Paul A. Fearn

12-YEAR OUTCOMES FOLLOWING PERMANENT PROSTATE BRACHYTHERAPY IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE We reviewed the outcomes in men treated with permanent prostate brachytherapy (PPB). MATERIAL AND METHODS A total of 1,449 consecutive patients with a mean age of 68 years treated with PPB between 1992 and 2000 and mean pretreatment prostate specific antigen (PSA) 10.1 ng/ml were included in this study. Of the patients 55% presented with Gleason 6 tumors and 28% had Gleason 7 disease. A total of 400 patients (27%) were treated with neoadjuvant hormones and 301 (20%) were treated in combination with external radiation plus PPB. Several biochemical freedom from recurrence (BFR) definitions were determined. Statistical analysis consisted of log rank testing, Kaplan-Meier estimates and Cox regression analysis. RESULTS Median followup was 82 months with 39 patients at risk at for 144 months. Overall and disease specific survival at 12 years was 81% and 93%, respectively. The 12-year BFR was 81%, 78%, 74% and 77% according to the American Society for Therapeutic Radiology and Oncology (ASTRO), ASTRO-Kattan, ASTRO-Last Call and Houston definitions, respectively. The 12-year ASTRO-Kattan BFR using risk stratification was 89%, 78% and 63% in patients at low, intermediate and high risk, respectively (p = 0.0001). Multivariate analysis identified the dose that 90% of the target volume received (p <0.0001), pretreatment PSA (p = 0.001), Gleason score (p = 0.002), the percent positive core biopsies (p = 0.037), clinical stage (p = 0.689), the addition of hormones (p = 0.655) and the addition of external radiation (p = 0.724) for predicting BFR-ASTRO. Five-year disease specific survival was 44% in patients with a PSA doubling time of less than 12 months vs 88% in those with a PSA doubling time of 12 months or greater (p = 0.0001). CONCLUSIONS PPB offers acceptable 12-year BFR in patients who present with clinically localized prostate cancer. Implant dosimetry continues as an important predictor for BFR, while the addition of adjuvant therapies such as hormones and external radiation are insignificant. In patients who experience biochemical failure it appears that PSA doubling time is an important predictor of survival.

Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

PURPOSE Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. PATIENTS AND METHODS Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. RESULTS The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). CONCLUSION We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.

A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy

PURPOSE The American Brachytherapy Society recommends that postprostate implant dosimetry be performed on all patients undergoing transperineal interstitial permanent prostate brachytherapy (TIPPB) utilizing CT scan clinical target volume reconstructions. This study was undertaken to assess the recommended dosimetry parameters from a large cohort of patients undergoing TIPPB that would predict for PSA relapse-free survival (PSA-RFS). METHODS AND MATERIALS Seven hundred nineteen consecutive patients with clinical stage T1/T2 adenocarcinoma of the prostate underwent TIPPB using either I-125 or Pd-103. Postimplant dosimetry was performed at 2 to 3 weeks with CT scan 3-dimensional reconstructions obtained on all patients. The D90 and D100 doses (defined as the minimum dose covering 90% and 100% of the prostate volume, respectively) and the V100 (defined as the percent of the prostate receiving 100% of the prescribed dose) were obtained for each patient. Regression analysis was performed on the D90 dose, D100 dose, and V100 to test for cutoff points that would predict for PSA-RFS, defined by a modification of the American Society for Therapeutic Radiology and Oncology consensus panel statement. A cutoff value was found and was subjected to subset analysis to assess for its robustness. Treatment-related factors were tested for their ability to achieve dosimetry at or above the cutoff dose. RESULTS The median follow-up from this cohort is 30 months (7-71 months) with a 48-month PSA-RFS of 89.5%. A D90 dose-response cutoff value > or =90% of the prescribed dose was identified. Prostate implants with a D90 dose <90% of the prescribed dose had an 80.4% 4-year PSA-RFS, while those with a D90 dose > or =90% of the prescribed dose had a 92.4% 4-year PSA-RFS (p = 0.001). No cutoff value was found for the V100 and D100 dose that predicted for PSA-RFS. Using the cutoff value, the D90 dose at 90% of the prescribed dose, a difference in 4-year PSA-RFS survival was identified for patients treated with I-125 (p = 0.04), Pd-103 (p = 0.01), TIPPB as monotherapy (p = 0.001), the addition of hormone therapy (p = 0.005), and TIPPB without hormone therapy (p = 0.001). The D90 dose was not significant for the group of patients treated with external beam radiotherapy and TIPPB (p = 0.15). The only significant finding from Cox regression analysis to predict for a poor D90 dose (<90% of the prescribed dose) was a CT/TRUS volume ratio >1.5 (p = 0.02). CONCLUSIONS The American Brachytherapy Society recommends that postimplant CT-based dosimetry be performed for all patients treated with TIPPB. This prospective study identified that the D90 dose > or =90% of the prescribed dose can be used as a factor for predicting PSA-RFS in patients treated with brachytherapy. A dose-response using the D90 dose was observed for several typical clinical treatment variations used in the practice of TIPPB. Using the D90 dose appears to be a satisfactory parameter for predicting outcome in patients treated with TIPPB.

Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer

OBJECTIVES To develop a prognostic nomogram to predict the freedom from recurrence for patients treated with permanent prostate brachytherapy for localized prostate cancer. METHODS We performed a retrospective analysis of 920 patients treated with permanent prostate brachytherapy between 1992 and 2000. The clinical parameters included clinical stage, biopsy Gleason sum, pretreatment prostate-specific antigen (PSA) value, and administration of external beam radiation. Patients who received neoadjuvant androgen deprivation therapy were excluded. Failure was defined as any post-treatment administration of androgen deprivation, clinical relapse, or biochemical failure, defined as three PSA rises. Patients with fewer than three PSA rises were censored at the time of the first PSA rise. Data from two outside institutions served as validation. RESULTS A nomogram that predicts the probability of remaining free from biochemical recurrence for 5 years after brachytherapy without adjuvant hormonal therapy was developed using Cox proportional hazards regression analysis. External validation revealed a concordance index of 0.61 to 0.64, and calibration of the nomogram suggested confidence limits of +5% to -30%. CONCLUSIONS The pretreatment nomogram we developed may be useful to physicians and patients in estimating the probability of successful treatment 5 years after brachytherapy for clinically localized prostate cancer.

Potency after permanent prostate brachytherapy for localized prostate cancer

PURPOSE The evaluation of potency preservation after treatment of localized prostate cancer with transperineal permanent prostate brachytherapy (PPB) and the efficacy of sildenafil were studied. METHODS AND MATERIALS This study comprised 482 patients who were able to maintain an erection suitable for intercourse before treatment from a cohort of 1166 patients with clinically localized prostate cancer treated with PPB. All patients have been followed prospectively, and actuarial analysis was performed to assess potency preservation over time. Patients treated with sildenafil were evaluated as to its efficacy. RESULTS The median follow-up of this cohort was 34 months (6--92), with a median age of 68 years (47--80). Potency was preserved in 311 of the 482 patients, with a 5-year actuarial potency rate of 52.7%. The 5-year actuarial potency rate for patients treated with PPB as monotherapy was 76%, and, for those treated with combination external beam radiotherapy (EBT) + PPB, 56% (p = 0.08). Patients treated with neoadjuvant androgen deprivation (NAAD) + PPB had a 5-year potency rate of 52%, whereas those with combination EBT + PPB + NAAD had a potency rate of 29% (p = 0.13). Cox regression analysis identified that pretreatment use of NAAD and patient age predicted for impotence (p = 0.0001 and 0.04, respectively). Of 84 patients treated with sildenafil, 52 had a successful outcome (62%). The response to sildenafil was significantly better in those patients not treated with NAAD (p = 0.04). CONCLUSIONS The actuarial potency rates at 5 years for patients treated with PPB are lower than generally acknowledged, except for those patients treated with PPB as monotherapy. Patients who received sildenafil exhibited improved potency in a majority of cases.

The Association Between Total and Positive Lymph Node Counts, and Disease Progression in Clinically Localized Prostate Cancer

PURPOSE We examined the association between the number of LNs removed, the number of positive LNs and disease progression in patients undergoing pelvic lymph node dissection and radical retropubic prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS We analyzed 5,038 consecutive patients who underwent radical retropubic prostatectomy between 1983 and 2003. Clinicopathological parameters, including the administration of neoadjuvant hormonal therapy, preoperative prostate specific antigen, specimen Gleason score, surgeon and pathological stage, were collected prospectively in our prostate cancer database. We excluded men treated with radiation or chemotherapy before surgery. BCR was defined as 2 postoperative prostate specific antigen increases greater than 0.2 ng/ml. Cox models were used to determine whether the number of nodes removed or the number of positive nodes predicted freedom from BCR after adjustment for prognostic covariates. RESULTS The 4,611 eligible patients had a median of 9 LNs (IQR 5 to 13) removed. Positive nodes were found in 175 patients (3.8%). Overall the number of LNs removed did not predict freedom from BCR (HR per additional 10 nodes removed 1.02, 95% CI 0.92 to 1.13, p = 0.7). Results were similar in patients receiving and not receiving neoadjuvant hormonal therapy. Finding any LN involvement was associated with a BCR HR of 5.2 (95% CI 4.2 to 6.4, p <0.0005). However, in men without nodal involvement an increased number of nodes removed correlated significantly with freedom from BCR (p = 0.01). CONCLUSIONS Nodal disease increased the risk of progression. Extensive lymphadenectomy enhances the accuracy of surgical staging. However, we were unable to determine that removing more nodes improves freedom from BCR uniformly. Since the proportion of patients with prostate cancer with positive nodes is low, the value of extensive lymphadenectomy requires a multi-institutional, randomized clinical trial.

