Predictive value of tumor recurrence using urinary vascular endothelial factor levels in patients receiving radiation therapy for Glioblastoma Multiforme (GBM).

BACKGROUND: Glioblastoma Multiforme (GBM) is the most common primary malignant tumor of the central nervous system. Standard of care includes maximal resection followed by chemoradiotherapy. Tumors need adequate perfusion and neovascularization to maintain oxygenation and for removal of wastes. Vascular endothelial growth factor (VEGF) is a well characterized pro-angiogenic factor. We hypothesized that the increases in urinary VEGF levels would occur early in the course of tumor recurrence or progression. We examine the feasibility of collecting and analyzing urinary VEGF levels in a prospective, multi-institutional trial (Radiation Therapy Oncology Group, RTOG, 0611) as well as the role of VEGF as a marker of tumor recurrence. METHOD: We evaluated VEGF levels in urine specimens collected post-operatively, at the conclusion of radiation therapy (RT) and one month following RT. Urinary VEGF levels were correlated with tumor progression at one year. VEGF levels were measured by enzyme-linked immunosorbant assay in urine specimens and normalized to urinary creatinine levels. Sample size was determined based on a 50% 1-year recurrence rate. With a sensitivity and specificity of 80%, the expected 95% confidence interval was (0.69, 0.91) with 100 patients. A failure was defined as documented disease progression, recurrence or death before one year. RESULTS: 202 patients were enrolled between February-2006 and October-2007. Four patients were ineligible as they did not receive RT. Of the remaining 198 patients, 128 had all three samples collected. In this group, 35 patients (27.3%) did not progress, 89 (69.5%) had progression and 4 (3.1%) died without evidence of progression. Median VEGF levels at baseline were 52.9 pg/mg Cr (range 0.2- 15,034.4); on the last day of RT, 56.6 (range 0-2,377.1); and at one month follow-up, 70.0 (range 0.1-1813.2). In patients without progression at 1-year, both baseline VEGF level and end of RT VEGF level were lower than those of patients who progressed: 40.3 (range 0.2-350.8) vs. 59.7 (range 1.3-15,034.4) and 41.8 (range 0-356.8) vs. 69.7 (range 0-2,377.1), respectively. This did not reach statistical significance. Comparison of the change in VEGF levels between the end of RT and one month following RT, demonstrated no significant difference in the proportions of progressors or non-progressors at 1-year for either the VEGF increased or VEGF decreased groups. CONCLUSION: Urine can be collected and analyzed in a prospective, multi-institutional trial. In this study of patients with GBM a change in urinary VEGF levels between the last day of RT and the one month following RT did not predict for tumor progression by one year.

Causes of mortality after dose-escalated radiation therapy and androgen deprivation for high-risk prostate cancer.

PURPOSE: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. METHODS AND MATERIALS: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥ 74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. RESULTS: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥ 1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥ 1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). CONCLUSIONS: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience.

BACKGROUND: Patients with locally advanced or recurrent rectal cancer often require multimodality treatment. Intraoperative radiation therapy (IORT) is a focal approach which aims to improve local control. METHODS: We retrospectively reviewed 42 patients treated with IORT following definitive resection of a locally advanced or recurrent rectal cancer from 2000-2009. All patients were treated with the Intrabeam® Photon Radiosurgery System (PRS). A dose of 5 Gy was prescribed to a depth of 1 cm (surface dose range: 13.4-23.1, median: 14.4 Gy). Median survival times were calculated using Kaplan-Meier analysis. RESULTS: Of 42 patients, 32 had recurrent disease (76%) while 10 had locally advanced disease (24%). Eighteen patients (43%) had tumors fixed to the sidewall. Margins were positive in 19 patients (45%). Median follow-up after IORT was 22 months (range 0.2-101). Median survival time after IORT was 34 months. The 3-year overall survival rate was 49% (43% for recurrent and 65% for locally advanced patients). Local recurrence was evaluable in 34 patients, of whom 32% failed. The 1-year local recurrence rate was 16%. Distant metastasis was evaluable in 30 patients, of whom 60% failed. The 1-year distant metastasis rate was 32%. No intraoperative complications were attributed to IORT. Median duration of IORT was 35 minutes (range: 14-39). Median discharge time after surgery was 7 days (range: 2-59). Hydronephrosis after IORT occurred in 10 patients (24%), 7 of whom had documented concomitant disease recurrence. CONCLUSIONS: The Intrabeam® PRS appears to be a safe technique for delivering IORT in rectal cancer patients. IORT with PRS marginally increased operative time, and did not appear to prolong hospitalization. Our rates of long-term toxicity, local recurrence, and survival rates compare favorably with published reports of IORT delivery with other methods.

