bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain metastases (BMs) from metastatic renal cell carcinoma (RCC) in patients (pts) treated with molecularly targeted agents (MTAs).
Authors: Ali Haris , Yan Jingsheng , Arriaga Yull Edwin , Xie Xian-Jin , Brugarolas James
Published: March 2020

e15066

Background: Historically, the frequency of BMs from RCC is ~11%. Recent reports have suggested an improvement in the incidence of BMs with tyrosine kinase inhibitors (TKIs). What is not known is the impact of MTAs on the prevalence of BMs in metastatic RCC. Methods: We conducted a retrospective review of all pts with metastatic RCC treated with MTAs at a tertiary care center, UT Southwestern Harold C. Simmons Comprehensive Cancer Center, from 2006–2010. Statistical analyses were performed using the Cox proportional hazards model and the Kaplan-Meier method. Results: Fifty nine pts met inclusion criteria. 8 more pts presented with BMs and were not included in the incidence and survival analyses. Median age was 64.6 yrs. Per MSKCC criteria, 3 pts were in favorable (5%), 41 in intermediate (70%), and 15 in poor (25%) prognostic groups. Sites of metastases at presentation included lungs (65%), lymph nodes (40%), bones (30%), and liver (25.4%). Mean follow up time was 16 months, and at last follow up 24 pts were alive. The incidence of BMs was 11.9% (7/59) and the prevalence was 22% (15/67). Median overall survival was 1.97 yrs (95% CI, 1.04-3.89). Median survival for pts who developed BMs vs. without BMs was 1.21 yrs vs. 1.98 yrs (p=0.17). In multivariable analyses, only lack of nephrectomy was associated with increased risk of BMs, HR=9.819 (95 CI, 1.65-58.38; p=0.012). Conclusions: In our study, the incidence of BMs in RCC pts treated with MTAs was similar to what has been historically reported. In contrast, the prevalence of BMs was much higher at 22%. This is the first study to report the prevalence of BMs in patients with metastatic RCC treated with MTAs. As in other tumor types, the life-time risk of BMs appears to increase with the availability of highly-active MTAs.
Long-term progression-free survival (PFS) in patients under sunitinib treatment: A SOG_GU experience.
Authors: Afonso Francisco Javier , Calvo Ovidio Fernández , Esteban Emilio , Fernández Gabriel Elena , Vazquez-Estevez Sergio , Anido Urbano , Lázaro Quintela Martin , Santomé Lucía , Ramos Vazquez Manuel , Campos Balea Begoña , Leon Mateos Luis , Firvida Jose-luis , Aparicio Luis Anton
Published: March 2020

e15067

Background:A multicenter retrospective analysis was performed in patients (pts) with metastatic RCC treated with sunitinib who achieved long-term PFS defined as ≥18 months. Methods: 46 pts (87% male) treated with sunitinib in first (74%) or subsequent lines were included. Median age was 59 years, most common histology was clear cell (93.5%), 89% had undergone prior nephrectomy, 28.3% were metastatic at diagnosis and 58.7% presented one site of metastasis, 28.3% two sites and 13% three or more and 12 (26%) had bone metastases. Good, medium, and poor prognosis (MKSCC) was presented in 30.4%, 67.4% and 2.2% of pts respectively. Median time from diagnosis to sunitinib treatment was 2.23 years and median duration of therapy was 27 months. At the time of analysis 37% were still receiving sunitinib. Reasons for discontinuation were progressive disease (83%), toxicity (10.3%) and death (3.4%). Results: Incidence of adverse events was as expected, with asthenia, hand food syndrome (HFS), hypertension, and mucositis as main toxicities. Efficacy results are described in the table. No significant differences in PFS with prior or nonprior history of hypertension, diabetes, or hyperlipidemia were observed. The emergence of drug-related toxicities, lack of bone metastasis, and being nonmetastatic at the time of diagnosis were independenly associated with a trend towards an improvement in PFS (p=NS)(see table). Conclusions: A comparison with a sunitinib-refractory population is planned and will provide additional information about prognostic biomarkers for long term response. [Table: see text]
Thymidine phosphorylase expression in metastatic kidney cancer as a potential predictor of outcome in patients treated with sunitinib.
Authors: Miscoria Manuela , Di Loreto Carla , Puglisi Fabio , Murray Paul Gerard , Deroma Laura , Atmadini Maizaton , Messahel Souad , Fasola Gianpiero , James Nicholas David , Porfiri Emilio
Published: March 2020

