Staging 68 Ga-PSMA PET/CT in 963 consecutive patients with newly diagnosed prostate cancer: incidence and characterization of skeletal involvement.

PURPOSE: The aim of the study was to elaborate the incidence and type of skeletal involvement in a large cohort of patients with newly diagnosed prostate cancer (PCa) referred for Ga-68 PSMA-11 PET/CT staging in a single center. METHODS: Study cohort included 963 consecutive patients with newly diagnosed PCa referred for Ga-68 PSMA-11 PET/CT study for staging. The incidence of bone involvement, type of bone metastases, and extent of disease were determined and correlated with the ISUP Grade Group (GG) criteria and PSA levels. RESULTS: Bone metastases were found in 188 (19.5%) of 963 patients. Bone metastases were found in 10.7% of patients with PSA < 10 ng/dL and in 27.4% of patients with PSA > 10 ng/dL and in 6.1% of patients with GG ≤ 2/3 and in 8.9% of patients with GG 4/5. In 7.6% of the patients, skeletal involvement was extensive, while 11.9% of patients had oligometastatic disease. Osteoblastic type metastases were the most common type of bone metastases presented in 133 of the patients with malignant bone involvement (70.7%). More than half of them had only osteoblastic lesions (72 patients (38.3%)), while the other (61 patients (32.5%)) had also intramedullary and/or osteolytic type lesions. Intramedullary metastases were found in 97 patients (51.6%), while 41 (21.8%) of them were only intramedullary lesions. Osteolytic metastases were detected in 36 patients (19.2%), of which 8 were only osteolytic lesions. CONCLUSION: Although traditionally bone metastases of PCa are considered osteoblastic, osteolytic and intramedullary metastases are common, as identified on PET with labeled PSMA. Skeletal spread may be present also in patients with GG ≤ 2/3 and PSA < 10 ng/dL.

Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Radium-223 dichloride (radium-223) is approved for patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no visceral disease using a dosing regimen of 6 injections (55 kBq/kg intravenously; 1 injection every 4 weeks). Early results from international, open-label, phase 1/2 study NCT01934790 showed that re-treatment with radium-223 was well tolerated with favorable effects on disease progression. Here we report safety and efficacy findings from 2-year follow-up of the radium-223 re-treatment study. METHODS: Patients with CRPC and bone metastases who completed 6 initial radium-223 injections with no disease progression in bone and later progressed were eligible for radium-223 re-treatment (up to 6 additional radium-223 injections), provided that hematologic parameters were adequate and chemotherapy had not been administered after the initial course of radium-223. Concomitant cytotoxic agents were not allowed during re-treatment but were allowed at the investigator's discretion during follow-up; other concomitant agents for prostate cancer (including abiraterone acetate or enzalutamide) were allowed at investigator's discretion. The primary objective was safety. Exploratory objectives included time to radiographic bone progression, radiographic progression-free survival (rPFS), time to total alkaline phosphatase (tALP), and prostate-specific antigen (PSA) progression, overall survival (OS), time to first symptomatic skeletal event (SSE), and SSE-free survival, all calculated from re-treatment start. Evaluation of safety and exploratory efficacy objectives included active 2-year follow-up. Safety results from active follow-up and updated efficacy are reported. RESULTS: Overall, 44 patients were re-treated with radium-223; 29 (66%) completed all 6 injections, and 34 (77%) entered 2-year active follow-up, during which no new safety concerns and no serious drug-related adverse events were noted. rPFS events (progression or death) occurred in 19 (43%) of 44 patients; median rPFS was 9.9 months. Radiographic bone progression occurred in 5 (11%) of 44 patients. Median OS was 24.4 months. Median times to first SSE and SSE-free survival were 16.7 and 12.8 months, respectively. Median time to tALP progression was not reached; median time to PSA progression was 2.2 months. CONCLUSIONS: Re-treatment with radium-223 in this selected patient population was well tolerated, led to minimal hematologic toxicity, and provided continued disease control in bone at 2-year follow-up.

Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program.

BACKGROUND: Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking. METHODS: This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline. RESULTS: Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease. CONCLUSIONS: Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.

Outcome of Patients With Metastatic Chromophobe Renal Cell Carcinoma Treated With Sunitinib.

