Treatment modalities and survival outcomes in prostate cancer parenchymal brain metastasis.

BACKGROUND: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes. METHODS: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups. RESULTS: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022). CONCLUSIONS: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

MRI-guided Cryoablation of Prostate Cancer Lymph Node Metastasis.

PURPOSE: To evaluate the safety and effectiveness of MRI-guided cryoablation of prostate cancer metastatic lymph nodes(LN). MATERIALS AND METHODS: Fifty-two patients with prostate cancer who underwent MRI guided lymph node (LN) ablation from September 2013 to June 2022 were retrospectively reviewed. Of these, 6 patients were excluded because adequate ablation margins (3-5mm) could not be achieved secondary to adjacent structures. The remaining 46 patients (mean age, 70±7 years) underwent 55 MRI-guided cryoablation procedures of metastatic LN (25 in pelvic side wall, 20 within pelvic region and 10 in the abdomen) with procedural intent of complete ablation. Locoregional tumor control (i.e. technical success in the target LN) was evaluated on initial follow-up PET scans at mean of 4±2 months. Pre- and post-ablation prostate specific antigen (PSA) levels were recorded. Imaging follow-up continued until a median of 27.5 months (3-108 months). RESULTS: Ninety-five percent (52/55) of treated LN demonstrated no considerable activity on PET scans at initial follow-up at 4±2 months. PSA decreased to undetectable level of <0.1ng/mL after cryoablation in 14/46 patients (30.4%) with corresponding lack of activity in 13/46 (28.2%) patients on continued PET imaging follow-up. Only 6/55 (10.9%) patients had transient adverse events which all resolved with no long term sequalae. CONCLUSIONS: MRI-guided percutaneous cryoablation of metastatic LN is a safe and technically effective technique for treating metastatic prostate cancer in LN.

Coping Mechanisms for Financial Toxicity Among Patients With Metastatic Prostate Cancer: A Survey-based Assessment.

PURPOSE: Assessments of financial toxicity among patients with metastatic prostate cancer are lacking. Using patient surveys, we sought to identify coping mechanisms and assess characteristics associated with lower financial toxicity. MATERIALS AND METHODS: Surveys were administered to all patients seen at a single center's Advanced Prostate Cancer Clinic over a 3-month period. Surveys included the COST-FACIT (COmprehensive Score for Financial Toxicity) and coping mechanism questionnaires. Patients with metastatic disease (lymph nodes, bone, visceral) were included for analysis. Coping mechanisms were compared between patients experiencing low (COST-FACIT >24) vs high (COST-FACIT ≤24) financial toxicity using Fisher's exact test. Multivariable linear regression was used to evaluate characteristics associated with lower financial toxicity. RESULTS: Overall, 281 patients met inclusion criteria of which 79 reported high financial toxicity. In multivariable analysis, characteristics associated with lower financial toxicity included older age (estimate: 0.36, 95%CI: 0.21-0.52), applying for patient assistance programs (estimate: 4.42, 95%CI: 1.72-7.11), and an annual income of at least $100,000 (estimate: 7.81, 95%CI: 0.97, 14.66). Patients with high financial toxicity were more likely to decrease spending on basic goods (35% vs 2.5%, P < .001) and leisure activities (59% vs 15%, P > .001), as well as use savings (62% vs 17%, P < .001) to pay for their treatment. CONCLUSIONS: In this cross-sectional study, patients with metastatic prostate cancer and high financial toxicity were more likely to decrease spending on basic goods and leisure activities and use savings to pay for care. Understanding the impact of financial toxicity on patients' lives is crucial to inform shared decision-making and interventions designed to mitigate financial toxicity in this population.

Radiographic paradoxical response in metastatic castrate-resistant prostate cancer (mCRPC) managed with new generation anti-androgens: a retrospective analysis.