e15091

Background: Aberrant tumour angiogenesis is a hallmark of Renal Cell Carcinoma (RCC). Sunitinib is a small molecule targeting angiogenesis licensed for advanced RCC (aRCC) treatment. Thymidine Phosphorylase (TP) is an enzyme involved in pyrimidine nucleotide metabolism with a role in angiogenesis upregulation in cancer. In RCC, TP expression is associated with poor prognosis. We studied TP immunohistochemical expression in RCC samples and its association with the outcomes in a cohort of aRCC patients treated with sunitinib. Methods: We identified 59 consecutive patients with aRCC treated with sunitinib at our Institution. Nuclear (N) and cytoplasm (C) scoring for TP, using the validated Tsuda scoring, was performed. TP expression and clinico-pathological variables were studied to assess their association with the outcome of S therapy. The log rank test has been used for the univariate analysis and the Cox regression for the multivariate analysis. Results: Thirty-four patients received sunitinib as first line treatment. Fifty patients (84%) had clear cell RCC, 7 (12%) showed sarcomatoid features. Forty-five patients (76%) achieved either an objective response or stable disease. At the time of the analysis 32 patients had died, 46 had progressed and 41 had stopped the treatment. After an average follow up of 21 months, median OS and PFS were 21.2, 12.8 months respectively. N TP staining was positive in 19 patients (32%) and C staining in 36 (61%) patients. A significant association was observed between the N and C expression (p=0.004). The univariate analysis identified an association between N TP expression and longer OS (29.8 vs 17.8 months; p=0.0463) even if the association was not significant in the multivariate analysis (HR=0.56; CI 0.19-1.6). No associations were noted with PFS. Conclusions: In our study TP was overexpressed in a significant percentage of kidney cancers. In patients treated with sunitinib, N TP expression was associated with better OS. The results of the multivariate analysis were probably affected by the limited sample size. Larger and prospective studies are necessary to define the role of TP in RCC.
Efficacy and safety of sunitinib (SU) in patients (pts) with metastatic renal cell carcinoma (mRCC) and lung metastases (mets) only at baseline.
Authors: Shinohara Nobuo , Akaza Hideyuki , Tomita Yoshihiko , Yuasa Takeshi , Fujimoto Hiroyuki , Niwakawa Masashi , Ozono Seiichiro , Mugiya Soichi , Miki Tsuneharu , Uemura Hirotsugu , Nonomura Norio , Takahashi Masayuki , Hasegawa Yoshihiro , Ueda Eiji , Shibata Atsushi , Kawai Norisuke , Naito Seiji
Published: March 2020

e15098

Background: The lungs may be the sole site of mets in RCC.In this retrospective analysis, we analyzed the efficacy and safety of SU in mRCC pts from a global phase (ph) III study and a Japanese ph II study who had lung mets only at baseline. Methods: In the ph III study, treatment (Tx)-naïve mRCC pts were randomized 1:1 to SU 50 mg/d on a 4-weeks-on-2-weeks-off schedule (n=375) or interferon-a (IFN) 9 MU subcutaneously TIW (n=360). In the single-arm ph II study, Tx-naïve (n=25) and cytokine refractory (n=26) mRCC pts received the same SU Tx. In the ph III study, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method, with median values compared by log-rank test. In both studies, objective response rate (ORR) was calculated with a two-sided 95% CI. PFS, OS, ORR, and safety were analyzed at final data cutoff. Results: In the ph III study, 31 (8%) and 42 (11%) pts in the SU and IFN groups, respectively, had lung mets only, compared with 12 (24%) in the ph II study. Baseline characteristics in lung mets pts were similar to all pts. In lung mets pts from the ph III study, ORR was higher with SU than with IFN (58.1% [95% CI: 39.1–75.5] vs. 19.0% [95% CI: 8.6–34.1]; P<0.001); there was a trend for longer median PFS with SU (14.1 vs. 7.8 months; HR: 0.531 [95% CI: 0.278–1.015]; P=0.0513); and median OS was comparable in both Tx subgroups (HR: 0.739 [95% CI: 0.335–1.628]; P=0.4507), although, at 25% of events, median OS was 22.9 months with SU vs. 15.8 months with IFN. In lung mets pts from the ph II study, ORR was 75.0% (95% CI: 42.8–94.5); at the time of analysis, median PFS and OS had not been reached; 4 pts (33%) had died due to any cause and 8 (67%) were alive without disease progression. The most common grade ≥3 SU-related AEs were fatigue, hand-foot syndrome, and diarrhea (all 19%) in the ph III study, and decreased platelets (100%), white blood cells (92%), and neutrophils (92%) in the ph II study. Conclusions: In the ph III study, Tx-naïve mRCC pts with lung mets only had significantly higher ORR and a trend for improved PFS and OS with SU compared with IFN. In the Japanese ph II study, ORR with SU was 75% in lung mets pts. Thus, 1st-line use of SU in mRCC pts with lung mets should be encouraged.
Use of video endoscopic inguinal lymphadenectomy (VEIL) in patients with urogenital malignancies: An observational study.
Authors: S K Raghunath , Rawal Sudhir , Khanna Samir
Published: March 2020

