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PURPOSE The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. RESULTS The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. CONCLUSIONS The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.

INTRODUCTION AND OBJECTIVE:Multiparametric magnetic resonance imaging (mpMRI) fusion biopsy has been commonly utilized in the management of patients with prostate cancer on active surveillance (AS)...

INTRODUCTION AND OBJECTIVES:There is an unmet need for methods to better identify patients most likely to benefit from repeat prostate biopsy after an initial negative biopsy. ConfirmMDx is a molec...

195 Background: This study evaluated the ability of the combined clinical cell-cycle risk score (CCR) to prognosticate the risk of prostate cancer metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods: The CCR score is a validated model that combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR score and a CCR-based multimodality threshold score (2.112) were evaluated in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Center (NCCN) intermediate- or high-risk localized disease (N = 741) who received single (RT) or multimodality therapy (ADT with RT). Effects of prognostic variables were analyzed using Kaplan-Meier and Cox regression methods. Results: Median follow-up was 5.9 years. CCR predicted metastasis [hazard ratio (HR) 2.21, 95% Confidence Interval (CI) 1.70-2.87, p < 0.001]. The CCR score was a better prognosticator of metastasis (C-index 0.78) than either NCCN-risk group (C-index 0.70), CAPRA score (C-index 0.71), or CCP score (C-index 0.69) alone. In bivariate analyses, the CCR score remained highly prognostic for metastasis when comparing any ADT vs none (HR 2.19, 95% CI 1.62 to 2.97, p < 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p < 0.001), or ADT use given as less than or at the recommended duration for each NCCN risk group (HR 2.22, 95% CI 1.71-2.88, p < 0.001). Men with CCR scores either below or above the threshold (2.112) had a 10-year risk of metastasis of 4.2% and 25.3%, respectively. For men below the threshold receiving RT alone versus RT+ADT, the 10-year risk of metastasis was 4.2% and 3.9%, respectively. Conclusions: CCR is a highly precise and accurate predictor of metastasis in men undergoing dose-escalated RT, with or without ADT. CCR adds clinically actionable information relative to guideline recommended therapies that are based on NCCN risk groups or CAPRA alone. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis with the addition of ADT.

94 Background: There is an unmet need for methods to better identify patients most likely to benefit from repeat prostate biopsy after an initial negative biopsy. ConfirmMDx is a molecular test clinically validated for detection of prostate cancer (PCa) in tissue from PCa-negative biopsies. In this clinical utility study, we evaluated the impact of ConfirmMDx on the management of patients being considered for repeat prostate biopsy in a community urology practice. Methods: The study population consisted of 605 men with a prior PCa-negative prostate biopsy, who were counseled on the need to undergo repeat biopsy at a large community urology practice due to persistent elevated risk of PCa. All tissue cores from each PCa-negative patient were tested with the ConfirmMDx methylation-specific PCR test, and positive or negative ConfirmMDx results based on the presence or absence of GSTP1, APC or RASSF1 methylation in the biopsy tissue. ConfirmMDx results were provided to the physician for use in repeat biopsy decision-making. Medical record review was conducted at a minimum of nine months after ConfirmMDx results were reported. Results: Of the 605 subjects enrolled, 308 (51%) had a negative ConfirmMDx test result and 297 (49%) were positive. For the entire study population, average age was 64 (median 64, interquartile range 59 to 69), average serum PSA level 6.8 ng/mL (5.7, 4.3 to 8.1). The median follow-up for both Confirm positives and negatives was 10 months post-testing. Repeat biopsy rates for ConfirmMDx positive and negative men were 32.3% (96/297) and 5.8% (15/308), respectively (P < 0.001). For patients who received a biopsy during the follow-up period, the time between ConfirmMDx and repeat biopsy was shorter for ConfirmMDx positive men versus ConfirmMDx negatives (median 4 vs. 8 months, P = 0.007). Conclusions: In this utility study, ConfirmMDx had a significant impact on repeat prostate biopsy decision-making in a U.S. community urology setting. Repeat biopsy rates in ConfirmMDx positive men were six-fold higher than in ConfirmMDx negatives. These results reflect the clinical utility of ConfirmMDx for biopsy decision-making in real world clinical practice.

Radiation therapy for prostate cancer is associated with the development of post-treatment erectile dysfunction. Use of 3-dimensional (D) conformal delivery techniques has reduced delivery of radiation to periprostatic tissues. However, the exact magnitude of radiation that the corporeal bodies are exposed to using this delivery technique is currently unknown. This study was undertaken to calculate the radiation dose delivered to the corporeal bodies during 3-D conformal radiotherapy.Ten patients with proven prostate adenocarcinoma who underwent pre-therapy computerized tomography simulation and radiation delivery planning had the proximal corporeal bodies outlined on axial computerized tomography. The dose to the proximal penile tissues was then calculated using computer modeling.The total dose of radiation administered to the prostate and seminal vesicles was 73.8 Gy. Mean radiation delivered to the most proximal 2 cm. of the corporeal bodies was 31 +/- 12.8 Gy., equating to 43% of the total dose of radiation delivered to the prostate and seminal vesicles.These data indicate that large doses of radiation are being delivered to erectile tissue in the proximal penis despite careful pretreatment planning for 3-D conformal radiation therapy for prostate cancer. These data should encourage the development of radiation delivery strategies that minimize corporeal tissue exposure.

