bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of pathologic T-stage and Gleason score on cancer-specific survival for specimen-confined high-risk prostate cancer.
Authors: Tosco Lorenzo , Van Poppel Hendrik , Van den Broeck Thomas , Bastian Patrick , Briganti Alberto , Chun Felix K. , Gontero Paolo , Hsu Chien Yeh , Karnes R. Jeffrey , Marchioro Giansilvio , Sanchez-Salas Rafael , Spahn Martin , Tombal Bertrand , Van Der Poel Henk , Joniau Steven
Published: February 2017

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Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach. The indication for adjuvant therapy after surgery for HRPC patients who have specimen-confined disease (R0, pN0, <pT3b) is still difficult. The current study aims to analyze postoperative pathological features which help to predict CSS in specimen-confined HRPC and thus may aid in the decision to administer adjuvant EBRT or ADT. Methods: From a multi-institutional retrospective cohort of 5876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1391 patients with specimen-confined disease were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and final Gleason score (GS≥8 and GS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age was 65 years (43-84). Of all patients, 346 (24.9%) had GS≥8 and 794 (57.1%) had pT≥3 at definitive histopathology. Patients were classified into COMBO groups: C1 (478; 34.4%; GS<8,pT<3), C2 (567; 40.8%; GS<8, pT≥3), C3 (119; 8.6%; GS≥8, pT<3), C4 (227; 16.3%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 2%/2%, C2 15%/22%, C3 3%/10%, C4 18%/25%. Kaplan Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97.4%, C2 95.2%, C3 89.9% and C4 84.4% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide specimen-confined HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]
Current clinical presentation and treatment of localized prostate cancer in the United States.
Authors: Mahmood Usama , Levy Lawrence B. , Nguyen Paul Linh , Lee Andrew , Kuban Deborah A. , Hoffman Karen Elizabeth
Published: February 2017

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Background: This year, the Surveillance, Epidemiology, and End Results (SEER) database released individual patient clinical Gleason score (GS) at the time of biopsy/transurethral resection of the prostate (TURP), which, along with the previously available clinical stage and prostate-specific antigen (PSA), allows a unique opportunity to study the clinical presentation and treatment selection of prostate cancer in the US. Methods: The SEER database was used to identify men diagnosed with localized prostate cancer in 2010 who were then assigned National Comprehensive Cancer Network (NCCN) risk group based on clinical factors at diagnosis. We determined sociodemographic factors associated with having high-risk disease and analyzed the impact of NCCN risk, along with sociodemographic factors, on local treatment selection. Results: A total of 42,403 men were identified of which 16,171 (38%) had low-risk, 16,990 (40%) had intermediate-risk, and 9,242 (22%) had high-risk disease. Older, non-white, and non-married patients living in counties with higher poverty rates, were most likely to be diagnosed with high-risk disease on multivariable analysis. Of the 38,634 men for whom prostate cancer was the first malignancy, 8,832 (23%) had no local treatment, 15,421 (40%) had prostatectomy, 13,855 (36%) had radiation treatment (including external beam radiation and/or brachytherapy), and 526 (1%) had another form of local tumor destruction (predominantly cryotherapy). In total, 29% of low-risk, 16% of intermediate-risk, and 25% of high-risk patients received no local treatment (p < 0.001). On multivariable analysis, older, non-white, and non-married patients living in counties with higher poverty rates who had low-risk disease, were least likely to receive local treatment. Conclusions: Our analysis provides information regarding the current clinical presentation and treatment of localized prostate cancer in the US. We note persistent disparities in the presentation and treatment of prostate cancer according to sociodemographic factors and potential under treatment of high-risk disease.
Does tumor grade affect the relationship between preoperative prostate-specific antigen (PSA) and biochemical recurrence (BCR)?
Authors: Sankin Alexander , Kent Matthew , Sjoberg Daniel , Scardino Peter T.
Published: February 2017

123

Background: It has been previously hypothesized that higher grade prostate tumors exhibit less predictable PSA secretion patterns as a consequence of cellular dedifferentiation. The purpose of this study is to investigate whether the relationship between PSA and BCR is different for high and low grade disease. Methods: We identified 6,616 patients who underwent radical prostatectomy (RP) from 1992-2012 for clinically localized prostate cancer without neoadjuvant treatment. We first created a Cox models to test for an interaction between PSA and both clinical and pathologic high grade cancer (Gleason grade (GG) < 8 vs. GG 8-10). We then plotted five year risk of BCR as a function of PSA for patients with negative extracapsular extension (ECE), seminal vesical invasion (SVI), and lymph node invasion (LNI). Results: 6,125 (93%) patients in the cohort had GG < 8, and 491 (7%) had GG 8-10. In total, 780 had BCR and 165 had distant metastasis. We found a significant interaction between PSA and pathologic high grade cancer (p=0.002). The risk of BCR increases at slightly different rates for low and high grade tumors as PSA increases. For example, an increase in PSA from 10 ng/ml to 20 ng/ml increases relative recurrence risk by 38% and 8% for low and high grade cancers, respectively. This interaction remained significant when patients with PSA < 2.5 were excluded (P=0.006). There was no significant interaction between PSA and clinical high grade tumors (p=0.3). Conclusions: There appears to be a small statistically significant difference in relationship between preoperative PSA and BCR in high grade tumors when compared to lower grade tumors. This difference is not observed, however, when using biopsy GG rather than RP specimen GG.
Results of a phase II trial of abiraterone acetate (AA) combined with dutasteride (DUT) for men with metastatic castration resistant prostate cancer (mCRPC).
Authors: McKay Rana R. , Werner Lillian , Zukotynski Katherine A. , Domachevsky Liran , Elfiky Aymen , Pomerantz Mark M, , Bubley Glenn J. , Montgomery Robert B. , Kantoff Philip W. , Taplin Mary-Ellen
Published: February 2017

