Impact of biochemical failure classification on clinical outcome: a secondary analysis of Radiation Therapy Oncology Group 9202 and 9413.

BACKGROUND: Biochemical failure (BF) after radiation therapy is defined on the basis of a rising prostate-specific antigen (PSA) level (A1 failure) or any event that prompts the initiation of salvage androgen-deprivation therapy without PSA failure (A2). It was hypothesized that A2 failure may have a different prognosis. METHODS: Data for 2799 eligible patients from Radiation Therapy Oncology Group (RTOG) 9202 and RTOG 9413 were analyzed. BF was defined according to the 1997 American Society for Therapeutic Radiology and Oncology consensus definition as A1 for PSA failure or as A2 for the start of salvage hormone therapy before 3 consecutive PSA rises. RESULTS: Rates of all-cause mortality (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-2.0; P < .0001) and distant metastasis (DM; HR, 1.6; 95% CI, 1.3-2.0; P < .0001) were greater with A2 failure. The 5-year overall survival (OS) rates were 88.2% and 74.6% for A1 and A2, respectively (P < .0001), and the DM rates were 15.7% and 29.0%, respectively (P < .0001). The DM rate was greater at 5 years for A2 patients with DM as the first sign of failure versus patients with other A2 failures (87.3% vs 11.7%, P < .001), and this also correlated with worse OS at 5 years: 81.1% for A2 failure without DM and 52.8% with DM (P < .001). After the removal of patients with DM, the difference between A1 and A2 BF persisted for OS (P = .002) but not for DM (P = .16) CONCLUSIONS: These results suggest that patients with rising PSA levels alone have less risk than those with A2 failures; although DM was the largest contributor of adverse risk to A2 failure, it did not account for all excess risk in A2 failure.

Prostate-Specific Antigen After Neoadjuvant Androgen Suppression in Prostate Cancer Patients Receiving Short-Term Androgen Suppression and External Beam Radiation Therapy: Pooled Analysis of Four NRG Oncology Radiation Therapy Oncology Group Randomized Clinical Trials.

PURPOSE: To validate whether prostate-specific antigen (PSA) level after neoadjuvant androgen suppression (neoAS) is associated with long-term outcome after neoAS and external beam radiation therapy (RT) with concurrent short-term androgen suppression (AS) in patients with prostate cancer. METHODS AND MATERIALS: This study included 2404 patients. The patients were treated with neoAS before RT and concurrent AS (without post-RT AS) and were pooled from NRG Oncology/RTOG trials 9202, 9408, 9413, and 9910. Multivariable models were used to test associations between the prespecified dichotomized post-neoAS, pre-RT PSA level (≤0.1 vs >0.1 ng/mL) groupings, and clinical outcomes. RESULTS: The median follow-up for surviving patients was 9.4 years. The median post-neoAS, pre-RT PSA level was 0.3 ng/mL, with 32% of patients having levels ≤0.1 ng/mL. Race, Gleason score, tumor stage, node stage, pretreatment PSA level, and duration of neoAS were associated with the groups of patients with PSA levels ≤0.1 and >0.1 ng/mL. In univariate analyses, post-neoAS, pre-RT PSA level >0.1 ng/mL was associated with increased risks of biochemical failure (hazard ratio [HR], 2.04; P < .0001); local failure (HR, 2.51; P < .0001); distant metastases (HR, 1.73; P = .0006); cause-specific mortality (HR, 2.36; P < .0001); and all-cause mortality (HR, 1.24; P = .005). In multivariable models that also included baseline and treatment variables, post-neoAS, pre-RT PSA level >0.1 ng/mL was independently associated with increased risk of biochemical failure (HR, 2.00; P < .0001); local failure (HR, 2.33; P < .0001); and cause-specific mortality (HR, 1.75; P = .03). CONCLUSIONS: Patients with a PSA level >0.1 ng/mL after neoAS and before the start of RT had less favorable clinical outcomes than patients whose PSA level was ≤0.1 ng/mL. The role of post-neoAS, pre-RT PSA level relative to PSA levels obtained along the continuum of medical care is not presently defined but could be tested in future clinical trials.