Metastatic renal cancer is responsive in some cases to immunotherapeutic agents. Indications for nephrectomy in the face of metastatic disease have traditionally included palliation of symptoms caused by the primary tumor, and nephrectomy combined with metastatectomy in patients with resectable metastases. Recent findings from a Southwest Oncology Group trial strongly suggest that cytoreductive nephrectomy, combined with immunotherapy, may also result in improved survival in patients with unresectable metastases.

Background. The mechanisms underlying cyclosporine neurotoxicity remain undefined. Particularly, whether cyclosporine (CyA) enters cerebrospinal fluid (CSF) or brain tissue is disputed. Methods. We analyzed CSF from 17 lumbar punctures performed in 14 liver recipients receiving CyA and experiencing neurological complications, fever of unknown origin, seizures, or altered mental status. Whole blood samples were assayed for CyA and its metabolites. Liver function tests, serum electrolytes, and cholesterol were also analyzed. Results. Four patients had cyclosporine metabolites in the CSF. These patients had acute renal insufficiency and significantly higher blood urea nitrogen (BUN) and total and direct bilirubin and alkaline phosphatase levels than patients without CyA metabolites in CSF (P

Overall, 30-50% of patients with renal cell carcinoma (RCC) will eventually develop metastatic cancer at some point during their illness. Approximately 20–30% of patients present with metastatic disease, while 20 to 40% undergoing nephrectomy for clinically localized RCC will develop clinically detectable metastases during postoperative surveillance.L1,2 Common sites of metastases are the lung, liver, bone, brain, and adrenal gland, with case reports detailing this cancer’s capacity to manifest itself almost anywhere in the body. Metastatic RCC predicts a dismal prognosis, with a median survival of only 6 to 10 months and a 2-year survival of 10 to 20%3(Table 1).

The role of cytoreductive nephrectomy in the management of metastatic renal cancer remains controversial. Recent trials, like SWOG 8949 have suggested the usefulness of this approach at least in selected patients with good performance status and other favorable indicators. The timing of cytoreductive nephrectomy has also been controversial and remains so to this time. Commentary An estimated 30,000 new cases of renal cell carcinoma (RCC) are detected annually in the U.S. In approximately one-third of these cases, metastatic disease is diagnosed at presentation. Multi-modality treatment combines biologic response modifier (BRM) therapy with surgery in an attempt to improve survival with either form of treatment alone. The optimal timing of surgery relative to BRM therapy continues to be debated. Prior to the advent of multi-modality therapy, there were relatively few indications for nephrectomy in patients with metastatic RCC. The incidence of spontaneous regression of metastatic RCC following removal of the primary tumor is only 1–4% and, therefore, nephrectomy on this basis is not justified. There is a palliative role for nephrectomy in selected patients with metastatic RCC who are experiencing severe disability from associated local symptoms; however, some patients in this category can be managed with percutaneous renal angioinfarction. A small subset of patients with a solitary metastasis may benefit from nephrectomy and resection of the metastatic lesion based on reported 5-year survival rates of up to 30–35%. There has been controversy concerning the appropriate timing of adjuvant or cytoreductive nephrectomy in the multi-modality approach to treatment of metastatic RCC. Many protocols have involved preliminary removal of the primary tumor before the administration of BRM therapy. The rationale for this has been to enhance response rates to BRM therapy by reducing tumor volume and, in some cases, to provide immunoreactive cells for treatment. A drawback of this approach was that many patients underwent nephrectomy without subsequently receiving BRM therapy due to postoperative morbidity/mortality or rapid tumor progression. This prompted interest in an alternative approach of delayed adjuvant nephrectomy wherein BRM therapy was administered initially and nephrectomy was subsequently performed only in those patients who demonstrated a response to systemic therapy. The relative merits of initial versus delayed adjuvant nephrectomy in conjunction with BRM therapy for metastatic RCC have recently been clarified through two phase III prospective multicenter clinical trials conducted in Europe (EORTC) and the United States (SWOG). The results of both of these carefully done studies have indicated improved survival with initial nephrectomy followed by BRM therapy. The latter comprised interferon monotherapy in both studies, which opens the studies to criticism, however the essential observation of extended survival with preliminary nephrectomy appears to be valid. On this basis, there is now objective evidence to suggest that initial cytoreductive nephrectomy is the preferred approach in patients with metastatic RCC who are candidates for multi-modality therapy. The most appropriate candidates for such therapy remain patients with good performance status and low-volume (preferably pulmonary) metastatic disease. The ability to perform cytoreductive nephrectomy laparoscopically in some of these patients, with reduced morbidity, is a further development that has strengthened the argument in favor of initial nephrectomy. Andrew C. Novick, M.D.