bluuebunny/crossref_metadata_2025 huggingface dataset:
Worldwide comparison of prostate needle biopsy quality in the reduction by dutasteride of prostate cancer events (REDUCE) study: Improvement with investigator training
Authors: Bostwick D. G. , Teloken C. , Brawley O. W. , Marberger M. , Qian J. , Drewnowska K. , Niyuhire F. , Rittmaster R. R. , Fowler I. L. , Somerville M. C.
Published: August 2020

e16029

Background: The accuracy of prostate cancer detection by biopsy is influenced by the number and length of needle biopsy cores. We compared these two biopsy quality factors among study sites worldwide for the pre-study entry biopsies (6–12 cores) and study-mandated biopsies (10 cores) at year 2 of the REDUCE study. Methods: Prostate biopsy quality indicators were evaluated retrospectively. Data were compared from entry and year 2 biopsies for subjects enrolled in the study in 6 geographic regions (see table ). Investigator training was provided for REDUCE study protocol-required standardization prior to year 2 biopsies. Training included emphasis on quality of the biopsies. Results: Data were collected from 4638 entry and 6275 year 2 subjects, respectively. At entry, the aggregate length of biopsies, number of cores per subject, and core length differed significantly among regions (p < 0.0001). Aggregate length was longest in biopsies obtained in Australia and the highest core number was observed in South America. At year 2, each region collected a mean of 10 cores per subject (per protocol), and the aggregate length and mean core length were greater than the entry biopsies (for each analyzed parameter, p < 0.0001); variance among sites was reduced for all quality measures. Conclusions: There were significant differences in biopsy quality (number of cores and length of tissue obtained) around the world at entry. Following the REDUCE study protocol-required standardization and investigator training, biopsies obtained at year 2 showed an increase in the mean aggregate length, mean core number, and mean core length compared with the entry biopsies. Our data suggests that variance in biopsy quality may be reduced by investigator training, thereby optimizing quality and cancer detection. [Table: see text]

[Table: see text]
Phase II study of docetaxel-prednisone (DP) in combination with metronomic cyclophosphamide (CTX) and celecoxib (C) as first-line treatment in castration resistant prostate cancer (CRPC) patients (Pts)
Authors: Fontana A. , Bocci G. , Galli L. , Derosa L. , Minuti G. , D'Arcangelo M. , Santini D. , Landi L. , Bursi S. , Falcone A.
Published: August 2020

e16032

Background: Metronomic oral CTX and C has demonstrated activity and a favourable toxicity profile in CRCP. Combination of such strategy with the standard DP could be of interest. Methods: Pts with CRPC received D 60 mg/sqm iv day 1 every 3 weeks up to 12 cycles and from day 2 continuously: P 5 mg po BID, CTX 50 mg po daily, and C 200 mg po BID. Primary objective is the percentage of pts free of progression at 6 months; secondary are: PSA levels decrease ≥ 50%, objective responses (RECIST), toxicities (NCI-CTC criteria) survival and pharmacodynamic evaluations. Results: To date 29 pts have been enrolled. Main pts characteristics are: median age 72 years (52–78 years), median PS 0 (0–2), median baseline PSA level 38,8 ng/mL (2.5–1309 ng/mL); main sites of disease: bone 23 pts (79%), lymphnodes 6 pts (21%), liver 1 pt (3,5%). Twenty-nine pts are evaluable for toxicity whereas 28 for PSA response (1 pt abandoned the study due to allergic reaction after first D administration). Median number of D cycles delivered is 10 (1–12) and median duration of metronomic CTX plus P and C is 224 days (35–874 days). Main grade 3 side-effects are: neutropenia (2 pt; 7%), thrombocytopenia, diarrhoea, stomatitis and onycholysis (1 pt; 3.5%). No grade 4 toxicities have been observed.The rate of pts free of progression at 6 months is 80%. Overall 18 pts (64%) showed a PSA decrease ≥ 50% and 23 pts (82%) showed any PSA decrease from baseline (range: 4%-99%of decrease). Four pts are evaluable according to RECIST criteria: we observed 1 CR, 2 SD and 1 PD. At a median follow up of 12,4 months median time to PSA progression is 11.6 months (95% CI 8,3–15). Conclusions: Metronomic CTX plus C in combination with DP is a feasible and tolerable regimen with a promising preliminary activity. The evaluation of plasma levels of thrombospondin-1 (TSP-1), VEGF, sVEGFR-2, VE-cadherin mRNA, and the expression of TSP-1 and VEGF in peripheral blood mononuclear cells, as potential surrogated markers of antiangiogenic activity of the combination, is ongoing.

No significant financial relationships to disclose.
Prognostic factors in advanced seminoma in the era of etoposide- and cisplatin-based chemotherapy: Importance of pretreatment LDH-level
Authors: Tryakin A. , Fedyanin M. , Bulanov A. , Titov D. , Allakhverdiyeva G. , Mitin A. , Sergeev J. , Zaharova T. , Garin A. , Tjulandin S.
Published: August 2020