Redefining high-risk prostate cancer based on distant metastases and mortality after high-dose radiotherapy with androgen deprivation therapy.

PURPOSE: Modern outcomes of high-dose external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT) for high-risk (HR) prostate cancer are not well described. METHODS AND MATERIALS: We identified 585 patients who met HR criteria by 2010 National Comprehensive Cancer Network guidelines, who were treated with EBRT consisting of ≥74 Gy from 1996 to 2008 at Cleveland Clinic, of whom 95% received ADT. We analyzed biochemical relapse-free survival (bRFS), distant metastases-free survival (DMFS), and prostate cancer-specific mortality (PCSM). RESULTS: The median EBRT dose was 78 Gy, and median ADT duration was 6 months. At 10 years, the bRFS was 50.2%, the DMFS was 71.6%, and the PCSM was 14.4%. On multivariate analysis, significant predictors of bRFS were biopsy Gleason score (bGS) of 8 to 10, stage T3, and prostate-specific antigen (PSA) concentration; predictors of DMFS were bGS of 8 to 10 and stage T3; the only predictor of PCSM was bGS of 8 to 10. The duration of ADT was not predictive of any endpoint. We identified an unfavorable high-risk (UHR) group of stage T1-T2 tumors consisting of bGS of 8 with PSA of >10 ng/ml or bGS of 9 to 10 with any PSA level; the remaining clinically localized cancers comprised the favorable high-risk (FHR) group. Comparing FHR, UHR, and stage T3 groups, the DMFS rates were 81.4%, 57.8%, and 59.1% (p < 0.0001), and the PCSM rates were 7.5%, 28.4%, and 20.6% at 10 years, respectively (p = 0.006). CONCLUSION: A bGS of 8 to 10 is the strongest predictor of bRFS, DMFS, and PCSM after high-dose EBRT with ADT. The duration of ADT did not correlate with outcome. Future studies should account for the heterogeneity in HR prostate cancer.

Prostate intrafraction translation margins for real-time monitoring and correction strategies.

The purpose of this work is to determine appropriate radiation therapy beam margins to account for intrafraction prostate translations for use with real-time electromagnetic position monitoring and correction strategies. Motion was measured continuously in 35 patients over 1157 fractions at 5 institutions. This data was studied using van Herk's formula of (αΣ + γσ') for situations ranging from no electromagnetic guidance to automated real-time corrections. Without electromagnetic guidance, margins of over 10 mm are necessary to ensure 95% dosimetric coverage while automated electromagnetic guidance allows the margins necessary for intrafraction translations to be reduced to submillimeter levels. Factors such as prostate deformation and rotation, which are not included in this analysis, will become the dominant concerns as margins are reduced. Continuous electromagnetic monitoring and automated correction have the potential to reduce prostate margins to 2-3 mm, while ensuring that a higher percentage of patients (99% versus 90%) receive a greater percentage (99% versus 95%) of the prescription dose.

Early intervention with phosphodiesterase-5 inhibitors after prostate brachytherapy improves subsequent erectile function.

