Decision models for distinguishing between clinically insignificant and significant tumors in prostate cancer biopsies: an application of Bayes' Theorem to reduce costs and improve outcomes.

Prostate cancer is the second leading cause of death from cancer, behind lung cancer, for men in the U. S, with nearly 30,000 deaths per year. A key problem is the difficulty in distinguishing, after biopsy, between significant cancers that should be treated immediately and clinically insignificant tumors that should be monitored by active surveillance. Prostate cancer has been over-treated; a recent European randomized screening trial shows overtreatment rates of 40%. Overtreatment of insignificant tumors reduces quality of life, while delayed treatment of significant cancers increases the incidence of metastatic disease and death. We develop a decision analysis approach based on simulation and probability modeling. For a given prostate volume and number of biopsy needles, our rule is to treat if total length of cancer in needle cores exceeds c, the cutoff value, with active surveillance otherwise, provided pathology is favorable. We determine the optimal cutoff value, c*. There are two misclassification costs: treating a minimal tumor and not treating a small or medium tumor (large tumors were never misclassified in our simulations). Bayes' Theorem is used to predict the probabilities of minimal, small, medium, and large cancers given the total length of cancer found in biopsy cores. A 20 needle biopsy in conjunction with our new decision analysis approach significantly reduces the expected loss associated with a patient in our target population about to undergo a biopsy. Longer needles reduce expected loss. Increasing the number of biopsy cores from the current norm of 10-12 to about 20, in conjunction with our new decision model, should substantially improve the ability to distinguish minimal from significant prostate cancer by minimizing the expected loss from over-treating minimal tumors and delaying treatment of significant cancers.

The use of serum hCG as a marker of tumor progression and of the response of metastatic urothelial cancer to systemic chemotherapy.

This case confirms the observation that urothelial carcinomas can secrete beta-hCG, and that beta-hCG can potentially be used as a marker of a patient's clinical response to treatment. Prospective studies are clearly warranted by these observations.

Vascularity of primary and metastatic renal cell carcinoma specimens.

PURPOSE: Anti-angiogenic therapies are among the most commonly used drugs in renal cell carcinoma. Tumor vascularity, defined by microvessel area, may be associated with response to these drugs. Clinical studies suggest that metastatic sites are more responsive than primary tumors. Our purpose was to characterize microvessel area (MVA) in matched primary and metastatic samples and in samples of different histologies. METHODS: We employed a method of automated, quantitative analysis of in situ tumor components to identify the area of CD-34 staining endothelial cells within renal cell carcinoma tumors. MVA was assessed in corresponding primary and metastatic samples from 34 patients, as well as in 334 primary nephrectomy specimens with variable histologies. RESULTS: MVA measurements from different parts of the same tumor correlated well (R = 0.75), indicating that MVA was fairly uniform within a tumor. While MVA was slightly higher in primary tumors than corresponding metastatic sites, the difference was not statistically significant (P = 0.1). MVA in paired primary and metastatic samples correlated moderately well (R = 0.36). MVA was higher in clear cell than papillary histology and oncocytomas (P < 0.0001 and P = 0.018, respectively). CONCLUSIONS: Lack of significant differences MVA in matched primary and metastatic samples suggests that both types of tumors should respond to anti-angiogenic drugs. This should be confirmed on additional cohorts. Given the small cohort, future predictive biomarker studies entailing MVA measurements should include specimens from both sites. Clear cell carcinomas are more vascular than other histologic subtypes, which may explain the higher response rates to anti-angiogenic therapies in clear cell tumors.

An Internet intervention for management of uncertainty during active surveillance for prostate cancer.

PURPOSE/OBJECTIVES: To provide preliminary data on an Internet intervention that incorporates cognitive reframing and self-management strategies to help older men undergoing active surveillance (AS) self-manage disease-related issues and improve quality of life (QOL). DESIGN: Single-subject design. SETTING: Two participating urologic practices at major academic medical centers in the northeastern United States. SAMPLE: 9 patients undergoing AS. METHODS: Baseline data were compared to data immediately after completion of the intervention and five weeks later. Telephone interviews were used to determine overall feasibility as well as the ease of use, user friendliness, and acceptability of the intervention in patients undergoing AS. MAIN RESEARCH VARIABLES: Self-efficacy, uncertainty, and QOL. FINDINGS: The results revealed change between baseline (time 1) and intervention completion (time 2) in the majority of variables, with a return toward baseline after the intervention (time 3). Ten of the 12 measures of intervention acceptability were met. The results showed positive trends in the impact of the intervention and good overall acceptability. CONCLUSIONS: The results of this pilot study will lead to further research aimed at helping men manage issues related to AS and improve QOL. IMPLICATIONS FOR NURSING: The intervention may reduce the overtreatment of prostate cancer in men who are clinically appropriate for this management option.