e16038

Background: The commonly used IGCCCG classification probably underestimates other prognostic factors (tumor markers, stage) for advanced seminoma, which was shown later (Fossa S., 1997). Furthermore, in contrast to nonseminoma different cisplatin-based regimens have not been directly compared in this population. We performed an analysis to review the outcome and prognostic factors of patients (pts) with advanced seminoma treated in our center during the last two decades. Methods: From 1983 to 2005, 250 chemotherapy (CT)-naïve pts with advanced seminoma received induction platinum-based CT, which was divided as an “older” (76 pts) and “modern” (174 pts) one. “Older CT” included cyclophosphamide + cisplatin (46 pts), ifosfamide + carboplatin (12 pts), PVB (8 pts) and other regimens (10 pts). “Modern CT” contained BEP (26 pts) and EP (148 pts) regimens. 227 (91%) pts had primary testicular tumor, 241 (96%) pts belonged to IGCCCG good prognostic group. Median follow-up was 57 (range, 3–276) months for the pts who survived. Prognostic factors were analyzed in “modern CT” group. Progression-free survival (PFS) was an end-point for Cox‘ stepwise regression analysis. Results: “Modern CT” significantly improved PFS (5-years, 91% and 74%, p = 0.002) but not OS (5-years, 92% and 89%, p = 0.28), which could be explained by effective salvage CT. Univariate analysis revealed following factors as significant: number of metastatic sites, presence of pulmonary metastases, RPLN size, hCG level, and LDH level. Cox‘ regression analysis showed pre-CT LDH as the only prognostic factor for PFS (HR 7,6, 95% CI 1,6–36.3). Using cut-off 2 x upper limit of normal for LDH level, “modern CT” group can be divided into favorable (105 [60%] pts) and unfavorable (69 (40%) pts) groups with 5-years DFS 98% vs. 78% (HR 11.1, 95% CI 3.2–33.3) and 5-years OS 99% vs. 80% (HR 11.07, 95% CI 3.09–27.92), respectively. Conclusions: Comparing with older cisplatin-based regimens, the new ones (BEP or EP) improved PFS without significant influence on OS in pts with advanced seminoma. Pre-treatment LDH level is an important independent prognostic factor, which could help stratify pts better into risk groups. Further studies with risk-adapted policy in advanced seminoma are warranted.

No significant financial relationships to disclose.
Survival advantage in patients treated with high-dose interleukin-2 (HDIL2) for metastatic renal cell carcinoma (mRCC)
Authors: Lee S. , Baig M. , Rusciano V. , Gao Y. , Malik S. , Wiernik P. H. , Dutcher J. P.
Published: August 2020

e16039

Background: A prognostic index developed at MSKCC(Memorial-Sloan-Kettering Cancer Center) relates to survival in mRCC patients (pts) treated with interferon. We evaluated 79 pts treated first line with HDIL2 to see if this prognostic index is applicable. Eligibility for HDIL2 was based on cardiopulmonary screening and performance status (PS). Method: Medical records were analyzed retrospectively from 2000–2008. Pts were categorized into favorable, intermediate & poor risk category according to MSKCC prognostic index, which includes time from diagnosis to treatment, serum calcium & LDH, hemoglobin and PS. Median survival (OS) & median progression free survival (PFS) were compared between risk categories. Results were evaluated taking into consideration potential confounders such as subsequent treatment with tyrosine kinase inhibitors (TKI) & time from nephrectomy to metastasis interval of more than 1 year. Statistical analysis utilized SPSS. Results: 29 pts (36.7%) were treated with TKIs subsequently and this had no impact on median OS compared to those not receiving TKIs. 19 pts (24%) had nephrectomy to metastasis interval of more than 1 year and this also did not impact on OS analysis compared to those with shorter time to metastasis. Poor risk group was not analyzed due to small sample size. Conclusions: Median OS for mRCC pts eligible for and treated with HDIL2 as first line therapy exceeds reports of other first line treatment, either cytokines or TKIs. The survival advantage occurs regardless of being in either favorable or intermediate risk category and this benefit is not confounded by subsequent treatment with TKIs or nephrectomy to treatment interval more than 1 year. HDIL2 pts requires good PS and organ function, but 72% were intermediate risk pts. Thus, MSKCC risk categories do not predict for HDIL2 treatment outcome. HDIL2 should still be considered as a first line agent for mRCC, in the era of TKIs, as long as patients meet the eligibility criteria, as it infers survival advantage. [Table: see text]

[Table: see text]
A combined phase I/II trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of refractory non–muscle- invasive transitional cell bladder cancer
Authors: Barlow L. , Laudano M. , Mann M. , Desai M. , Petrylak D. , Benson M. , McKiernan J.
Published: August 2020

e16047

Background: Up to 50% of patients treated with intravesical agents for non-muscle-invasive bladder cancer will recur. Response rates to current second line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Our previously completed phase I trial showed docetaxel to be a safe and efficacious agent for intravesical therapy. Nanoparticle albumin-bound (nab-) paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy and is therefore an appropriate candidate for further investigation as an intravesical agent. Methods: The ongoing phase I component of this combined phase I/II trial began enrollment on 1/1/08 and has reached 72% accrual as of 1/1/09. Inclusion criteria include recurrent high grade (HG) Ta, T1 and Tis transitional cell carcinoma failing at least one prior regimen with any intravesical agent. In phase I, 6 weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg with a dose escalation model used until a maximal tolerated dose (MTD) was achieved. The primary endpoints were dose- limiting toxicity (DLT) and MTD; the secondary endpoint was response rate. Efficacy was evaluated by cystoscopy with biopsy, cytology, and CT imaging. Results: 13/18 patients have enrolled in this phase I trial to date, and the distribution of stages included 5 patients with Tis, 4 patients with HGTa, and 4 patients with HGT1. No patient has had any systemic absorption of nab-paclitaxel as measured by HPLC assays, and no grade 3 or 4 DLT has been encountered. Fifty-four percent (7/13) patients were noted to experience grade 1 toxicities, with dysuria being the most common. Forty-two percent (5/12) of completed patients had no evidence of disease at their post-treatment cystoscopy. None of the patients who developed recurrent disease have had disease progression. Conclusions: Intravesical nab-paclitaxel has exhibited minimal toxicity and no systemic absorption in the first ever human intravesical dose escalation trial. Upon completion of this ongoing phase I trial, we plan to evaluate this agent in a larger phase II efficacy study.