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis.

Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown. Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa. Design, Setting, and Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out. Main Outcomes and Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT. Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively). Conclusions and Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.

Long-term treatment sequelae after external beam irradiation with or without hormonal manipulation for adenocarcinoma of the prostate: analysis of radiation therapy oncology group studies 85-31, 86-10, and 92-02.

PURPOSE: Late gastrointestinal (GI) and genitourinary (GU) morbidity from external beam irradiation used to treat adenocarcinoma of the prostate continue to be a concern of physicians and patients alike. In addition, for locally advanced/high-risk cancer, the appropriate use of hormonal manipulation in addition to radiation therapy (RT) may increase toxicity. We analyzed three large Radiation Therapy Oncology Group (RTOG) studies (85-31, 86-10, and 92-02) to try to address these issues. METHODS AND MATERIALS: A total of 2,922 patients were accrued with a median follow-up of 10.3 years for surviving patients. The RTOG scoring scheme was used to assess GI, GU, and other toxicities. Toxicity reported was Grade 3 or higher late toxicity. Patient toxicity level was assessed by study and by treatment type combining RT only vs. RT + short-course hormone therapy (STH) vs. RT + long-term hormone therapy (LTH). RESULTS: Multivariate analysis reveals that age >70 was statistically significantly associated with a decrease in late any Grade 3+ toxicity (hazard ratio [HR] = 0.78, p = 0.0476) adjusted for treatment type. Comparing treatment type, patients treated with RT+STH had a statistically significant lower probability of Grade 3+ GI, GU, and other toxicity compared with RT alone (p = .00006; p = 0.0037; p = 0.0127, respectively). Patients treated with RT+LTH had a statistically significant lower probability of Grade 3+ GU toxicity compared with RT alone (p = 0.023). CONCLUSIONS: These data show that external beam radiation therapy remains a safe option for locally advanced/high-risk prostate cancer, and the use of hormonal manipulation does appear to be protective for GU and GI toxicity depending upon length of treatment.

Bcl-2 and Bax expression predict prostate cancer outcome in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol 92-02.

PURPOSE: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT). EXPERIMENTAL DESIGN: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure. RESULTS: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT. CONCLUSIONS: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities.

PURPOSE: A meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. METHODS AND MATERIALS: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. RESULTS: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (<1%). The multivariate analysis showed that patients who received prostate-only RT+HT had a lower risk of experiencing grade ≥2 bowel toxicities than those who received whole-pelvic RT+long-term (LT) HT (hazard ratio: 0.36; 95% confidence interval, 0.18-0.73; P = .0046 and hazard ratio: 0.43; 95% confidence interval, 0.23-0.80; P = .008, respectively). Patients who received whole-pelvic RT had similar chances of having grade ≥2 bowel or bladder toxicities no matter whether they received LT or short-term HT. CONCLUSIONS: Patients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes.

Prognostic value of abnormal p53 expression in locally advanced prostate cancer treated with androgen deprivation and radiotherapy: a study based on RTOG 9202.

PURPOSE: The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short-term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca). METHODS AND MATERIALS: Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes. RESULTS: Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause-specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 - 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13-2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32-4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40-10.37; p = 0.0087). CONCLUSIONS: Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53.

Who enrolls onto clinical oncology trials? A radiation Patterns Of Care Study analysis.

