Kerri Cote

Determinants of Prostate Cancer–Specific Survival After Radiation Therapy for Patients With Clinically Localized Prostate Cancer

PURPOSE Identifying pretreatment and posttreatment predictors of time to prostate cancer-specific death (PCSD) after external-beam radiation therapy (RT) was the subject of this study. PATIENTS AND METHODS A Cox regression analysis was used to evaluate the ability of the pretreatment risk group to predict time to PCSD for 381 patients who underwent RT for clinically localized prostate cancer. Posttreatment factors analyzed for the 94 patients who experienced prostate-specific antigen (PSA) failure included the time to PSA failure, the posttreatment PSA doubling time (DT), and the timing of salvage hormonal therapy. RESULTS Despite the median age of 73 years at diagnosis, 45% of patients with high-risk disease were estimated to die from prostate cancer within 10 years after RT compared with 0% (P =.004) and 6% (P =.05) for patients with low- or intermediate-risk disease, respectively. Predictors of time to PCSD after PSA failure included PSA DT (P =.01) and delayed use of hormonal therapy (P <or=.002). Nearly identical estimates of PCSD and all-cause death after PSA failure were noted for patients with a short PSA DT (ie, <or= 12 months). CONCLUSION Prostate cancer was a major cause of death during the first decade after RT for patients with clinically localized but high-risk disease, and the cause of death for patients with a short PSA DT after RT was nearly always prostate cancer. These data provide evidence to propose the hypothesis that a short posttreatment PSA DT may serve as a possible surrogate for PCSD. Prospective validation is needed.

Impact of the Percentage of Positive Prostate Cores on Prostate Cancer–Specific Mortality for Patients With Low or Favorable Intermediate-Risk Disease

PURPOSE We investigated whether pretreatment factors predicted time to prostate cancer-specific mortality (PCSM) after conventional-dose and conformal radiation therapy (CRT). PATIENTS AND METHODS Between 1988 and 2002, 421 patients with low (prostate-specific antigen [PSA] level < or = 10 ng/mL and biopsy Gleason score < or = 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score 3 + 4, but not both factors) disease underwent CRT (median dose, 70.4 Gy). Cox regression multivariable analysis was performed to determine whether the PSA level, Gleason score, T category, or the percentage of positive cores (% PC) predicted time to PCSM after CRT. After a median follow-up of 4.5 years, 117 (28%) patients have died. RESULTS The % PC was the only significant predictor (Cox P < or =.03). The relative risk of PCSM after CRT for patients with > or = 50% as compared with less than 50% PC was 10.4 (95% CI, 1.2 to 87; Cox P =.03), 6.1 (95% CI, 1.3 to 28.6; Cox P =.02), and 12.5 (95% CI, 1.5 to 107; Cox P =.02) in men with a PSA < or = 10 and Gleason score < or = 6, PSA < or = 10 and Gleason score < or = 7, and PSA < or = 15 and Gleason score < or = 6, respectively. By 5 years after CRT, 5% to 9% compared with less than 1% (log-rank P < or =.01) of these patients experienced PCSM if they had > or = 50% compared with less than 50% PC, respectively. CONCLUSION CRT dose-escalation techniques, the addition of hormonal therapy, or both should be considered in the management of patients with low or favorable intermediate-risk disease and > or = 50% PC.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer

PURPOSE To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

ENDORECTAL MAGNETIC RESONANCE IMAGING AS A PREDICTOR OF BIOCHEMICAL OUTCOME AFTER RADICAL PROSTATECTOMY IN MEN WITH CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE Endorectal magnetic resonance imaging (MRI) of the prostate is sometimes performed before radical prostatectomy but to our knowledge its role for predicting outcome after radical prostatectomy is not yet established. We evaluated the clinical usefulness of endorectal MRI for predicting time to prostate specific antigen (PSA) failure after radical prostatectomy in 1,025 consecutive men with clinically localized or PSA detected prostate cancer. Our analysis controlled for PSA level, biopsy Gleason score, clinical T stage and percent of positive biopsies. MATERIALS AND METHODS Using Cox regression analysis we prospectively assessed time to PSA failure to determine the role of endorectal MRI in predicting PSA outcome after radical prostatectomy at our institution, where an expert prostate magnetic resonance radiologist is available. The main outcome measure was actuarial freedom from PSA failure. RESULTS Endorectal MRI did not add clinically meaningful information in 834 of our 1,025 cases (81%) after accounting for the prognostic value of PSA, biopsy Gleason score, clinical T stage and percent of positive biopsies. However, this modality provided a clinically and statistically relevant stratification of 5-year PSA outcome in the remaining 191 patients at intermediate risk based on established prognostic factors. Specifically when endorectal MRI was interpreted as indicating extracapsular versus organ confined disease the relative risk of PSA failure was 3.6 (95% confidence interval 2.0 to 6.3), and 5-year actuarial freedom from PSA failure was 33% versus 72% (p <0.0001). CONCLUSIONS Despite expert radiological interpretation endorectal MRI had potential clinical value in less than 20% of the cases in our study after accounting for established prognostic factors. While further study of the value of this modality for predicting clinical outcome after radical prostatectomy should be performed in this select cohort, routine use of endorectal MRI cannot be justified based on these data.