No significant financial relationships to disclose.
Cardiovascular toxicity follwing sunitinib therapy in metastatic renal cell cancer: A multicenter analysis
Authors: Di Lorenzo G. , De Placido S. , Cartenì G. , Autorino R. , Gonnella A. , Rizzo M. , Perdona S. , Ricevuto E. , Aieta M. , Ewer M.
Published: August 2020

e16051

Background: Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. Methods: The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian Institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with pre-existing cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. Results: Grade 3 hypertension was seen in 17 patients (9.7%); in twelve of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left-ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were of classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). A significant univariate association for predictors of CHF were history of hypertension (p=0.008), history of coronary heart disease (p=0.0005) and prior treatment with an angiotensin converting enzyme inhibitor (ACE) (p= 0.04). Multivariate analysis suggested that a history of coronary artery disease (OR 18, 95% CI, 4–160 p 0.005) and hypertension (OR 3, 95% CI, 1.5–80 p 0.04) were the only significant independent predictors of CHF. Conclusions: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.

[Table: see text]
Tolerability of ongoing phase II study of concomitant radiation and docetaxel followed by docetaxel in prostate cancer patients with a persistent or rising PSA after radical prostatectomy
Authors: Harris A. M. , Eng T. Y. , Karnad A. B. , Swanson G. P. , Jenkins C. , Greene R.
Published: August 2020

e16054

Background: Patients with a detectable PSA after radical prostatectomy (RRP) have persistent disease and inevitably succumb to disease as progression ensues. Radiation has been used in the salvage setting, but has only been found to cure less than half of these patients. SWOG 8794 has recently reported a significant increase in metastasis free survival in 15 years with adjuvant radiation for patients with high risk findings after RRP. It is of particular interest if adjuvant chemoradiation (CRT) can improve the rate of reaching a PSA nadir of zero after RRP in men with persistent or rising PSA. This ongoing IRB approved trial has thus far evaluated the tolerability of CRT utilizing the radiosensitizing agent Docetaxel (DX) for 7 weeks after RRP followed by adjuvant full dose DX (75mg/m2). Methods: Patients: Chemotherapy/hormone naïve, status post RRP, post-op PSA > 0.2 ng/mL on two separate occasions, ECOG ≤ 2; treated with taxane-based chemotherapy (DX 20mg/m2 weekly) concurrent with standard dose radiation for 7 weeks, and post-radiation chemotherapy DX (75mg/ m2) given every 21 days for 4 cycles with premedication intravenous dexamethasone. Primary endpoint: Rate of PSA decline; Number of subjects reaching PSA nadir of zero. Secondary endpoints: Progression Free Survival (PFS) based on PSA progression, toxicity graded via Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE), and overall survival (OS). Results: From 5/07 to 12/08, 16 pts with detectable PSA after RRP were treated; Median age 65 [48–74]; 16/16 completed CRT; 11/16 completed CRT and adjuvant DX; 3/16 dropped out due to adverse events after CRT; Toxicity: 19% (3/16) patients experienced Grade 3 toxicity during CRT and adjuvant DX; 29% (4/14) patients had Grade 3 toxicity during adjuvant DX; no Grade 4 toxicities. See Table . Conclusions: DX in combination with standard radiation appears to be well tolerated in patients with persistent PSA after RRP. [Table: see text]

No significant financial relationships to disclose.
Long-term safety of sorafenib (SOR) for the treatment (tx) of advanced clear-cell renal-cell carcinoma (RCC): Data analysis from patients (pts) treated for over 1 year in the phase III TARGET study
Authors: Hutson T. E. , Bellmunt J. , Porta C. , Staehler M. , Szczylik C. , Nadel A. , Anderson S. , Bukowski R. M. , Eisen T. , Escudier B.
Published: August 2020

e16057

Background: Results of the phase III multicenter TARGET study, a randomized, double-blind, placebo (PBO)- controlled study of tx with SOR in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective (PFS 5.5 vs 2.8 mo, HR=0.44, P<0.000001, and 39% increase in survival for SOR vs PBO, HR=0.71, P=0.015) and safe in pts with advanced RCC (Escudier et al. N Engl J Med. 2007). With a database cut-off of Sept 8, 2006, we analyzed the safety of long-term use of SOR in pts in TARGET (study start Nov 2003). Methods: Pts (N=903) with advanced metastatic clear-cell RCC that had progressed after 1 systemic tx, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or PBO. End points included OS, PFS, and safety. A single planned analysis of PFS showed a significant benefit of SOR over PBO; consequently, pts assigned to PBO were offered SOR. Descriptive analysis of safety and efficacy of pts treated >1 year (y) was conducted. Results: 169/903 pts were randomized to SOR and treated >1 y and 27 pts treated >2 y. Due to crossover of PBO to SOR, only 6 pts randomized to PBO were treated with SOR >1 y. Pts treated with SOR >1 y had median PFS of 10.9 months and a response rate of 22.5%. Median tx duration was 20 months. Drug-related adverse events (AEs) were mainly grades 1 and 2 and occurred early during tx (see Table ); 31% and 22% of pts required dose interruption and reduction, respectively, because of AEs. Conclusions: Long-term tx with SOR did not result in new toxicities or an increase in overall incidence of tx-related AEs. Toxicity was not cumulative and no increase in grades 3/4 AEs was observed. Pts with preexisting cardiac disease or hypertension tolerated long-term tx with SOR; no dose reduction was required. No increase in cardiovascular toxicity was observed in this pt population. Long-term tx of pts with advanced RCC with SOR is medically manageable, with a predictable AE profile. [Table: see text]