PURPOSE: To identify factors significantly influencing accrual to clinical protocols by analyzing radiation Patterns of Care Study (PCS) surveys of 3,047 randomly selected radiotherapy (RT) patients. METHODS AND MATERIALS: Patterns of Care Study surveys from disease sites studied for the periods 1992-1994 and 1996-1999 (breast cancer, n = 1,080; prostate cancer, n = 1,149; esophageal cancer, n = 818) were analyzed. The PCS is a National Cancer Institute-funded national survey of randomly selected RT institutions in the United States. Patients with nonmetastatic disease who received RT as definitive or adjuvant therapy were randomly selected from eligible patients at each institution. To determine national estimates, individual patient records were weighted by the relative contribution of each institution and patients within each institution. Data regarding participation in clinical trials were recorded. The factors age, gender, race, type of insurance, and practice type of treating institution (academic or not) were studied by univariate and multivariate analyses. RESULTS: Overall, only 2.7% of all patients were accrued to clinical protocols. Of these, 57% were enrolled on institutional review board-approved institutional trials, and 43% on National Cancer Institute collaborative group studies. On multivariate analysis, patients treated at academic facilities (p = 0.0001) and white patients (vs. African Americans, p = 0.0002) were significantly more likely to participate in clinical oncology trials. Age, gender, type of cancer, and type of insurance were not predictive. CONCLUSIONS: Practice type and race significantly influence enrollment onto clinical oncology trials. This suggests that increased communication and education regarding protocols, particularly focusing on physicians in nonacademic settings and minority patients, will be essential to enhance accrual.

What dose of external-beam radiation is high enough for prostate cancer?

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Racial differences in CYP3A4 genotype and survival among men treated on Radiation Therapy Oncology Group (RTOG) 9202: a phase III randomized trial.

PURPOSE: Inherited genotypes may explain the inferior outcomes of African American (AA) men with prostate cancer. To understand how variation in CYP3A4 correlated with outcomes, a retrospective examination of the CYP3A4 *1B genotype was performed on men treated with Radiation Therapy Oncology Group (RTOG) 92-02. METHODS AND MATERIALS: From 1,514 cases, we evaluated 56 (28.4%) of 197 AA and 54 (4.3%) of 1,274 European American (EA) patients. All patients received goserelin and flutamide for 2 months before and during RT (STAD-RT) +/- 24 months of goserelin (long-term androgen deprivation plus radiation [LTAD-RT]). Events studied included overall survival and biochemical progression using American Society for Therapeutic Radiology and Oncology consensus guidelines. RESULTS: There were no differences in outcome in patients in with or without CYP3A4 data. There was an association between race and CYP3A4 polymorphisms with 75% of EAs having the Wild Type compared to only 25% of AA men (p <0.0001). There was no association between CYP3A4 classification or race and survival or progression. CONCLUSIONS: The samples analyzed support previously reported observations about the distribution of CYP3A4 *1B genotype by race, but race was not associated with poorer outcome. However, patient numbers were limited, and selection bias cannot be completely ruled out.

Effect of Long-Term Hormonal Therapy (vs Short-Term Hormonal Therapy): A Secondary Analysis of Intermediate-Risk Prostate Cancer Patients Treated on NRG Oncology RTOG 9202.

PURPOSE: NRG Oncology RTOG 9202 was a randomized trial testing long-term adjuvant androgen deprivation (LTAD) versus initial androgen deprivation only (STAD) with external beam radiation therapy (RT) in mostly high-risk and some intermediate-risk prostate cancer patients. RTOG 9408 found an overall survival (OS) advantage in patients with cT1b-T2b disease and prostate-specific antigen (PSA) <20 ng/mL, with benefit observed mostly among intermediate-risk patients. It was still unknown whether intermediate-risk patients would experience an additional survival benefit with LTAD; thus, we performed a secondary analysis to explore whether LTAD had any incremental benefit beyond STAD among the intermediate-risk subset of RTOG 9202. The study endpoints were OS, disease-specific survival (DSS), and PSA failure (PSAF). METHODS AND MATERIALS: An analysis was performed for all patients enrolled in RTOG 9202 defined as intermediate-risk (cT2 disease, PSA<10 ng/mL, and Gleason score = 7 or cT2 disease, PSA 10-20 ng/mL, and Gleason score <7). This review yielded 133 patients: 74 (STAD) and 59 (LTAD). The Kaplan-Meier method was used to estimate OS; the cumulative incidence approach was used to estimate DSS and PSAF. A 2-sided test was used, with significance level defined to be .05. RESULTS: With over 11 years of median follow-up, 39 STAD patients were alive and 33 LTAD patients were alive. There was no difference in OS (10-year estimates, 61% STAD vs 65% LTAD; P=.53), DSS (10-year DSS, 96% vs 97%; P=.72), or PSAF (10-year PSAF, 53% vs 55%; P=.99) between groups. CONCLUSION: LTAD did not confer a benefit in terms of OS, DSS, or PSAF rates in the intermediate-risk subset in this study. Whereas the subset was relatively small, treatment assignment was randomly applied, and a trend in favor of LTAD would have been of interest. Given the small number of disease-specific deaths observed and lack of benefit with respect to our endpoints, this secondary analysis does not suggest that exploration of longer hormonal therapy is worth testing in the intermediate-risk prostate cancer subset.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202.