BACKGROUND: Prostatic specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration-resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti-androgens (SGA) post-chemotherapy using combined conventional imaging, and new generation imaging in the form of C-11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan. METHODS: We retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3-6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C-11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging. RESULTS: We identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75-21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group-A), whereas 39.6% displayed a paradoxical response (PR) (Group-B), defined as increased choline avidity combined with stable or down-trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group-A, 4.6 for Group-B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group-A versus Group-B, respectively (Log-Rank = 0.0063). CONCLUSION: Nearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C-11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

Prognostic role of 11C-choline PET/CT scan in patients with metastatic castrate resistant prostate cancer undergoing primary docetaxel chemotherapy.

BACKGROUND: We sought to assess the prognostic utility of 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with metastatic castrate resistant prostate cancer (mCRPC) undergoing primary docetaxel chemotherapy. METHODS: We performed a single institution retrospective analysis of 77 mCRPC patients who were treated with 6 cycles of docetaxel chemotherapy, and who also underwent 11C-choline PET/CT scans at baseline (before chemotherapy), mid-course (after 3 cycles), and posttherapy (after 6 cycles). We evaluated treatment response based on percent change in blood pool-corrected maximum standardized uptake value (SUVmax) of the target lesion on PET/CT, as well as percent change in serum prostate specific antigen (PSA). Logistic regression analysis was used to identify factors associated with complete treatment response. Progression free survival (PFS) analysis was performed using log-rank test and shown on Kaplan-Meier plot. RESULTS: Percent change in blood pool-corrected SUVmax on mid-course scan was a significant predictor of complete response (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-0.99, p = .0003), whereas percent change in PSA was not (OR: 0.99, 95% CI: 0.99-1.01, p = .6025). 57 of 77 patients (74%) achieved ≥20% reduction in blood pool-corrected SUVmax on mid-course; these patients were 3.6 times more likely to achieve complete response after full 6 cycles of docetaxel chemotherapy, compared to patients with <20% reduction in blood pool-corrected SUVmax (OR: 3.56, 95% CI: 1.04-16.52, p = .0420). Median PFS in the complete response group was 35.1 months (95% CI: 26.0-52.7 months), compared to 9.4 months (95% CI: 6.9-13.0 months) in the incomplete response group (p = .0005). CONCLUSIONS: Our study showed that mid-course and posttherapy 11C-choline PET/CT evaluation for mCRPC patients undergoing primary docetaxel chemotherapy can predict full course treatment response and PFS, respectively. 11C-choline PET/CT imaging may provide valuable prognostic information to guide treatment choices for patients with mCRPC.

Metastasis-directed Therapy Without Androgen Deprivation Therapy in Solitary Oligorecurrent Prostate Cancer.

PURPOSE: As controversy remains regarding the role of metastasis-directed therapy in patients with oligometastatic prostate cancer, we sought to characterize outcomes of metastasis-directed therapy without concomitant androgen deprivation therapy in the specific subset of patients with a solitary metastatic lesion on C-11 choline positron emission tomography imaging whose primary tumor has already been treated. MATERIALS AND METHODS: We identified 124 consecutive prostate cancer patients from 2008 to 2018 with a solitary oligorecurrent metastatic lesion on positron emission tomography imaging who were treated with metastasis-directed therapy without androgen deprivation therapy from the Mayo Clinic C-11 choline registry. Metastasis-directed therapy consisted of either stereotactic body radiation therapy or surgical excision. RESULTS: Of these 124 patients, 67 were treated with surgery (median follow-up 54 months) and 57 patients were treated with stereotactic body radiation therapy (median follow-up 53 months). Of patients treated with surgery, 80.5% had >50% decline in prostate specific antigen at first follow-up, and the 3-year radiographic progression-free survival was 29%. Median time to initiation of systemic therapy in this cohort was 18.5 months (interquartile range 8.4-44.7 months). Meanwhile, for patients treated with stereotactic body radiation therapy, 40.3% had >50% decline in prostate specific antigen at first follow-up, and the 3-year radiographic progression-free survival was 17%. Similarly, median time to initiation of systemic therapy was 17.8 months (interquartile range 7.1-42.3 months). CONCLUSIONS: This study represents the first reported series of metastasis-directed therapy without androgen deprivation therapy in patients with solitary oligorecurrent metastatic prostate cancer. These results suggest that metastasis-directed therapy without androgen deprivation therapy can delay initiation of systemic therapy and highlight the need for further prospective study for select patients with solitary metastatic recurrences of prostate cancer.