BACKGROUND: Sunitinib is a standard treatment for metastatic clear cell renal cell carcinoma (mccRCC). Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC), are limited. We aimed to analyze the activity of sunitinib in a relatively large and homogenous international cohort of mchRCC patients in terms of outcome and comparison with mccRCC. METHODS: Records from mchRCC patients treated with first-line sunitinib in 10 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC patients were individually matched to mccRCC patients. We compared the clinical benefit rate, progression-free survival (PFS), and overall survival (OS) between the groups. RESULTS: Between 2004 and 2014, 36 patients (median age, 64 years; 47% male) with mchRCC were treated with first-line sunitinib. Seventy-eight percent achieved a clinical benefit (partial response + stable disease). Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the Heng risk (hazard ratio [HR], 3.3; p = .03) and pretreatment neutrophil-to-lymphocyte ratio (NLR) >3 (HR, 0.63; p = .02). Factors associated with OS were the Heng risk (HR, 4.1; p = .04), liver metastases (HR, 3.8; p = .03), and pretreatment NLR <3 (HR, 0.55; p = .03). Treatment outcome was not significantly different between mchRCC patients and individually matched mccRCC patients. In mccRCC patients (p value versus mchRCC), 72% achieved a clinical benefit (p = .4) and median PFS and OS were 9 (p = .6) and 25 (p = .7) months, respectively. CONCLUSION: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may be associated with similar outcome and toxicities as in metastatic clear cell renal cell carcinoma. The Heng risk and pretreatment NLR may be associated with PFS and OS. IMPLICATIONS FOR PRACTICE: Data on the activity of sunitinib in metastatic chromophobe renal cell carcinoma (mchRCC) are limited. This study analyzed the activity of sunitinib in a cohort of mchRCC patients. Of 36 patients with mchRCC who were treated with first-line sunitinib, 78% achieved a clinical benefit. Median PFS and OS were 10 and 26 months, respectively. Treatment outcome was not significantly different between mchRCC patients and individually matched metastatic clear cell RCC patients.

[THE CURRENT APPROACH TO ADVANCED LUNG CANCER].

Non-small cell lung cancer (NSCLC) is a subtype of lung cancer and accounts for approximately 80% of lung cancer cases. For several years, chemotherapy treatment was the only optional treatment. The combination of two drugs - based on the platinum group, was the first line therapy. However the prognosis for patients with metastatic stage lung cancer is poor with a median survival time of 9-12 months. Recent studies of molecular biology in lung cancer have expanded our understanding of the processes involved in cancer. Subsequently developed targeted drugs operate on cancer cell mechanisms, such as antibodies and kinase inhibitors. However, the majority of patients with metastatic lung cancer still do not benefit from clinical therapy. One reason for this is the development of drug resistance. Today, the major focus is on the development of a personal pharmacological approach - targeted therapy. Progress has been made in the understanding of molecular biomarkers in the cell, due to the execution of many studies that incorporate the new treatments for these patients.

[THE CURRENT APPROACH TO METASTATIC RENAL CELL CARCINOMA].

Renal cell carcinona is the most common kidney tumor. In Israel more than 600 cases are diagnosed annually. Risk factors for renal cell carcinoma include obesity, smoking, hypertension, and diabetes; 20-30% of the patients are diagnosed with metastatic disease, and 70-80% of patients are diagnosed with an early non-metastatic tumor. The treatment of an early non-metastatic tumor is resection. At present, the role of adjuvant systemic therapy has not been established; 20-40% of the patients operated on for an early tumor will suffer from metastatic disease recurrence. The lungs are the most common site of metastases. Renal cell carcinoma is relatively refractory to chemotherapy and radiation. In the last decade, an improved understanding of the biology of the tumor, led to the development of biologic therapies targeting specific molecular mechanisms involved in the process of the disease, and a significant expansion of treatment horizon in these patients. The biologic therapies for metastatic renal cell carcinoma belong to two main groups: angiogenesis inhibitors (VEGF-R inhibitors like sunitinib, sorafenib, pazopanib and axitinib), and inhibitors of the mTOR protein (everolimus and temsirolimus). These biologic therapies led to a significant improvement in the patients' survival. Nonetheless, these therapies are associated with a unique profile of side effects like hypertension, mucositis, and hand-foot syndrome with VEGF-R inhibitors therapy, and non-infectious pneumonitis with mTOR inhibitors therapy. The present review will focus on the modern approach to metastatic renal cell carcinoma.

