; Bolla, P <0.01; and a trend toward significance with Houston/Phoenix, P = 0.07) and for the addition of AD to SD-EBRT (Bolla, P <0.01 and Houston/Phoenix, P = 0.03). The year of treatment trended toward significance (P = 0.077) on multivariate analysis using the ASTRO definition. For patients with intermediate-risk prostate cancer, brachytherapy-based treatment and the addition of AD to SD-EBRT resulted in improved biochemical outcomes compared with the outcomes with SD-EBRT alone; however, these findings were dependent on the definition of biochemical failure used. The year of treatment may be an important prognostic factor in intermediate-risk prostate cancer.

Radiation dose and late failures in prostate cancer

To quantify the impact of radiation dose escalation on the timing of biochemical failure (BF) and distant metastasis (DM) for prostate cancer treated with radiotherapy (RT) alone. The data from 667 men with clinically localized intermediate- and high-risk prostate cancer treated with three-dimensional conformal RT alone were retrospectively analyzed. The interval hazard rates of DM and BF, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and Phoenix (nadir + 2) definitions, were determined. The median follow-up was 77 months. Multivariate analysis showed that increasing radiation dose was independently associated with decreased ASTRO BF (p < 0.0001), nadir + 2 BF (p = 0.001), and DM (p = 0.006). The preponderance (85%) of ASTRO BF occurred at < or =4 years after RT, and nadir + 2 BF was more evenly spread throughout Years 1-10, with 55% of BF in < or =4 years. Radiation dose escalation caused a shift in the BF from earlier to later years. The interval hazard function for DM appeared to be biphasic (early and late peaks) overall and for the <74-Gy group. In patients receiving > or =74 Gy, a reduction occurred in the risk of DM in the early and late waves, although the late wave appeared reduced to a greater degree. The ASTRO definition of BF systematically underestimated late BF because of backdating. Radiation dose escalation diminished and delayed BF; the delay suggested that local persistence may still be present in some patients. For DM, a greater radiation dose reduced the early and late waves, suggesting that persistence of local disease contributed to both.

In regards to Roach et al. defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG–ASTRO Phoenix Consensus Conference (Int J Radiat Oncol Biol Phys 2006;65:965–974)

I read with great interest the article by Roach et al. (1Roach M. Hanks G. Thames H.J. et al.Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference.Int J Radiat Oncol Biol Phys. 2006; 65: 965-974Abstract Full Text Full Text PDF PubMed Scopus (1975) Google Scholar). The panel’s recommendation is to use the Phoenix (previously also called the current nadir + 2) definition as a new standard to define biochemical failure (1Roach M. Hanks G. Thames H.J. et al.Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference.Int J Radiat Oncol Biol Phys. 2006; 65: 965-974Abstract Full Text Full Text PDF PubMed Scopus (1975) Google Scholar, 2Thames H. Kuban D. Levy L. et al.Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995.Int J Radiat Oncol Biol Phys. 2003; 57: 929-943Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). The ASTRO definition is recommended to continue be used with strict adherence to guidelines. As the debate on the most appropriate definition of biochemical failure is settling, I would like to draw attention to how much impact this change of definition may have on the radiation dose–response analysis of prostate cancer. The position, the steepness, and time dependence of the dose–response curves can be very different for each risk group using the two definitions (3Cheung R. Tucker S.L. Lee A.K. et al.Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 61: 993-1002Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 4Cheung R. Tucker S.L. Lee A.L. et al.Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 61: 14-19Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) for the intermediate-risk patients. For example, the Phoenix definition projected much smaller benefit for further dose escalation beyond 78 Gy than when the ASTRO definition was used (3Cheung R. Tucker S.L. Lee A.K. et al.Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 61: 993-1002Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). For the high-risk group, TD50, the dose to achieve 50% tumor control, increased from 70.4 Gy using the Phoenix definition to 75.5 Gy using the ASTRO definition (4Cheung R. Tucker S.L. Lee A.L. et al.Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 61: 14-19Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). As we are still searching for the optimal dose to treat our prostate cancer patients, accurate dose–response modeling is important to project benefit of further dose escalation. Furthermore, the interest on using hypofractionation to treat prostate cancer has surged since Brenner and Hall published a lower-than-expected α/β ratio for prostate cancer (5Brenner D.J. Hall E.J. Fractionation and protraction for radiotherapy of prostate carcinoma.Int J Radiat Oncol Biol Phys. 1999; 43: 1095-1101Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar). It should be noted that the steepness of the dose–response curve could also have an impact on the estimation of the α/β ratio of prostate cancer (6Bentzen S.M. Ritter M.A. The alpha/beta ratio for prostate cancer: what is it, really?.Radiother Oncol. 2005; 76: 1-3Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). In reply to Dr. CheungInternational Journal of Radiation Oncology, Biology, PhysicsVol. 66Issue 4PreviewDr. Cheung is absolutely correct. Using the so-called “Phoenix” definition (defined as nadir + 2 ng/mL) significantly changes the biochemical failure pattern compared with using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition (1). In addition to his retrospective studies, at least one Phase III randomized trial demonstrated that the use of the Phoenix definition could have an impact on the interpretation of dose–response data (2–4). In the Dutch trial reported by Peeters et al. Full-Text PDF

Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference

In 1996 the American Society for Therapeutic Radiology and Oncology (ASTRO) sponsored a Consensus Conference to establish a definition of biochemical failure after external beam radiotherapy (EBRT). The ASTRO definition defined prostate specific antigen (PSA) failure as occurring after three consecutive PSA rises after a nadir with the date of failure as the point halfway between the nadir date and the first rise or any rise great enough to provoke initiation of therapy. This definition was not linked to clinical progression or survival; it performed poorly in patients undergoing hormonal therapy (HT), and backdating biased the Kaplan-Meier estimates of event-free survival. A second Consensus Conference was sponsored by ASTRO and the Radiation Therapy Oncology Group in Phoenix, Arizona, on January 21, 2005, to revise the ASTRO definition. The panel recommended: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined "at call" (not backdated). They recommended that investigators be allowed to use the ASTRO Consensus Definition after EBRT alone (no hormonal therapy) with strict adherence to guidelines as to "adequate follow-up." To avoid the artifacts resulting from short follow-up, the reported date of control should be listed as 2 years short of the median follow-up. For example, if the median follow-up is 5 years, control rates at 3 years should be cited. Retaining a strict version of the ASTRO definition would allow comparisons with a large existing body of literature.

Prostate-specific antigen (PSA) bounce and other fluctuations: Which biochemical relapse definition is least prone to PSA false calls? An analysis of 2030 men treated for prostate cancer with external beam or brachytherapy with or without adjuvant androgen deprivation therapy

To determine the false call (FC) rate for prostate-specific antigen (PSA) relapse according to nine different PSA relapse definitions after a PSA fluctuation (bounce) has occurred after external beam radiation therapy (EBRT) or brachytherapy, with or without adjuvant androgen deprivation therapy. An analysis of a prospective database of 2030 patients was conducted. Prostate-specific antigen relapse was scored according to the American Society for Therapeutic Radiology and Oncology (ASTRO), Vancouver, threshold + n, and nadir + n definitions for the complete data set and then compared against a truncated data set, with data subsequent to the height of the bounce deleted. The FC rate was calculated for each definition. The bounce rate, with this very liberal definition of bounce, was 58% with EBRT and 84% with brachytherapy. The FC rate was lowest with nadir + 2 and + 3 definitions (2.2% and 1.6%, respectively) and greatest with low-threshold and ASTRO definitions (32% and 18%, respectively). The ASTRO definition was particularly susceptible to FC when androgen deprivation therapy was used with radiation (24%). New definitions of biochemical non-evidence of disease that are more robust than the ASTRO definition have been identified. Those with the least FC rates are the nadir + 2 and nadir + 3 definitions, both of which are being considered to replace the ASTRO definition by the 2005 meeting of the Radiation Therapy Oncology Group-ASTRO consensus panel.

