bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of TRC105 (anti-CD105 [endoglin] antibody) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H , Apolo Andrea Borghese , Adelberg David E. , Madan Ravi Amrit , Gulley James L. , Arlen Philip M. , Parnes Howard L. , Pierpoint Ann , Kohler David R. , Price Douglas K. , Steinberg Seth M , Trepel Jane B. , Figg William Douglas , Dahut William L.
Published: February 2017

117

Background: Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS).

Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Five cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10 or 15 mg/kg IV every 2 weeks (cohorts 1, 2, 3, and 5) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter.

Results: Seventeen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Two patients remain on study (in cohort 5).

Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.
Is clinical stage T2c prostate cancer intermediate- or high-risk disease? Results from the SEARCH database.
Authors: Singh Abhay A , Gerber Leah , Freedland Stephen J. , Aronson William J , Terris Martha K. , Presti Joseph C. , Amling Christopher L , Banez Lionel Lloyds ,   Shared Equal-Access Regional Cancer Hospital
Published: February 2017

123

Background: Clinical stage T2c is a nebulous factor in the algorithm for prostate cancer risk stratification. According to D’Amico risk stratification cT2c is high-risk category where NCCN guidelines place this stage in intermediate-risk. As diagnostic work up with the use of MRI continues to escalate clinical staging may become more important. As cT2c represents a possible decision fork in treatment decisions we sought to investigate which risk group the clinical behavior of cT2c tumors more closely resembles.

Methods: We retrospectively analyzed data from 1089 men who underwent radical prostatectomy (RP) from 1988 to 2009 who did not have low-risk CaP from the SEARCH database. We compared time to BCR between men with cT2c disease, those with intermediate-risk (PSA 10-20 ng/ml or Gleason sum (GS) =7), and those with high-risk (PSA>20 ng/ml, GS 8-10, cT3) using Cox regression models adjusting for age, race, year of RP, center, and percent cores positive. We also compared predictive accuracy of two Cox models wherein cT2c was considered either intermediate- or high-risk by calculating concordance index c.

Results: A total of 68 men (3.4%) had cT2c tumors. After a median follow-up of 47.5 months, there was no difference in BCR risk between men with intermediate-risk CaP and those with cT2c tumors (HR=0.90; p=0.60). In contrast, there was a trend for men with high-risk CaP to have nearly 50% increased BCR risk compared to men with cT2c tumors (HR=1.50; 95% CI=0.97-2.30; p=0.07) which did not reach statistical significance. Concordance index c was higher in the Cox model wherein cT2c tumors were considered intermediate-risk (c=0.6147) as opposed to high-risk (c=0.6106).

Conclusions: BCR risk for patients with clinical stage T2c was more comparable to men who had intermediate-risk CaP than men with high-risk. In addition, a model which incorporates cT2c disease as intermediate-risk has better predictive accuracy. These findings suggest men with cT2c disease should be offered treatment options for men with intermediate-risk CaP. As clinical staging more routinely incorporates MRI there is the potential to better identify bilateral organ-confined CaP and further establish risk classification.
Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).
Authors: Nabhan Chadi , Patel Anand , Villines Dana , Tolzien Kathy , Kelby Susan K. , Lestingi Timothy M.
Published: February 2017

128

Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts)

Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL).

Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN).

Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.
High-risk prostate cancer treated with I-125 brachytherapy.
Authors: Stockham Abigail Lauren , Reddy Chandana A. , Stephans Kevin L. , Ciezki Jay P. , Tendulkar Rahul D.
Published: February 2017

134

Background: High-risk prostate cancer (HRPC) is commonly defined as Gleason score (GS) ≥ 8, PSA ≥ 20 ng/ml, and/or T3-T4 disease, or having a combination of two intermediate risk factors. Multimodality therapy is commonly utilized for HRPC due to concerns of extra-prostatic extension or seminal vesicle invasion. The purpose of this study was to examine the outcomes of HRPC patients treated with wide brachytherapy implant alone.

Methods: From our IRB-approved registry, we performed a retrospective review of all patients with HRPC and no radiographic evidence of metastatic disease who were treated with I-125 prostate brachytherapy at Cleveland Clinic. Patients who received supplemental external beam radiation were excluded. Characteristics analyzed on univariate analysis included initial PSA, GS, clinical stage, use of androgen deprivation (AD), dose to 90% of the prostate (D90), and volume of the gland receiving 100% of the prescribed dose (V100) of 144 Gy. Endpoints included biochemical relapse free survival (bRFS) defined by nadir PSA + 2 ng/ml, and distant metastases.

Results: From 7/1997- 6/2011, 389 patients with HRPC were treated with I-125 prostate brachytherapy. Median age was 70 years. Patients with GS 8-10 accounted for 40% of cases, 72% were clinical stage T1c, and the median initial PSA was 11.3 ng/ml. Concurrent AD was utilized in 67% of patients and the median D90 was 144.8 Gy (range 75.7 – 248.33 Gy). At a median follow-up of 27 months, the 5-year bRFS was 75.7% and the 5-year distant metastases-free survival was 93.1%. Nine patients died of prostate cancer (crude rate 2.3%). No clinical or treatment factors were identified that correlated with the development of biochemical failure, including the use of AD (p = 0.19, HR 0.612).