Pattern of Prostate-Specific Antigen (PSA) Failure Dictates the Probability of a Positive Bone Scan in Patients With an Increasing PSA After Radical Prostatectomy

PURPOSE Physicians often order periodic bone scans (BS) to check for metastases in patients with an increasing prostate-specific antigen (PSA; biochemical recurrence [BCR]) after radical prostatectomy (RP), but most scans are negative. We studied patient characteristics to build a predictive model for a positive scan. PATIENTS AND METHODS From our prostate cancer database we identified all patients with detectable PSA after RP. We analyzed the following features at the time of each bone scan for association with a positive BS: preoperative PSA, time to BCR, pathologic findings of the RP, PSA before the BS (trigger PSA), PSA kinetics (PSA doubling time, PSA slope, and PSA velocity), and time from BCR to BS. The results were incorporated into a predictive model. RESULTS There were 414 BS performed in 239 patients with BCR and no history of androgen deprivation therapy. Only 60 (14.5%) were positive for metastases. In univariate analysis, preoperative PSA (P = .04), seminal vesicle invasion (P = .02), PSA velocity (P < .001), and trigger PSA (P < .001) predicted a positive BS. In multivariate analysis, only PSA slope (odds ratio [OR], 2.71; P = .03), PSA velocity (OR, 0.93; P = .003), and trigger PSA (OR, 1.022; P < .001) predicted a positive BS. A nomogram for predicting the bone scan result was constructed with an overfit-corrected concordance index of 0.93. CONCLUSION Trigger PSA, PSA velocity, and slope were associated with a positive BS. A highly discriminating nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.

Mode of presentation of renal cell carcinoma provides prognostic information

PURPOSE Broadened applications of imaging modalities have increased the incidental detection of renal cell carcinoma (RCC) over the past decade. Previous small series have suggested a prognostic benefit for incidental presentation. This study utilizes a large contemporary patient cohort to examine patterns of RCC presentation and their clinical implications. MATERIALS AND METHODS Retrospective analysis was performed on 721 patients (260 women, 461 men) who underwent 750 nephrectomies for treatment of RCC between 7/1/89 and 12/31/97; 29 patients required two operations for bilateral RCC. Median age and follow-up were 63 years and 41 months, respectively. Indicators of symptomatic presentation included flank pain, flank mass, hematuria, varicocele, constitutional symptoms, paraneoplastic syndromes, and bone pain related to metastatic disease. Mode of presentation was compared with clinicopathologic parameters using Chi-square and t-test analyses. Survival analysis was performed using Kaplan-Meier estimates (log-rank test) and Cox regression modeling. RESULTS Incidental and symptomatic presentation occurred in 57% and 42% of cases, respectively. When compared to incidental cases, symptomatic presentation was predominantly detected in younger patients (mean age, 59 years; P < .001), in males (P < .04), and in tumors with conventional (clear cell) histology (P < .001), larger size (mean, 8 cm; P < .001), and non-organ confined pathology (P < .001). In univariate analysis, symptomatic cases had a more adverse disease-free (P < .0001) and disease-specific (P < .0001) survival. In multivariate analysis, mode of presentation was an independent predictor of disease-free (P < 0.0001) and disease-specific survival (P < 0.005). CONCLUSIONS Symptomatic presentation correlates with an aggressive histology and advanced disease. Incidental tumors may be frequently detected in female and elderly patients, as these groups traditionally seek general medical care more regularly. Mode of presentation can independently predict an adverse patient outcome and should be included in RCC-specific modeling systems.

Long-term outcome among men with conservatively treated localised prostate cancer

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10–30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.

Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy.

PURPOSE To investigate the biochemical control rates and survival for Gleason score 7-10 prostate cancer patients undergoing permanent prostate brachytherapy as a function of the biologic effective dose (BED). METHODS AND MATERIALS Six centers provided data on 5,889 permanent prostate brachytherapy patients, of whom 1,078 had Gleason score 7 (n = 845) or Gleason score 8-10 (n = 233) prostate cancer and postimplant dosimetry results available. The median prostate-specific antigen level was 7.5 ng/mL (range, 0.4-300). The median follow-up for censored patients was 46 months (range, 5-130). Short-term hormonal therapy (median duration, 3.9 months) was used in 666 patients (61.8%) and supplemental external beam radiotherapy (EBRT) in 620 (57.5%). The patients were stratified into three BED groups: <200 Gy (n = 645), 200-220 Gy (n = 199), and >220 Gy (n = 234). Biochemical freedom from failure (bFFF) was determined using the Phoenix definition. RESULTS The 5-year bFFF rate was 80%. The bFFF rate stratified by the three BED groups was 76.4%, 83.5%, and 88.3% (p < 0.001), respectively. Cox regression analysis revealed Gleason score, prostate-specific antigen level, use of hormonal therapy, EBRT, and BED were associated with bFFF (p < 0.001). Freedom from metastasis improved from 92% to 99% with the greatest doses. The overall survival rate at 5 years for the three BED groups for Gleason score 8-10 cancer was 86.6%, 89.4%, and 94.6%, respectively (p = 0.048). CONCLUSION These data suggest that permanent prostate brachytherapy combined with EBRT and hormonal therapy yields excellent bFFF and survival results in Gleason score 7-10 patients when the delivered BEDs are >220 Gy. These doses can be achieved by a combination of 45-Gy EBRT with a minimal dose received by 90% of the target volume of 120 Gy of (103)Pd or 130 Gy of (125)I.