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Background: Although abiraterone acetate (AA), a CYP17 inhibitor, increases survival in men with metastatic castration resistant prostate cancer (mCRPC), tumors eventually progress on therapy. The primary purpose of this study was to identify mechanisms of resistance to AA via analysis of the androgen receptor signaling pathway in serial tumor biopsies of men receiving AA and dutasteride (DUT), a type I and II 5-α reductase inhibitor. In this analysis, we report secondary endpoints including prostate specific antigen (PSA) response, toxicity, and incidence of flare. Methods: We enrolled 40 men with mCRPC. Patients initially received AA (1,000 mg daily) and prednisone (5 mg daily). After two months (mos), DUT (3.5 mg daily) was added. Therapy was continued until radiographic progression. A flare was recorded on bone scan, CT, or both if there were worsening lesions from baseline to 3 mos, decreasing PSA more than 50% from baseline at 3 mos, and stabilization or reduction of lesions at 6 mos. Results: Median follow-up was 13 mos. At the time of analysis, nine men remain on treatment. Twenty five percent and 18% of men received prior therapy with ketoconazole and/or chemotherapy, respectively. The median PSA at baseline was 28.8 ng/mL. After 2 mos of AA, median PSA declined by 54% to 10.9 ng/mL. Median PSA nadir was 6.3 ng/mL, reached at a median of 3.2 mos from baseline. 34 men (85%) experienced some degree of PSA decline. Twenty four men (60%) had a greater than or equal to 50% PSA decline and 12 (30%) had a greater than or equal to 90% PSA decline, reached at a median of 1.4 and 2.4 mos from baseline, respectively. There were 73% grade 1, 23% grade 2, 4% grade 3, and no grade 4 adverse events (AEs).AEs of interest included fatigue (45%), hypertension (38%, n=2 grade 3), hypokalemia (15%, n=0 grade 3), liver function test increases (15%), and edema (2%, n=0 grade 3). Seventeen men had imaging available for analysis, of whom four (23%) had flare on both 3 mos CT and bone scan and four (23%) had flare on only 3 mos CT scan. Conclusions: Given time of median PSA nadir, DUT may enhance efficacy of AA, though this warrants further investigation. Therapy with AA, prednisone (5 mg daily), and DUT is well tolerated with low rates of severe mineralocorticoid toxicity. Flare is seen on imaging in 47% of patients receiving AA. Biopsy data evaluating mechanisms for resistance to AA are not yet available. Clinical trial information: NCT01393730.
Associations between uncertainty, anxiety, and quality of life in men with favorable-risk prostate cancer on active surveillance: Two-and-a-half years' follow-up.
Authors: Parker Patricia A. , Davis John W. , Latini David , Baum George , Wang Xuemei , Ward John Francis , Kuban Deborah A. , Frank Steven J. , Lee Andrew , Logothetis Christopher , Kim Jeri
Published: February 2017

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Background: Active surveillance (AS) has emerged as a viable option for many men with early stage prostate cancer (PC). This approach of careful monitoring with prostate-specific antigen (PSA) level, digital rectal examination, and prostate biopsy may allow men to avoid or delay the potentially debilitating side effects of such aggressive treatments as surgery or radiation; however, AS may create uncertainty and anxiety for men with PC. We examined the associations between illness uncertainty and anxiety and general and PC-specific quality of life (QOL) of 191 men with favorable-risk PC participating in the AS program at MD Anderson Cancer Center. Methods: Men completed measures of uncertainty (Mishel Uncertainty in Illness Scale), anxiety (State-Trait Anxiety Inventory), and general (SF-12, Physical Health [PCS] and Mental Health Component Score [MCS]) and disease-specific (Expanded Prostate Index Composite [EPIC]) QOL questionnaires upon study entry and every 6 months. These results are through a 2.5 year follow-up. Results: Men were primarily (86%) white and an average age of 67.2 (SD=8.9). Average baseline PSA was 3.3 ng/mL (SD=1.6), 98% had a Gleason score of 6, and 85% had cT1c disease. Both general and PC-specific QOL were relatively unchanged across the 2.5 year study period, except for statistically significant declines in the EPIC Sexual score (p<0.05). Controlling for demographic (age, ethnicity) and clinical characteristics (study entry PSA, PSA density, testosterone, BMI, baseline number of biopsies, family history of cancer, whether patients were taking a 5-alpha-reductase inhibitor, and whether the tumor was reclassified during the study), illness uncertainty was a significant predictor of all EPIC summary scores, PCS, and MCS (all, p<0.05). Anxiety was also a significant predictor of all EPIC summary scores and MCS (all, p<0.05), but not PCS (p=0.08). Conclusions: Both increased anxiety and increased illness uncertainty were associated with poorer general and disease specific QOL. Interventions that focus on reducing uncertainty and anxiety may enhance the QOL of men on AS for PC.
A feasible and time-efficient adaption of the neurosafe intraoperative frozen section technique to robotic-assisted radical prostatectomy.
Authors: Beyer Burkhard , Tennstedt Pierre , Boehm Katharina , Schiffmann Jonas , Schlomm Thorsten , Steuber Thomas , Graefen Markus , Haese Alexander
Published: February 2017