OBJECTIVE: To examine the early use of phosphodiesterase-5 inhibitor (PDE-5i; sildenafil citrate) in preventing subsequent erectile dysfunction (ED) after (monotherapy) prostate brachytherapy (PB, an accepted option for Gleason 6 or low-volume Gleason 7 prostate cancer), as PB is currently being offered more frequently in younger patients, and ED can be a side-effect often within the first 12 months after treatment. PATIENTS AND METHODS: We examined a single-surgeon series of 69 patients who had been treated with PB from 2002 to 2005. All patients had a follow-up of ≥ 1 year; prospectively, and patients had baseline, 6- and 12-month assessments using the Sexual Health Inventory for Men (SHIM) and International Index of Erectile Function (IIEF)-6 scores. The 69 patients were divided into early treatment with PDE-5i (31) and not treated with PDE-5i (38), and their SHIM and IIEF-6 scores were compared at baseline, 6 and 12 months. Daily sildenafil (25-50 mg) was given immediately after PB for 12 months. Overall, for the entire group, the mean prostate-specific antigen (PSA) level was 6.8 ng/mL; 78% had Gleason 6 cancer and 20% had Gleason 7 (3 + 4) cancer. The mean age in the early PDE-5i group was 64.8 years, and was 66.0 years in the no-PDE-5i group. The mean radiation dose in the early PDE-5i group was 50.2 Gy, and 43.9 Gy in the other group (P= 0.08). RESULTS: In the no-PDE-5i group, the mean baseline SHIM score of 17.1 decreased rapidly to 9.1 at 6 months (P= 0.01) and stayed at 9.3 at 12 months (P= 0.01). In the early PDE-5i group, the mean baseline SHIM score of 21.8 decreased slightly to 17.6 at 6 months (P= 0.2), and was maintained at 17.9 at 12 months (P= 0.2). Using the Wilcoxon rank-sum test, the 6- and 12-month SHIM scores in the two groups (P < 0.001). The IIEF-6 questionnaire confirmed the SHIM analysis. CONCLUSIONS: After PB patients had a significant decline in SHIM/IIEF-6 scores at 6 and 12 months. Our results indicate a 50% decrease in the quality of their erections. This provides an opportunity to initiate early intervention with PDE-5i or perhaps vacuum constriction devices or intraurethral alprostadil. In this study, the early use of PDE-5i after PB maintained erectile function at both 6 and 12 months.

Outcomes for intermediate risk prostate cancer: are there advantages for surgery, external radiation, or brachytherapy?

The treatment of localized prostate cancer remains controversial because of the lack of conclusive well-controlled or randomized studies comparing outcome of various forms of radiotherapy (RT) to radical prostatectomy (RP). We review recent results from an institutional database and prospective quality of life study comparing cancer-related and quality of live (QOL) outcomes among different treatment modalities for intermediate risk prostate cancer. The results suggest similar short-term survival but domain-specific effects on QOL after treatment with radical prostatectomy, brachytherapy, or external beam radiotherapy.

Prediction of intrafraction prostate motion: accuracy of pre- and post-treatment imaging and intermittent imaging.

PURPOSE: To evaluate whether pre- and post-treatment imaging (immediately before and after a radiation therapy treatment fraction) and intermittent imaging (at intervals during a treatment fraction) are accurate predictors of prostate motion during the delivery of radiation. METHODS AND MATERIALS: The Calypso 4D Localization System was used to continuously track the prostate during radiation delivery in 35 prostate cancer patients, for a total of 1,157 fractions (28-45 per patient). Predictions of prostate motion away from isocenter were modeled for a pre- and post-treatment imaging schedule and for multiple intermittent intrafraction imaging schedules and compared with the actual continuous tracking data. The endpoint was drift of the prostate beyond a certain radial displacement for a duration of more than 30 s, 1 min, and 2 min. Results were used to evaluate the sensitivity and specificity of these models as an evaluation of intrafraction prostate motion. RESULTS: The sensitivity of pre- and post-treatment imaging in determining 30 s of intrafraction prostate motion greater than 3, 5, or 7 mm for all fractions was low, with values of 53%, 49%, and 39%, respectively. The specificity of pre- and post-treatment imaging was high for all displacements. The sensitivity of intermittent imaging improved with increasing sampling rate. CONCLUSIONS: These results suggest that pre- and post-treatment imaging is not a sensitive method of assessing intrafraction prostate motion, and that intermittent imaging is sufficiently sensitive only at a high sampling rate. These findings support the value of continuous, real-time tracking in prostate cancer radiation therapy.

Comparison of biochemical relapse-free survival between primary Gleason score 3 and primary Gleason score 4 for biopsy Gleason score 7 prostate cancer.