e15101

Background: Surgical morbidity especially skin related necrosis is seen in 50% of patients following open radical inguinal lymphadenectomy in patients with urogenital malignancies. Inguinal lymphadenectomy helps in local control of disease and survival but had significant associated morbidity. We evaluated the post operative morbidity associated with minimally invasive video endoscopic Inguinal Lymphadenectomy (VEIL). Methods: Twenty two patients with urogenital malignancies who underwent thirty nine VEIL surgeries were evaluated for postoperative outcomes and morbidity. None of the patients required conversion to open surgery. Results: The mean operative time was 125 min, drain retention was 5.4 days, mean duration of postoperative stay was 3 days and a mean of 10.5 nodes were removed. 4.5% (1/22) developed skin flap necrosis, 4.5% (1/22) developed post operative venous bleeding that was controlled with dressing, 18.1% (4/22) developed lymphocoele that was resolved within 1-3 weeks with aspirations. Persistent drain output >50ml/day was observed in 18.1 % (4/22) that was resolved by readjusting the drain. Histologically positive nodes were seen in 40.9% (9/22) of patients. Conclusions: These observations offer further support for using minimally invasive VEIL surgeries over open radical inguinal lymphadenectomy in patients with urogenital malignancies in reducing both surgical and skin related morbidity. Further randomized controlled studies are needed to validate these findings.
Effect of PEDF on survival and in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.
Authors: Gaines Natalie , Nelius Thomas , Gillen Jessica , Rinard Katherine , Lopez Jose , Hirsch Jennifer , Cobos Everardo , Reynolds C. Patrick , Filleur Stephanie
Published: March 2020

e15103

Background: The development of metronomic/low-dose treatment with conventional chemotherapeutic drugs has recently shown promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is downregulated in prostate cancer. Previously we demonstrated that overexpression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validate PEDF anti-tumor properties in highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxic 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 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 SC xenografts in mice treated with Doc (5mg/kg IP every 4 days, 1mg/kg IP daily for 10 days, 0.5mg/kg IP every other day), CTX (10-20mg/kg in drinking water) or placebo. Survival studies were performed by injecting CL1 cells that express PEDF or control into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF inhibits proliferation and induces differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of SC PC3 and CL1 tumors, respectively. In the survival study, we found that PEDF expression prolongs significantly (p=0.01; 95% confidence interval) median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Most importantly, we demonstrated that PEDF enhances the cytotoxic 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: This data reinforces the significance of PEDF as a potential new target when treating 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.
Analysis of time to castration-resistant prostate cancer (CRPC) after initiating primary androgen depletion therapy (PADT) of prostate cancer.
Authors: Akaza Hideyuki , Hinotsu Shiro ,   Japan Prostate Cancer Study Group (J-CaP)
Published: March 2020

e15106

Background: Recent clinical trials for developing new drugs for castration resistant prostate cancer (CRPC) have been done for the patients who are surgically or medically castrated, with castration level of testosterone. Although patients who received combined androgen blockade (CAB) with anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to study enrollment, such patients are analyzed together with patients with castration monotherapy. Methods: We analyzed the time to CRPC among the patients with primary androgen depletion therapy (PADT); LH-RH agonist or CAB (LH-RH agonist + anti-androgen) who have registered to the J-CaP study and were followed up for >10 years. Time to CRPC was defined as PSA progression or other disease progression. Patients were stratified into three risk groups using JCAPRA score (JCO 2009; 26: 4309). In addition to the time to CRPC, overall survival length (OS) after initiating PADT was analyzed. Results: Time to CRPC was significantly longer in the CAB group than monotherapy group in intermediate and high risk groups (Table). In addition, in the intermediate and high risk groups, OS was significantly longer for the patients with CAB (Log-rank test). Conclusions: The significant differences of the time to CRPC and OS will influence to the outcome of clinical trials of CRPC. It is important to take the type of ADT in to consideration when we analyze the results of clinical study of CRPC. [Table: see text]
A QTc study of cabazitaxel in patients with advanced solid tumors.
Authors: Wade James Lloyd , Dakhil Shaker R. , Baron Ari David , Rottey Sylvie , Millard Frederick E. , Daugaard Gedske , Machiels Jean-Pascal H. , Conkright William A. , Sharma Sunil , Soetekouw Patricia M.M.B. , Yachnin Jeffrey , Sengeløv Lisa , van Veldhuizen Peter , Agarwala Sanjiv S. , Nguyen TX Quyen , Chadjaa Mustapha , Maison-Blanche Pierre
Published: March 2020

e15115

Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; p<0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. Methods: This prospective, multinational, open-label study (NCT01087021) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula [QTcF]). Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n=65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n=63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1–7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n=94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n=91) and AUC (n=92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. Conclusions: Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.
Taxane-based chemotherapy in senior adults with metastatic castration-resistant prostate cancer (mCRPC): A prospective international registry.
Authors: Droz Jean-Pierre , Efstathiou Eleni , Heidenreich Axel , Yildirim Asif , Cabrera Paula , Kim Choung-Soo , Horchani Ali , Rinck Jose A. , Ozen Haluk ,   for MATuRITY investigators
Published: March 2020