[Table: see text]
A phase II study of single agent abraxane as second-line therapy in patients with advanced urothelial carcinoma
Authors: Sridhar S. S. , Canil C. M. , Eisen A. , Tannock I. F. , Knox J. J. , Reaume N. , Mukherjee S. D. , Winquist E. , Chung A. , Ko Y. J.
Published: August 2020

e16058

Background: Metastatic urothelial cancer progressing on or after first-line platinum-based chemotherapy is incurable and has a very poor prognosis. There is no standard second-line therapy, but the taxanes including paclitaxel, have previously shown activity. Abraxane (ABI-007) is a novel well tolerated albumin-bound nanoparticle formulation of paclitaxel. The goal of this study was to determine the efficacy and tolerability of single agent Abraxane in the second-line metastatic urothelial cancer setting. Methods: Patients with measureable metastatic urothelial cancer, who progressed on or after first-line cisplatin based chemotherapy were enrolled onto this phase II, two-stage multicenter trial. Patients received Abraxane 260 mg/m2 intravenously every 3 weeks. Clinical evaluation, CBC and blood chemistries were performed every cycle and restaging CT scans every 2 cycles. Results: Fourteen patients have been enrolled to date. Patient demographics: M: F 12:2; mean age 64 (range 45–80); ECOG 0:1:2 4:5:5. A total of 57 cycles, avg 4 cycles/ patient (range 1–9) have been administered. There were three dose delays due to neuropathy, pain, and low neutrophil count respectively. There were two dose reductions due to fatigue and neuropathy. Most frequent adverse events (AE) were fatigue, alopecia, anorexia, cough and joint pain; the most frequent grade 3+ AE were fatigue, joint pain, hypertension, joint stiffness and back pain. Fourteen patients are currently evaluable for best response using RECIST criteria. There have been 5 partial responses (PR), 5 stable disease (SD) and 4 progressive disease (PD). Conclusions: Single agent Abraxane was well tolerated in the 2nd line, cisplatin refractory/resistant metastatic urothelial cancer setting. Preliminary efficacy results are encouraging with a clinical benefit rate of 71% (10 out of 14 evaluable pts having either SD or PR). Stage 1 response criteria have been met and accrual is ongoing to a total of 48 patients.

No significant financial relationships to disclose.
The robotic era of radical prostatectomy: A retrospective analysis of patient characteristics in contemporary robotic and open prostatectomy
Authors: Murphy A. , Barlow L. , Mann M. , Badani K. , Benson M. , McKiernan J.
Published: August 2020

e16061

Background: As new treatment options become available without being tested in randomized controlled trials, trends in the patient populations receiving these novel therapies often emerge prior to the determination of ideal patient selection factors. In the case of robotic-assisted laparoscopic radical prostatectomy (RALRP), biases in patient selection for this relatively new procedure may influence the evaluation of postoperative outcomes in comparison to open retropubic radical prostatectomy (RRP). This study describes the disease-specific characteristics of patients currently undergoing RALRP and RRP in a contemporary fashion at a single institution. Methods: A total of 1,088 patients who had surgery since the inception of RALRP at our institution (2003–2007) were identified for analysis. The cohort was divided into two groups based on surgical technique (RALRP versus open RRP). Characteristics of the patient pool analyzed included age at surgery, Kattan Nomogram (KN) score, preoperative prostate-specific antigen (PSA), Gleason sum (GS) at biopsy, and pathological tumor stage. Unpaired t-tests with Welch correction and Mann-Whitney tests were used to determine the differences in patient characteristics between the two surgical approaches. Results: The median age was 61. The mean preoperative PSA was 6.2, and GS 2–6, 7, and 8–10 of 48.2%, 40.4%, and 11.4%, respectively. 519 and 569 patients underwent RALRP and RRP, respectively. There was a significant difference between GS (p<0.0001) and tumor stage (p=0.002) between patients undergoing the two approaches. There were trends in favor of younger age, decreased preoperative PSA, and better KN scores in the RALRP group, but these observations lacked statistical significance (age: p=0.06, PSA: p= 0.07, KN: p=0.15). Conclusions: Although there is insufficient evidence to declare an overall difference in patient characteristics between these two surgical approaches in our patient population, trends toward lower-risk patients in the RALRP group suggest a series of patient selection forces for this procedure. These observations have the potential to influence the results obtained in retrospective analyses comparing outcomes between RALRP and open RRP.