PURPOSE: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. METHODS AND MATERIALS: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). RESULTS: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48). CONCLUSIONS: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

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.

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02.

PURPOSE: Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. PATIENTS AND METHODS: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. RESULTS: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), the cause of which is not clear. CONCLUSION: The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.

Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer.

PURPOSE: To link posttreatment biochemical profiles to distant failure and cause-specific survival by assessing the relationship between posttreatment prostate-specific antigen (PSA) nadir and PSA doubling time (PSADT) with these outcome measures. METHODS AND MATERIALS: A total of 615 men were treated at the Fox Chase Cancer Center between April 1989 and December 1995 with three-dimensional conformal radiotherapy alone (median dose 73 Gy). The median follow-up was 64 months (range 2-135). Kaplan-Meier methods were used to estimate the rates of biochemical control, freedom from distant metastasis (FDM), and cause-specific survival. Multivariate predictors of outcome were assessed using stepwise Cox regression analysis. RESULTS: Multivariate analyses demonstrated that the predictors of improved biochemical control were a lower PSA nadir (p <0.0001), lower pretreatment PSA level (p <0.0001), Gleason score of 2-6 (p = 0.001), Stage T1-T2a tumors (p = 0.03), and higher RT dose (p = 0.02). The predictors of improved FDM were a lower PSA nadir (p <0.0001), longer interval to nadir from start of treatment (p = 0.0002), Gleason score of 2-6 (p = 0.005), androgen deprivation for biochemical failure (p = 0.001), and Stage T1-T2a tumors (p = 0.01). The predictors of improved cause-specific survival were a lower PSA nadir (p = 0.006) and longer interval to nadir from the start of treatment (p = 0.03). The 8-year FDM rate was 96%, 89%, and 61% for PSA nadir values of 2.0 ng/mL (p <0.0001), respectively. The 8-year cause-specific survival rate was 97%, 96%, and 78% for posttreatment PSA nadir values of 2.0 ng/mL (p <0.0001), respectively. For patients with sufficient PSA follow-up for PSADT calculations (n = 136), multivariate analysis of FDM from the time of biochemical failure demonstrated that androgen deprivation (p = 0.001), longer PSADT (p = 0.003), lower PSA nadir (p = 0.02), and longer interval to nadir from start of treatment (p = 0.04) were independent predictors of improved FDM. CONCLUSION: This is the first study, to our knowledge, to demonstrate the overwhelming predictive power of posttreatment PSA nadir for distant failure and death from prostate cancer. It is also the first study, to our knowledge, to demonstrate a strong association between posttreatment PSADT and distant failure. The results provide new information regarding disease progression as a function of posttreatment PSA profiles (time to achieve nadir from start of treatment, nadir, and PSADT) and the timing of androgen deprivation for biochemical relapse. This study may be used for the early identification of patients at high risk of distant metastasis and who may be directed to applicable systemic treatment clinical trials.

Short-term androgen deprivation and PSA doubling time: their association and relationship to disease progression after radiation therapy for prostate cancer.