The impact of a delay in initiating radiation therapy on prostate‐specific antigen outcome for patients with clinically localized prostate carcinoma

To determine whether a delay in initiating external beam radiation therapy (RT) following diagnosis could impact prostate‐specific antigen (PSA) outcome for patients with localized prostate cancer, 460 patients, who received 3D conformal RT to a median dose of 70.4 Gy for clinically localized prostate cancer between 1992 and 2001, were studied.

Changing prostate-specific antigen outcome after surgery or radiotherapy for localized prostate cancer during the prostate-specific antigen era.

PURPOSE To evaluate the change in prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) or external beam radiotherapy (EBRT), controlling for follow-up during the PSA era. METHODS AND MATERIALS The study cohort consisted of 1440 patients with clinically localized prostate cancer managed with RP (n = 1059) or EBRT (n = 381) between 1989 and 2000. A single genitourinary pathologist reviewed all pathology specimens. For patients with a 2-year minimal follow-up, the 2-year actual PSA outcome stratified by risk group (low vs. high) was calculated for three periods (January 1, 1989 to December 31, 1992; January 1, 1993 to December 31, 1996; and January 1, 1997 to December 31, 2000) and compared for each treatment modality. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition for all patients, and comparisons were made using a chi-square metric. RESULTS During the study period, the proportion of patients treated with RP and EBRT with low-risk disease increased significantly (p <0.0001) from 60% to 89% and from 26% to 76%, respectively. In addition, the 2-year actual PSA outcome also improved from 60% to 82% (RP: p < 0.0001) and from 67% to 91% (RT: p = 0.0008). The 2-year actual PSA outcome was not significantly different in the low-risk patients but improved during the three periods in the high-risk patients treated with RP (from 20% to 39% to 75%, p = 0.0004) or EBRT (from 50% to 59% to 83%, p = 0.01). This improvement in PSA outcome could be explained by a shift toward a more favorable PSA level (RP: p = 0.0002; RT: p = 0.006) and clinical T stage (RP: p = 0.0008, RT: p < 0.0001) distribution for patients with biopsy Gleason score >or=7 disease. CONCLUSION Improved PSA outcome during the PSA era after RP or EBRT has resulted from a shift in presentation toward low-risk disease and earlier detection of high-grade disease.

Clinical utility of the percentage of positive prostate biopsies in predicting prostate cancer-specific and overall survival after radiotherapy for patients with localized prostate cancer

PURPOSE To determine whether the percentage of positive prostate biopsies provides clinically relevant information to a previously established risk stratification system with respect to the end points of prostate cancer-specific survival (PCSS) and overall survival after radiotherapy for patients with clinically localized prostate cancer. METHODS AND MATERIALS A Cox regression multivariable analysis was used to evaluate the ability of the percentage of positive prostate biopsies to predict PCSS and overall survival for 381 men who underwent radiotherapy for localized prostate cancer during the prostate-specific antigen era. RESULTS At a median follow-up of 4.3 years (range 0.8-13.3), the presence of < or =50% positive biopsies vs. >50% positive biopsies provided a clinically relevant stratification of the 7-year estimates of PCSS (100% vs. 57%, p = 0.004) in intermediate-risk patients. Moreover, all patients could be stratified into a minimal or high-risk cohort on the basis of the 10-year estimates of PCSS (100% vs. 55%, p <0.0001) and overall survival (87% vs. 40%, p = 0.02) by incorporating the percentage of positive prostate biopsy information into a previously established risk stratification system. CONCLUSION The clinically relevant stratification of PCSS using the percentage of positive prostate biopsies in intermediate-risk patients confirms previous findings based on prostate-specific antigen outcome. These data provide evidence to support the ability to stratify newly diagnosed patients with clinically localized disease into a minimal-risk (low-risk + low biopsy volume [< or =50%] intermediate-risk) or high-risk (high biopsy volume [>50%] intermediate-risk + high-risk) cohort for prostate cancer-specific death after conventional dose radiotherapy. Additional follow-up and independent validation are needed to confirm these findings.