Conclusions: Brachytherapy for patients with HRPC yields favorable outcomes at early follow up time. Longer follow-up and prospective studies are needed for further analysis.
Role of 5-alpha-reductase inhibitors in active surveillance of patients with low-risk prostate cancer.
Authors: Chiang Andrew Szehsun , Loblaw D. Andrew , Jethava Vibhuti , Sethukavalan Perakaa , Zhang Liying , Vesprini Danny , Mamedov Alexandre , Nam Robert , Klotz Laurence
Published: February 2017

14

Background: Active surveillance (AS) is a recognized management option for low-risk prostate cancer. Many institutions use serial PSA values to determine when to reclassify patients into higher risk categories. The impact of 5-alpha-reductase inhibitors (5-ARIs) in this setting has not been well studied. The purpose of this retrospective review was to compare PSA doubling time prior to the initiation of a 5-ARI (pre-5-ARI) to that after the PSA nadir (post-nadir) has been reached.

Methods: Between 1996 and 2010, a total of 100 patients with a history of 5-ARI use were captured from our AS database. Of these, twenty-nine had a sufficient number of PSA values to determine both pre-5-ARI and post-nadir doubling times. The majority had stage T1c disease (89.7%) and Gleason scores of six or lower (93.1%). The average PSA at presentation was 6.93 µg/L. More patients were prescribed dutasteride (79.3%) than finasteride (20.7%). PSA doubling time was calculated using the general linear mixed-model method. Statistical analysis was performed using the non-parametric sign test.

Results: Median follow-up was 69.5 months (mo). For the twenty-nine patients analyzed, the median pre-5-ARI PSA doubling time was 55.8 mo (6-556.8 mo), while that for the post-nadir values was 25.2 mo (6-231 mo) (p=0.0081). Six patients were ultimately reclassified after an average of 67.7 mo (59-95 mo), due to progression in either PSA doubling time (n=2) or Gleason score (n=4). The median pre-5-ARI and post-nadir doubling times for this group were 48.2 mo (32.4-91.1 mo) and 23.3 mo (6-44.3 mo), respectively. Five of the patients underwent radical prostatectomy, while one underwent radiotherapy with androgen deprivation. Of the six patients, one had biochemical failure after an average post-treatment follow-up of 21.3 mo (0-52 mo).

Conclusions: In AS for low-risk prostate cancer, it was found that 5-ARIs significantly decreased PSA doubling time. This effect may be related to preferential suppression of benign prostatic tissue, thereby providing a more accurate depiction of the true cancer-related doubling time. If validated with a larger cohort, 5-ARIs may enhance the utility of PSA doubling time as a biomarker of disease progression in AS.
Patterns of referral for adjuvant radiotherapy after radical prostatectomy in men with prostate cancer: A population-based analysis.
Authors: Quon Harvey , Suderman Derek , Guilbert Kimi , Lambert Pascal
Published: February 2017

140

Background: Randomized trials have shown improved biochemical disease free survival after adjuvant radiotherapy (ART) in patients with pT3 or margin positive disease after radical prostatectomy for prostate cancer. This study examines the rates of referral to a radiation oncologist for patients with high risk pathologic features after prostatectomy. Also, the impact of the presentation of these randomized trials will be examined.

Methods: All men diagnosed in the province of Manitoba with prostate adenocarcinoma between 2003 and 2008 who underwent radical prostatectomy were identified through a central cancer registry database. Manual chart review was performed and detailed demographic and clinico-pathologic data were analyzed to determine their influence on referral to a radiation oncologist within 6 months of surgery. Analysis of referral rates before and after the presentation of 2 randomized trials were also examined.

Results: A total of 1080 patient records of men undergoing prostatectomy for prostate cancer were reviewed. Of these, 546 (50.6%) men had at least one high risk pathologic feature. This includes pT2 margin positive disease in 298/546 (54.6%), pT3a in 154/546 (28.2%), and pT3b in 94/546 (17.2%). Multivariable logistic regression was performed adjusting for age, distance from cancer centre, Gleason score, T stage, perineural invasion, and margin status. Gleason score 8-10 (p<0.0001), higher pathologic T stage (p<0.0001), and farther distance (p=0.0028) were associated with referral for ART. Age and margin status were not significantly associated. Men with pT3a (odds ratio 3.35) and pT3b disease (odds ratio 5.32) were more likely to be referred than pT2 margin positive disease (p<0.0001). There were 78/546 (14.3%) patients with a high risk factor who were referred for ART within 6 months of surgery. The rates of referral were not significantly different before and after the presentation of randomized trials (p=0.60).