Out-of-Pocket Cost Burden Associated With Contemporary Management of Advanced Prostate Cancer Among Commercially Insured Patients.

PURPOSE: Out-of-pocket costs represent an important component of financial toxicity and may impact patients' receipt of care. Herein, we evaluated patient-level factors associated with out-of-pocket costs for contemporary advanced prostate cancer treatment options. MATERIALS AND METHODS: We identified all commercially insured men receiving treatment for advanced prostate cancer between 2007 and 2019 within the OptumLabs Data Warehouse®. Patients were categorized into 3 treatment groups: androgen deprivation monotherapy, novel hormonal therapy, and nonandrogen systemic therapy. The primary outcome was out-of-pocket costs in the first year of treatment. The associations of treatment and patient variables with out-of-pocket costs were assessed using multivariable regression models. All costs were adjusted to reflect 2019 U.S. dollars using the Consumer Price Index. RESULTS: In a cohort of 13,409 men 81% (n = 10,926) received androgen deprivation monotherapy, 6% (n = 832) novel hormonal therapy, and 12% (n = 1,651) nonandrogen systemic therapy. Mean treatment-related out-of-pocket costs in the first year were $165, $4,236, and $994 for androgen deprivation monotherapy, novel hormonal therapy, and nonandrogen systemic therapy, respectively. The adjusted difference in annual treatment-related out-of-pocket costs for novel hormonal therapy and nonandrogen systemic therapy were $2,581 (95% CI: $1,923-$3,240) and $752 (95% CI: $600-$903) higher than androgen deprivation monotherapy, respectively. Patient characteristics associated (P < .05) with higher treatment-related out-of-pocket costs included older age (65-74 years), Black race, lower comorbidity scores, and lower household income. CONCLUSIONS: Patients receiving novel hormonal therapy for advanced prostate cancer had substantially higher treatment-related out-of-pocket costs. In addition to raising awareness among prescribers, these data support the inclusion of treatment associated financial toxicity in shared decision making for advanced prostate cancer and call attention to subgroups of patients particularly vulnerable to financial toxicity.

Systemic treatment for metastatic castrate resistant prostate cancer: Does seqence matter?

BACKGROUND: Optimal sequencing of systemic therapy in the management for metastatic castration resistant prostate cancer (mCRPC) remains poorly elucidated. The CHAARTED and STAMPEDE studies have proven that early chemotherapy in the hormone-sensitive setting yields a greater net survival advantage than docetaxel for mCRPC. In a retrospective study, we attempt to investigate the two most common treatment sequences for mCRPC and investigate whether earlier chemotherapy for mCRPC is consequential to survival outcomes. METHODS: We identified 112 patients with mCRPC treated at the Mayo Clinic between 2011 and 2017. We identified two cohorts, 80 patients (group A) received full course docetaxel chemotherapy followed by second generation hormone therapy (2nd gen androgen deprivation therapy [ADT]; Abiraterone or Enzalutamide) and 32 patients (group B) treated with 2nd gen ADT followed by docetaxel. The primary endpoint evaluated was 3-year cancer-specific survival. RESULTS: Mean prostate specific antigen at initiation of first treatment was 32.0 in group A and 21.7 in group B (P = .4). Bone metastases were more prevalent in group B (87% vs 58%, P = .01). All other clinicopathologic variables were statistically similar between group A and group B. Three-year cancer-specific survival was 87.4% vs 64.1% for group A and group B, respectively (P = .016). We report a univariate hazard ratio of 3.61 (95% CI, 1.74-9.5, 0 P = .01). Three-year overall survival was 82.4% and 60.8% for group A and group B, P = .01. These results held true when excluding patients with lymph node only metastasi. CONCLUSION: Our data indicates that sequence of systemic therapy may influence outcomes for mCRPC and that docetaxel should be considered before 2nd generation ADT. Our results support the importance of earlier chemotherapy in the castration resistant state.

Adding carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in postsecond generation hormone therapy setting: Impact on treatment response and survival outcomes.