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Background: In robotic-assisted radical prostatectomy (RARP) intraoperative frozen sections are often avoided due to suspected difficulties in harvesting the prostate during this procedure, loss in pneumoperitoneum, increased blood loss and lacking impact on functional outcome. We demonstrate the technique, feasibility and beneficial impact of our NeuroSAFE technique on the rate of nerve-sparing (NS) in RARP and analyse the oncological outcome. Methods: We analyzed 1,570 consecutive patients undergoing RARP from 2004 to 2012. NeuroSAFE was done in 1,178 pts. We compared OR-time, blood loss, frequency of nerve-sparing (NS) and PSM in non-NeuroSAFE versus NeuroSAFE-RARP. The prostate was intraoperatively harvested via an extension of the camera trocar incision without undocking the system. Instrument arms were not undocked. Blood spillage from the dorsal vein complex due to loss of pneumoperitoneum was avoided by upward traction on the transurethral catheter. After prostate removal, pneumoperitoneum was reestablished by closing the extended incision and repositioning of the optical trocar. NeuroSAFE-procedure consisted of intraoperative bilateral frozen sections covering the entire contact area of the prostate and the neurovascular bundles. Results: There was no significant difference in blood loss (253.5±204.4 ml vs. 265.8±246.7 ml, p=0.49) and OR-time. (220 min ± 51 vs. 224 min ± 64, p=0.22). No complications associated with specimen harvesting occurred. NS-rate increased significantly with vs. without NeuroSAFE (overall 97% vs. 81%, pT2 99% vs. 90%, pT3a 94% vs. 74%, pT3b 91% vs. 30). PSM rate dropped significantly with NeuroSAFE (overall 16% vs. 24%, pT2 8% vs. 15%, pT3a 22% vs. 39%, pT3b 49% vs. 67%, all p<0.05). Conclusions: We demonstrate a time-efficient adaption of the NeuroSAFE without patient side cart undocking, easy harvesting process, no increased blood loss or OR-time increased rate of nerve-sparing frequency and reduction of PSMs.
In vitro reproduction and explanation of an abiraterone acetate withdrawal phenomenon.
Authors: Thelen Paul , Jarry Hubertus , Trojan Lutz , Brookman-May Sabine , Bremmer Felix
Published: February 2017

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Background: Androgen deprivation and direct androgen receptor (AR) antagonism are standard treatments for castration resistant prostate cancer (CRPC). The advent of new drugs such as abiraterone acetate (AA) and enzalutamide rendered highly efficient implementations of both anti-androgen strategies. However, reports of therapy resistance or cross resistance soon accompanied reports of successful clinical trials of these new drugs. Moreover, case reports of an AA-withdrawal phenomenon surfaced, an outcome normally associated with AR antagonism e.g. by bicalutamide with high AR-affinity and the potential to switch from antagonism to AR-activation. Methods: CRPC cell model VCaP and VCaP resistant to permanent treatment of 5 µmol/L AA (Janssen-Cilag, Germany) were analyzed under AA and for AA withdrawal. Expression of AR, AR-V7, androgen regulated genes, CYP17A1 and AKR1C3 was quantitated by real time RT-PCR. Further analyses were performed by western blots, prostate-specific antigen (PSA) ELISA kits and cell proliferation BrdU tests. Results: VCaP cells resistant to 5 µmol/L AA after 7 months revealed excessive AR and CYP17A1 expression and a marked decline of tumor cell proliferation in response to AA withdrawal or to a similar extent to added 1 nmol/L testosterone. Proliferation dropped to less than 50% when both procedures were combined. Elimination of tumor cells was accompanied by a massive release of PSA which was most pronounced in the combined treatment. Conclusions: Overexpression of AR turning into a liability as a therapeutic target for a testosterone surge has been reported by several research groups. AA withdrawal from AA resistant cells complies with these necessities by overexpression of AR and CYP17A1 formerly arrested by AA. In patients a PSA decline upon AA withdrawal may be explained by an excessive loss of PSA secreting tumor cells. Therefore, AA qualifies uniquely for effective intermittent androgen deprivation of CRPC.
Clinical activity of enzalutamide against metastatic castration-resistant prostate cancer (mCRPC) in patients who have progressed on abiraterone acetate: The Princess Margaret experience.
Authors: Vera-Badillo Francisco Emilio , Leibowitz-Amit Raya , Templeton Arnoud , Seah Jo-An , Sridhar Srikala S. , Knox Jennifer J. , Tannock Ian , Joshua Anthony Michael
Published: February 2017

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Background: In men with mCRPC enzalutamide and abiraterone acetate have been shown individually to prolong survival after progression on chemotherapy with docetaxel. Little is known about the sequential use of enzalutamide and abiraterone. A PSA response rate of 8% and progression free survival (PFS) of 2.7 months has been reported for 38 men who received abiraterone following enzalutamide [Loriot, Ann Onc, 2013]. Here we report our experience with enzalutamide following abiraterone. Methods: We reviewed all patients with mCRPC treated with enzalutamide following abiraterone and docetaxel at our institution. Primary outcomes were PSA response rate (confirmed decline ≥ 50%) and time to treatment failure (TTF, defined as the time from treatment initiation to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death.). Data were analyzed using the Kaplan-Meier method. Results: Twenty-six patients were treated between August 2012 and July 2013. Median age was 72 years (range 56-88); 85% had ECOG performance status 0 or 1; metastatic sites included bone (N=25, 96%), lymph nodes (N=19, 73%) and visceral (N=1, 3.4%). Median number of prior cycles of docetaxel was 8 (range 1 – 12), 6 patients (29%) had previous exposure to ketoconazole, and median duration of previous abiraterone was 8.7 (range 1.4-22.7) months. Seven pts (27%) had a PSA response ≥ 50% and an additional 7 patients (27%) had a ≥ 30% PSA response. Median TTF on enzalutamide was 4.9 (95% CI 3.8-6.2) months. Reasons for discontinuation of enzalutamide were clinical and/or biochemical progression in 24 patients (92%), and toxicity (fatigue grade 3-4) in 3 patients (11.5%). An update of patient numbers and analysis will be presented at the meeting. Conclusions: Treatment of patients with mCRPC with enzalutamide after progression on docetaxel and abiraterone has modest clinical activity.
Patient-reported sexual outcomes and potency following proton therapy for the management of prostate cancer.
Authors: Hoppe Bradford S. , Nichols Romaine Charles , Henderson Randal H. , Mendenhall William M. , Morris Christopher G. , Bryant Curtis , Su Zhong , Williams Christopher R , Li Zuofeng , Mendenhall Nancy Price
Published: February 2017