PURPOSE: The goal of this study was to investigate the relationship between PSA doubling time (PSADT) and initial management of prostate cancer with short-term androgen deprivation (STAD) and the impact of these factors on disease progression after radiation therapy. METHODS AND MATERIALS: Between May 1989 and October 1998, 284 patients treated with 3D-CRT experienced biochemical failure (BF) as defined under the ASTRO consensus statement. All patients had sufficient follow-up data for PSADT calculations. Linear regression was used to assess predictors of PSADT among STAD, time to biochemical failure (TTBF), Gleason Score, tumor stage, dose, posttreatment PSA nadir, pretreatment PSA, and age. A composite covariate was created from the various combinations of factors found to be predictive of PSADT. The composite covariate was then included, along with PSADT and the factors previously mentioned, in proportional hazards modeling of freedom from distant metastasis (FDM), cause-specific survival (CSS), and overall survival (OS). RESULTS: Fifty-four (19%) patients developed distant metastasis, 20 (7%) died of prostate cancer, and 53 (19%) died of any cause. The median PSADT was 12 months. Predictors of a longer PSADT were TTBF >12 months, Gleason Score 2-6, and STAD. An ordinal composite covariate was created with eight levels on the basis of the magnitude of observed mean PSADT within the eight possible combinations of the three dichotomized predictors. The most significant predictor of higher FDM rates in Cox modeling was the composite covariate, followed by longer PSADT, STAD, lower PSA nadir, higher RT dose, and Gleason Score 2-6. Predictors of higher CSS rates were lower nadir, longer PSADT, T1/T2ab tumors, the composite covariate, and STAD. The most significant predictor of a higher OS rate was STAD, followed by longer PSADT, younger age at diagnosis, the composite covariate, lower nadir, and T1/T2ab tumors. CONCLUSIONS: Longer TTBF, Gleason Score 2-6 tumors, and STAD were predictive of longer PSADT. Even after adjusting for these factors in the capacity of their predictive properties for PSADT, STAD and observed PSADT continued to be significant independent predictors of FDM, CSS, and OS. STAD appears to have a pronounced impact on disease progression, probably the result partly of the prolongation of PSADT.

Dose response in prostate cancer with 8-12 years' follow-up.

PURPOSE: This communication reports the long-term results of the original group of prostate cancer patients who participated in the first prospective Fox Chase Cancer Center radiation dose escalation study for which 8-12 years of follow-up is now available. METHODS AND MATERIALS: Between March 1, 1989 and October 31, 1992, 232 patients with clinically localized prostate cancer received three-dimensional conformal radiotherapy only at Fox Chase Cancer Center in a prospective dose-escalation study. Of these patients, 229 were assessable. The 8-, 10-, and 12-year actuarial rates of biochemical control (biochemically no evidence of disease [bNED]), freedom from distant metastasis (FDM), and morbidity were calculated. The Cox proportional hazards model was used to assess multivariately the predictors of bNED control and FDM, including pretreatment prostate-specific antigen (PSA) level (continuous), tumor stage (T1/T2a vs. T2b/T3), Gleason score (2-6 vs. 7-10), and radiation dose (continuous). The median total dose for all patients was 74 Gy (range 67-81). The median follow-up for living patients was 110 months (range 89-147). bNED control was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. RESULTS: The actuarial bNED control for all patients included in this series was 55% at 5 years, 48% at 10 years, and 48% at 12 years. Patients with pretreatment PSA levels of 10-20 ng/mL had statistically significant differences (19% vs. 31% vs. 84%, p = 0.0003) in bNED control when stratified by dose (<71.5, 71.5-75.6, and > 75.6 Gy, respectively) on univariate analysis. For the 229 patients with follow-up, 124 (54%) were clinically and biochemically without evidence of disease. Sixty-nine patients were alive at the time of last follow-up, and 55 patients were dead of intercurrent disease. On multivariate analysis, radiation dose was a statistically significant predictor of bNED control for all patients and for unfavorable patients with a pretreatment PSA <10 ng/mL. For the patients with a pretreatment PSA level of 10-20 ng/mL, the radiation dose was a statistically significant predictor across all groups. No radiation dose response was seen for those patients with a pretreatment PSA level >20 ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels <10 ng/mL, all four covariates (radiation dose, Gleason score, pretreatment PSA, and palpation T stage) were significant predictors of distance metastasis. Using the Radiation Therapy Oncology Group morbidity scale, no difference was noted in the frequency of Grade 2 and 3 genitourinary and Grade 3 gastrointestinal morbidity when patients in this data set were stratified by radiation dose. However, a significant increase occurred in Grade 2 gastrointestinal complications as the radiation dose increased. CONCLUSION: The long-term results of the original Fox Chase radiation dose escalation study with >9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure.