BACKGROUND: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting. METHODS: We retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo-naïve while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate-specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30-month overall survival. RESULTS: Patients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15-5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04-8.54) (P = .0442). 30-month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31-7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58-11.06; P = .0037) between patients in group (C) compared to those in group (B) CONCLUSION: This data demonstrates improved response and overall survival in treatment-refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.

Tumor Seeding after Robot-Assisted Radical Prostatectomy: Literature Review and Experience from a Single Institution.

PURPOSE: Seeding of tumor cells is a rare complication of minimally invasive surgery. We reviewed and improved current knowledge of prostate cancer seeding. MATERIALS AND METHODS: A literature review was performed using MEDLINE®, Embase® and the Cochrane Library, including cases of peritoneal and port site seeding reported after minimally invasive prostatectomy. In addition, after institutionally approved chart review a descriptive summary of a single institution experience on the topic is provided. RESULTS: The data from 9 reported cases of port site metastases from prostate cancer in the world literature are summarized along with 3 additional cases from our experience. Similarly, 5 cases of peritoneal seeding are reviewed from the literature with the addition of 3 more cases from our institution. Good long-term outcomes are achievable with multimodality and individualized regimens, including seeding directed treatments. CONCLUSIONS: Although no definitive recommendation can be made for treatment strategies for these patients, there is a need for awareness and further discussion of this atypical presentation.

Identification of Recurrence Sites Following Post-Prostatectomy Treatment for Prostate Cancer Using 11C-Choline Positron Emission Tomography and Multiparametric Pelvic Magnetic Resonance Imaging.

PURPOSE: We describe anatomical sites of recurrence in patients with prostate cancer who had biochemical recurrence following radical prostatectomy and who received radiotherapy and/or androgen deprivation therapy postoperatively. We performed 11C-choline positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging. MATERIALS AND METHODS: After radiotherapy and/or androgen deprivation therapy patients who underwent radical prostatectomy were evaluated by 11C-choline positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging to determine recurrence patterns and clinicopathological features. Recurrent sites were described as local only (seminal vesicle bed/prostate fossa, vesicourethral anastomosis and bladder neck) or distant metastatic disease. Features associated with the identification of any distant metastatic disease were evaluated by multivariable logistic regression. RESULTS: A total of 550 patients were identified. Treatment included androgen deprivation therapy in 108, radiotherapy in 201, and androgen deprivation therapy and radiotherapy in 241. Median prostate specific antigen at evaluation was 3.9, 3.6 and 2.8 ng/ml in patients treated with androgen deprivation therapy, radiotherapy and a combination, respectively. Recurrence developed locally in 77 patients (14%), as distant metastasis only in 411 (75%), and as local and distant metastatic disease in 62 (11%). On multivariable analysis treatment with radiotherapy (OR 7.18, 95% CI 2.92-17.65), and radiotherapy and hormonal therapy (OR 9.23, 95% CI 3.90-21.87, all p <0.01) was associated with increased odds of distant failure at evaluation. CONCLUSIONS: The combination of 11C-choline positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging successfully identified patterns of recurrence after postoperative radiotherapy and/or androgen deprivation therapy at a median prostate specific antigen of less than 4 ng/ml. Half of this cohort had local only recurrence and/or a low disease burden limited to pelvic lymph nodes. These patients may benefit from additional local therapy. These data and this analysis may facilitate the evaluation of such patients with biochemically recurrent prostate cancer.

Contemporary Mapping of Post-Prostatectomy Prostate Cancer Relapse with 11C-Choline Positron Emission Tomography and Multiparametric Magnetic Resonance Imaging.