Conclusions: Men with higher pathologic stage (pT3) and grade (Gleason 8-10) are more likely to receive ART. However, referral for ART did not increase significantly after presentation of the randomized trials and remains underutilized.
The effects of body mass index on pretreatment characteristics, treatment choice, and response to treatment of intermediate- and high-grade prostate cancer.
Authors: Ansley Katherine Cox , Ramahi Emma Holliday , Swanson Gregory P. , Basler Joseph W. , Du Fei
Published: February 2017

142

Background: The relationship between obesity and prostate cancer outcomes remains unclear. A retrospective cohort study was performed to determine the effect of body mass index (BMI) on patients with intermediate to high-grade prostate cancer.

Methods: Our retrospective study cohort included 1077 men from the South Texas Veteran’s Healthcare System Tumor Registry diagnosed with Gleason 7-10 prostate cancer in 1998-2008 and treated with either radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT). Mean follow up was 4.6 ± 2.7 years. Patients were stratified into four groups on the basis of their BMI at the time of prostate cancer diagnosis (<25, 25-30, 30-35 or >35). Statistical analysis included Kruskal-wallis test and Pearson’s Chi-square test.

Results: There was an inverse relationship between PSA and BMI at diagnosis; however, we found no difference in Gleason score at diagnosis. There was a difference in the primary treatment modality chosen between the BMI groups. Primary treatment modality decision was likely influenced by PSA at diagnosis, among other pre-treatment characteristics. Patients with a BMI >35 were significantly less likely to undergo RP. However, after controlling for age, primary treatment modality, Gleason score, pre-treatment PSA and diabetes diagnosis, there was no difference in overall mortality.

Conclusions: Patients with an increasing BMI have a lower PSA at diagnosis, are less likely to receive RP but do not have significantly worse overall survival.
Overall survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy according to their participation (or not) in clinical trials.
Authors: Goyal Jatinder , Huang Peng , Tyagi Prachi , Oh Daniel , Carducci Michael Anthony , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: February 2017

148

Background: There is insufficient evidence to determine whether clinical trial participation can itself lead to improved clinical outcomes in patients with mCRPC treated with docetaxel chemotherapy. We compared clinical characteristics and survival outcomes of patients with mCRPC receiving first-line docetaxel-containing therapy on a clinical study (trial participants) or outside of a clinical trial (non-participants).

Methods: We retrospectively reviewed the records of 245 consecutive chemotherapy-naïve patients with mCRPC who received docetaxel-containing therapy between 1/1/1998 and 1/1/2010, either as trial participants (n=142; 11 separate studies) or as non-participants (n=103). Patient demographics, baseline clinical characteristics, treatment details and follow-up data were recorded.

Results: In unadjusted analysis, trial participants were more likely to be white (83 vs 70%, p=0.005), to have better ECOG performance status (p=0.01), higher baseline hemoglobin (12.4 vs 11.6 g/dL, p=0.0003), higher albumin (4.3 vs 4.0 g/dL, p=0.009), lower creatinine (0.90 vs 1.04 mg/dL, p=0.01), and to have received a higher number of chemotherapy cycles (6.6 vs 5.1, p=0.001) than non-participants. In Kaplan-Meier analysis, median overall survival was significantly longer among trial participants vs non-participants (21.3 vs 17.1 months, p=0.024). In multivariable analysis, trial participation (HR 0.53, p=0.013), more chemotherapy cycles (HR 0.87; p=0.0002), baseline hemoglobin >12 g/dL (HR 0.67, p=0.016), lower ECOG score (HR 0.57, p=0.026) and lower baseline (log) PSA (HR 0.85, p=0.012) were all found to be independent predictors of survival.

Conclusions: Clinical trial participation is an independent positive predictor of overall survival in men undergoing first-line docetaxel-containing chemotherapy for mCRPC. Improved survival in trial participants may reflect better medical oversight typically seen in patients enrolled in clinical trials, more regimented follow-up schedules, or a positive effect on caregivers’ attitudes due to greater contact with medical services.
Promoting consultation recording practice in oncology: Identification of critical implementation factors and determination of patient benefit.
Authors: Hack Thomas F , Ruether Joseph D. , Weir Lorna , Grenier Debjani , Degner Lesley F
Published: February 2017

155

Background: The objectives of this implementation study were to 1) identify and address the evidentiary, contextual, and facilitative mechanisms that serve to retard or promote the transfer and uptake of consultation recording use in oncology practice, and 2) follow patients during the first few days following receipt of the consultation recording to document, from the patient’s perspective, the benefits realized from listening to the recording.

Methods: Nine medical and 9 radiation oncologists from cancer centers in three Canadian cities (Calgary, Vancouver, Winnipeg) recorded their primary treatment consultations for 228 patients newly diagnosed with prostate or breast cancer. The Digital Recording Use Semi-Structured Interview (DRUSSI) was conducted at two days post-consultation and at 1-week post-consultation. Each oncologist was given a feedback letter summarizing the consultation recording benefits reported by their patients.