Predictors of preferences and utilities in men treated with 3D-CRT for prostate cancer.

PURPOSE: To assess the preferences and utilities for prostate cancer health state scenarios of men treated with three-dimensional conformal radiotherapy and the predictors of treatment preferences. METHODS AND MATERIALS: The preferences and utilities for probabilistic health states of impotence and incontinence associated with prostate cancer therapies were elicited from prostate cancer registry participants using a modified time trade-off interview. Sociodemographic, disease, and treatment characteristics, as well as quality-of-life scores, were assessed to determine the predictors of preferences. RESULTS: Fifty-seven men treated with three-dimensional conformal radiotherapy completed the time trade-off interview. Of these men, 83% had Stage T1-T2 and 30% were receiving hormonal therapy. The utilities followed a linear trend with declining scores for increasing risk of poorer health states. Men showed an increased preference for health states associated with radiotherapy compared with surgery or hormonal therapy. Univariate predictors of preference included income and marital status. Multivariate predictors of preferences included more aggressive therapy and better prognostic indicators. Current quality-of-life scores in terms of global, sexual, or urinary function were poor predictors of preferences. CONCLUSION: Preference elicitation can assist in decision-making, and understanding the predictors of patient preferences can assist in identifying factors that may increase patient perceptions of poorer outcomes.

Advantages of using noncoplanar vs. axial beam arrangements when treating prostate cancer with intensity-modulated radiation therapy and the step-and-shoot delivery method.

PURPOSE: The focus of this work was to compare noncoplanar beam arrangements used for intensity-modulated radiation therapy (IMRT) step-and-shoot delivery to several axial beam arrangements used in the treatment of clinically localized prostate cancer. METHODS AND MATERIALS: A 5-field coronal crossfire beam arrangement was developed for IMRT with the objective of improving upon the rectal and bladder dose-volume histograms obtained using 5-, 7-, and 9-field axial beam arrangements. Additionally, a modified 7-field crossfire technique was developed yielding improved dose distributions. The average values of dose-volume histograms and the time for treatment delivery were evaluated for all plans for 10 randomly chosen patients. RESULTS: Both crossfire IMRT techniques exhibited a 15-25% decrease in dose to the hottest 10% and 20% of the rectum relative to all three axial IMRT techniques. The 5-field crossfire orientation yields slightly higher bladder doses when compared to the other techniques. In selected cases, the 7-field crossfire beam arrangement demonstrates decreased dose to the bladder when compared to all three axial techniques. A mean delivery time of 14 to 17.5 min is noted for the noncoplanar arrangements after positioning and localization. CONCLUSIONS: A technique is described that allows additional normal tissue sparing during dose escalation to the prostate during IMRT delivery. This technique takes advantage of the spatial orientation between the prostate, rectum, and bladder. With patient setup and target localization time aside, a mean treatment time of 14 to 17.5 min allows the delivery of the crossfire plans to conform to standard treatment times.

Biochemical failure rates in prostate cancer patients predicted to have biologically insignificant tumors treated with three-dimensional conformal radiation therapy.

PURPOSE: It has been suggested that patients with prostate cancer meeting the following criteria have pathologically determined potentially biologically insignificant (PBI) tumor and therefore should be considered for observation: clinical stage T1c, PSA density <0.1 ng/mL per gram, absence of Gleason pattern 4 or 5, three or fewer biopsy cores positive for tumor, and tumor involvement of no more than 50% of any core. We compared the biochemical control rates in men meeting the above criteria to those of all low-risk patients (clinical T1c, PSA