Comparison of abiraterone acetate versus ketoconazole in patients with metastatic castration resistant prostate cancer refractory to docetaxel.

BACKGROUND: Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. METHODS: Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023). CONCLUSIONS: In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases?

One third of patients with metastatic renal cell carcinoma (RCC) suffer from bone metastases. Skeletal involvement in RCC is associated with the occurrence of skeletal-related events, and may negatively impact on the outcome of patients treated with systemic therapies. In patients with RCC and bone metastases, therapies that inhibit osteoclasts, as bisphosphonates and denosumab, are used as adjunct to systemic targeted therapies to prevent skeletal-related events. Data suggest that they may also improve the outcome of systemic targeted therapies. Herein we review the preclinical and clinical data on their use, as well as remaining open questions.

Experience with sunitinib treatment for metastatic renal cell carcinoma in a large cohort of Israeli patients: outcome and associated factors.

BACKGROUND: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported. OBJECTIVES: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients. METHODS: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006-2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors. RESULTS: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n = 115) had clinical benefit (complete response 5%, n = 7; partial response 33%, n = 48; stable disease 41%, n = 60); 21% (n = 30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.0041, pre-sunitinib treatment neutrophil-to-lymphocyte ratio < or = 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n = 57). CONCLUSIONS: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that in international data.

Staging Prostate Cancer with 68Ga-PSMA-11 PET/CT in the Elderly: Is Preimaging Biopsy Imperative?

Although prostate-specific membrane antigen (PSMA) PET/CT has been shown valuable for staging biopsy-proven [B(+)] high-risk prostate cancer, elderly patients are occasionally referred for PSMA PET/CT without a preimaging confirming biopsy [B(-)]. The current study evaluated the rate, clinical characteristics, and PET-based stage of elderly B(-) patients and explored whether biopsy status affects therapeutic approach. Methods: One hundred consecutive patients at least 80 y old who underwent staging 68Ga-PSMA-11 PET/CT were included. For each patient, we documented whether preimaging biopsy was performed, the clinical parameters, the PET-based staging parameters, and the primary therapy received. Results: Thirty-four (34%) of the elderly patients included in the study had no preimaging biopsy. Compared with B(+) patients, B(-) patients were older (median age, 87 vs. 82 y; P < 0.01), with worse performance status (P < 0.01) and higher prostate-specific antigen (PSA) levels (median, 57 vs. 15.4 ng/mL; P < 0.01). On 68Ga-PSMA-11 PET/CT, all B(-) patients had avid disease, with trends toward higher rates of bone metastases (47.1% vs. 28.8%) and overall advanced disease (50% vs. 33.3%) than in B(+) patients. Among patients with localized (n = 36) or locally advanced (n = 25) disease, B(-) patients were less commonly referred than B(+) patients for definitive therapies (P < 0.01). However, higher age, Eastern Cooperative Oncology Group performance status, and PSA were other probable factors determining their therapeutic approach. Among 39 patients with advanced disease, 38 received hormonal therapy irrespective of their biopsy status. Among B(-) patients with advanced disease who were referred for hormonal therapy, 12 of 13 with follow-up data showed a biochemical or imaging-based response. Conclusion: Real-life experience with 68Ga-PSMA-11 PET/CT indicates that around one third of elderly patients are referred for imaging without a preimaging confirming biopsy. These patients are likely to be older, with a worse clinical status and higher PSA levels. Advanced disease might be more likely to be identified on their 68Ga-PSMA-11 PET/CT images, and if it is, their biopsy status does not preclude them from receiving hormonal therapy.

Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Long-Term Results of a Prospective Phase II Study.

The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol®-Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% (n = 33) had a durable long-term response, with 62% (n = 24) showing decreased/stable PSA, 90% (n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

Erdafitinib treatment in metastatic urothelial carcinoma: a real-world analysis.