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Background: The present study investigates sexual outcomes and potency rates in men treated with proton therapy for prostate cancer. Methods: Between 2006 and 2010, 1063 men were treated with proton therapy alone (no androgen deprivation therapy) for prostate cancer at University of Florida on an IRB approved outcomes tracking protocol. 99% of men were treated with 78-82 Gy (RBE). The expanded prostate index composite (EPIC) was collected prior to treatment and every 6-12 months after treatment. Potency was defined by question 59 of the EPIC, “How would you describe the usual Quality of your erections during the last 4 weeks”, where an answer of “firm enough for intercourse” was considered potent, while any other answer was considered “impotent”. Results: The EPIC was answered by 97%, 89%, 88%, and 84% at baseline, 6 months, 1 year, and 2 years after treatment. The median sexual summary (SS), sexual function (SF), sexual bother (SB) scores and potency over time are listed in the Table. A restricted analysis of SS, SF, SB and potency rates adjusted to baseline sexual score of 100 (best score) or potency is also included in the Table. Multiple logistic regression of 2 year impotency rate showed that age (<65 vs >=65, p=0.004) and baseline SS score (<68 vs68-99 vs100, p<0.0001) were significant prognostic factors. Among men with baseline potency (n=687), two years following treatment potency rates were 48% if the patient had baseline SS score of <=67 , 68% if the patient had a baseline SS score of 68 to 99 and 84% if their SS score at baseline was 100. Among just men with baseline SS of 100 (n=119), 87% of those age <65 were potent at 2 years, while 78% men age>=65 were potent at 2 years. Conclusions: Although sexual scores and potency decline following proton therapy, men with excellent baseline sexual function have very high rates of potency 2 years following treatment. Longer follow-up is needed. [Table: see text]
Incidence, distribution, and outcomes of node positive patients at radical prostatectomy: Manitoba Prostate Center experience.
Authors: Kaler Kamaljot Singh , Kroczak Tadeusz Jozef , Patel Premal , Rittberg Rebekah , Saranchuk Jeffery Walter , Drachenberg Darrel E
Published: February 2017

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Background: Pelvic lymph node dissection at the time of radical retropubic prostatectomy (RRP) varies among surgeons and institutions. Differences focus on candidacy for node dissection and the limit of dissection. Standard lymph node dissection is typically above the obturator nerve to external iliac vessels. We analyzed our local experience of lymph node metastases at time of surgery. Methods: Data from the Manitoba Prostate Center were collected on consective patients undergoing RRP from January 2003 to June 2013 by two urologists with subspecialty training in oncology. Information extracted includes age, prostate-specific antigen (PSA), biochemical recurrence characteristics, and biopsy and pathological results. Results: Four hundred twenty consecutive patients comprised the data set and of whom 411 underwent a RRP and nine aborted prostatectomies. Average age of patients was 60 with an average preoperative PSA of 11. Overall lymph node metastases rate is 16.1%. Of the N1 patients, average number of positive nodes was 2.3. Average nodes removed for all patients were 13.4. Positive nodes on the right were found 53% of the time and 47% on the left. Locations of nodes are as follows: right external iliac, obturator, and hypogastric, 12%, 6%, and 19%, respectively; and for left external iliac, obturator, and hypogastric 9%, 3%, and 16%, respectively of all total nodes. One node was identified as other, and one surgeon sent packets as right pelvic and left pelvic with positive nodes 16% and 19% of all total positive nodes respectively. When looking at zones of a pelvic lymph node dissection separately, 54% are hypogastric, 13% obturator, and 33 external iliac. With an average of 37 months follow-up two patients with N1 disease died and only one from prostate cancer. Seventy nine percent had biochemical recurrence. Median time to treatment for biochemical recurrence was 4.5 months (0 to 33 months) with a median PSA of 0.28. Conclusions: This contemporary series of pelvic lymph node dissection with RRP represents high lymph node metastases (16%) relative to literature. Performing a limited pelvic lymph node dissection would under stage 54% of our patients. Despite high biochemical recurrence only one patient died of prostate cancer.
Effect of prior abiraterone (ABI) or enzalutamide (ENZ) on sipuleucel-T (sip-T) manufacture in PROCEED patients (pts).
Authors: Vogelzang Nicholas J. , Vacirca Jeffrey L. , Kantoff Philip W. , Scholz Mark C. , Dakhil Shaker R. , Nordquist Luke T. , Higano Celestia S. , Sartor A. Oliver , Cooperberg Matthew R. , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Armstrong Andrew J.
Published: February 2017