e15122

Background: Docetaxel every 3 weeks is the standard of care in mCRPC. Efficacy and toxicity of taxanes in older men (70+) is poorly documented. Their enrolment in randomized trials is limited by exclusion criteria. This prospective international registry evaluates taxane toxicity and efficacy in such men in real life. Methods: 333 men with mCRPC (median age 76) were evaluated. PS, grade 3-4 comorbidities (Cumulative Illness Scoring Rate-Geriatrics [CISR-G]), dependence (Activity Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy received and outcomes (overall survival (OS), progression-free survival (PFS), best clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) were collected. Follow-up under therapy was 6 months. Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within the past 3 months. According to SIOG (International Society of Geriatric Oncology, BJU Int 2010; 106: 462-69) algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal illness. Most patients (62.4%) had pain at enrolment. Primary therapy was a taxane in 58% (3-weekly, 84.4%; median, 5 months) and another therapy in 42%. Clinical characteristics of men treated by taxanes and other therapies were comparable. At 6 months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 0.53 [0.30-0.93] p=0.027). Taxanes also significantly increased PFS (66% vs 50%, HR 0.55 [0.40-0.76], p<0.001), best clinical benefit (60% vs 36%, HR 2.05 [1.47-2.85], p<0.001) and PSA response ≥50% (52.5% vs 37.4%, p=0.018). Main grade 3-4 toxicities with taxanes were fatigue (17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change (6.7%) and febrile neutropenia (2.6%). Conclusions: Taxanes appear the most effective first-line therapy in older men with mCRPC and show an acceptable and manageable toxicity. Further analyses will compare health status measured by SIOG algorithm to physician independent evaluation and identify the most pertinent geriatric predictors of health status.
Post docetaxel treatment for castration-resistant prostate cancer (CRPC): Does sequencing matter?
Authors: Malik Zafar I , Montazeri Amir H , Wong Helen , Eswarvee Chinnamani
Published: March 2020

e15135

Background: Two phase 3 studies have demonstrated efficacy for cabazitaxel (CAB) and abiraterone (AB) post docetaxel (DT) for CRPC. Both studies show survival benefit in patients who have progressed during or shortly after DT. Currently there is no data to show which agent is superior. It may be possible that as these agents have different mechanisms of resistance and the benefits are additive. Currently no predicative markers are available to identify response to therapy or optimal sequencing. Both agents are available for prescription at our centre. In this study we investigated the number of patients who were able to receive both treatments sequentially and whether therapy sequencing matters. Methods: In this retrospective study, patients with CRPC treated with CAB or AB after DT between Jan2011- Jan 2012 were included. Baseline patient characteristics were recorded as well as treatments following progression. In particular patient numbers receiving both CAB & AB were recorded. Statistical analysis was performed using SPSS v18. Results: 42 consecutive patients post DT included, 24 CAB and 18 AB. Median follow up was 7.9 months for CAB and 2.5 months for AB. At analysis, 18 CAB patients and 9 AB patients had progressed. Of those who progressed following CAB, 13 received AB, 1 restarted Goserelin and 4 patients received best supportive care (BSC). 9 patients progressed on AB and none were able to receive CAB, 4 received BSC, 1 was treated with stilboestrol and 4 remained on AB despite progression. Conclusions: Our series provides insight into the sequencing of these agents in the real world. As these agents have different resistant mechanisms it is possible that the benefits may be additive .Our study suggests that if patients receive CAB as the first option, they are more likely to receive AB subsequently whilst the converse does not apply. At this time the series is not mature enough to determine if differences in sequencing will impact on survival benefit, however progression free survival and overall survival will be updated for the meeting. [Table: see text]
Survival in metastatic castration resistant prostate cancer (mCRPC) trial participants.
Authors: Pezaro Carmel Jo , Omlin Aurelius Gabriel , Mukherji Deborah , Bianchini Diletta , Sandhu Shahneen Kaur , Mulick Cassidy Amy , Maier Gal , Olmos David , Thompson Emilda , Attard Gerhardt , De Bono Johann Sebastian
Published: March 2020

e15136

Background: Median overall survival (mOS) in patients (pts) with metastatic prostate cancer progressing despite castrate levels of testosterone (mCRPC) was 13-16 months (m) in the pre-docetaxel era. These data, obtained from clinical trials, were used to construct currently available prognostic nomograms. We hypothesise that these models no longer reflect survival. Pts and physicians urgently require updated prognostic data on which to base management decisions. Methods: Pts with mCRPC treated on phase I-III trials at our institution were identified and data retrospectively collected. Predicted survival by Halabi and Smaletz nomograms were compared to calculated survival using Kaplan-Meier analysis. Cox model multivariate (MV) analysis used variables at referral, including performance status (PS), Gleason (GS), prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hemoglobin (Hb), visceral disease and albumin. Results: 423 pts with CRPC treated between 2003 and 2011 were included. At diagnosis median age was 62 years (y; 41.8 – 82.7); 226 (53.4%) had metastatic disease. Median interval from diagnosis to CRPC was 2.7y (0.2 – 21.7). At referral 248 pts (58.6%) were chemotherapy-naïve. Halabi and Smaletz models predicted mOS in chemo-naïve pts of 21m and 18m respectively, however the observed mOS was 32m (95%CI 28 – 38). Survival from CRPC was 43m (CI 37 – 46) and 39m (CI 34 - 44) in pre- and post-chemo pts, respectively. Conclusions: Despite aggressive disease characteristics, our pts lived significantly longer than predicted by current nomograms. MV analysis confirmed the importance of several previously identified prognostic factors. Survival data from this large cohort of CRPC pts should encourage men considering clinical trial participation. Previously developed nomograms no longer accurately predict survival.
Effect of inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumor activity and bone turnover in prostate cancer (PCa) models in vivo relative to inhibition of either kinase alone.
Authors: Dayyani Farshid , Araujo John C. , Carboni Joan M. , Gottardis Marco M. , Trudel Geralyn Carol , Logothetis Christopher , Gallick Gary E.
Published: March 2020