Results: Sixty-nine percent of patients listened to at least a portion of the recording within the first week following the consultation. Consultation recording favourableness ratings were high: 93.6% rated the intervention between 75–100 on a 100-point scale. Four main areas of benefit were reported: 1) Anxiety reduction; 2) Enhanced retention of information; 3) Better informed decision making; and 4) Improved communication with family members. Eight fundamental components of successful transfer and uptake of consultation recording practice were identified.

Conclusions: Implementation research and additional randomized trials are needed to facilitate the transfer and uptake of consultation recording use so that far more patients and significant others may realize the associated benefits.
Active surveillance for prostate cancer: Scottish experience.
Authors: Ansari Jawaher , White Lillian , Glen Hilary , McGlynn Brian , Nairn Robert , Balsitis Margaret , Hollins Graham , Smith Kathleen , Nair Biju , Gurun Murat , Little Brian , Meddings Robert , Al-Saffar Neil , Hussain Syed A. , Glaholm John , Mahmood Rana I.
Published: February 2017

167

Background: Prostate cancer is the second most common malignancy in men worldwide with 910,000 cases registered in 2008. The prognosis for low-risk prostate cancer patients remains excellent and arguably the majority may either not require radical treatment or may benefit from deferred radical treatment. Active surveillance involves serial prostate-specific antigen (PSA) monitoring, digital rectal examinations, and periodic trans-rectal ultrasound guided prostate biopsies. Patients for active surveillance are carefully selected, counselled and actively followed-up. Radical treatment is deferred until there is evidence of biochemical, pathological or clinical disease progression.

Methods: Retrospective review of prostate cancer patients enrolled on to the active surveillance program within NHS Ayrshire and Arran Hospitals. Clinical examination and PSA monitoring was undertaken 3-monthly in year 1, 4-monthly in year 2 and 6-monthly thereafter. The protocol stipulates repeat TRUS biopsies at years 1, 4, 7 and every 3 years thereafter.

Results: 105 patients with low-intermediate risk prostate cancer with a median age of 68yrs (48–78yrs) were followed for a median duration of 30 months (4–152 months). The median PSA at presentation was 7ng/ml (0.5-31). Repeat biopsies were performed in 82 patients and 37% had no histological evidence of cancer. The median time to re-biopsy was 16 months (10–85 months). Of the patients who received radical treatment; 3 underwent radical prostatectomy and 23 received radical radiotherapy. The indications for radical treatment were pathological progression in 73%, PSA progression in 23% and co-existing bladder cancer in 4%. One patient died due to unrelated medical problems and one patient developed metastatic disease.

Conclusions: With appropriate counselling, a significant percentage of men with low-moderate risk prostate cancer choose active surveillance. In this study, active surveillance does not appear to compromise outcomes for patients with low-intermediate risk prostate cancer. Less then 25% of patients needed radical treatment and therefore this approach appears cost-effective and avoids treatment-related morbidity.
Response to abiraterone acetate in the postchemotherapy setting in patients with castration-resistant prostate cancer whose disease progresses early on docetaxel.
Authors: Mukherji Deborah , Pezaro Carmel Jo , Bianchini Diletta , Zivi Andrea , De Bono Johann Sebastian
Published: February 2017

17

Background: Abiraterone acetate (AA) has recently been approved for men with metastatic castration-resistant prostate cancer (CRPC) following docetaxel chemotherapy. AA inhibits CYP17, reducing androgen production and thereby impacting androgen receptor (AR) signalling. Recent evidence suggests taxanes also impact AR signalling, raising concerns about potential cross-resistance. We have previously shown that docetaxel has no antitumor activity in AA refractory patients. We have now evaluated the antitumor activity of AA post-docetaxel to determine the activity of AA in docetaxel refractory patients.

Methods: Forty four men with CRPC treated with docetaxel (75 mg/m2 every 21 days) followed by post-chemotherapy AA at the Royal Marsden Hospital were identified. Radiological response by RECIST, PSA response by PSAWG2 criteria and symptomatic benefit were evaluated.

Results: An average of 9 cycles of docetaxel were given (range 3-17); 7 patients discontinued chemotherapy due to progression of disease and 10 for toxicity. Of 40 patients with PSA data available, 26 (65%) had a PSA decline of at least 50%. At commencement of AA, median age was 68 years. Bone, nodal and visceral metastases were present in 38 (86%), 23 (52%) and 6 (14%) of the cohort respectively. An average of 5 months of treatment were delivered and 23 patients continue on AA. Of the 44, 7 (16%) patients had a 50% or greater PSA decline on AA. None of the 7 patients who were docetaxel refractory had a subsequent PSA, radiological or clinical response to AA. Of the 6 patients who received less than 5 cycles of docetaxel due to toxicity, 2 had subsequent PSA response on AA. There was no relationship between length of time on LHRH agonist and PSA response to AA.