Dose–response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy

In this era of dose escalation, the benefit of higher radiation doses for low-risk prostate cancer remains controversial. For intermediate-risk patients, the data suggest a benefit from higher doses. However, the quantitative characterization of the benefit for these patients is scarce. We investigated the radiation dose-response relation of tumor control probability in low-risk and intermediate-risk prostate cancer patients treated with radiotherapy alone. We also investigated the differences in the dose-response characteristics using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition vs. an alternative biochemical failure definition. This study included 235 low-risk and 387 intermediate-risk prostate cancer patients treated with external beam radiotherapy without hormonal treatment between 1987 and 1998. The low-risk patients had 1992 American Joint Committee on Cancer Stage T2a or less disease as determined by digital rectal examination, prostate-specific antigen (PSA) levels of < or =10 ng/mL, and biopsy Gleason scores of < or =6. The intermediate-risk patients had one or more of the following: Stage T2b-c, PSA level of < or =20 ng/mL but >10 ng/mL, and/or Gleason score of 7, without any of the following high-risk features: Stage T3 or greater, PSA >20 ng/mL, or Gleason score > or =8. The logistic models were fitted to the data at varying points after treatment, and the dose-response parameters were estimated. We used two biochemical failure definitions. The ASTRO PSA failure was defined as three consecutive PSA rises, with the time to failure backdated to the mid-point between the nadir and the first rise. The second biochemical failure definition used was a PSA rise of > or =2 ng/mL above the current PSA nadir (CN + 2). The failure date was defined as the time at which the event occurred. Local, nodal, and distant relapses and the use of salvage hormonal therapy were also failures. On the basis of the ASTRO definition, at 5 years after radiotherapy, the dose required for 50% tumor control (TCD(50)) for low-risk patients was 57.3 Gy (95% confidence interval [CI], 47.6-67.0). The gamma50 was 1.4 (95% CI, -0.1 to 2.9) around 57 Gy. A statistically significant dose-response relation was found using the ASTRO definition. However, no dose-response relation was noted using the CN + 2 definition for these low-risk patients. For the intermediate-risk patients, using the ASTRO definition, the TCD(50) was 67.5 Gy (95% CI, 65.5-69.5) Gy and the gamma50 was 2.2 (95% CI, 1.1-3.2) around TCD(50). Using the CN + 2 definition, the TCD(50) was 57.8 Gy (95% CI, 49.8-65.9) and the gamma50 was 1.4 (95% CI, 0.2-2.5). Recursive partitioning analysis identified two subgroups within the low-risk group, as well as the intermediate-risk group: PSA level <7.5 vs. > or =7.5 ng/mL. Most of the benefit from the higher doses for the low- and intermediate-risk group was derived from the patients with the higher PSA values. For the low-risk group, the dose-response curves essentially plateaued at 78 Gy. A dose-response relation was found using the ASTRO definition for low-risk prostate cancer. However, we found only marginal or no dose-response relation when the CN + 2 definition was used. Most of the benefit from the higher doses derived from low-risk patients with higher PSA levels. In all cases, little projected gain appears to exist at doses >78 Gy for these patients. A dose-response relation was noted for the intermediate-risk patients using either the CN + 2 or ASTRO definition. Most of the benefit from the higher doses also derived from the intermediate-risk patients with higher PSA levels. Some room for improvement appears to exist with additional dose increases in this group.

DEFINITIONS OF BIOCHEMICAL FAILURE THAT BEST PREDICT CLINICAL FAILURE IN PATIENTS WITH PROSTATE CANCER TREATED WITH EXTERNAL BEAM RADIATION ALONE: A MULTI-INSTITUTIONAL POOLED ANALYSIS

Pooled data on 4,839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions have previously provided long-term biochemical failure (BF) and clinical outcomes using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. In this report we determined the sensitivity and specificity of several BF definitions using distant failure (DF) alone or clinical failure (CF), defined as local failure (LF) and/or DF. The pooled cohort was treated between 1986 and 1995 with external beam RT (60 Gy or greater) without pre-RT androgen suppression or planned post-RT adjuvant androgen suppression. Median followup was 6.3 years. The sensitivity and specificity of 102 definitions of BF relative to DF and LF were assessed. The BF definitions with higher sensitivity and specificity than the ASTRO definition for DF only and CF are reported. The sensitivity and specificity of the ASTRO definition to predict DF alone was 55% and 68%, respectively. Three definitions had higher sensitivity and specificity, namely prostate specific antigen (PSA) greater than current nadir (lowest PSA prior to current measurement) plus 3 ng/ml (sensitivity 76% and specificity 72%), dated at the call (failure date as the date when the criterion was met), PSA greater than absolute nadir plus 2 ng/ml (sensitivity 72% and specificity 70%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 69% and specificity 73%). The sensitivity and specificity of the ASTRO definition to predict CF was 60% and 72%, respectively. Three definitions had higher sensitivity and specificity, namely PSA greater than current nadir plus 3 ng/ml (sensitivity 66% and specificity 77%), dated at the call, PSA greater than absolute nadir plus 2 ng/ml (sensitivity 64% and specificity 74%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 67% and specificity 78%). Using what is to our knowledge the largest data set of patients with prostate cancer treated with RT alone we correlated multiple definitions of BF with the strict clinical end points of DF alone and CF (DF or local failure). Defining BF as PSA greater than absolute nadir plus 2 ng/ml, dated at the call, PSA greater than current nadir plus 3 ng/ml, dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated, had higher sensitivity and specificity for DF alone or CF compared with the ASTRO definition. This information should contribute to the discussion regarding suggested modifications to the ASTRO definition of biochemical failure.