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Background: Sip-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). PROCEED is an ongoing phase 4 registry, enrolling pts receiving commercial sip-T. There are no exclusions based on prior prostate cancer treatments, so sip-T product parameters can be evaluated in pts receiving prior hormonal agents such as ABI or ENZ. Methods: Pts treated with sip-T within ≤6 mo were eligible to provide informed consent. Prior anticancer interventions were recorded at baseline. Sip-T product parameters were assessed. Results: Of 1,376 pts (as of May 2013), 108 (7.8%) received prior ABI and 58 (4.2%) received ENZ. Patients with ABI or ENZ generally had more advanced disease vs. pts without prior ABI or ENZ (WPT) and a greater proportion of the ABI and ENZ pts received prior docetaxel. There were slight differences in some sip-T product parameters in the ABI and ENZ groups, but neither manufacture nor receipt of sip-T were inhibited, as indicated by the percentage of pts with 3 successful infusions. All groups showed evidence of immune prime boost (Table). Conclusions: A subset of patients in PROCEED have received ABI or ENZ prior to sip-T. We observed no impact of prior ABI/ENZ on sip-t manufacturing or delivery, despite these men having more advanced disease. These results are consistent with prior analyses demonstrating a positive sip-T treatment immune effect in patients who have received prior therapies, including chemotherapy. Further immune monitoring and outcome studies are currently ongoing in the pre-docetaxel mCRPC setting where these agents will likely be used clinically. Clinical trial information: NCT01306890. [Table: see text]
Response of blood flow to hyperthermia in human prostate tumors: Opportunities for enhanced radiation effect and drug delivery.
Authors: Hurwitz Mark , Martin Gregory T , Sidney Daniel A , Welch Charles J , Hansen Jorgen L , Bornstein Bruce A , Kaplan Irving D. , Bowman H F
Published: February 2017

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Background: Tissue perfusion may be a significant factor affecting outcome of prostate cancer treatment. Hyperthermia has been shown to have beneficial anti-cancer effects when combined with other anti-neoplastic modalities including radiation, chemotherapy, and immunotherapy. For instance, hyperthermia may increase prostate perfusion resulting in radiosensitization through increased oxygenation and chemotherapy through enhanced drug delivery. We previously reported significant benefit to the addition of hyperthermia to radiation on a phase II trial for men with locally advanced prostate cancer. To better understand tissue perfusion in patients with prostate cancer and response to hyperthermia, we measured perfusion levels in patients on this trial before and after hyperthermia. Methods: Prostate perfusion was measured before and immediately after heating in a total of 21 hyperthermia treatments in 14 patients with prostate cancer. A trans-rectal ultrasound device with a water cooled jacket was used to heat the prostate. Prostate tissue temperatures were measured using three multisensory thermocouple probes. Perfusion was measured with the TDP-200 Thermal Diffusion Probe, a thermistor-based device which quantifies perfusion with a modified wash-out technique. Results: In 19 treatments in which perfusion was measured before heating, average and standard deviation was 18.3 ± 10.6 ml/100g-min and in 17 treatments in which perfusion was measured after heating, it was 30.7 ± 20.8 ml/100g-min. This represents a statistically significant increase of 68% (p = 0.018). Perfusion increased 12 of 15 treatments in which measurements were obtained before and after hyperthermia. Notably, prostate tissue that was most ischemic prior to heating experienced the largest heat-induced perfusion increase. Conclusions: Prostate perfusion increased significantly with a majority of hyperthermia treatments. Enhanced prostate oxygenation may have been a contributing factor to the benefit noted with hyperthermia in this phase II trial. The use of hyperthermia to augment prostate perfusion to enhance radiation, chemotherapy, and immunotherapy warrants further investigation.
Phase II study of weekly cabazitaxel for "unfit" metastatic castration resistant prostate cancer patients progressing after docetaxel treatment: Preliminary toxicity analysis (SOGUG-CABASEM trial).
Authors: Climent Duran Miguel Angel , Perez-Valderrama Begoña , Fernandez Parra Eva , Mellado Begoña , Domenech Montserrat , Fernandez Calvo Ovidio , Anido Urbano , Polo Susana Hernando , Arranz Jose Angel , Caballero Cristina , Ochoa de Olza Maria , Castellano Daniel E.
Published: February 2017

190

Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement in second line CRPC in a three-weekly dose schedule. Its main toxicity is hematological, especially in unfit patients. We aimed to evaluate efficacy and safety of weekly C/pred. in "unfit" mCRPC previously treated with D. Methods: Unfit pts (ECOG 2, dose reduction due to febrile neutropenia during treatment with D or radiation therapy affecting more than 25% of bone marrow reserve) with advanced CRPC progressing after D treatment with ECOG <=2 and adequate bone marrow, liver and kidney functions were included. C 10 mg/m2 was administered on days 1, 8, 15, and 22 of 5-week cycles with daily pred. 5 mg b.i.d. Radiological and prostate-specific antigen response was evaluated according to the PCCTWG II criteria and toxicity according NCI-CTC AE. Results: To date 47 pts have been enrolled and data are available for 38. Median age was 72 (range 56 to 83), 20 (53%) pts had ECOG 2, 29 (83%) had bone metastases. Cycles administered: 124 (median: 3; range: 1 to 9) and 446 weekly administrations (median 11; range 1 to 35). Mean dose intensity was 94%. Most frequent toxicities of all grades as % of cycles were: asthenia (20%), anemia (50%), leukopenia (13%), thrombocytopenia (14%), diarrhea (9%), rash (6%), nauseas (5%), dysgeusia (7%), xerostomia (6%), anorexia (5%), hand-foot syndrome (5%), and neuropathy (2%). Grade 3: thrombocytopenia (10%), anemia (6%), neutropenia (1%), asthenia (3%), anorexia (1%), mucositis (1%), nausea (1%), and vomiting (1%). No grade 4 toxicities were reported. Three patients discontinued the study due to asthenia G3 (2) and mucositis G3 (1). No grade III/IV diarrhea or febrile neutropenia were observed. Conclusions: Administration of weekly C (10 mg/m2) to unfit pts seems to be safe with no grade 3 or greater neutropenia, diarrhea, or febrile neutropenia reported. If activity is confirmed, weekly C may represent an attractive option for unfit pts with mCRPC progressing after D treatment. Clinical trial information: NCT01518283.
Evaluating the safety of abiraterone acetate (AA) and docetaxel (D) administered in combination in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Nanus David M. , Posadas Edwin M. , Petrylak Daniel Peter , Bruce Justine Yang , Lim Emerson A. , Peng Weimin , Maul Raymond Scott , Gonzalez Martha , Tran Namphuong
Published: February 2017