Radical prostatectomy vs. intensity-modulated radiation therapy in the management of localized prostate adenocarcinoma.

BACKGROUND AND PURPOSE: To determine whether radical prostatectomy (RP) or intensity-modulated radiation therapy (IMRT) to > or =72 Gy, plus hormonal therapy if indicated, results in improved biochemical disease-free survival (BDFS) in localized prostate adenocarcinoma. MATERIALS AND METHODS: Between 1997 and 2005, a consecutive sample of 556 patients who underwent RP (n=204) or IMRT (n=352) at two referral centers was analyzed. The patients were stratified into prognostic groups based on clinical stage, Gleason score, and pretreatment prostate-specific antigen (PSA). The outcome measure was BDFS. RESULTS: IMRT patients had more advanced disease at baseline (p<.001). There was no difference in five-year BDFS rates between RP and IMRT in the favorable (92.8% vs. 85.3%, p=.20) or intermediate prognosis (86.7% vs. 82.2%, p=.46) subsets. A difference favoring IMRT plus hormonal therapy was seen in the poor prognosis (38.4% vs. 62.2%, p<.001) subset. Within the entire cohort, after adjustment for confounding variables, Gleason score (p<.001) and clinical stage (p<.001) predicted BDFS, but treatment modality (p=.06) did not. Within the poor prognosis subset, treatment modality (p=.006) predicted BDFS. CONCLUSIONS: BDFS is similar between RP and IMRT for patients with a favorable or intermediate prognosis. Patients with a poor prognosis display higher BDFS when treated with IMRT to > or =72 Gy plus hormonal therapy.

Whole pelvic radiotherapy versus prostate only radiotherapy in the management of locally advanced or aggressive prostate adenocarcinoma.

PURPOSE: To determine whether whole pelvic radiotherapy (WPRT) or prostate-only radiotherapy (PORT) yields improved biochemical disease-free survival (BDFS) in patients with advanced or aggressive prostate adenocarcinoma. METHODS AND MATERIALS: Between 2000 and 2007, a consecutive sample of 277 patients with prostate adenocarcinoma and at least a 15% likelihood of lymph node involvement who had undergone WPRT (n = 68) or PORT (n = 209) at two referral centers was analyzed. The median radiation dose in both arms was 75.6 Gy. The outcome measure was BDFS, as determined using the prostate-specific antigen nadir + 2 ng/mL definition of failure. BDFS was calculated using the Kaplan-Meier method and compared with the log-rank test. A multivariate analysis was performed to assess for confounding. Treatment-related toxicity was assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events guidelines. The median follow-up was 30 months. RESULTS: WPRT patients had more advanced and aggressive disease at baseline (p < .001). The 4-year BDFS rate was 69.4% in the PORT cohort and 86.3% in the WPRT cohort (p = .02). Within the entire cohort, after adjustment for confounding variables, the pretreatment prostate-specific antigen (p < .001), Gleason score (p < .001), use of hormonal therapy (p = .002), and use of WPRT (vs. PORT, p = .006) predicted for BDFS. Patients undergoing WPRT had increased acute gastrointestinal toxicity (p = .048), but no significant difference in acute genitourinary toxicity was seen (p = .09). No difference in late toxicity was found. CONCLUSION: WPRT may yield improved BDFS in patients with advanced or aggressive prostate adenocarcinoma, but results in a greater incidence of acute toxicity.

Surgery versus implant for early prostate cancer: results from a single institution, 1992-2005.