e15151

Background: Growth of prostate cancer (PCa) metastases relies on bidirectional interactions between the tumor and microenvironment.The Src family kinases (SFK) and insulin-like growth factor-1 receptor (IGF-1R) signaling axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are small molecule inhibitors that target SFK and IGF-1R/IR, respectively. This study examined the in vitro and in vivo effects of BMS-754807 and dasatinib on PCa growth. Methods: Antitumor effects of both reagents were tested alone and in combination in vitro in PC3 and LNCaP cells, using proliferation and apoptosis assays. Signaling pathways were interrogated by western blots. Tumor growth in vivo was assessed by orthotopic and intratibial injection of PC3 cells and subcutaneous growth of primary human xenograft PCa-133b. Serum markers were measured by ELISA. Results: In vitro, dasatinib decreased proliferation and migration of PCa cells whereas BMS-754807 induced apoptosis. All observed anti-tumor effects were enhanced when dual blockade was used. IGF-1 induced phosphorylation of Akt1, but not Akt2, was partially inhibited by either drug alone and almost completely abrogated by the combination. Dasatinib and BMS-754807 inhibited in vivo orthotopic and intratibial tumor growth of PC3 cells more potently than either as a single agent alone with a corresponding decrease in bone turnover markers. Both drugs also exhibited synergism in primary human xenograft tumors. Potent target inhibition (p-Src, p-IGF-1R, p-Akt) by the drug combination was also demonstrated in xenografts. Conclusions: The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.
Modafinil for fatigue associated with docetaxel-based chemotherapy: A randomized controlled trial.
Authors: Hovey Elizabeth J. , De Souza Paul L. , Marx Gavin M. , Rapke Tal , Parente Phillip , Hill Andrew , Bonaventura Antonino , Michele Antonio , Craft Paul Stanley , Abdi Ehtesham A. , Lloyd Andrew R.
Published: March 2020

e15152

Background: Docetaxel is the standard of care for castrate-resistant prostate cancer, but is associated with a high level of fatigue, limiting dosage and leading to premature withdrawal from therapy. Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel group study in patients with metastatic prostate or breast cancer suffering significant chemotherapy-related fatigue whilst undergoing docetaxel-based chemotherapy. Patients were enrolled at the start of their 3rdor subsequent cycles of docetaxel which was continued for up to four further cycles (defined here as ‘treatment periods’). Patients were randomized 2:1 to receive modafinil 200mg daily or placebo for 15 days during each treatment period. Fatigue was evaluated by the MD Anderson Symptom Inventory (MDASI). The primary endpoint was MDASI area under the curve (AUC) during the first 7 days of study medication for the first two treatment periods (possible range 0-70). Other validated tools were used to record disturbances in sleep, mood and functional status. Results: Eighty-three patients (65 with prostate cancer) were randomized and received at least one dose of study medication. The number of grade 3 or 4 adverse events (AEs) was 16/55 (29.1%) in the modafinil group and 5/28 (17.9%) in the placebo group. The toxicity profile was largely consistent with docetaxel-based chemotherapy and with previously reported AEs associated with modafinil use in the community; 11 AEs were possibly related to docetaxel; 1 to modafinil and 9 to neither treatment. Conclusions: Assessing and managing chemotherapy-related fatigue remains a major challenge. Despite not reaching the primary endpoint, there was a consistent trend towards improvement of chemotherapy-related fatigue in the modafinil arm. Further studies are needed to better address the significant symptom of docetaxel-related fatigue. Funding sanofi-aventis; Study ID NCT00917748. [Table: see text]
Potential predictors of fear of progression among long-term prostate cancer survivors: Do illness perceptions and family history matter?
Authors: Herkommer Kathleen , Hahn Astrid , Dinkel Andreas , Marten-Mittag Birgitt , Herschbach Peter , Gschwend Jürgen E.
Published: March 2020