PURPOSE: We identify sites and patterns of cancer recurrence in patients with post-prostatectomy biochemical relapse using 11C-choline positron emission tomography/computerized tomography and endorectal coil multiparametric magnetic resonance imaging. MATERIALS AND METHODS: Between January 2008 and June 2015, 2,466 men underwent choline positron emission tomography for suspected prostate cancer relapse at our institution. Of these men 202 did not receive hormone or radiation therapy, underwent imaging with choline positron emission tomography and multiparametric magnetic resonance imaging, and were found to have disease recurrence. Overall patterns of recurrence were described, and factors associated with local only recurrence were evaluated using univariable and multivariable logistic regression. RESULTS: Median prostate specific antigen at positive scan was 2.3 ng/ml (IQR 1.4-5.5) with a median time from prostate specific antigen relapse to lesion visualization of 15 months (IQR 4.8-34.2). Of these 202 men 68 (33%) exhibited local only, 45 (22%) local plus metastatic and 89 (45%) metastatic only relapse. Pelvic node only relapse was observed in 39 (19%) men. Median prostate specific antigen at positive imaging for patients with local only, metastatic only and local plus metastatic relapse was 2.3, 2.7 and 2.2 ng/ml (p=0.46), with a median interval from biochemical recurrence to positive scan of 33.5, 7.0 and 15.0 months, respectively (p <0.001). On multivariable analysis time from biochemical recurrence to positive imaging was independently associated with local only recurrence (OR 1.10 for every 6-month increase, p=0.012). CONCLUSIONS: Combined choline positron emission tomography and multiparametric magnetic resonance imaging evaluation of biochemical recurrence after prostatectomy reveals an anatomically diverse pattern of recurrence. These findings have implications for optimizing the salvage treatment of patients with prostate cancer with relapse following surgery.

Impact of Radical Prostatectomy on Long-Term Oncologic Outcomes in a Matched Cohort of Men with Pathological Node Positive Prostate Cancer Managed by Castration.

PURPOSE: Long-term data supporting the role of primary tumor resection in node positive prostate cancer are lacking. We evaluated the impact of adding radical retropubic prostatectomy to surgical castration on long-term oncologic outcomes in pathological node positive prostate cancer. MATERIALS AND METHODS: We identified men who underwent pelvic lymphadenectomy and orchiectomy within 90 days for pathological node positive prostate cancer from 1966 to 1995. Men treated with radical retropubic prostatectomy in addition to orchiectomy were matched 1:1 to men who underwent orchiectomy alone based on age, year of surgery, clinical grade, clinical T stage, number of positive nodes and preoperative serum prostate specific antigen, the latter from 1987 and thereafter. Kaplan-Meier and Cox regression analyses were done to compare cancer specific and overall survival. RESULTS: The matched cohort included 158 men with 79 in each group. Of men who underwent orchiectomy alone 76 died, including 60 of prostate cancer. Of patients treated with radical retropubic prostatectomy plus orchiectomy 70 died, including 28 of prostate cancer. On Kaplan-Meier analyses prostatectomy plus orchiectomy vs orchiectomy alone was associated with prolonged cancer specific survival (at 20 years 59% vs 18%, log rank p <0.001) and overall survival (at 20 years 22% vs 9%, log rank p <0.001). In Cox models prostatectomy plus orchiectomy vs orchiectomy alone was associated with improved cancer specific survival (HR 0.28, 95% CI 0.17-0.46, p <0.001) and overall survival (HR 0.48, 95% CI 0.34-0.66, p <0.001). Findings were similar in the subset with available preoperative prostate specific antigen values. CONCLUSIONS: With lifelong followup in nearly the entire cohort, this study demonstrates that adding radical retropubic prostatectomy to surgical castration for pathological node positive prostate cancer is associated with improved cancer specific and overall survival. When technically feasible in well selected patients, aggressive locoregional resection should be considered for node positive prostate cancer as part of a multimodal approach.

Retrospective Review of Percutaneous Image-Guided Ablation of Oligometastatic Prostate Cancer: A Single-Institution Experience.