High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy’s 10-year results

To present the long-term outcome and morbidity of high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT) for localized prostate cancer. Between September 1991 and December 1998, 209 consecutive patients with no prior androgen suppression were treated with HDR-BT plus EBRT. The median follow-up was 7.25 years (range, 5-12 years). The patients were stratified into three risk groups: low (Stage T2a or less, Gleason score </=6, and prostate-specific antigen [PSA] level </=10 ng/mL), intermediate (Stage T2b,c, Gleason score 7, and PSA level 10-20 ng/mL), and high (Stage T3, Gleason score 8-10, and PSA level >20). Four definitions of PSA progression were compared with the general clinical failure outcome: the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, nadir plus 2.0 ng/mL, two consecutive rises >/=0.5 ng/mL, and PSA level >0.2 ng/mL. Morbidity was scored using Radiation Therapy Oncology Group criteria. The general clinical control rate was 90% (188 of 209), and the general clinical failure rate was 10% (21 of 209). The overall survival rate was 79%, and the cause-specific survival rate was 97%. The PSA progression-free survival (ASTRO definition) rate was 90%, 87%, and 69% for the low-, intermediate-, and high-risk groups, respectively. The nadir plus 2 ng/mL and two rises >/=0.5 definitions correlated better with the actual clinical outcome than did the ASTRO and PSA >0.2 ng/mL definitions. The rate of Grade 3 and 4 late urinary morbidity was 6.7% and 1%, respectively, mostly occurring in patients who had undergone post-RT transurethral prostate resection. No late Grade 3 or 4 rectal morbidity developed. The sexual potency preservation rate was 67%. Our 10-year results have demonstrated HDR-BT plus EBRT is a proven treatment for all stages of localized prostate cancer. The morbidity was low, but post-RT transurethral resection should be avoided.

Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy

The American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition has recently been compared with various alternative definitions. We assessed the effect of using an alternative failure definition on the dose-response characteristics of high-risk prostate cancer treated with radiotherapy alone. This study included 363 high-risk prostate cancer patients treated with external beam radiotherapy alone from 1987 to 1999. These patients have one or more of the following: 1992 American Joint Committee on Cancer (AJCC) digital rectal examination (DRE) stage > or = cT3, prostate-specific antigen (PSA) > 20 ng/mL, and/or biopsy Gleason score > or = 8. We previously reported the dose response based on the ASTRO definition for these patients. In this study, a biochemical failure is defined as a PSA rise > or = 2 ng/mL above the current nadir PSA (CN + 2). The failure date is defined as the time at which the event occurred (i.e., the call date). Using CN + 2, the tumor control probability (TCP) continues to decrease with time as opposed to reaching a plateau as with the ASTRO definition. At 5 years, TCD50 (95% CI), the dose to achieve 50% tumor control, for high-risk prostate cancer, is 70.4 (68.0-72.9) Gy using CN + 2 [ASTRO: 75.5 (70.7-80.2) Gy]. The relative slope, gamma50 (95% CI) is 1.8 (0.8-2.8) [ASTRO: 1.7 (0.7-2.7)]. Recursive partitioning again identified two subgroups: PSA < vs. > or = 13 ng/mL (ASTRO: PSA < or = vs. > 20 ng/mL). The difference in TCD50 between the two subgroups is about 20 Gy at 5 years (ASTRO: about 15 Gy at 5 years). This analysis using the CN + 2 failure definition continues to show a dose response for the high-risk group of patients. However, the dose-response characteristics differ from those estimated using the ASTRO definition. We observed that the position (TCD50) and steepness (gamma50) of the dose-response curve changed with time as long as the TCP continued to decrease. This suggests that the dose response characteristics derived from data with longer follow-up may be different from those derived with shorter follow-up using the CN + 2 or similar failure definitions which do not back-date the failure. These changes in dose-response characteristics as well as the time dependence of dose response should be noted when investigators design dose escalation trials for the high-risk prostate cancer patients.

Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995

Purpose To assess the merit of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after external beam radiotherapy for prostate cancer by testing alternative prostate-specific antigen (PSA) failure definitions against the “gold standard” of clinical failure and to study the effect of backdating the time of failure. Methods and materials Nine participating institutions agreed to submit follow-up results for all patients with clinically localized prostatic cancer (Stage T1b, T1c, T2, N0M0) treated between 1986 and 1995 by external beam radiotherapy only, to doses of ≥60 Gy, with no androgen deprivation before treatment. A total of 4839 men met the study criteria, with a median follow-up time of 6.3 years. The prediction of clinical failure by 102 definitions of biochemical failure was assessed using various quantitative measures. Results Four definitions were superior as measured by the sensitivity, specificity, positive and negative predictive values, and hazard of clinical failure after biochemical failure: two rises of at least 0.5 ng/mL backdated, PSA level at or greater than the absolute nadir plus 2 ng/mL at the call date, and PSA level at or greater than the current nadir plus 2 or 3 ng/mL at the call date. The absolute nadir was the lowest measured PSA level during all of follow-up, and the current nadir was the lowest PSA measured previous to a particular PSA measurement during follow-up. With the possible exception of patients in the low-risk group, the likelihood of ultimate clinical failure decreased as the time of biochemical failure increased. Failure definitions based on PSA levels >0.2 or 0.5 ng/mL were inferior to other definitions. Backdating the failure time introduced bias into the estimate of freedom from biochemical failure, which was increasingly overestimated at shorter median follow-up times. This bias can be circumvented either by using a failure definition based on the call date or by backdating the censoring times of patients with one or two rises who could potentially have failure at a future (unobserved) time. A short follow-up time as such does not result in bias unless the failures are backdated; in the absence of backdating, it is the precision of failure-free survival that is increasingly compromised as the follow-up time is reduced. Conclusion The ASTRO failure definition ended the confusion resulting from different failure definitions that had been in use, and it did so accurately enough that it is probably not necessary to recalculate previously published results. Nevertheless, for the current pooled analysis of outcome in 4839 men with a 6.3-year median follow-up, other definitions of biochemical failure were superior as assessed by various quantitative measures of concordance of biochemical and ultimate clinical failure. An additional disadvantage of the ASTRO definition is the bias introduced by backdating failures, as well as the necessarily retrospective nature of its application. Some “current” definitions, but not those based on the PSA level rising above a fixed threshold, have significantlyhigher sensitivity and specificity, do not lead to biased estimations of biochemical disease-free survival, and are directly applicable during patient counseling. These are all issues that would play a role in replacing the ASTRO consensus definition.

Influence of follow-up bias on PSA failure after external beam radiotherapy for localized prostate cancer: Results from a 10-year cohort analysis