No significant financial relationships to disclose.
Benefit of radiotherapy dose escalation in localized prostate cancer with respect to expression of intrinsic markers of hypoxia
Authors: McVey G. P. , Morgan S. C. , Vergis R. , Corbishley C. , Thomas K. , Cooper C. , Horwich A. , Huddart R. , Dearnaley D. P. , Parker C. C.
Published: August 2020

e16068

Background: Dose escalation improves the efficacy of prostate cancer radiotherapy (RT) at the cost of increased toxicity. Tumor hypoxia causes radioresistance, so the benefit of RT dose escalation may be greater in more hypoxic cancers. Methods: Cases had localized prostate cancer treated with neo-adjuvant androgen deprivation and radical RT at the Royal Marsden in two randomized trials of dose escalation (64 vs 74Gy). Tumour expression of three markers (vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α(HIF-1α), and osteopontin) was assessed immunohistochemically using a semi-quantitative scale by a uro-pathologist, and analyzed with respect to freedom from biochemical failure (FFBF) using the Phoenix definition. Expression of each marker was dichotomised about the median for analysis of the impact of dose-escalation on outcome. Results: 201 cases with a median follow-up of 7 years were evaluable. Seven-year FFBF was 67% vs 40% (HR: 0.42, 95% CI 0.26–0.7, p=0.001) for 74 Gy versus 64Gy, respectively, among cases with high osteopontin expression, and 70% vs 82% (HR: 1.41, 95% CI 0.53–3.76, p=0.49) for 74Gy vs 64Gy among cases with low osteopontin expression. The benefit of RT dose escalation was similar regardless of VEGF or HIF- 1α expression. Conclusions: These data generate the hypothesis that osteopontin expression could inform RT dose individualisation. If validated, patients with low tumor expression of osteopontin could elect to receive less toxic, standard dose RT.

No significant financial relationships to disclose.
Biochemical failure after radiation therapy for prostate cancer: Racial differences
Authors: Chi D. , Hirsch A. E. , Gignac G. A.
Published: August 2020

e16071

Background: Many guidelines for prostate cancer treatment are based on clinical trials with predominantly white patient (pt) populations. The generalizability of these results assumes similar tumor biology among all races. We set out to examine biochemical failure (PSA failure) rates in a cohort of pts after definitive external beam radiation (EBRT) in the racially diverse population at our institution. Methods: We conducted an IRB-approved retrospective review of pts treated with definitive EBRT from January 2000 to April 2008. We excluded from analysis pts who received brachytherapy, salvage, adjuvant or palliative radiation. Race, country of origin, diagnostic data, pre- and post-treatment PSA, Gleason score (GS), clinical stage (CS), and treatment history were reviewed. CS was based on the original clinician's assessment at time of diagnosis. PSA failures were defined using 1996 ASTRO criteria. Two cohorts were grouped by race: white and nonwhite. Statistical analysis was performed using Fisher's Exact test. Results: One hundred seventy-four pts were treated with definitive EBRT. Forty-four pts were white and 130 were nonwhite. Both cohorts demonstrated similar distributions in GS and CS (see Table ). The white cohort had a high proportion of pts with a pretreatment PSA <10 ng/ml (66%) as compared to the nonwhite cohort (46%). Distribution of race/region of origin is: White 44 (25%), Black-American 78 (45%), Black-Caribbean 28 (16%), Black-African 2 (1%), Hispanic 21 (12%), Asian 1 (1%). Just under 50% of each group received neoadjuvant androgen deprivation therapy. PSA failure rate was 7% for the white cohort and 13% for nonwhite (p = 0.41). Conclusions: In this retrospective analysis, there was no statistical difference among races with regard to PSA failure rates. The PSA and Gleason trends in each cohort were consistent with published data on this topic. Dedicated evaluation of the prognostic value of traditional risk stratification in nonwhite pt populations in a prospective trial is warranted. [Table: see text]

No significant financial relationships to disclose.
A phase II trial of gemcitabine(G), capecitabine (C), and bevacizumab (B) in patients (pts) with metastatic renal cell carcinoma (RCC)
Authors: Chung E. K. , Posadas E. M. , Kasza K. , Karrison T. , Manchen E. , Michalak L. , Hahn O. M. , Stadler W. M.
Published: August 2020

e16072

Background: RCC is resistant to most traditional DNA and DNA repair targeted chemotherapy; although modest response rates to nucleotide analog based therapy, including GC, have been reported. Bevacizumab has activity in RCC. We thus performed a single center phase II trial of GCB in pts with metastatic RCC. Methods: Eligibility included clear cell or unclassified histologies, performance status 0–1, measurable disease, normal organ function and no prior treatment with VEGF binding agents or pyramidine analogs. Following significant hematotoxicity in the first 7 of 8 pts, chemotherapy was modified to G 1,000 mg/m2 (days 1, 8), C 1,000 mg po bid (days 1–14) and B 15 mg/kg (day 1) on a 21 day cycle with disease re-evaluation every 3 cycles. Primary endpoint was objective response rate (ORR) using a Bayesian continuous reassessment method designed to detect an improvement in the ORR from a 15% historical rate to 27%. Maximum planned enrollment = 55. Results: 30 pts enrolled from March 2005-May 2008 of which 29 were evaluable: 1 never treated. Pt characteristics: male 83%, median age 58 (36–82), prior nephrectomy 83%, prior radiation 52%, prior cytokine therapy 28%, prior VEGFR tyrosine kinase inhibitor 69%. MSKCC prognostic group: good 24%, intermediate 66%, poor 10%. 7 pts had a partial response (24%). Median overall and progression free survival were 9.8 mo (95%CI: 6.2, 14.9) and 5.3 mo (95%CI: 3.9, 9.9). Grade 3 or 4 toxicities: leucopenia 17%, neutropenia 31%, thrombocytopenia 7%, anemia 14%, proteinuria 3%, rash/hand foot syndrome 7%, fatigue 21%. Average change in mean arterial pressure after 2 cycles: 5.6 (p = 0.040). Serious adverse events: bowel perforation resulting in death 1 pt (3%), sepsis 1 pt (3%), PE/DVT 3 pts (10%), seizure 1 pt (3%). Conclusions: The trial was terminated early despite not meeting protocol criteria for success or futility due to slow accrual and the fact that the historical response rate on which the trial was based became irrelevant with emerging data using sequential VEGF pathway directed therapies. Nevertheless, the observed progression free and overall survival compare favorably to other phase II trials in this population.