Background: Erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor is a standard post chemotherapy advanced treatment line for metastatic urothelial carcinoma harboring FGFR2/3 genomic alterations. It was approved based on a phase 2 clinical trial, revealing a 40% response rate, and 13.8 months overall survival. These FGFR genomic alterations are uncommon. Thus, real-world data on erdafitinb use is scant. We herein describe erdafitinib treatment outcome in a real world patient cohort. Methods: We retrospectively reviewed the data of patients treated with erdafitinib from 9 Israeli medical centers. Results: Twenty-five patients with metastatic urothelial carcinoma (median age 73, 64% male, 80% with visceral metastases) were treated with erdafitinib between January 2020 to October 2022. A clinical benefit (complete response 12%, partial response 32%, stable disease 12%) was seen in 56%. Median progression-free survival was 2.7 months, and median overall survival 6.73 months. Treatment related toxicity ≥ grade 3 occurred in 52%, and 32% discontinued therapy due to adverse events. Conclusions: Erdafitinib therapy is associated with a clinical benefit in the real world setting, and associated with similar toxicity as reported in prospective clinical trials.

Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer: clinical factors associated with PSA response and disease progression.

BACKGROUND: Adrenal/intratumoral androgen biosynthesis contributes to ligand-dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole. METHODS: Data were retrospectively analyzed in all mCRPC patients treated with ketoconazole. Patients continued GnRH-agonist, and treated with ketoconazole 200-400 mg 3× a day until dose-limiting toxicity or disease progression. A multivariate cox regression model was used to identify clinical factors associated with PSA response and disease progression. RESULTS: From 1999 to 2010, 114 mCRPC patients were treated with ketoconazole. With a median follow-up time of 31 months (range 5-129), 25 patients (22%) had grade 3/4 toxicity, most commonly fatigue, abdominal discomfort, nausea, and dizziness. Sixty-one patients (54%) had ≥50% PSA decline. Median time to progression was 8 months (range 1-129). Factors associated with PSA response and disease progression were response to prior antiandrogen (≥6 vs. <6 months), pre-treatment PSADT (≥3 vs. <3 months) and extent of disease (limited-axial skeleton and/or nodal vs. extensive-appendicular skeleton and/or visceral). CONCLUSIONS: Ketoconazole is effective and safe in mCRPC. Prior response to antiandrogen, pre-treatment PSADT, and disease extent are associated with PSA response and disease progression, and further supports a therapeutic role in suppressing adrenal androgens in mCRPC.

Lenalidomide modulates IL-8 and anti-prostate antibody levels in men with biochemically recurrent prostate cancer.

BACKGROUND: We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5 or 25 mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression. METHODS: Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect. Estimates were obtained using generalized estimating equations. Changes in circulating anti-prostate antibodies were evaluated using a high-throughput immunoblot technique. RESULTS: Treatment with lenalidomide was associated with global changes in immunoreactivity to a number of prostate-associated antigens, as well as with changes in circulating levels of the T(H) 2 cytokines IL-4, IL-5, IL-10, and IL-13. Disease progression in treated patients was associated with an increase in circulating IL-8 levels, while IL-8 levels decreased significantly in non-progressors. CONCLUSIONS: Lenalidomide demonstrates immunomodulatory properties in patients with biochemically recurrent prostate cancer. The induction of novel anti-prostate antibodies is a potential mechanism for lenalidomide response. Changes in serum IL-8 levels may serve as a potential biomarker in treated patients. These hypotheses require formal testing in future prospective trials.

Changes in PSA kinetics predict metastasis- free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of 4 phase II trials.

BACKGROUND: Several phase II trials in men with noncastrate PSA-recurrent prostate cancer have assessed the impact of novel nonhormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS). METHODS: We performed a retrospective post hoc analysis of 146 men treated in 4 phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n = 39), imatinib (a tyrosine kinase inhibitor; n = 25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n = 22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n = 60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation. RESULTS: After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P = .05), baseline PSA slope (P = .01), on-study change in PSADT (P = .02), and on-study change in PSA slope (P = .03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% confidence interval [CI], 34.6-not reached) and 28.9 months (95% CI, 13.5-68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively. CONCLUSIONS: This hypothesis generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients.

An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy.