e15157

Background: Fear of illness progression (FoP) or recurrence is known to be one of the most prominent fears in patients with prostate cancer (PCa) even years after treatment. To improve detection of men at risk, possible predictors need to be discovered. So far, little is known about the influence of patients' illness perceptions (IP) and family history on dysfunctional FoP (dysFoP). Methods: A nationwide mail survey was sent out to a total of 6.305 men who had been treated with radical prostatectomy. Median time since diagnosis was 7.4 years. Patients were divided into 2 subgroups according to their family history: 68.9% (n=4.341) sporadic and 31.1% (n=1.964) familial (at least 1 first-degree relative with PCa). FoP was assessed with the short form of the Fear of Progression Questionnaire (FoP-Q-SF), IP were assessed with the Brief Illness Perception Questionnaire (B-IPQ). We also evaluated sociodemographic and clinical parameters and their influence on FoP. Results: Dysfunctional FoP was identified in 3.4% of all patients. Patients worried most about family, being dependent on others, and whether the children would also be diagnosed with PCa. Younger age, worse subjective economic situation, shorter time since diagnosis and disease progression were significantly associated with dysFoP (p<.01). IP and prevalence of dysFoP did not differ significantly between patients with sporadic and familial PCa, but familial PCa was associated with a higher mean level of FoP. IP explained a high amount of variance in FoP (R²=.435). Stronger perceptions of worry and negative emotions were significant predictors of FoP (p<.001). Furthermore, having at least one son (p=.004), time since diagnosis <5 years (p=.006) and worse subjective economic situation (p=.030) were predictive of dysFoP. Conclusions: In this study only a minority of patients reported dysFoP. The study findings suggest the importance of addressing IP, especially worries, negative emotions, and perceived consequences as key factors of FoP. Prevalence of dysFoP did not differ depending on family history, however patients with familial PCa showed higher mean levels of FoP.
Early results of prostate cancer radiation therapy at Korle Bu Teaching Hospital: An analysis with emphasis on research strategies to improve treatment delivery and outcomes among patients in Ghana.
Authors: Yamoah Kosj , Beecham Kwamena , Hegarty Sarah , Hyslop Terry , Showalter Timothy Norman , Yarney Joel
Published: March 2020

e15163

Background: Although there is interest in racial disparities in prostate cancer outcomes among persons of African descent living in the United States there is scant data available regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT). Methods: A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy and Nuclear Medicine, Ghana, from January 2003 to December 2009. Data were collected regarding patient- and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score, clinical stage, and use of hormonal therapy. For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using Kaplan-Meier analysis. Results: The median age at diagnosis was 65 years. Of 379 patients referred for treatment 69.6% of all patients had initial PSA >20ng/ml, and the median iPSA was 39.0 ng/ml. A total of 128 men representing 33.8% of overall cohort were diagnosed with metastatic disease at time of referral. We identified 166 men treated with EBRT or brachytherapy +/- androgen depravation therapy (ADT), and an additional 139 men treated with ADT alone (including orchiectomy in 38 patients). The median EBRT dose was 70 Gy, in 2 Gy per fraction. Among all EBRT patients with at least 2 years of follow-up after treatment (n=52; median follow-up time: 38.9 months), 5-year actuarial FFbF was 65.1%: 67.0% for patients with PSA < 30.0 ng/mL and 63.2% for PSA ≥ 30.0 ng/mL [log-rank, p=0.586]. Conclusions: This is the largest series reporting on outcomes for prostate cancer treatment in West Africa. That one-third of patients presented with metastatic disease suggests potential need for earlier detection of prostate cancer to permit curative-intent local therapy. Data from this study will aid in the strategic development of a prostate cancer research roadmap in Ghana, with a focus on improving therapeutic approach as well as fostering a prudent allocation of scarce resources.
Actual total hospital costs of primary localized prostate cancer treatments analyzed by risk group.
Authors: Lavery Hugh J. , Levinson Adam W. , Phalen Adrien , Stone Nelson , Stock Richard , Sebrow Dov , Hobbs Adele , Samadi David B.
Published: March 2020

e15164

Background: Radical prostatectomy (RP) and radiotherapy (RT) provide comparable HRQOL and oncologic outcomes of localized prostate cancer (PCa), yet no studies have evaluated their relative costs when investigated by risk group. We evaluated hospital costs associated with modern PCa therapies at a multidisciplinary program. Methods: Institutional billing data was queried for hospital patients from 2005 to 2009 with a primary admission for prostate cancer and primary procedure codes for RP, brachytherapy (BT), intensity modulated RT (IMRT) or combination treatment. All hospital costs related to the primary procedure were analyzed as assigned by the hospital. Costs were adjusted to 2009 USD and analyzed per patient and pretreatment D’Amico risk group. Results: 1969 localized PCa patients with a median age of 62 were identified with complete clinical information. There was a marked increase in the use of robotic-assisted laparoscopic prostatectomy (RALP) starting in 2007. The median total hospital costs for IMRT monotherapy ($16,673), BT+IMRT ($22,145) and RP+ adjuvant IMRT ($24,380) combination therapies were significantly higher than any other treatment type, although these patients had worse pathologic features. BT was the least expensive treatment with a total cost of $7,506, but was not routinely used as monotherapy for high-risk patients. The total cost of RALP ($7,676) was lower than open radical prostatectomy (RRP) ($8,991, p<0.001) and similar to laparoscopic radical prostatectomy (LRP) ($7,769).These trendsremained consistent when stratified by risk group (Table). Conclusions: In a high volume setting, RALP and BT are the least expensive modalities for treating low and intermediate risk PCa. For high risk patients, all forms of RP and IMRT alone were less expensive than combination therapy. [Table: see text]
Safety and feasibility of salvage robot-assisted radical prostatectomy for recurrent prostate cancer.
Authors: Abreu Andre Luis de Castro , Chauhan Sanket , Fairey Adrian Stuart , Camacho Ignacio , Goh Alvin , Park Daniel , Desai Mihir , Patel Vipul , Gill Inderbir S , Aron Monish
Published: March 2020