PURPOSE: To determine whether the primary grade (PG) of biopsy Gleason score (GS) 7 prostate cancer (CaP) was predictive for biochemical relapse-free survival (bRFS). Most of the present data regarding the PG of GS7 CaP refer to surgical specimens. Our goal was to determine whether the biopsy GS used at the time of medical decision making predicted for the biochemical outcome. METHODS AND MATERIALS: We reviewed the data from 705 patients with biopsy GS7 CaP, from a prospectively maintained database, who had been treated at our institution between September 1996 and March 2005 with radical prostatectomy (n = 310), external beam radiotherapy (n = 268), or prostate radioactive seed implantation (n = 127). The bRFS rates were estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was used for univariate and multivariate analyses examining these factors in relation to bRFS: PG of biopsy GS, initial prostate-specific antigen level, clinical T stage, use of androgen deprivation, risk group (high or intermediate), and treatment modality. RESULTS: The 5-year bRFS rate was 78% and 71% (p = 0.0108) for biopsy GS7 PG3 CaP and biopsy GS7 PG4 CaP, respectively. Comparing PG3 and PG4 within treatment modalities, only prostate implantation patients had a significant difference in the 5-year bRFS rate, 88% vs. 76%, respectively (p = 0.0231). On multivariate analysis, the PG of biopsy GS remained an independent predictor of bRFS, with PG3 having better bRFS than PG4 (relative risk, 0.655; 95% confidence interval, 0.472-0.909; p = 0.0113). CONCLUSION: Biopsy GS7 PG4 CaP carries a worse bRFS than biopsy GS7 PG3 CaP.

Quality of life and satisfaction with outcome among prostate-cancer survivors.

BACKGROUND: We sought to identify determinants of health-related quality of life after primary treatment of prostate cancer and to measure the effects of such determinants on satisfaction with the outcome of treatment in patients and their spouses or partners. METHODS: We prospectively measured outcomes reported by 1201 patients and 625 spouses or partners at multiple centers before and after radical prostatectomy, brachytherapy, or external-beam radiotherapy. We evaluated factors that were associated with changes in quality of life within study groups and determined the effects on satisfaction with the treatment outcome. RESULTS: Adjuvant hormone therapy was associated with worse outcomes across multiple quality-of-life domains among patients receiving brachytherapy or radiotherapy. Patients in the brachytherapy group reported having long-lasting urinary irritation, bowel and sexual symptoms, and transient problems with vitality or hormonal function. Adverse effects of prostatectomy on sexual function were mitigated by nerve-sparing procedures. After prostatectomy, urinary incontinence was observed, but urinary irritation and obstruction improved, particularly in patients with large prostates. No treatment-related deaths occurred; serious adverse events were rare. Treatment-related symptoms were exacerbated by obesity, a large prostate size, a high prostate-specific antigen score, and older age. Black patients reported lower satisfaction with the degree of overall treatment outcomes. Changes in quality of life were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners. CONCLUSIONS: Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and hormonal function. These changes influenced satisfaction with treatment outcomes among patients and their spouses or partners.

Impact of image guidance on outcomes after external beam radiotherapy for localized prostate cancer.

PURPOSE: To verify whether rectal distention at the time of planning impacts outcomes in patients with localized prostate cancer treated with daily image guidance. METHODS AND MATERIALS: Between 1998 and 2002, a total of 488 prostate cancer patients were treated with intensity-modulated radiotherapy. The radiation dose was 70 Gy delivered at 2.5 Gy per fraction in all cases. All cases were treated with a 4-mm margin posteriorly. In all cases the total rectal volume documented on the CT scan was used for treatment planning. No special bowel preparation instructions were given, either for the simulation or the daily treatments. Before each daily treatment, alignment of the prostate was performed with the B-mode acquisition and targeting (BAT) transabdominal ultrasound system. The median follow-up for all 488 patients was 60 months (range, 24-96 months). RESULTS: For all patients the biochemical relapse-free survival (bRFS) rate at 5 years was 86%. The 5-year bRFS rate for the rectal distention<50 cm3, 50 to <100 cm3, and >or=100 cm3 groups was 90%, 83%, and 85%, respectively (p=0.18). To adjust for other potential variables affecting bRFS rates, a multivariate time-to-failure analysis using the Cox proportional hazards model was performed. Rectal distention was not an independent predictor of biochemical failure on multivariate analysis (p=0.80). Rectal distention was not a predictor of rectal or urinary toxicity. CONCLUSION: The use of daily image guidance eliminates errors such as rectal distention at the initial planning stage that can affect outcomes after radiotherapy for localized prostate cancer.

Effect of increasing radiation doses on local and distant failures in patients with localized prostate cancer.