Conclusions: Our data suggest that patients who are refractory to docetaxel do not respond to AA. Overall, in conjunction with our other evidence that in AA-refractory patients docetaxel has no antitumor activity, these data provide further evidence for cross-resistance between these two agents.
Volumetric modulated arctherapy (VMAT) compared with sliding window intensity-modulated radiotherapy (IMRT) for whole pelvis irradiation (WPI) of locally advanced prostate cancer (LAPC).
Authors: Riou Olivier , Regnault de la Mothe Pauline , Azria David , Vieillot Sabine , Ailleres Norbert , Dubois Jean-Bernard , Fenoglietto Pascal
Published: February 2017

171

Background: Concurrent radiotherapy to the pelvis plus a prostate boost with long term androgen deprivation is a standard of care for LAPC. IMRT has the ability to deliver highly conformal dose to the target while lowering the irradiation of critical organs around the prostate. However, delivery time is signicantly prolonged with static gantry IMRT. VMAT is able to reduce treatment time but results concerning organ sparing are controversial when compared to static gantry IMRT.

Methods: 10 patients with locally advanced prostate cancer were included in this dosimetric study. The planning target volumes (PTV) 1 was defined as the pelvic lymph nodes, the prostate and the seminal vesicles plus set up margins. The PTV 2 consisted of the prostate with set up margins. The aimed dose to PTV1 was 54 Gy in 37 fractions and to PTV2, 74 Gy in 37 fractions, in a single plan using the integrated boost method, by means of a 7 coplanar static split fields IMRT, a one arc (RA1) and a two arc (RA2) Rapidarc planification.

Results: All three techniques allow a very good coverage of both PTVs with an acceptable homogeneity. Static IMRT enables a better homogeneity for PTV 2 than Rapidarc techniques. Sliding-window IMRT and VMAT permitted to maintain doses to OAR within acceptable levels with a low risk of side-effects for each organ. Nevertheless, VMAT plans result in clinically and statistically significant reduction in doses to bladder (IMRT Vs RA2: Mean dose: 50.1 ± 4.6 Vs 47.1 ± 3.9 Gy, p = 0.037), rectum (Mean dose: 44 ± 4.5 Vs 41.6 ± 5.5 Gy, p = 0.006) and small bowel (V30: 76,47 ± 14,91% Vs. 47,49 ± 16,91%, p = 0.002).

Conclusions: VMAT allows for better OAR sparing as compared to sliding-window IMRT while maintining PTV coverage into acceptable levels for WPI of LAPC.
The different genetic alterations between Western and Chinese prostate cancers and the underlying mechanisms.
Authors: Mao Xueying , Coll Bastus Nuria , Boyd Lara , Yu Yongwei , Ren Guoping , Beltran Luis , Oliver R. , Young Bryan D , Berney Dan , Lu Yong-Jie
Published: February 2017

184

Background: Prostate cancer shows a wide variation in the clinical incidence and mortality rates of different geographical regions. While it is the most common male cancer in Western countries, it is much less frequent in Asian countries. We investigated genomic changes in prostate cancers from UK and China using microarrays to determine the genetic similarities and differences as well as the underlying mechanisms.

Methods: We determined genome-wide genomic alterations using Affymetrix SNP array 6.0, and evaluated data using fluorescence in situ hybridisation (FISH) and immunohistochemistry. In addition, we assess androgen induced TMPRSS2 and ERG co-localization and fusion. Microsatellite analysis was used for AR CAG repeat polymorphism in UK and Chinese population.

Results: Genome-wide analysis of 32 UK and 39 Chinese samples revealed that losses of 21q22 (leading to TMPRSS2:ERG fusion) and 10q23.3 (PTEN) were at much higher frequency in Western than Chinese prostate cancers. Using FISH analysis of 160 UK and 143 Chinese samples, we showed that PTEN deletion and ERG rearrangements were at a significantly higher frequency in samples from UK than China (p<0.001 for both). We found that PTEN and ERG protein were also differentially expressed (p<0.001) in the two populations. Investigating this further, we induced TMPRSS2 and ERG gene proximity and TMPRSS2:ERG fusion in two immortalised prostate epithelial cell lines by exposure to high dose of androgen. This androgen treatment did not cause increased global DNA damage but was associated with low expression of PIWIL1, which is involved in repairing double-strand breaks. Overexpression of PIWIL1 by transfection inhibited androgen induced TMPRSS2:ERG fusion. We found that AR CAG repeat lengths, which associated with AR activity, are significantly shorter in the UK than Chinese patients (p<0.05).