PURPOSE: The aim of this study was to compare the biochemical disease-free survival rates for radical prostatectomy versus transperineal ultrasound-guided prostate implant for patients with early prostate cancer treated at a single institution from 1992 through 2005. MATERIALS AND METHODS: The charts of 741 patients with early prostate cancer (350 implant and 391 surgery) treated from 1992 through 2005 were retrospectively reviewed. Surgery patients were treated by members of the academic Urology Section at Yale University School of Medicine. Implant patients were treated by a combined team from the Urology Section and the Department of Therapeutic Radiology at Yale Medical School. For the 350 implant patients, 35% were treated with iodine-125 and 65% with palladium-103. Of the implant patients 92% were treated with an implant alone and 8% with combined external beam radiation therapy plus an implant and 25% received short-term hormone therapy to downsize the prostate before the implant. Both surgery and implant patients were analyzed based on a group with favorable cancers (clinical stage T1c or T2, prostate-specific antigen <10, and Gleason score <7), an intermediate group (any 1 factor increased compared with the favorable group), and a poor group (any 2 factors increased compared with the favorable group). The follow-up time varied from 12 to 120 months with a mean/median follow-up time of 44 months/42 months for implant patients and 42 months/40 months for surgery patients. Prostate-specific antigen recurrence for surgery was defined as any detectable prostate-specific antigen after surgery. Prostate-specific antigen recurrence for implant was defined as the prostate-specific antigen nadir plus 2 ng/mL after implant. The biochemical disease-free survival rates were calculated using the life-table method. RESULTS: The 5-year biochemical disease-free survival rates for radical prostatectomy versus implant were identical for the favorable group (93% versus 92%), intermediate group (70% versus 70%), and poor group (50% versus 52%) patients. CONCLUSIONS: From 1992 through 2005, implant therapy produced equivalent 5-year biochemical disease-free survival rates compared with surgery in patients with early prostate cancer treated at a single institution.

The effect of age on prostate implantation results.

PURPOSE: The current study was undertaken to determine the effect of young age (60 years or younger) on the 5-year biochemical disease-free survival rate following ultrasound-guided transperineal prostate implantation. PATIENTS AND METHODS: The radiation therapy charts of 330 patients who underwent ultrasound-guided transperineal prostate implantation who were treated from 1992 through 2004 were retrospectively reviewed. Follow-up ranged from 12 to 120 months, with a mean of 48 months. A total of 63 patients were 60 years of age or younger, and 267 patients were over 60 years of age. Prostate-specific antigen (PSA) recurrence was defined as three successive increases following ultrasound-guided transperineal prostate implantation. Biochemical disease-free survival was determined using the life-table method. RESULTS: There were no statistically significant differences in the 5-year biochemical disease-free survival rates for the younger versus the older group. On univariate analysis, age was not a statistically significant factor in predicting PSA failure. Univariate analysis revealed that Gleason score, PSA at diagnosis, and clinical T stage were significant in predicting for PSA failure. Patients with Gleason score<7, PSA<10, and clinical stage T1c disease had statistically significant lower PSA failure rates than patients with Gleason score>or=7, PSA>or=10, and clinical stage T2 disease, respectively. CONCLUSIONS: Patients who are 60 years of age or younger who are treated with ultrasound-guided transperineal prostate implantation can expect 5-year biochemical disease-free survival rates similar to those of older patients treated with ultrasound-guided transperineal prostate implantation therapy.

Iodine 125 versus palladium 103 implants for prostate cancer: clinical outcomes and complications.