PURPOSE: To retrospectively review and report the efficacy and safety of percutaneous image-guided ablation (cryoablation or radiofrequency ablation) in the treatment of oligometastatic prostate cancer. MATERIALS AND METHODS: An institutional registry was retrospectively reviewed and revealed 16 patients with oligometastatic prostate cancer (median age, 67 y; range, 50-86 y) who underwent percutaneous image-guided ablation to treat 18 metastatic sites. A subgroup of 7 patients with 8 metastases were androgen-deprivation therapy (ADT)-naïve and underwent ablation to delay initiation of ADT. Local tumor control, progression-free survival (PFS), ADT-free survival, and procedural complications were analyzed. RESULTS: Local tumor control was achieved in 15 of 18 metastases (83%) at a median follow-up of 27 months (range, 5-56 mo). Local tumor recurrence was found in 3 of 18 metastases (17%), with a median time to local recurrence of 3.5 months (range, 3-38 mo). Estimated PFS rates at 12 and 24 months were 56% (95% confidence interval [CI], 30%-76%) and 43% (95% CI, 19%-65%), respectively. In the 7 ADT-naïve patients, local tumor control was achieved in all metastases, and the median ADT-free survival period was 29 months. There were no major procedural complications. CONCLUSIONS: In this cohort of patients with oligometastatic prostate cancer, percutaneous image-guided ablation was feasible and well tolerated and achieved acceptable local tumor control rates. Percutaneous ablation may be of particular utility in patients who wish to delay initiation of ADT.

BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor.

BACKGROUND: BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; however, the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown. Additionally, while intra-tumor heterogeneity has been shown to be common in primary ccRCC, little is known regarding heterogeneity in metastatic ccRCC tumors. MATERIALS AND METHODS: We analyzed BAP1 and PBRM1 loss of protein expression in patient-matched primary and metastatic tumors from 97 patients. Expression was determined using a validated immunohistochemistry assay, which has been shown to be correlated with mutation status. RESULTS: Of the 97 patients evaluated, 20 and 57% showed loss of BAP1 and PBRM1 in their primary tumors, respectively. Comparing expression across patient-matched primary-metastatic tumor pairs, 98 and 90% had concordant BAP1 and PBRM1 expression, respectively. Both patients who demonstrated discordant BAP1 expression showed loss of BAP1 expression during progression to metastatic ccRCC. Similarly, seven of the ten patients that demonstrated discordant PBRM1 expression showed loss of PBRM1 expression during progression to metastatic ccRCC. We evaluated intra-metastatic tumor heterogeneity using 12 patients who had multiple blocks available from the same tumor with representative pathology; 100 and 92% showed concordant BAP1 and PBRM1 expression, respectively. Amongst 32 patients who had serial metastatic tumors available, both BAP1 and PBRM1 had 97% concordant expression. CONCLUSIONS: We observed minimal intra- and inter- tumor heterogeneity in metastatic ccRCC tumors. Patients with discordant BAP1 or PBRM1 expression across their matched primary and metastatic tumors usually showed loss of expression during progression to metastatic ccRCC.

Risk Stratification of pN+ Prostate Cancer after Radical Prostatectomy from a Large Single Institutional Series with Long-Term Followup.

PURPOSE: Lymph node positive (pN+) prostate cancer after radical prostatectomy has wide variability in long-term oncologic outcomes. We present a large institutional series with extended followup to create an oncologic risk stratification system that clarifies the prognostic heterogeneity for patients with pN+ disease after radical prostatectomy. MATERIALS AND METHODS: Men with pN+ prostate cancer after radical prostatectomy during 1987 to 2012 were included in the study. Regression models were created to identify significant predictors of biochemical recurrence, metastasis, cancer specific mortality and overall mortality. A cancer specific mortality risk score was then created and internally validated to stratify patients in terms of risk of cancer specific mortality. RESULTS: For our cohort of 1,011 men with a median followup of 17.6 years the 20-year rate of cancer specific mortality was 31%. On multivariate Cox regression modeling 3 or more positive nodes (HR 1.75, p=0.003), pathological Gleason score 7 vs 6 (HR 1.74, p=0.04) and 8-10 vs 6 (HR 2.63, p=0.001), and positive surgical margins (HR 1.96, p=0.001) were significantly associated with increased cancer specific mortality, while adjuvant radiotherapy (HR 0.40, p=0.008) was associated with decreased cancer specific mortality. A cancer specific mortality risk score was then created using these 4 variables to stratify patients with markedly different prognoses, yielding 20-year cancer specific mortality rates of 19.1% vs 34% vs 46% (p <0.001) for low, intermediate and high risk categories, respectively. CONCLUSIONS: The prognosis of patients with pN+ prostate cancer varied significantly after radical prostatectomy. A risk score created using the number of positive nodes, pathological Gleason score, margin status and adjuvant radiotherapy status successfully separated patients into low, intermediate and high risk groups.