[Table: see text]
An open, randomized, multicentre, phase III trial comparing the efficacy of two tamoxifen (T) schedules in preventing gynecomastia (gy) induced by bicalutamide monotherapy (BM) in prostate cancer patients (pca pts)
Authors: Bedognetti D. , Rubagotti A. , Conti G. , Francesca F. , De Cobelli O. , Canclini L. , Gallucci M. , Aragona F. , Di Tonno P. , Boccardo F.
Published: August 2020

e16080

Background: BM is a valuable option for pca pts who wish to avoid the consequences of androgen deprivation and to mantain sexually active.BM is commonly well tolerated:however gy and mastalgia virtually develop in all pts and represent a major cause of treatment discontinuation. We had previously demonstrated that T is safe and effective in preventing breast events induced by BM without affecting B tumor activity (Boccardo, J Clin Oncol. 2005;23:808). However possible interferences between B and T,especially after prolonged administration, remain a matter of concern.In order to reduce the exposure to T,we considered the putative advantages of a weekly administration based on T effects being dose -dependent and on drug long half-life. Methods: This was a non inferiority trial. 80 pts with localized, locally advanced or biochemically recurrent pca were randomly assigned to receive daily B (150 mg) plus T 20 (mg) continuously (d group: n = 41) or same but with T at 20 mg/weekly after the first 8 weeks (wk group: n = 39). Gy (primary endpoint), breast pain (bp), serum PSA levels and sexual functioning scores were evaluated. Results: At a median F.U. of 24.2 mos (95% CI: 23.7 -24.6) gy developed in 31.7% of pts in d group and in 74.4% of pts in wk group (p < 0.000). Bp occurred in 12.2% and 46.1% of pts respectively (p = 0.008) and it was more severe in patients switched to weekly T. The incidence of Aes was comparable (d group:58.8%;wk goup: 56.4%). However most events were mild and easily manageable. There were no major differences among treat. schedules relative to sexual functioning scores, PSA behaviour and disease progression. Conclusions: This study failed to demonstrate that it might be possible to maintain comparable prophylactic effect of T by switching from a daily to a weekly schedule and confirms that T at the daily dose of 20mg is safe and effective in preventing the incidence and severity of BM induced breast events.

No significant financial relationships to disclose.
Quality-of-life and LhRH agonist therapy among prostate cancer patients following PSA failure
Authors: Undevia-Yedavalli N. , Dandade N. , Luu T. , Samaras A. , Sartor O. , Nonzee N. , Bennett C.
Published: August 2020

e16083

Background: Growing numbers of prostate cancer patients experience biochemical relapse (PSA failure) after initial treatment. LhRH agonist (hormonal) therapy can reduce PSA levels, but there is no clear evidence that it slows disease progression or reduces mortality. Quality of Life (QoL) issues are essential when deciding between observation (OBS) versus hormonal castration following biochemical relapse. We evaluated health related quality of life and treatment satisfaction among prostate cancer patients who experience PSA failure. Methods: Eligibility criteria were receipt of primary therapy for prostate cancer followed by a PSA nadir and subsequent PSA rise to at least 0.2 ng/ml. Data sources include medical records and interviewer administered surveys on health- related QoL at baseline, 3 and 12 months. Results: Castrated versus observed patients who are satisfied with their sexual activity report similar health-related QoL, with the exception of higher rates of maintaining an erection (73.3% vs. 32.0%) and not having prostate cancer affect sexual activity (66.7% vs. 28.6%). Castrated and expectant management patients with low levels of satisfaction and sexual activity report similar health-related QoL. Conclusions: Among patients with PSA Failure, the only health-related QOL difference is reflected in sexual activity related to erectile dysfunction, but not sexual satisfaction among patients who all have a high level of treatment decision satisfaction and sexual activity. [Table: see text]

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Docetaxel and imatinib every 21 days for castration resistant prostate cancer: A phase II trial
Authors: Gillison T. L. , Appleman L. J. , Friedland D. M. , Evans T. L. , Lara P. N. , Gooding W. E. , Lenzner D. E. , Strausser H. M. , Gingrich J. R. , Chatta G. S.
Published: August 2020

e16086

Background: Docetaxel (D) IV every 21 days, is the only cytotoxic agent that prolongs survival in men with castrate resistant prostate cancer (CRPC). Imatinib (I), a tyrosine kinase inhibitor, modulates PDGFR-ß in tumor vasculature. Based on phase I data from our institution, we hypothesized that D plus I would prolong time to progression (TTP) in patients (pts) with CRPC. Methods: Subjects with CRPC received D 60 mg/m2 IV every 21 days plus I 400 mg PO daily. After 10 pts, the study treatment was modified due to toxicity so that pts received I 400 mg on 10 of 21 days/cycle. The primary endpoint was TTP. Secondary endpoints were rate of PSA response and overall survival (OS). The sample size of 43 pts was designed to provide 90% power to detect an increase in TTP from 5 to 8 months. Results: 43 pts enrolled from 8/05 to 9/08. Age at enrollment ranged from 54–86 years (median 69 years). 14 pts received <1 cycle of D plus I and were unevaluable: 10 had significant toxicity, 4 due to non-treatment related reasons. Primary toxicities were hematologic: 21% G4 neutropenia, 5% G4 anemia, and no G4 thrombocytopenia. Fatigue, nausea, diarrhea, and electrolyte abnormalities were common, but <2 cases each of G3-G4 toxicity occurred. 1 case of G5 non-neutropenic sepsis occurred. 29 pts received >2 cycles of chemotherapy (mean 4.6). 12 pts had PR (41.4%), 9 had SD (31.0%), and 8 had no response (27.6%) by PSA. No objective responses were seen by CT imaging among 10 pts with measurable disease. 3 pts remain on trial. For evaluable pts, overall median TTP was 6.4 months (95% CL: 4.8, 8.4 months) compared with TTP of 5 months seen in previous trials. 23 (79%) pts had PSA progression, 3 pts died before progression, and 3 pts remain on trial. For all evaluable pts who had PR or SD by PSA (N = 21), median TTP was 7.1 months (95% CL: 5.5, 9.1 months). Median OS was 23.1 months (95% CL: 11.61 months, NR), compared with 18.9 months for GC Conclusions: Docetaxel on day 1 plus imatinib 10 days of each 21-day cycle resulted in meaningful improvement in TTP in the subset of pts who showed a response. Toxicity precludes its use in the general population, although its role in select pts with good performance status needs to be explored.