PURPOSE: To study the effect of radiation dose on local failure (LF) and distant metastasis (DM) in prostate cancer patients treated with external beam radiotherapy. METHODS AND MATERIALS: The study sample consisted of 919 Stage T1-T3N0M0 patients treated with radiotherapy alone. Three separate dose groups were analyzed: <72 Gy (n = 552, median dose, 68.4 Gy), > or =72 but <82 Gy (n = 215, median dose, 78 Gy), and > or =82 Gy (n = 152, median dose, 83 Gy). The median follow-up period for all patients and those receiving <72 Gy, > or =72 but <82 Gy, and > or =82 Gy was 97, 112, 94, and 65 months, respectively. RESULTS: For all patients, the LF rate at 10 and 15 years was 6% and 13%, respectively. The 7-year LF rate stratified by dose group (<72 Gy, > or =72 but <82 Gy, and > or =82 Gy) was 6%, 2%, and 2%, respectively (p = 0.012). For all patients, the DM rate at 10 and 15 years was 10% and 17%, respectively. The 7-year DM rate stratified by dose group (<72 Gy, > or =72 but <82 Gy, and > or =82 Gy) was 9%, 6%, and 1%, respectively (p = 0.008). Multivariate analysis revealed T stage (p < 0.001), pretreatment prostate-specific antigen level (p = 0.001), Gleason score (p < 0.001), and dose (p = 0.018) to be independent predictors of DM. For all 919 patients, multivariate analysis revealed only Gleason score (p = 0.009) and dose (p = 0.004) to be independent predictors of LF. CONCLUSION: Although the effect of increasing radiation doses has been documented mostly for biochemical failure rates, the results of our study have shown a clear association between greater radiation doses and lower LF and DM rates.

Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience.

PURPOSE: To study the outcomes in patients treated for localized prostate cancer with 70 Gy delivered at 2.5-Gy/fraction within 5 weeks. METHODS AND MATERIALS: The study sample included all 770 consecutive patients with localized prostate cancer treated with hypofractionated intensity-modulated radiotherapy at the Cleveland Clinic between 1998 and 2005. The median follow-up was 45 months (maximum, 86). Both the American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition and the alternate nadir + 2 ng/mL definition were used. RESULTS: The overall 5-year ASTRO biochemical relapse-free survival rate was 82% (95% confidence interval, 79-85%), and the 5-year nadir + 2 ng/mL rate was 83% (95% confidence interval, 79-86%). For patients with low-risk, intermediate-risk, and high-risk disease, the 5-year ASTRO rate was 95%, 85%, and 68%, respectively. The 5-year nadir + 2 ng/mL rate for patients with low-, intermediate-, and high-risk disease was 94%, 83%, and 72%, respectively. The Radiation Therapy Oncology Group acute rectal toxicity scores were 0 in 51%, 1 in 40%, and 2 in 9% of patients. The acute urinary toxicity scores were 0 in 33%, 1 in 48%, 2 in 18%, and 3 in 1% of patients. The late rectal toxicity scores were 0 in 89.6%, 1 in 5.9%, 2 in 3.1%, 3 in 1.3%, and 4 in 0.1% (1 patient). The late urinary toxicity scores were 0 in 90.5%, 1 in 4.3%, 2 in 5.1%, and 3 in 0.1% (1 patient). CONCLUSION: The outcomes after high-dose hypofractionation were acceptable in the entire cohort of patients treated with the schedule of 70 at 2.5 Gy/fraction.

Renal radiosurgery: initial clinical experience with histological evaluation.

The purpose of this study was to determine whether radiosurgical technology can be safely applied to renal tumors. Patients received radiosurgical treatment of renal lesions. At 8 weeks after radiosurgical treatment, patients underwent a partial or radical nephrectomy and histologic evaluation. The patients received a radiation dose of 4 Gy per fraction for 4 fractions. Patients were followed, and radiation-induced toxicities were noted. Three patients were treated for a minimum of 1 year of follow-up. All patients completed the treatments, tolerating each of the 4 fractions with no adverse events. No acute toxicities or changes in renal function were noted. None of the patients had any evidence of acute radiation injury or toxicity noted at the time of surgery or within the subsequent 12 months after the radiosurgical treatment. The last patient treated was found to have a cavity with no microscopic evidence of viable tumor after radiosurgical treatment; pathology was consistent with necrotic renal cell carcinoma, papillary type. The other 2 tumors demonstrated pathologic evidence of viable renal cell carcinoma (grade I and grade II). Tumor size remained relatively unchanged for 8 weeks after the radiosurgical treatment in all patients. The authors are extremely encouraged and cautiously optimistic with the initial results. Radiosurgery for renal tumors appears to be safe at this initial dose level.