Salvage lymph node dissection for prostate cancer nodal recurrence detected by 11C-choline positron emission tomography/computerized tomography.

PURPOSE: We report salvage lymph node dissections for prostate cancer nodal recurrence detected by (11)C-choline positron emission tomography/computerized tomography in the setting of increasing prostate specific antigen after radical prostatectomy. MATERIALS AND METHODS: Retrospective chart review was performed for all patients who underwent salvage lymph node dissection for prostate cancer nodal recurrence. Only patients previously treated with radical prostatectomy were included in the study and those with evidence of local recurrence were excluded from analysis. Primary end points included biochemical recurrence, systemic progression and cancer specific mortality. RESULTS: From 2009 to 2013, 52 men underwent salvage lymph node dissection. Before salvage lymph node dissection 78.8% (41 of 52) had some form of therapy after radical prostatectomy. Median age at salvage lymph node dissection was 60 years and median prostate specific antigen was 2.2 ng/ml (IQR 1.4-3.7). The median number of lymph nodes dissected was 21.5 (IQR 16-30) and the median number of positive nodes was 3.5 (IQR 1.2-6.5). Since salvage lymph node dissection 46.2% of the men (24 of 52) have had no further treatment, 34.6% (18 of 52) are on hormonal therapy and 19.2% (10 of 52) have received multiple different treatments. At the last followup at a median of 20 months (IQR 8-33), 57.7% (30 of 52) had prostate specific antigen remain less than 0.2 ng/ml, 75% (39 of 52) remained free of systemic progression and 96.2% of the men (50 of 52) were alive. Two patients died of prostate cancer. Three-year biochemical recurrence-free, systemic progression-free and cancer specific survival was 45.5%, 46.9% and 92.5%, respectively. CONCLUSIONS: This represents the largest U.S. series of salvage lymph node dissection in the setting of lymph node metastatic prostate cancer after radical prostatectomy. Although followup was short and the study lacked a randomized control group, salvage lymph node dissection may represent a valid treatment option.

Immunotherapy in prostate cancer.

Immunotherapy for the treatment of malignant neoplasms has made significant progress over the last 20 years. Multiple molecular targets and clinical agents have been developed recently, particularly in the field of metastatic adenocarcinoma of the prostate. Sipuleucel-T is currently the only FDA approved immunotherapy for prostate cancer. PSA-TRICOM (Prostvac) currently has a phase III randomized trial underway after a phase II trial showed an improvement in overall survival. Interestingly, both these agents showed improvement in overall survival with no measurable change in disease state, leading to significant controversy as the utility of these agents in prostate cancer. Ipilimumab revealed a benefit for a sub-cohort of men in a post-docetaxel group and is currently undergoing investigation in a pre-docetaxel group. There are a number of other targets such as PD-1 which have shown effectiveness in other neoplasms that will likely be investigated in the future for use in prostate cancer.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

B7-H1 signaling is integrated during CD8(+) T cell priming and restrains effector differentiation.

A promising strategy in tumor immunotherapy is the use of activated dendritic cells as vehicles for tumor vaccines with the goal of activating anti-tumor T cell responses. Current formulations for dendritic cell-based immunotherapies have limited effects on patient survival, providing motivation for further investigation of ways to enhance dendritic cell priming of anti-tumor T cell responses. Using a brief in vitro priming model, we have found that B7-H1 expressed by activated dendritic cells is integrated during priming of naïve CD8(+) T cells and functions to limit the differentiation of effector T cell responses. CD8(+) T cells primed by B7-H1-deficient dendritic cells exhibit increased production of IFN-γ, enhanced target cell killing, and improved anti-tumor activity. Additionally, enhanced memory populations arise from CD8(+) T cells primed by B7-H1-deficient dendritic cells. Based on these findings, we suggest that early blockade of B7-H1 signaling should be investigated as a strategy to improve dendritic cell-based anti-tumor immunotherapy.