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Results at 5 years of intra vesical gemcitabine (G) single agent as adjuvant chemotheray in superficial transitional cell carcinoma (TCC) of the bladder
Authors: Smaili F. , Bounedjar A. , Ferhat R. , Bouzid K.
Published: August 2020

e16087

Background: Systemic intravenous gemcitabine is usually used in advanced bladder carcinoma, intravesical G is a novel treatment approach for TCC. In this study we evaluate the efficacy of intravesical Gemcitabine in patients (pts) with superficial bladder carcinoma. Methods: From February 2003 to June 2004, 60 pts (57M/3F) were enrolled in the study (M/F = 57/3). The median age was 59,5 years old (24–84). Nine pts had a carcinoma in situ (Cis) and 51 had pT1 lesions. Three weeks after a total transurethral resection (TUR), patients receive intravesical instillation of 2000 mg G every week for 6 weeks, than every month for six months. They received a total of 720 instillations, Follow up was with cystoscopy and urine cytology every six months. Results: At a median follow-up time 60 months, all patients were evaluable for tumor response: 23(38, 3%) patient had a persistant complete remission after treatment, 26 patients (43,3%) had a superficial relapse of TCC, six patients (10%) had progressive disease: four with muscle invasion and two with distant metastasis. Conclusions: Intravesical therapy with gemcitabine is active and well tolerated treatment in patients with superficial TCC carcinoma of the bladder. A phase III trial comparing GEM with intravesical BCG or MMC is warranted

No significant financial relationships to disclose.
The effect of naturopathic and nutritional supplement treatment on tumor response, control, and survival in prostate cancer patients treated with radiation therapy
Authors: Birdsall T. C. , Cain L. , Martin J. , Birdsall S. M. , Wiersum L. , Anderson K. , Eden B. , Flynn J. , Kelly D. , Braun D. P.
Published: August 2020

e16088

Background: Potential antagonism of clinical response to cancer treatment by naturopathic/nutritional supplements (NNS) with anti-oxidant activity has been suggested. This study assessed effects of NNS on tumor response to radiation therapy (RT) in prostate cancer patients (PCpts). Methods: Of 134 RT-treated PCpts with localized tumors, 69 received NNS (+NNS; median age=62.0 yrs) and 65 did not (-NNS; median age=61.5 yrs). Based on pre-RT PSA, 52low (4–10 ng); 13 intermediate (10–20 ng); and 4 high risk (> 20 ng) PCpts were +NNS and 50, 10, and 5 low, intermediate & high risk PCpts were -NNS. Tumor stages for +NNS were T1c (39%); T2a (44%); T2b (10%); T2c (5%) with 1 T3b tumor and were T1b (3%); T1c (46%); T2a (32%); T2b (12%); and, T2c (5%) with 1 T3a tumor for -NNS cohorts. RT consisted of external beam therapy (4500–5000 cGy) + HDR brachytherapy (600–650 cGy/fraction x 2–3 fractions) administered over 6–8 weeks. NNS regimens (range 1–7 antioxidants) included Green Tea Extract, Melatonin, high-potency multivitamins, vitamin C, and vitamin E. All pts were monitored ≥ 24 months post RT. Hormonal therapy (HT; oral bicalutamide (50 mg/day) ±leuprolide depot (22.5 mg IM q 3 months) as neoadjuvant or adjuvant HT was given to 39 (57%) and 38 (58%) PCpts in the +NNS and -NNS cohorts respectively. Results: For the +NNS cohort that did not receive HT, PSA levels were 5.05; 0.285; and 0.356 ng at pretreatment, nadir and ≥ 24 months followup respectively with PSA nadir at 27 months and median followup of 36 months. The corresponding values for the -NNS cohort were 5.6, 0.54, and 0.585 ng with PSA nadir at 25 months and median followup of 29.6 months. Differences were not statistically significant. For the +NNS cohort that did receive HT, PSA levels were 6.8, 0.03 and 0.12 ng at pretreatment, nadir and ≥ 24 months followup with median time to nadir = 4.3 months and median followup = 29.2 months. Corresponding values for -NNS cohort were 6.9, 0.03, and 0.11 with median time to nadir = 3.6 months and median followup = 30.5 months. Differences were also not statistically significant. Conclusions: This study shows that NNS with antioxidant activity do not interfere with clinical response to RT ± HT as definitive treatment for limited stage prostate cancer.