Conclusions: We revealed genomic differences in prostate cancer comparing the high-risk (Western) and low-risk (Chinese) populations. We further demonstrated that TMPRSS2:ERG fusion can be induced by androgen. The difference of CAG repeat length between the two populations are potentially associated with TMPRSS2:ERG fusion positive prostate cancers.
Personalizing treatment in patients with castrate-resistant prostate cancer: A study of predictive factors for secondary endocrine therapies activity.
Authors: Loriot Yohann , Massard Christophe , Albiges Laurence , Di Palma Mario , Blanchard Pierre , Bossi Alberto , Chauchereau Anne , Escudier Bernard J. , Fizazi Karim
Published: February 2017

213

Background: Several options have recently demonstrated activity, including survival improvement, in patients with prostate cancer progressing while on androgen deprivation therapy: chemotherapy (docetaxel, cabazitaxel), sipuleucel-T, and abiraterone. There is now an urgent need to identify predictive factors of efficacy for each of these treatments to assist decision-making in pts with castrate-resistant prostate cancer (CRPC). We attempted to identify predictive factors for activity of subsequent endocrine manipulations in patients with CRPC.

Methods: Patients with CRPC included in the Institut Gustave Roussy clinical trials database who received endocrine manipulations (abiraterone, ketoconazole-hydrocortisone, DES, bicalutamide) for CRPC were reviewed. The predictive role on response and progression-free survival (PFS) of a series of clinical, biological, and radiological parameters was studied (Khi-2 test for response, Logrank test and Cox model for PFS).

Results: 108 patients with CRPC who participated to 5 clinical trials were identified. The median duration of prostate cancer sensitivity to ADT (defined as the time from ADT initiation to the outset of castrate-resistance) was 16 months (range: 0–118 months). Timing of endocrine manipulation (before vs after docetaxel-based chemotherapy), presence of non-bone visceral metastases, the type of progression (clinical vs radiological), Performance Status, and PSA doubling time did not predict for response or PFS. In contrast, the previous duration of prostate cancer sensitivity to ADT (classified as ≥16 months and <16 months) significantly and strongly predicted for both PSA response (58% vs 18%, p=0.01) and PFS (median PFS rates: 5 months (95%CI: 3.46–6.53) and 3 months (95%CI: 2.10–3.89) p<0.043).

Conclusions: A previous duration of prostate cancer sensitivity to ADT ≥16 months is the only significant predictive factor for efficacy of subsequent endocrine manipulations in patients with CRPC. This parameter shall be integrated into the decision-making process for these patients.
Return-to-work after radiotherapy for prostate cancer.
Authors: Sveistrup Joen , Petersen Peter Meidahl , Mortensen Ole Steen , Engelholm Svend Aage
Published: February 2017

218

Background: Returning to work following cancer treatment is a sign of recovery. The purpose of this study was to determine how many patients return to work following definitive intensity-modulated radiotherapy for prostate cancer (PCa).

Methods: The Danish DREAM-database contains information on all social benefits paid out to Danish citizens. The data are recorded prospectively every week. Based on the DREAM-database it is possible to assess whether a patient is working, on sick leave, or retired. Data on 410 of the 451 Danish citizens, treated with definitive intensity-modulated radiotherapy for PCa at our center between January 1 2006 and May 1 2010, were obtained from the DREAM-database one year prior to radiotherapy, at the start and at the end of the radiotherapy, and finally one year after radiotherapy was completed. The median age was 66 (age range, 49–76). Patients were divided into five different categories. The categories were “Working or unemployed”, “Sick leave”, “Disability pension”, “Retirement” and “Dead”.

Results: The results are shown in the table. Nearly 30% of the patients are working or available for work one year prior to the radiotherapy. This number is reduced to about 12 % at the time of both the start and the end of the radiation treatment. One year after treatment nearly 20% are working.

Conclusions: This study shows that a substantial proportion of patients return to work following definitive radiotherapy for PCa. This indicates that the treatment in many cases does not affect the patients’ ability to work. Further research should be on why some patients stop working after completion of definitive radiotherapy for PCa.

[Table: see text]
Assessment of the American Joint Committee on Cancer (6th and 7th editions) for clinically localized prostate cancer and comparison to the National Comprehensive Cancer Network risk stratification method.
Authors: Buyyounouski Mark K , Zaorsky Nicholas G. , Li Tianyu , Devarajan Karthik , Horwitz Eric M.
Published: February 2017

23

Background: The purpose was to compare the prognostic value of the AJCC staging version 6 (v6), version 7 (v7), and the risk-stratification model of the NCCN.

Methods: 2,469 men (1989-2006) with clinical T1-4, N0/X-N1, M0 prostate cancer received definitive RT +/- ADT (median follow-up: 70 months). The NCCN grouping was: low-risk included T1-T2a, GS < 7, and PSA < 10 ng/mL; intermediate-risk included T2b-2c, GS = 7, and PSA 10 – 20 ng/mL; high-risk included T3, GS 8, and PSA > 20 ng/mL. The Benjamini and Hochberg adjustment was used to compute the false discovery rates in order to adjust for multiple comparisons.