e15171

Background: The safety and feasibility of salvage robot-assisted radical prostatectomy (sRARP) for recurrent prostate cancer is unclear. Herein we report short-term cancer control, functional, and perioperative outcomes in a multi-institutional cohort. Methods: Between July 2007 and October 2011, 38 consecutive men underwent sRARP for recurrent prostate cancer at the University of Southern California (n=14) or Global Robotics Institute (n=24). Failed primary therapy was varied (external beam radiotherapy [EBRT; n=14]; interstitial brachytherapy [IBT; n=11]; EBRT + IBT [n=5]; high-intensity focused ultrasound [n=3]; cryoablation [n=3]; other [n=2]). The main outcomes were immediate biochemical failure (IBF), positive surgical margins (PSM), urinary continence and erectile function at 3 months, and complications within 90 days of surgery. Immediate biochemical failure was defined as a PSA > 0.2 ng/ml. Urinary continence was defined as the use of no pads and erectile function was defined as a SHIM score > 21. Complications were classified and graded using the Clavien system. Results: The median age was 68 years (50-83 years) and median preoperative PSA was 4.1 ng/ml (0.4-15.2 ng/ml). Preoperative biopsy Gleason score was ≤6 (n=7), 7 (n=18), and ≥8 (n=12). All procedures were completed without the need for open conversion. No patient experienced an intra-operative complication. Median estimated blood loss was 100 ml (30-300 ml) and operative time was 1.5 h (1-6h). Median length of hospital stay was 1 day (1-7 days). The median duration of urethral catheterization was 12 days (4-48 days). IBF occurred in 9 (29%) patients and PSM occurred in 7 (18%) patients. Urinary continence and erectile function occurred in 9 (34%) and 0 patients, respectively. One or more postoperative complications occurred in 12 (31%) patients. Low grade (I-II) and high grade (III-IV) complications occurred in 8 (21%) and 4 (10%) patients, respectively. No patient died. Conclusions: Salvage robot-assisted radical prostatectomy is safe and feasible. Short-term cancer control and perioperative morbidity were acceptable; however, functional recovery was poor. To date, this is the largest series worldwide.
Provider mix and costs associated with treatment of patients with bone metastases secondary to prostate cancer.
Authors: Shermock Kenneth M. , Sullivan Sean D , Ramsey Scott David , Seal Brian S.
Published: March 2020

e15175

Background: Treatment of patients with bone metastases secondary to prostate cancer can involve several provider types and combinations of chemotherapy, surgery, radiation, and pharmaceutical treatment. This study evaluated the combinations of provider types and associated treatment patterns for a cohort of patients with bone metastases secondary to prostate cancer. Methods: Continuously enrolled patients older than 20 years of age in the MarketScan database between January 2004 and December 2010 with evidence of bone metastases (ICD9 code 198.5 or treatment with zolderonic acid, pamidronate, or demosumab) were included. Inpatient and outpatient medical claims data were used to define provider combinations. Treatment patterns were determined from prescription fill/refill claims and procedure codes from inpatient and outpatient medical claims. Results: A total of 4,493 patients had evidence of bone metastases. A radiologist was involved in care for a vast majority (n=4,054, 90%). Less than half of the population, (n=1,751, 39%) had an oncologist actively involved in care. Most patients (n=2633, 59%) had both an urologist and a radiologist involved in their care. The most common combinations of providers were urologist and radiologist (n=998, 22%); urologist, radiologist, and surgeon (n=951, 21%), and urologist, radiologist, and oncologist (n=781, 17%). About 15% (n=684) of patients had a surgeon, urologist, oncologist, and radiologist involved in their care. Only approximately half (n=2,274, 51%) of the population had evidence of receiving radiation therapy, suggesting that the radiologist plays a diagnostic role for many patients. A vast majority of patient were prescribed hormone therapy (89%) and 76% were prescribed steroid agents (mostly glucocorticoids). Less than half of the population (n=1,838, 41%) received surgery related to their prostate cancer. Conclusions: There is significant variation in combinations of provider types and associated treatment patterns for patients who have bone metastases secondary to prostate cancer. Follow-up studies should examine optimal conditions for different provider mixes and treatment patterns.
Biochemical survival and morbidity of high-intensity focused ultrasound (HIFU) as a primary monotherapy for low-risk localized prostate cancer: Outcomes from the @-registry following the ENLIGHT trial inclusion criteria.
Authors: Robertson Cary N. , Ward John Francis , Crouzet Sebastien , Brown Stephen CW , Berge Victor , Chaussy Christian G , Ganzer Roman , Paulsau Antonello , Gelet Albert , Thueroff Stefan , Blana Andreas
Published: March 2020