PURPOSE: The purpose of this study was to evaluate the clinical outcomes and compare complication rates for patients with prostate cancer treated with iodine 125 ((125)I) and palladium 103 ((103)Pd) prostate brachytherapy at a single institution. PATIENTS AND METHODS: Between 1992 and 2002, 272 patients with prostate cancer were treated with ultrasound-guided transperineal implantation incorporating (125)I (107 patients) or (103)Pd (165 patients). Three months of hormonal therapy was incorporated into the treatment program in 33% of the patients in both groups. Nineteen percent of those treated with (125)I were treated with a combination of implantation plus external-beam radiation therapy. Only 6% of the group receiving (103)Pd implants were treated with such a combination. For those treated with (125)I implantation alone, the minimum tumor dose was 145 Gy. The minimum tumor dose for those treated with (103)Pd alone was 125 Gy. Those treated with a combination of external-beam radiation therapy and (125)I received 45 Gy via 1.8-Gy fractions followed by implantation with a minimum tumor dose of 110 Gy. For those treated with external-beam radiation therapy and (103)Pd, the doses were 45 Gy via 1.8-Gy fractions followed by implantation with minimum tumor dose of 98 Gy. Outcomes were evaluated based on radionuclide used, T stage, Gleason score, prostate-specific antigen, and prognostic group. Complications were also evaluated for each radionuclide. The mean follow-up for the (125)I group was 55 months, and the range was 12-108 months. The mean follow-up for the (103)Pd group was 44 months, and the range was 12-72 months. RESULTS: The 5-year biochemical disease-free survival rates for those in the favorable group (clinical stage T1c or T2, prostate-specific antigen level <10, Gleason score <7) were 92% for the (125)I group and 92% for the patients treated with (103)Pd. The 5-year disease-free survival rates for those in the intermediate and poor prognostic groups, which were combined, was 72% and 74%, respectively, for (125)I and (103)Pd. There was no statistically significant difference for either modality for any treatment group tested. In those treated with implantation alone, patients treated with (125)I had higher complication rates than those treated with (103)Pd (15% vs 4%). (125)I-treated patients had a grade 2 complication rate of 8% and a grade 3-4 complication rate of 7%, compared with 3% and 1%, respectively, for the (103)Pd-treated patients. CONCLUSION: Despite the different management recommendations that evolved during the study period, the clinical outcome for patients treated with either radionuclide were similar with respect to biochemical disease-free survival. Although specific dosimetric comparisons are not valid given differences in imaging over the study course, the complication rate appears to be somewhat higher for (125)I, which is consistent with a radiobiologic model.

Effect of intravesical treatment of transitional cell carcinoma with bacillus Calmette-Guerin and mitomycin C on urinary survivin levels and outcome.

PURPOSE: Urine survivin is a predictive/prognostic molecular marker that detects transitional cell carcinoma (TCC) with high specificity and sensitivity. The presence of urine survivin in patients with TCC who receive intravesical instillation of bacillus Calmette-Guerin or mitomycin C may predict recurrence. MATERIALS AND METHODS: Urine from 25 subjects receiving 27 intravesical treatments of bacillus Calmette-Guerin or mitomycin C for TCC were collected prior to, during and after treatment. Urinary survivin levels were compared with outcome, as assessed by cytology and cystoscopy with or without biopsy 1 month and up to 12 months after the completion of treatment. RESULTS: Pretreatment survivin levels were higher in subjects in whom TCC recurred following treatment compared with those who achieved remission. Survivin levels increased several-fold during treatment with the highest survivin levels measured in subjects with recurrence. Median posttreatment values of survivin were zero in those who achieved remission and 1.0 ng/ml urine in subjects in whom TCC recurred. CONCLUSIONS: The presence of urinary survivin 1 month after the completion of treatment predicts TCC recurrence with 100% sensitivity and 78% specificity. Specificity to predict TCC recurrence increases to 92% after 1 year. No TCC recurred for 1 year in 12 of the 14 subjects with a posttreatment survivin level of 0.1 ng or less per ml urine. Three of the 4 subjects who were survivin positive but in remission 1 month after the completion of treatment had recurrent TCC within 1 year. Subjects who have urinary survivin after the completion of intravesical instillation have a high likelihood of TCC recurrence.

Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer.

Patients diagnosed with early prostate cancer after 2000 can expect better outcomes from treatment than patients who were diagnosed in the 1980s and early 1990s. These improved outcomes are the result of stage migration, new technologies such as three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated external-beam radiotherapy (IMRT), better implant techniques, and optimum use of hormone therapy. We review the outcomes for radical prostatectomy, permanent seed implant, 3DCRT, and IMRT. For patients with clinical stage T1c or T2 disease and a Gleason score of less than 8, 5-year biochemical disease-free survival is remarkably similar for all the above treatments. Furthermore, complication rates are acceptable for all these modalities. For patients with bulky T2-3 disease or a Gleason score of 8-10, hormone therapy plus 3DCRT or IMRT is an excellent treatment choice. Studies of radical prostatectomy show the most reliable long-term results, and the studies of external-beam radiotherapy have used the best scientific methods to assess efficacy. On the basis of current data, we recommend specific treatment options.