Results: There was a migration of stage II patients to stage I with version 7 (Stage I increased from 1% to 38%, while Stage II decreased from 91% to 55%). Pair-wise comparisons of Kaplan-Meier estimates of BF, DM, PCSS, and OS between stages were not statistically significant for AJCC v6 with one exception (PCSS: II vs III). On the other hand, 16/24 (67%) of comparisons were significant with AJCC v7. For NCCN, 9/12 (75%) of comparisons were significant, including all comparisons for OS. Concordance probability estimate (CPE) and standard error (SE) analysis showed uniform and significant improvement in the predictive power of AJCC v7 versus AJCC v6 for all outcomes. CPE±SE values for AJCC v6 versus AJCC v7 was .51±.009 vs .59±.02 for BF, .54±.02 vs. .70±.05 for DM, .57±.009 vs. .76±.007 for PCSS, and .52±.006 vs. .57±.01 for OS. There was further, albeit modest improvement with the NCCN method. CPE±SE values for AJCC v7 versus NCCN was .59±.02 vs. .59±.02 for BF, 0.70±.05 vs. 0.72±.05 for DM, .76±.007 vs. .80±.01 for PCSS, and .57±.01 vs. .57±.01 for OS.

Conclusions: AJCC v7 is a major improvement over AJCC v6 because it better distributes patients among the stages and is more prognostic. Further improvements are needed as the majority of men (55%) are Stage II and the sub-stratification into IIA and IIB was not prognostic. The NCCN model is superior to the AJCC v7 and remains the preferred method for risk-based clinical management of prostate cancer with RT +/- ADT.
Effect of PEDF on survival and the in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.
Authors: Nelius Thomas , Pardue Natalie , Gillen Jessica , Rinard Katherine , Hirsch Jennifer , Cobos Everardo , Reynolds C. Patrick , Filleur Stephanie
Published: February 2017

237

Background: The development of metronomic/low dose of conventional chemotherapeutic drugs have recently showed great promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is down-regulated in prostate cancer. We have previously demonstrated that the over-expression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validated PEDF anti-tumor properties in the highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxicity effects of low dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo.

Methods: Human PC3 and CL1 cell lines were genetically modified to stably express the fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and, for proliferation by growth curves and clone formation in matrigel. PEDF anti-tumor effects were assessed on established s.c. xenografts in mice treated with Doc (5mg/kg ip every 4 dy, 1mg/kg ip daily for 10 days, 0.5mg/kg every other day), CTX (10-20mg/kg in the drinking water) or placebo. Survival studies were performed by injecting CL1 cells with 50nM hrPEDF or carrier control into the left lobe of the dorsal prostate of anesthetized mice.

Results: We showed that PEDF inhibits the proliferation and induces the differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of s.c. PC3 and CL1 tumors, respectively. In the survival study, we found that all control animals die within 61 days after surgery while 50% of PEDF-pretreated animals were still alive. Most importantly, we demonstrated that PEDF enhances the cytotoxicity effects of low dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1).

Conclusions: These data reinforce the significance of PEDF as a potential new target for the treatment of advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low dose Doc and CTX chemotherapies.
Preliminary safety results of an Italian early-access program (EAP) with cabazitaxel plus prednisone (CbzP) in patients with docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bracarda Sergio , Di Lorenzo Giuseppe , Gasparro Donatello , Marchetti Paolo , Boccardo Francesco , Martoni Andrea , Carteni Giacomo , Fornarini Giuseppe , Baldazzi Valentina , Dogliotti Luigi , Messina Caterina , Sisani Michele
Published: February 2017

253

Background: A significant number of docetaxel (D) refractory mCRPC patients (pts) have a life expectancy of > 15 months and ask for additional efficacious treatments. In the phase 3 TROPIC trial treatment of mCRPC patients with CbzP who progressed during or after docetaxel resulted in a statistically significant overall survival benefit compared with mitoxantrone / prednisone (Lancet 2010). This survival benefit supported establishment of a global early access program (EAP), allowing pts with mCRPC to have access to the drug prior to its commercial availability. Here we describe preliminary safety results from the EAP in Italy.

Methods: We report here the data of the first 16 mCRPC patients (out of the 123 enrolled by 19 Italian centers until Sept 2011 in EAP) treated with Cbz (25mg/m2 Q3W) plus P(10mg bid).

Results: Pts were median age 73.5 years (>75 years 38%), ECOG PS-0 81.3% and had received a median of 7 prior cycles of D (median cumulative D dose 562.5mg). Median time from last D dose to inclusion was 7.1 months. Overall, 62.5% (10 Pts) had 2 or more metastatic sites (bone 94%, regional/distant lymph nodes 25% and 44%, lung 12.5%, other sites 19%). A limited number of relevant adverse events (AE) were observed. All grade AEs were seen in 14/16 pts (81.3%), with 4/16 pts experiencing grade 3/4 leukopenia, 8/16 pts grade 3 - 4 neutropenia, one patient with febrile neutropenia and one with hypertransaminasaemia. Grade 1-2 asthenia and fatigue were experienced respectively by 2 pts. No grade 3 / 4 diarrhea, vomiting or constipation were observed and no AEs results in death. All pts received at least 2 cycles of CbzP (2÷5) and only one patient permanently discontinued treatment (disease progression).