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Background: D and AA may have complementary mechanisms of action; coadministration may be beneficial. A phase Ib study assesses the safety of escalating doses of D + AA. Methods: Up to4 cohorts (C) of chemo-naïve mCRPC pts would receive D + AA. Data for C1 and C2 are presented. Primary end point: proportion of pts with dose-limiting toxicity (DLT) between Wks 2 and 7, defined as grade (Gr) ≥ 3 non-heme toxicity, Gr 4 neutropenia (absolute neutrophil count < 500/mm3) > 7 days (or febrile neutropenia), Gr 4 thrombocytopenia, or other intolerable toxicity. D + AA was deemed safe if ≤ 33% of pts experienced DLT. Pharmacokinetic (PK) parameters were evaluated for D and AA alone and in combination. Results: 15 pts were treated and 6 pts/C were evaluable for DLT assessment. 2 DLTs were observed in C1, and 1 in C2. 73% and 87% of pts had confirmed ≥ 90% and ≥ 50% prostate-specific antigen (PSA) decline, respectively. Median time to PSA progression has not yet been reached. Systemic exposure, based on maximum plasma concentration (Cmax) and area under the concentration–time curve [(AUC)∞ for D, AUC24 for abiraterone (ABI)], was comparable for both D and AA alone and for D + AA. 3 pts in C3 (D 75 mg/m2+ AA 1000 mg) have been treated past Wk 7 without DLT. Conclusions: D + AA was well tolerated in the cohorts tested. Preliminary results justify further evaluation of safety and efficacy in additional Cs. Clinical trial information: NCT01400555. [Table: see text]
Clinical activity of enzalutamide pre- and post-docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Nadal Rosa , Zhang Zhe , Raheja Hitesh , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: February 2017

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Background: Enzalutamide is an androgen receptor signaling inhibitor that is FDA-approved for post-docetaxel mCRPC patients. Overlapping mechanisms of action and clinical evidence for an interaction between taxanes and androgen-targeted therapies complicates optimal sequencing of taxanes and enzalutamide. We retrospectively evaluated the efficacy of enzalutamide pre- (preD) and post-docetaxel (postD) therapy. Methods: Men with mCRPC who received enzalutamide preD or postD were identified from a single institution database. We investigated factors influencing enzalutamide activity by using univariate and multivariable Cox regression models, with particular attention to whether or not prior docetaxel had been used. Outcome measures of interest were time-to-PSA-progression (TTPP) and progression-free-survival (PFS). Results: A total of 72 patients received enzalutamide at our institution: 22 were preD and 50 were postD. Median duration of enzalutamide therapy was 5.5 mo (range, 0.7–33.6 mo). In univariate Cox regression analysis, the following factors were predictive of TTPP: ECOG status (≥1 vs 0), number of metastases (>5 vs 0-5), hemoglobin and albumin. Prior docetaxel treatment was associated with a trend towards shorter TTPP on enzalutamide (HR 0.54, 95%CI 0.27–1.10, P=0.09). The following factors were predictive of PFS in univariate analysis: ECOG status, number of metastases, hemoglobin and albumin. Prior docetaxel therapy was associated with a trend towards shorter PFS on enzalutamide (HR 0.57, 95%CI 0.29–1.13, P=0.10). Conclusions: These data suggest numerically inferior TTPP and PFS outcomes to enzalutamide in men previously treated with docetaxel compared to men who were docetaxel-naïve, although the small sample size precludes statistically significant results. This potentially supports the hypothesis of cross-resistance between enzalutamide and docetaxel.
Simultaneous cone beam CT scanning during prostate radiotherapy to produce clinically useful images.
Authors: Choudhury Ananya , Dickinson Peter , Stratford Julia , Ryder David , Walshaw Richard C. , Mayes Sam , Logue John P. , Wylie James , Coyle Catherine , Livsey Jacqueline E. , Tran Anna , Alam Nooreen Sarah , Elliot Tony , Rowbottom Carl , Faivre-Finn Corinne , Boylan Christopher
Published: February 2017