e15194

Background: Prostate Cancer (PCa) HIFU (Ablatherm, EDAP-TMS, Lyon, France) is currently under investigation in the US. This study reports biochemical, biopsy and morbidity outcomes for a population of low risk localized PCa patients meeting ENLIGHT FDA trial inclusion criteria. These data were accrued from European HIFU centers using an online HIFU database (@-Registry) . Methods: The patient’s selection criteria for this study were: low risk prostate cancer patients (T1c to T2a, PSA<10ng/ml, Gleason≤6), with a prostate A-P diameter and volume of <25mm and <40cc, and no pre-treatment hormone therapy. Kaplan-Meier analysis was performed to determine biochemical survival with failure defined as the Phoenix definition (PSA nadir+2). Morbidity data, need for salvage treatment and biopsy data were analyzed. Results: From 12 European centers, 358 men met the inclusion criteria. The baseline mean age, PSA and median Gleason sum were 69.7±6.4 years, 5.8±2.4 ng/ml and 6, respectively. Stage was 65.9% T1c and 34.1% T2a. Patients were followed for 6.6±3.1 years (range: 0.6 to 18 years). Median PSA nadir was 0.09 which was reached 13.9±10.7 weeks after HIFU. The salvage treatment rate was 8.7%, and the negative biopsy rate was 90.2% Actuarial BDFS at 5 and 10 years was 87% and 73% respectively. The morbidity data identified GradeI, II and III stress incontinence in 12.3%, 4.5% and 1.7% of the population, respectively. The Bladder Outlet Obstruction rate was 20.7% (urinary retention, urethral stenosis ). Urethro-rectal fistula was not observed. Conclusions: HIFU achieved good biochemical control at 10 years of follow-up for low riskPCa patients and negative biopsy rates were high. HIFU demonstrated an acceptable morbidity, especially with the lack of any serious events(specifically fistula). Bladder Outlet Obstruction was the most bothersome adverse event. HIFU appears as a valuable and safe therapy for long term low risk PCa treatment.
Degarelix as neoadjuvant hormone therapy in patients with prostate cancer: Results from a phase IIIb randomized, comparative trial versus goserelin plus bicalutamide.
Authors: Mason Malcom , Steidle Christopher P , Deliveliotis Charalambos , Guerif Stephane , Maldonado Xavier , Khoo Vincent , Wiegel Thomas , van der Meulen Egbert , Bergqvist Peter
Published: March 2020

e15199^

Background: The current approach in patients with high-risk localised or locally advanced PCa is ADT prior to radiotherapy, which improves disease-specific and overall survival vs radiotherapy alone. Whether degarelix, a GnRH antagonist performs comparably with the use of GnRH agonist under flare protection in neoadjuvant settings has not yet been investigated. Methods: Patients with intermediate to high risk PCa were randomised (3:1) to receive either degarelix or goserelin plus bicalutamide (G+B) for 12 wks. The primary endpoint was the percentage reduction from baseline in prostate volume at wk 12 as measured by TRUS. The non-inferiority margin was -10%. Other endpoints included changes in the IPSS, testosterone and PSA. Results: 177 in the degarelix and 62 patients in the G+B arm have completed the trial. 62% and 38% of the patients had localised and locally advanced PCa, respectively. The primary endpoint was successfully met establishing noninferiority between the two treatments in terms of prostate volume reduction at wk 12 (Table). Conclusions: Degarelix was equally effective as prostate shrinking neoadjuvant hormone therapy in patients with intermediate to high risk PCa, but elicited more pronounced LUTS relief compared with G+B after 12 wks of treatment. Possible explanations may involve more pronounced effects on the tumour per se or differences in the action of these drugs on peripheral GnRH receptors expressed in the prostate and the urinary bladder. [Table: see text]
Risk of more advanced cancer at surgery in African American men eligible for active surveillance.
Authors: Salmasi Amirali H , Han Misop , Kim Isaac Yi
Published: March 2020

e15214

Background: African-American (AA) men have a higher risk for developing prostate cancer (PCa) and dying of PCa compared to Caucasian men. Active surveillance (AS) is an acceptable management for males with low volume and low grade PCa. In Caucasian men who were eligible for AS, the risk of non-organ-confined disease [NOC] at radical prostatectomy (RP) ranges between 7.8 and 10.9% (Kang et al 2011, Mufarrij et al 2010). It is unclear whether AA men with favorable risk PCa can undergo AS safely. We evaluated changes in staging and grading of PCa in a cohort of AA males that met the criteria for AS but underwent RP. Methods: Between 1997 and 2011, 1536 AA men underwent RP at either Johns Hopkins Medical Institutions or Cancer Institute of New Jersey. Pathological characteristics of patients who fulfilled the inclusion criteria under the National Cancer Institute (NCI) AS criteria were examined. NOC (ECE/SV+/LN+) and upgrading (Gleason <7 in biopsy to Gleason >6 in RP) was evaluated. We tried to identify preoperative predictors of more advanced cancer (NOC and/or upgrading). Results: We identified 212 men who underwent RP, eligible for AS based on NCI criteria. Among 212 men, 92 (37.7%) men showed NOC and/or upgrading, defined SV involvement in 5 (2.4%), ECE in 53 (25%), and increased Gleason (<7 to >6) in 69 (32%) men. Pre-operative PSA level (OR 1.2, p < 0.05) and age (OR 1.06, p < 0.01) were significantly associated with more advanced cancer. No significant association was found between BMI, tissue percentage, or positive cores with more advanced cancer. Conclusions: AS in AA with prostate cancer carries higher risk of NOC compared to non-AA population. More stringent AS entrance criteria may be necessary for AA men.