Multi-institutional clinical experience with the Calypso System in localization and continuous, real-time monitoring of the prostate gland during external radiotherapy.

PURPOSE: To report the clinical experience with an electromagnetic treatment target positioning and continuous monitoring system in patients with localized prostate cancer receiving external beam radiotherapy. METHODS AND MATERIALS: The Calypso System is a target positioning device that continuously monitors the location of three implanted electromagnetic transponders at a rate of 10 Hz. The system was used at five centers to position 41 patients over a full course of therapy. Electromagnetic positioning was compared to setup using skin marks and to stereoscopic X-ray localization of the transponders. Continuous monitoring was performed in 35 patients. RESULTS: The difference between skin mark vs. the Calypso System alignment was found to be >5 mm in vector length in more than 75% of fractions. Comparisons between the Calypso System and X-ray localization showed good agreement. Qualitatively, the continuous motion was unpredictable and varied from persistent drift to transient rapid movements. Displacements > or =3 and > or =5 mm for cumulative durations of at least 30 s were observed during 41% and 15% of sessions. In individual patients, the number of fractions with displacements > or =3 mm ranged from 3% to 87%; whereas the number of fractions with displacements > or =5 mm ranged from 0% to 56%. CONCLUSION: The Calypso System is a clinically efficient and objective localization method for positioning prostate patients undergoing radiotherapy. Initial treatment setup can be performed rapidly, accurately, and objectively before radiation delivery. The extent and frequency of prostate motion during radiotherapy delivery can be easily monitored and used for motion management.

Improved biochemical relapse-free survival for patients with large/wide glands treated with prostate seed implantation for localized adenocarcinoma of prostate.

OBJECTIVES: To analyze whether prostate size affects biochemical relapse-free survival (bRFS). METHODS: The bRFS outcomes for 390 patients with a minimum of 2 years of follow-up were determined from a review of a prospectively maintained database. All patients were treated with iodine-125 alone as the radiotherapeutic modality and had a minimum of four posttreatment prostate-specific antigen values. None were treated with androgen deprivation. The factors examined in the univariate and multivariate analyses predicting for bRFS included gland volume, patient age, initial prostate-specific antigen value, biopsy Gleason score, clinical stage, and postimplant dosimetric variables. RESULTS: Most patients had low-risk disease, and the median follow-up was 45 months (range 24 to 102). Using the American Society for Therapeutic Radiology Oncology definition of biochemical failure, the overall 5-year bRFS rate was 89.3%. On separate multivariate analyses, only the pretreatment prostate width and volume significantly influenced bRFS favorably (P = 0.0069 and P = 0.0255, respectively). No association was found between gland size/width and postimplant dosimetry. CONCLUSIONS: The results of our study have shown that implantation of large/wide prostates independently confers better bRFS.

Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer.

OBJECTIVES: To report biochemical relapse-free survival (bRFS) after radiotherapy (RT) for localized prostate cancer with two separate failure definitions and compare the results with those after radical prostatectomy (RP). METHODS: The study sample comprised 2516 patients with a median follow-up of 78 months. Biochemical relapse after RT was defined as either the American Society for Therapeutic Radiology Oncology definition (definition A [DefA]) or a prostate-specific antigen elevation of more than 2 ng/mL greater than the nadir prostate-specific antigen level (definition N [DefN]). Failure after RP was defined as a prostate-specific antigen level greater than 0.2 ng/mL. RESULTS: Compared with DefA, DefN resulted in a 13% greater bRFS rate at 5 years and a 12% lower bRFS rate at 10 years. On multivariate analysis, the treatment modality (RP versus RT) was a significant predictor of bRFS using DefA in favor of RP (P <0.001), but was not with DefN (P = 0.87). Higher radiation doses were independently associated with a better outcome with either definition. CONCLUSIONS: Compared with DefA, DefN resulted in better outcomes for up to 7 years after RT, but worse outcomes thereafter. The use of DefA versus DefN resulted in opposite conclusions about the relative efficacies of RT and RP, with DefN suggesting RT is equivalent to RP and DefA that it is worse than RP. Different definitions of biochemical failure after RT can result in differences in the conclusions about treatment efficacy in men with localized prostate cancer, thereby potentially affecting clinical decisions.