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Background: Cone beam CT (CBCT) images can be acquired during delivery of rotational radiotherapy. We assessed the quality of simultaneous CBCTs captured during prostate radiotherapy and studied the effects of arc delivery time on image quality. Methods: Fifty patients with localised prostate cancer were treated with radical rotational radiotherapy. Treatment was delivered using a single eight or 10 MV arc on an Elekta Synergy linear accelerator. Standard (stCBCT) and simultaneous CBCTs (siCBCT) were captured on fractions 1, 6, 11, and 16. The siCBCT image was reconstructed and optimised using in-house software. The image quality was assessed by four observers using a validated scoring tool. The scoring clinician was blinded to whether the scan was stCBCT or siCBCT. Results: Seventy-four siCBCT scans were performed with a mean arc delivery time of 120 seconds during which 688 CBCT frames were acquired. Following a software upgrade the subsequent 122 siCBCTs were obtained with a mean arc delivery time of 83 seconds during which 502 CBCT frames were acquired. There was moderate agreement between the four observers regarding the quality of the CBCTs (Fleiss’ kappa statistic 0.51). StCBCTs were of good quality and the four observers agreed that 98 to 100% of these scans were of sufficient quality to be used to make a clinical decision. The four observers assessed that 35 to 79% of siCBCTs were of sufficient quality to be used to make clinical decisions. Before the software upgrade 65 to 93% of siCBCTs were judged to be of sufficient quality to make a clinical decision ("slow" simultaneous CBCT). Following the software upgrade this proportion fell to 16 to 69% ("fast" simultaneous CBCT). Conclusions: SiCBCT can produce images which are clinically useful. Image quality is affected by bowel gas, patient habitus and scatter from the MV beam. Reducing arc delivery time and the number of CBCT frames acquired by approximately one-third reduces the quality of siCBCTs. Further development and refinement of siCBCT scanning is warranted. Future reductions in arc delivery times may have to be limited if the use of siCBCT scanning becomes standard practice.
Correlation between recurrent chromosomal deletions status obtained on tissue cores and local invasive and systemic prostate cancer growth.
Authors: Adam Meike , Wenzel Philipp , Lanwehr Dominik , Tennstedt Pierre , Kluth Martina , Burkhardt Lia , Krohn Antje , Fisch Margit , Graefen Markus , Minner Sarah , Sauter Guido , Simon Ronald , Schlomm Thorsten
Published: February 2017

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Background: A variety of chromosomal deletions are known to occur frequently in prostate cancer, but the clinical significance of most of these deletions is unknown. To learn more about epidemiology, associations with other molecular features, and relevance for key clinical endpoints, several recurrent deletions were analyzed on a large-scale tissue microarray platform. Methods: A tissue microarray containing 11,156 prostate cancers was analyzed by fluorescence in situ hybridization (FISH) with dual-labeling probes including PTEN (10q23), TP53 (17p13.1), CHD1 (5q21), and MAP3K7 (6q15) together with their respective centromere probes. Patients were stratified into three major biological groups (organ confined, locally advanced, and systemic tumor growth) according to their multidimensional long-term follow up data. In addition, ERG fusion status and tumor cell proliferation (Ki67 labeling index) of all cancers were determined by immunohistochemistry. Results: Deletions were seen for PTEN in 17.9% of 6,122, TP53 in 14.7% of 7,604, CHD1 in 9.9% of 7,026, and for MAP3K7 in 18.7% of 3,528 interpretable cases. All deletions were strongly linked to a positive (PTEN, TP53) or negative ERG status (CHD1, MAP3K7, p<0.0001 each) and early prostate-specific antigen recurrence. The combination of deletion information provided even better prognostic information, showing a dose dependent relationship between the number of deletions and the growth pattern (organ confined, local invasive, or systemic) of the tumor. Patients with no deletion had a 16.8% risk for local invasive and only 8.9% risk for systemic tumor growth, whereas the respective figures were 17.9% and 44.6% in patients with more than or equal to three deletions (p<0.001). The chance of having an organ confined tumor was 68.0% for patients with no deletion and 23.1% for patients with more than or equal to three deletions (p<0.001), respectively. Conclusions: Our data show, that these analyzed chromosomal deletions are tightly linked with ERG status in prostate cancer and that the deletion status obtained on small tissue cores correlates with key biological tumor features. Combinatorial analysis of genomic alterations in prostate biopsies might provide clinically relevant information.
Enzalutamide after abiraterone in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Sandhu Gurprataap Singh , Parikh Rahul Atul , Appleman Leonard Joseph , Friedland David
Published: February 2017

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Background: Abiraterone is a 17a hydroxylase and C17,20-lyase inhibitor that blocks androgen biosynthesis and is approved for treatment in patients with mCRPC. Enzalutamide, a second-generation androgen receptor signaling inhibitor was recently approved for use in patients with mCRPC post-docetaxel. There is paucity of information regarding sequential use of enzalutamide after abiraterone. Methods: This is a single-center, retrospective analysis of 23 patients with mCRPC who received enzalutamide after progression on abiraterone. Post-treatment prostate specific antigen(PSA) response and time to PSA progression were used to determine enzalutamide efficacy. Patients were followed for 6 months post initiation of enzalutamide. Results: At the time of enzalutamide initiation, median age was 70 years, with average Gleason score of 7 at the time of diagnosis. All patients were on ongoing androgen deprivation therapy, and 15 patients had received prior docetaxel chemotherapy. Median duration of abiraterone and enzalutamide treatment was 7 and 4.5 months respectively. 12 patients had at least one declining PSA value post enzalutamide treatment, with 5 patients showing >25% decline in PSA and 4 patients > 50%. Median time to PSA progression in patients receiving enzalutamide following abiraterone was 2.3 months. Conclusions: Sequential enzalutamide in patients with CRPC post-abiraterone showed only modest activity, indicating that the clinical benefit of sequential use of highly potent androgen pathway inhibitors cannot be assumed, and should be measured in prospective studies.
Association of alkaline phosphatase (ALP) with clinical outcomes in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Yu Evan Y. , Saad Fred , Londhe Anil , Shore Neal D. , Van Poppel Hendrik , Rathkopf Dana E. , Smith Matthew R. , Logothetis Christopher , De Souza Paul L. , Fizazi Karim , Mulders Peter F.A. , Mainwaring Paul N. , Hainsworth John D. , Beer Tomasz M. , North Scott A. , Small Eric Jay , Scher Howard I. , Griffin Thomas W. , Yu Margaret K. , Ryan Charles J.
Published: February 2017