BACKGROUND: Loss of the tumor suppressor PTEN is common in prostate cancer and may have prognostic significance. The authors examined PTEN and additional protein markers in primary tumors from patients with high-risk, localized prostate cancer who received adjuvant docetaxel in a prospective multicenter trial (TAX2501). METHODS: Fifty-six of 77 patients enrolled in TAX2501 had primary prostatectomy specimens available for immunohistochemical analysis of PTEN, MYC, ERG, tumor protein p53 (p53), antigen KI-67 (Ki67), and phosphorylated forms of Akt, mammalian target of rapamycin (mTOR), and S6 ribosomal protein. Protocol-defined progression included a prostate-specific antigen (PSA) level ≥ 0.4 ng/mL, radiologic/clinical recurrence, or death. Univariate and multivariable proportional hazards regression analyses were used to investigate the influence of PTEN status (and other protein markers) on progression-free survival (PFS). RESULTS: In this exploratory, post hoc analysis, PTEN protein loss (vs presence) was observed in 61% of patients and was associated with lower preoperative PSA levels, higher clinical stage, lower Ki67 expression, the presence of p53, and the presence of ERG. In univariate analysis, the factors associated with PFS included Gleason sum, seminal vesicle invasion, PTEN status, MYC expression, and Ki67 expression. In multivariable analysis, only 3 variables emerged as independent prognostic factors for PFS: PTEN status (P = .035), MYC expression (P = .001), and Ki67 expression (P < .001). A prognostic model was constructed that incorporated clinical covariates as well as information on PTEN, MYC, and Ki67. CONCLUSIONS: The current results indicated that PTEN status, MYC expression, and Ki67 expression in primary tumor samples may predict PFS more accurately than clinical factors alone in men with high-risk prostate cancer who receive adjuvant docetaxel after prostatectomy. If validated, these hypothesis-generating findings may have prognostic and therapeutic implications and may aid clinical trial design.

Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS: This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS: Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS: In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.

[Metastatic hormone refractory prostate cancer: new treatment horizon].

Prostate cancer is the second leading cause of cancer death in men in the western world. Most deaths will occur due to the progression of cancer into a hormone refractory state. Until recently, docetaxel-based chemotherapy was the only established treatment (shown to increase survival) for patients with metastatic hormone refractory prostate cancer. The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways, and significant expansion of treatment horizons for these patients. In 2010-2011, three more agents, with different mechanisms of action, were shown to be associated with a survival benefit in mHRPC, including the dendritic cell vaccine sipuleucel-T (immunotherapy), the 17,20 lyase inhibitor abiraterone (hormonal therapy), and the taxane cabazitaxel (chemotherapy). A fourth agent, denosumab (bone targeted therapy) was also recently approved by the FDA for patients with bone metastasis after showing a reduction in the occurrence of skeletal-related events. This review will focus on recent advances in the standard treatments paradigm in mHRPC.

68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography for patients with favorable intermediate-risk prostate cancer.

INTRODUCTION: Current guidelines do not support the use of pretreatment imaging in patients with favorable intermediate-risk prostate cancer. 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is more accurate than conventional imaging for preoperative staging. We aimed to evaluate whether pretreatment 68Ga-PSMA PET/CT is beneficial for identifying pathological lymph node involvement (LNI) and adverse pathology among patients with favorable intermediate-risk prostate cancer. METHODS: We reviewed 88 patients with favorable intermediate-risk prostate cancer who underwent 68Ga-PSMA PET/CT prior to radical prostatectomy and lymph node dissection from 2016-2020. The primary endpoint was the presence of pathological LNI. Association between pretreatment characteristics and outcomes were evaluated. RESULTS: Preoperative 68Ga-PSMA PET/CT showed suspicious uptake in lymph nodes in 4/88 patients (5%), hence, 20 patients would need to be scanned to identify a patient with a positive lymph node on imaging. Two patients had pathological LNI, only one of whom showed 68Ga-PSMA PET/CT uptake prior to surgery. The sensitivity, specificity, positive predictive value, and negative predictive values of 68Ga-PSMA PET/CT for identifying LNI were 50%, 97%, 25%, and 99%, respectively. After surgery, four patients had evidence of prostate-specific antigen (PSA) persistence. The rate of PSA persistence was higher among patients with LNI on preoperative 68Ga-PSMA PET/CT (2/4, 50% vs. 2/84, 2%, p=0.009). CONCLUSIONS: Preoperative imaging of favorable intermediate-risk prostate cancer patients using 68Ga-PSMA PET/CT showed a low yield for identifying patients at higher risk. Consistent with current guidelines, our findings do not support the routine use of PET/CT in this group of patients. Future prospective studies are needed to validate our findings.