No significant financial relationships to disclose.
A novel selective therapeutic targeting heme oxygenase-1 revealed a potent antimetastatic activity in androgen-refractory human prostate cancer models
Authors: Alaoui-Jamali M. A. , Gupta A. , Szarek W. A. , Bismar T. A. , Gheorghe R. , Schipper H. M.
Published: August 2020

e16090

Prostate cancer is a highly prevalent disease. Despite a significant improvement in the overall survival attributed in part to early detection and introduction of novel therapeutic modalities, many cancer patients at primary diagnosis present advanced disease or experience recurrence of the cancer. The progression of prostate cancer (PCA) to hormone-refractory phenotype (HRPCA) and to metastasis is an ominous event in patients with advanced PCA. Currently, clinically available drugs for hormone refractory PCA have only marginal efficacy. In this study, we identified heme oxygenase 1 (HO-1) to be significantly upregulated in epithelial PCA cells, but not in surrounding stromal cells, from hormone refractory prostate cancer cases compared to hormone-responsive prostate cancer and to benign tissues. We validated HO-1 as a novel therapeutic target for HRPCA. Specifically, inhibition of HO-1 gene in androgen-independent and highly invasive prostate cancer cells, PC3M, decreased HO-1 activity, oxidative stress, MAPKs activation, cell proliferation, and cell migration and invasion in vitro, as well as inhibition of prostate tumor growth and lymph nodes and lung metastases in vivo. The impact of HO-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively downregulates HO-1 activity, oxidative stress, and significantly inhibits cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity in inhibiting HRPCA metastasis formation was observed when OB-24 was combined with the chemotherapy drug taxol. The molecular and potential clinical impact of OB-24 alone and in combination with taxanes on HRPCA will be discussed.

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Effects of sorafenib on proliferation of hormone-sensitive and hormone-insensitive prostate cancer cells
Authors: Culig Z. , Oh S. Jung , Santer F. R. , Puhr M. , Steiner H. , Hobisch A.
Published: August 2020

e16092

Background: Sorafenib is a multi-targeted kinase inhibitor approved for treatment of renal and hepatocellular cancer. In patients with castration therapy-resistant prostate cancer sorafenib treatment is associated with discordant prostate-specific antigen (PSA) and clinical responses, possibly due to an effect on PSA expression. The mechanisms of its action in advanced prostate tumors are not investigated so far. The aim of the present study was to evaluate the effects of sorafenib in androgen-sensitive (LNCaP) and -insensitive (PC 3) prostate cancer cell lines. Methods: Proliferation was evaluated by measurement of cell number and protein. Expression of cell cycle and apoptosis regulatory proteins of the Bcl-2 family was determined by Western blot. Results: Treatment of those cells by sorafenib for 48 hours resulted in a concentration-dependent inhibition of proliferation. Maximal inhibition was achieved with 25 μM of the compound. Cell number was reduced by 50% in both cell lines. We observed inhibition of expression of cyclin-dependent kinase 2 in LNCaP and PC3 cells. In addition, Mcl-1 protein, that is frequently overexpressed in prostate cancer, was down-regulated by sorafenib in both cellular models. Conclusions: Sorafenib caused inhibition of growth of prostate cancer cells regardless of their androgen sensitivity. Its inhibitory effects on cyclin- dependent kinase 2 and Mcl-1 imply that sorafenib regulates cell cycle progression and apoptosis in prostate cancer. On the basis of these results experiments with chemotherapy-resistant prostate cells are being performed.

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Deleted in cancer 1: Search for a function in prostate cancer
Authors: Hirsch J. , Nelius T. , Pfarr C. , De Riese W. , Wieland I. , Filleur S.
Published: August 2020

e16095

Background: Deleted In Cancer 1 (DICE1/INTS6) gene was recently identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in many solid tumors including prostate cancer (PrCa). DICE1 missense mutations have been previously detected in PrCa cell line LNCap, and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in PrCa cells. DICE1 is a highly conserved nuclear protein suggesting its involvement in DNA repair, transcription, or RNA splicing. In mouse, the DICE1 homologue interferes with the response to insulin-like growth factor 1 and suppresses anchorage-independent growth of transformed mouse cells. The totality of these results suggests that DICE1 is a tumor suppressor gene and insist on the need to better characterize DICE1 function in PrCa. Methods: Expression of DICE1 was evaluated by Northern Blot in PrCa cell lines LNCap, DU145, PC3, PC3ml and CPTX1532 and compared to expression level in normal prostate cell line NPTX1532. DICE1 growth inhibitory effects were analyzed by colony formation assay on PC3 and DU145 cells transfected with DICE1 expression plasmid or control vector. Apoptosis was assessed by visualization of genomic DNA fragmentation on agarose gel. PCR arrays (SABiosciences) were used to identify specific signaling pathways modulated in response to DICE1 expression. Results: Markedly decreased DICE1 mRNA levels were detected in PrCa cell lines LNCap, DU145, PC3 and PC3ml as well as CPTX1532 as compared to NPTX1532, a cell line derived from normal prostate tissue. Ectopic expression of DICE1 cDNA in DU145 and PC3 cells substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis suggesting growth suppression by other pathways. Expression profiling identified multiple pathways, such as Wnt, Hedgehog, PI-3 Kinase, NFκB and Insulin pathways, regulated in response to ectopic DICE1 expression. Furthermore, various transcription factors including Fos, Jun, CEBPA and PPAR-γ were up-regulated in response to DICE1. Conclusions: These results clearly illustrate the growth inhibitory ability of DICE1 in PrCa. Expression profiling links DICE1 function to growth factor signaling and cell-cell communication.

No significant financial relationships to disclose.