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Background: Prognostic models have been developed for men with mCRPC. In this analysis we undertook a pragmatic approach to focus on commonly obtained markers. Baseline ALP and normalization of elevated ALP post-docetaxel have prognostic value for overall survival (OS). We examined the association between ALP and prostate-specific antigen (PSA) elevation at baseline and after 4 cycles of therapy (C5D1), when both markers were assessed, with long-term clinical outcomes in COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in chemotherapy-naive mCRPC pts. Methods: 1,088 pts were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P. Radiographic progression-free survival (rPFS) and OS were co-primary end points. The study design, as well as primary and secondary end point results obtained at the time of a prespecified interim analysis at 55% OS events, have been described in detail previously. The effect of elevated ALP (above upper limit of normal) and PSA (above 106.2 µg/mL, baseline third quartile) status on rPFS and OS was assessed retrospectively using a stratified Cox regression model that included treatment and baseline factors log (lactate dehydrogenase), hemoglobin, whether patient had only bone metastasis, and age. Results: Elevated status of ALP and PSA were independent significant predictors of increased risk for outcomes at baseline as well as after 4 cycles of therapy (Table). Conclusions: These post hoc analyses of data from COU-AA-302 suggest that elevated ALP and PSA at baseline and during treatment confers individual and additive risk for adverse clinical outcomes in chemotherapy-naive mCRPC. Clinical trial information: NCT00887198. [Table: see text]
Duration of response to androgen-deprivation therapy (ADT) and efficacy of secondary hormone therapy, docetaxel (D), and cabazitaxel (C) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Angelergues Antoine , Maillet Denis , Flechon Aude , Ozguroglu Mustafa , Mercier Florence , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , De La Motte Rouge Thibault , Delanoy Nicolas , Elaidi Reza-Thierry , Oudard Stephane
Published: February 2017

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Background: Early CRPC (<12 months, m) with 1st hormonal therapy (HT) was found to predict poor efficacy of 2nd HT, but did not seem to impair the benefit of D-based chemotherapy. We evaluated the impact of this variable in our cohort of patients (pts) treated also with second-line chemotherapy C. Methods: Records of 132 consecutive mCRPC pts were retrospectively collected in 9 centers. PSA response ≥ 30% and time to biochemical progression (TTBP) with 1st- and 2nd-HT, D and C were evaluated according to time to progression to CRPC (<12 m and ≥12 m). PSA-response, TTBP and Overall Survival (OS) were compared using exact, Wilcoxon and log-rank tests, respectively. Results: All patients received first HT, D and C, and 94 of them received second HT. Time to CRPC <12 m was associated with a reduced OS and poor PSA-response and TTBP with second HT. Taxanes showed a similar PSA response whatever the time to CRPC but TTBP was slightly shorter in men with time to CRPC <12m. Conclusions: This retrospective analysis of 132 pts with mCRPC suggests that rapid progression to CRPC (<12 m) is associated with a poor prognosis and a low response to second-HT. PSA response to taxanes does not seem to be affected by time to CRPC, but TTBP is shorter in men with early CRPC. Prospective randomized trials are needed to confirm these results. [Table: see text]
Evaluation of outcomes following centralization of cystectomy services in the United Kingdom.
Authors: Patel Prashant , Evison Felicity , Goodfellow Henry , Bryan Richard , James Nicholas David
Published: February 2017

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Background: NICE-Improving Outcomes in Urological cancers (2002) recommended that providers in UK carry out a cumulative total of at least 50 radical cystectomies or prostatectomies per year. Surgeons should perform ≥5 cystectomies per year and 30-day mortality rates of 3.5% or less must be achieved. We evaluated this effect of centralisation on cystectomy outcomes over the past decade. Methods: The Health Episode Statistic (HES) database for cystectomies in England over a period of 2001 to 2012 for patients with bladder cancer was interrogated. Banded provider volumes (<10, ≥10 to < 16, ≥16) and surgeon volumes (<5, ≥5 to <8, ≥8) with respect to age, sex, Charlsons’ comorbidity index, deprivation index are presented with outcomes related to 30, 60, 90 day mortality; length of stay (LOS); re-admission; complications; operation specific re-intervention; and overall survival related outcome data is analysed. Results: 14,693 cystectomies for bladder cancer were performed over the study period. 85.5% providers (35% of all cystectomies) and 70.9% Surgeons (40% of all cystectomies) were performing less than the recommend standard prior to the NICE 2002 recommendations. A decade later 50% providers (3.5% of all cystectomies) and 42% surgeons continue to perform less than the recommended standard but only 12.5% of all cystectomes were carried in non-compliant centres/surgeons. The 30-day mortality rate fell from 3.7% to 2.4%. There was no difference in age, sex or deprivation scores amongst the bands for providers/surgeons. However, high volume providers and surgeons operated on patients with higher comorbidity scores but achieved shorter LOS. No difference in complications was seen amongst the bands, but re-intervention rates were higher amongst low volume surgeons. Mortality (early and overall) was lower in high volume provider and surgeons when compared to low bands. Conclusions: The UK data suggests 87.5% cystectomies are carried out in a compliant centre indicative of centralisation. The 30-day mortality rates have fallen. Overall mortality is lower in high volume providers and surgeons despite these groups with higher co-morbidity scores reflective of improved service provision through centralisation.