Purpose To estimate the biases inherent in prostate cancer outcome that arise from different failure end points and variations in follow-up time and intensity using a cohort of men with long follow-up. Methods and materials The study cohort consisted of 205 men with T1–T2N0-Nx prostate cancer treated with conventional radiotherapy between 1991 and 1993. The median follow-up was 103 months. Outcome was assessed using different definitions of biochemical failure, including the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria and the “nadir plus two” criteria (any rise of 2 ng/mL greater than the current nadir). Patient subgroups were created according to where patients had received their last 2 years of follow-up. Patients were also stratified according to whether they were initially present in the departmental database (under regular surveillance) or were uncovered after more vigorous investigation (previously “lost to follow-up”). Results In this series with maximized follow-up, the 10-year biochemical disease-free survival rate did not change significantly with varying definitions of failure, 49% and 45% for ASTRO and “nadir plus two” criteria, respectively. Patients followed by outside physicians ( n = 99) were faring better at 10 years than those followed at the treating institution by either their radiation oncologist ( n = 50) or their medical oncologist or urologist ( n = 52). This was by all measures of outcome, including overall survival, and metastasis-free survival. Patients previously lost to follow-up ( n = 43) who were tracked down also appeared to be doing better than those on our database for whom information had been readily available ( n = 161). This, however, may have been an artifact of the ASTRO criteria, which underestimates failure when insufficient prostate-specific antigen values are available. Conclusion The ASTRO definition of failure underestimates late failure. This bias may be compensated for by the use of cohorts with long follow-up or the use of the “nadir plus two” definition of failure. The use of institutional prostate cancer databases may overestimate failure rates because patients followed outside of the treating institution fared better with respect to both survival and biochemical recurrence. Vigorous attempts to obtain follow-up beyond the hospital walls may correct this bias.

Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias

Purpose To validate the Houston prostate-specific antigen relapse definition in a mature cohort of men treated with external beam radiotherapy (EBRT) and adjuvant androgen ablation (AA) and men treated with EBRT monotherapy, and to compare these results with the American Society for Therapeutic Radiology and Oncology (ASTRO) and Vancouver prostate-specific antigen relapse (biochemical no evidence of disease) definitions. Methods and materials A prospective database of 1490 men treated with EBRT, with or without AA, was examined. The impact on hazard proportions, as well as the predictive ability, of the Houston, ASTRO, and Vancouver definitions was tested. Results For all patients, the Houston definition was more accurate (79.5%) than the ASTRO (76.7%) or Vancouver (77.2%) definitions in predicting subsequent clinical relapse. The Houston definition was superior to the ASTRO definition in those treated both with and without AA and equivalent to the Vancouver definition in those receiving AA. The Houston definition demonstrated proportional hazards when categorized for the use of AA, unlike the ASTRO and Vancouver definitions. The effect of inadequate follow-up on the projected relapse rates was negligible with the Houston definition. Conclusion The Houston relapse definition is favored after EBRT monotherapy or combined EBRT and AA. Use of the Cox proportional hazard multivariate analysis is appropriate with the Houston definition, but not with the ASTRO or Vancouver definitions if AA and non-AA patients are combined.

The Outcome of Neoadjuvant Hormonal Therapy with Radiation Therapy Depends on the Definition of Biochemcial Failure

Purpose: We compared biochemical control rates of 3D conformal radiation therapy (3DCRT) plus neoadjuvant hormonal therapy (NHT) with those of prostate 3DCRT alone. We also examined the effect that two definitions of biochemical failure had on the comparison. Patients and Methods: We studied 126 men with stage T1-3B prostate cancer, who were treated with 3DCRT (Median dose of 72.0 Gy prescribed to the PTV) to the prostate alone (minimum follow-up duration of 1 year). Thirty-nine men received 4 to 6 months of NHT and 87 had 3DCRT alone. Hormonal therapy consisted of a LHRH agonist +/- an anti-androgen. We subdivided the patients into risk categories according to their baseline PSA and Gleason score: Low risk (Gleason Scores >7 and baseline PSA >10), Intermediate risk (Gleason Scores >7 and baseline PSA ≥10 or Gleason Scores ≥7 and baseline PSA >10), and High risk (Gleason Scores ≥7 and baseline PSA ≥10). We used two definitions of biochemical failure. First we defined failure according to the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus statement. In the second analysis, biochemical failure was defined as three serial rises in the PSA with a rise above 1.5 ng/ml. Results: According to the ASTRO definition, the use of neoadjuvant hormonal therapy resulted in a significantly lower PSA control rate in low and intermediate risk patients (P = .0028). When the data was reanalyzed using the second definition for PSA failure, the results were reversed, in that the biochemical outcomes of HT patients were better than the outcomes of patients who received 3DCRT alone. Conclusion: This reversal of outcome indicates that treatment outcome depends on definition of biochemical failure in patients receiving NHT. Given this limitation, it is important that ASTRO address the use of hormonal therapy in devising a new consensus statement defining biochemical failure.