Conclusions: This preliminary analysis of Italian pts enrolled in the EAP provides real world safety data and suggests a good safety profile of cabazitaxel even in heavily pretreated pts, which is in agreement with Italian experience in TROPIC. Results of the entire Italian cohort with a longer follow-up will be presented.
Meta-analysis of impact of circumcision and vitamin D on occurrence of prostate cancer: Could they act by suppressing anaerobes colonizing areas of prostatic proliferative inflammatory atrophy?
Authors: Oliver R.
Published: February 2017

259

Background: There is evidence that some false positive PSA tests can reflect prostatic inflammation that leads to Proliferative Inflammatory atrophy (PIA) that promotes malignant change. Report from circumcision trials in Africa suggest that dominant bacterial flora in un-circumcised men was anaerobes. As circumcised men have a lower incidence of PC this presentation reviews the literature on lack of circumcision and that on Vitamin D deficiency and as a cause of diminished host surveillance that could have potential to synergise as causes of PC.

Methods: Three papers reporting incidence of PC in Jewish and non-Jewish men undergoing prostate biopsy for prostate symptoms and 7 series reporting case controlled studies published between 1952 and 2001 have provided data on circumcision and PC risk. There were 10 papers referred to in the IARC 2008 report on plasma 25-hydroxyvitamin D and PC. These have been reviewed together with 8 more published from 2008-10 and 3 that have examined impact of an index of life-time sun exposure on PC risk.

Results: The 2 of 3 series of prostate biopsy reported 1951-65 demonstrated significant excess and 1 a non-significant excess of PC in the non-Jewish population. Of the 7 case controlled reported from 1971-2001, only 1 reported significant (OR 1.38) and 1 non-significant (OR 1.15) excess of lack of circumcision in those with prostate cancer, the remaining 6 studies having an excess cancer in those who have been circumcised (OR 0.50 – 0.82 pooled risk 0.70). Only 1 of the 18 plasma 25-OH Vit D series showed significant reduction of PC overall (6 did have reduction in prognostic subsets though 2 had higher incidence in the same sub-groups. In contrast all 3 series that have examined an index of life-time sun exposure showed significant reduction of PC (OR 0.18, 0.32 and 0.52 n= 850).

Conclusions: The inconsistencies in the circumcision data suggest that it is not the surgery alone but the confounding variable of the hygiene rules that at least contribute to the reduced PC in Jewish men, and mirrors the similar differences seen in the protective value against AIDS of circumcision in Xhosa African and Asian Muslim men.
Receipt of aggressive therapies for muscle-invasive bladder cancer: Results from the National Cancer Data Base.
Authors: Gray Phillip J. , Fedewa Stacey A. , Shipley William U. , Efstathiou Jason Alexander , Virgo Katherine S. , Zietman Anthony L.
Published: February 2017

272

Background: Over 17,000 patients are diagnosed with muscle-invasive bladder cancer (MIBC) in the United States each year. Despite its lethal potential, emerging data has suggested that many patients do not receive aggressive therapy consistent with established practice standards. Using data from American College of Surgeons Commission on Cancer accredited facilities, we seek to characterize treatment patterns for patients with MIBC according to demographic, clinical, pathologic and facility variables.

Methods: 28,691 adult patients diagnosed with MIBC (stages II-IV), excluding those with T4b tumors or distant metastases between 2004 and 2008 were selected for analyses from the National Cancer Database. Treatments included radical or partial cystectomy +/− chemotherapy (CT), chemoradiotherapy (CRT), radiotherapy (RT) or CT alone and surveillance. Aggressive therapy (AT) was defined as any open surgery or RT with a total dose ≥50 Gy. Determinants of AT were assessed by multivariate generalized estimating equations accounting for facility clustering.

Results: 52.5% of patients received AT (45% were treated surgically while 7.5% received CRT or RT), 11.7% received palliative CT or RT, and 25.9% received surveillance only. Receipt of AT decreased significantly with advancing age (OR 0.29 for age >80 vs. 18-59, p<.001). AT was also received less frequently by minorities (OR 0.72 for blacks p<.001), the uninsured (OR 0.72, p<.001), Medicaid-insured patients (OR 0.81, p=.006) and by those patients treated at low-volume centers (OR 0.63 vs. high-volume, p<.001). Receipt of AT increased with more advanced stage (OR 2.33 for stage III vs. stage II, p<.001) and in patients with non-urothelial histology (OR 1.32 and 1.50 for squamous and adenocarcinoma histology respectively, p<.001). Hydronephrosis was associated with decreased use of AT (OR 0.70, p<.001).

Conclusions: Aggressive therapies for MIBC are received less frequently by the elderly and those with historically poorer socioeconomic status. These data indicate a significant unmet clinical need for physician education regarding appropriate selection of patients for cystectomy and RT-based bladder sparing therapy.