Aggressiveness of familial prostate cancer.

PURPOSE: To report on the aggressiveness of sporadic versus familial prostate cancer. PATIENTS AND METHODS: The study sample consisted of 4,112 stage T1-3 prostate cancer patients. The outcome of interest was biochemical relapse-free survival (bRFS). The analysis was performed for two distinct time periods, 1986 to 1992 (year < or = 1992) and 1993 to 2002 (year > or = 1993), to encompass both the early and late prostate-specific antigen (PSA) eras. RESULTS: A positive family history (FH positive) was reported in 16%. The 10-year bRFS rates for patients with negative family history (FH negative) versus FH positive were 59% and 63%, respectively (P = .90). However, in the year < or = 1992 period, the 10-year bRFS rates for FH negative versus FH positive were 45% and 34%, respectively (P = .015). In the year > or = 1993 period, the 10-year bRFS rates for FH negative versus FH positive were 61% and 67%, respectively (P = .54). Multivariate analysis failed to reveal family history as an independent predictor of relapse (P = .42). However, in the subset of patients in each era, family history was an independent predictor of relapse only for those treated in the year < or = 1992 period (P = .038). CONCLUSION: Family history was an independent predictor of biochemical failure only early in the PSA era, and men with an FH positive presented with more favorable disease later in the PSA era. This suggests that with stage migration and improved therapy, the impact of family history on prognosis has become minimal. However, underlying genetic factors affecting prostate cancer behavior in individuals with familial prostate cancer may still be important in determining individual prognosis.

PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time.

PURPOSE: To analyze prostate-specific antigen (PSA) kinetics in patients treated with prostate brachytherapy (PI) with a minimum of 5 years of PSA follow-up. METHODS AND MATERIALS: The records of 162 patients treated with PI for localized prostate cancer with a minimum of 5 years of PSA follow-up were reviewed. A variety of pretreatment and posttreatment variables were examined. Patients were coded as having a PSA bounce if their PSA achieved a nadir, elevated at least 0.2 ng/mL greater than that nadir, and decreased to, or below, the initial nadir. Two definitions of biochemical failure (bF) or biochemical relapse-free survival (bRFS) were used: the classic American Society for Therapeutic Radiology and Oncology consensus definition of three consecutive rises (bF3) and the nadir plus 2 ng/mL definition (bFn+2). Associations between a PSA bounce and the various pre- and posttreatment factors were assessed with logistic regression analysis, and the association between a PSA bounce and bF was examined with the log-rank test. The Mann-Whitney U test was applied to test for differences in the PSA doubling time (PSADT) and the time to a PSA rise between the PSA bounce patients and the bF patients. PSADT was calculated from the nadir to the time of the first PSA rise, because this point is known first in the clinical setting. RESULTS: The 5-year overall bRFS rate was 87% for the bF3 definition and 96% for the bFn+2 definition. A PSA bounce was experienced by 75 patients (46.3%). Patients who experienced a PSA bounce were less likely to have a bF, regardless of the bRFS definition used (bF3: p=0.0015; bFn+2: p=0.0040). Among the pre- and posttreatment factors, only younger age predicted for a PSA bounce on multivariate analysis (p=0.0018). The use of androgen deprivation had no effect on PSA bounce. No difference was found in the PSADT between patients who had a PSA bounce and those with bF. The median PSADT for those with a PSA bounce was 8.3 months vs. 10.3 months using the bF3 definition and 8.8 months using the bFn+2 definition. However, a significant difference was found in the time to the first rise in PSA after PI for patients with a PSA bounce vs. patients with bF. The median time to the first rise in PSA after nadir for those with a PSA bounce was 15.1 months vs. 30.0 months using the bF3 definition (p=0.001) and 22.3 months using the bFn+2 definition (p=0.013). CONCLUSION: Patients experiencing a PSA bounce are more likely to be younger and will have a better bRFS. The PSADT cannot differentiate a PSA bounce from bF. The time to the initial PSA rise after nadir is an excellent discriminator of bF from PSA bounce. The time of the PSA rise after nadir occurs far sooner for a PSA bounce than for bF. This factor should be considered when assessing a patient with a rising PSA level after PI before a patient is administered salvage therapy.