Advanced age at diagnosis is an independent predictor of time to death from prostate carcinoma for patients undergoing external beam radiation therapy for clinically localized prostate carcinoma

Whether age at diagnosis is predictive of time to prostate carcinoma specific death after external beam radiation therapy (RT) for patients who are diagnosed with clinically localized prostate carcinoma during the prostate specific antigen (PSA) era has not been investigated previously.

Quantifying the change in endorectal magnetic resonance imaging-defined tumor volume during neoadjuvant androgen suppression therapy in patients with prostate cancer

OBJECTIVES To quantify the changes seen in the endorectal magnetic resonance imaging (erMRI)-defined prostate volume, predominant tumor volume, and secondary tumor volume during neoadjuvant total androgen suppression (TAS). METHODS Between July 1997 and April 2001, 152 consecutive patients with clinical Stage T1b-T3cNXM0 prostate cancer were treated with 6 months of TAS and external beam radiotherapy. erMRI was conducted before and after 2 months of neoadjuvant TAS. The median values and percentage of changes in the erMRI-measured prostate volume and primary and secondary tumor volumes during neoadjuvant TAS were calculated and compared, using the Wilcoxon matched-pairs signed-rank method, for the patients overall and stratified by pretreatment risk group. RESULTS All patients had a significant decline in their erMRI-defined median prostate volume (36.6 versus 25.7 cm(3), P <0.0001) during 2 months of neoadjuvant TAS. The median primary tumor volume decreased significantly in the intermediate-risk (0.77 versus 0.52 cm(3), P <0.0001) and high-risk (2.48 versus 0.83 cm(3), P <0.0001) patients. The median secondary tumor volume approached a significant decline in only the high-risk patients (0.45 versus 0.31 cm(3), P = 0.15). Fourteen percent of patients had an increase in their primary tumor volume during neoadjuvant TAS. CONCLUSIONS The erMRI-defined primary and secondary tumor volumes generally decreased in the study population during neoadjuvant TAS. However, 14% of patients had an increase in their primary tumor volume during androgen suppression therapy. The clinical significance of this awaits further study.

The impact of a delay in initiating radiation therapy on prostate-specific antigen outcome for patients with clinically localized prostate cancer

4503 Background: While a delay in initiating external beam radiation therapy (RT) following diagnosis is known to decrease local control in patients with breast or head and neck cancer, its effect on PSA outcome in prostate cancer is unknown. METHODS We studied 460 patients who received 3D conformal RT without hormonal therapy for clinically localized prostate cancer from 1994-2001. The primary endpoint was PSA failure (ASTRO definition); estimates of PSA control were made using the Kaplan-Meier method. Delay was defined as the time between diagnosis and RT start date. Cox multivariable regression was used to determine the ability of treatment delay to predict time to PSA failure after adjusting for the distribution of baseline PSA, clinical T-category, Gleason score, and percent of cores positive for tumor. RESULTS Treatment delay independently predicted for time to PSA failure (p=0.013) after controlling for baseline PSA, clinical T-category, Gleason score, and percent of cores positive. Patients with high-risk disease (n=161) had 5-year estimates of PSA-failure free survival of 53% vs. 38% (Plog-rank=0.037) for those with delay less vs. greater than the median delay (2.5 months) respectively. Low-risk patients (n=299) had no detectable difference in PSA outcome (p=0.621) between those with a delay less vs. greater than the median delay (2.6 months). CONCLUSIONS A treatment delay of approximately 3 months adversely affected PSA outcome for patients with high-risk but not low-risk disease following RT alone. Whether this effect remains after the use of RT plus concomitant hormonal therapy in patients with high-risk disease requires further study. No significant financial relationships to disclose.