Definitions of biochemical failure in prostate cancer following radiation therapy

Purpose: The American Society for Therapeutic Radiology and Oncology (ASTRO) published a consensus panel definition of biochemical failure following radiation therapy for prostate cancer. In this paper, we develop a series of alternative definitions of biochemical failure. Using data from 688 patients, we evaluated the sensitivity and specificity of the various definitions, with respect to a defined “clinically meaningful” outcome. Methods and Materials: The ASTRO definition of biochemical failure requires 3 consecutive rises in prostate-specific antigen (PSA). We considered several modifications to the standard definition: to require PSA rises of a certain magnitude, to consider 2 instead of 3 rises, to require the final PSA value to be greater than a fixed cutoff level, and to define biochemical failure based on the slope of PSA over 1, 1.5, or 2 years. A clinically meaningful failure is defined as local recurrence, distant metastases, initiation of unplanned hormonal therapy, unplanned radical prostatectomy, or a PSA > 25 later than 6 months after radiation. Results: Requiring the final PSA in a series of consecutive rises to be larger than 1.5 ng/mL increased the specificity of biochemical failure. For a fixed specificity, defining biochemical failure based on 2 consecutive rises, or the slope over the last year, could increase the sensitivity by up to approximately 20%, compared to the ASTRO definition. Using a rule based on the slope over the previous year or 2 rises leads to a slightly earlier detection of biochemical failure than does the ASTRO definition. Even with the best rule, only approximately 20% of true failures are biochemically detected more than 1 year before the clinically meaningful event time. Conclusion: There is potential for improvement in the ASTRO consensus definition of biochemical failure. Further research is needed, in studies with long follow-up times, to evaluate the relationship between various definitions of biochemical failure and true clinical outcome.

DEFINING PROSTATE SPECIFIC ANTIGEN PROGRESSION AFTER RADICAL PROSTATECTOMY: WHAT IS THE MOST APPROPRIATE CUT POINT?

The most appropriate definition of biochemical progression after radical prostatectomy and radiation therapy is uncertain. We analyzed the effect of using various prostate specific antigen (PSA) end point definitions for defining biochemical progression after radical prostatectomy and attempted to determine the best PSA cut point to use. Aspects of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after radiation therapy are also analyzed in our radical prostatectomy cases. A total of 2,782 men with clinically localized prostate cancer (cT1-T2) who had undergone radical prostatectomy between 1987 and 1993 were reviewed. All patients had regular PSA determinations from surgery through followup. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Biochemical, PSA progression-free percent after radical prostatectomy was determined by the Kaplan-Meier method using several PSA cut points, including 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater, as well as 0.4 ng./ml. or greater and increasing. Progression-free percent was also assessed using the ASTRO definition, which is 3 increases in PSA. To determine which PSA level was most appropriate to define progression after radical prostatectomy, the percentage of patients with a continued PSA increase after reaching each cut point was determined. The relationship between the maximum PSA within 3 years of surgery and subsequent development of clinical disease was also assessed. Progression-free percent was dependent on the PSA cut point used. Biochemical progression-free percentages for cut points 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater were 62%, 72%, 76% and 78% at 5 years, and 43%, 54%, 59% and 61% at 10 years, respectively. A subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA 0.2, 0.3 and 0.4 ng./ml., respectively. Subsequent clinical progression (local or systemic) was directly related to the maximum PSA attained within 3 years of radical prostatectomy (p=0.0001). Progression-free percent for definitions requiring multiple increases in PSA were dependent on when the event was said to occur. Backdating of events at or before the first PSA (ASTRO definition) resulted in poorer, short-term progression-free percent (78% at 5 years), with little apparent likelihood of long-term failure (78% at 10 years). Coding the event at the last PSA increase when all event criteria had been met resulted in more realistic progression-free percent estimates (85% at 5 and 59% at 10 years). Biochemical, PSA progression rates vary markedly depending on the method used to define PSA failure. Methods that require multiple increasing PSA values, for example the ASTRO definition, give misleading results, especially if the event time is backdated. Standards for defining PSA progression would allow more consistent and comparable progression estimates after radical prostatectomy. PSA 0.4 ng./ml. or greater may be the most appropriate cut point to use since a significant number of patients with lower PSA do not have a continued increase in it.