bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond metastatic renal cell carcinoma (mRCC) clinical trials: Targeted therapy use and overall survival in community oncology clinics.
Authors: Harrison Michael Roger , George Daniel J. , Walker Mark S. , Hudson Lori L. , Chen Connie , Korytowsky Beata , Stepanski Edward J. , Abernethy Amy Pickar
Published: March 2020

e15061

Background: Targeted therapies are now the standard of care for mRCC with use and expected outcomes defined by clinical trials. What are "real world" patterns of use and survival outcomes in mRCC patients (pts) treated in community oncology (COMM) settings? Methods: We reviewed a retrospective registry of adult mRCC pts from 11 COMM oncology practices, diagnosed since 1/2007 and not enrolled in a trial. Demographics, disease characteristics, treatment patterns and outcomes were recorded from the EMR and supplemented with chart abstraction.Pts were grouped by treatment sequence reflecting up to 3 exposures based on drug mechanism of action (VEGFR TKI [TKI] or mTOR inhibitor [mTOR]). Other pts received a non-TKI, non-mTOR therapy in the 1st three exposures (e.g., bevacizumab, cytokines, combinations, etc.). No Therapy pts received no systemic therapy as of data analysis. Survival analyses included Kaplan-Meier methods and Cox regression. Results: 255 patient/disease characteristics included: age 65±11 yrs; 68% male; 71% Caucasian; 62% clear cell histology (25% unknown); 1.6 ±0.9 metastatic sites. MSKCC risk was: 28% good, 63% intermediate, 10% poor. Median overall survival (OS) was 12.1 mo (95% CI: 8.7-15.4); median OS by sequence was: No Therapy (n=38; 3.7), mTOR (n=28; 5.2), TKI (n=79; 8.7), mTOR/TKI (n=10; 9.3), TKI/mTOR (n=32; 13.7), TKI/TKI (n=24; 20.7), Other (n=20; 22.5), TKI/mTOR/TKI (N=14; 29.8), TKI/TKI/mTOR (N=10; 33.1). Cox regression identified subgroups with differential outcomes. After significant covariates were controlled, compared with No Therapy, all regimens with TKI as 1st exposure had hazard ratios (HR) <1.0 (range=0.14 – 0.51; all p values ≤ 0.02). Other treatment had HR=0.31 (P=0.001), but when mTOR was the only treatment HR=1.04 (p=0.88). MSKCC scores of intermediate (HR=2.4) or poor (HR=4.5) were a significant risk (p<0.001). Conclusions: Only pts treated with two TKI exposures (≥20.7 mo) approached the best OS seen in trials (26 mo). For mTOR only, 1st line treatment in sicker patients, OS (5.2 mo) was shorter than trials (11 mo). Outcome differences between trial and community practice settings offer insights into opportunities to optimize care.
Retrospective data study evaluating resource utilization among metastatic renal cell carcinoma patients receiving oral versus intravenous mTOR inhibitors.
Authors: Bhor Menaka , Hutson Thomas E. , Dhanda Rahul , Liu Zhimei , Vogelzang Nicholas J.
Published: March 2020

e15063

Background: The purpose of this retrospective study was to compare healthcare resource utilization among metastatic renal cell carcinoma (mRCC) patients (pts) receiving everolimus (oral mTOR inhibitor), relative to pts receiving temsirolimus (intravenous mTOR inhibitor). Methods: Using US Oncology’s iKnowMed EMR in conjunction with claims and pharmacy data, we identified mRCC pts who initiated a treatment regimen of everolimus or temsirolimus from 2009 –2010 with a minimal six month follow-up period. Healthcare encounters were estimated and presented using the per patient per month metric. Poisson regression models were used to examine the impact of treatment on resource use after controlling for covariates including stage, ECOG status, and insurance type, and were stratified by line of therapy (LOT) as LOT was the most significant different baseline characteristic between the two treatment groups. Results: A total of 461 pts were identified: 143 were treated with everolimus, and 318 with temsirolimus. The everolimus group had lower usage of all types of services than the temsirolimus group and the results were statistically significant for most of the categories as per the bivariate analysis. In the multivariate analysis stratified by LOT and adjusted for baseline characteristics, the temsirolimus group had statistically significant more acute care services (1st line), drug usages (1st and 2nd line), lab visits (2nd and 3rd line), radiation treatment and minor services (2nd line), non-drug and other services (1st, 2nd, and 3rd line), than the everolimus group. Conclusions: Results of this retrospective study suggest that overall everolimus is associated with lower patient burden in terms of health care resource utilization relative to temsirolimus.
Hypertension and cardiotoxicity in metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).
Authors: Prati Veronica , Ortega Cinzia , Ballatore Valentina , Galizia Danilo , Ruatta Fiorella , Bonzano Alessandro , Aliberti Sandra , Grignani Giovanni , Aglietta Massimo
Published: March 2020

e15073

Background: Recent data have shown that cardiotoxicity (CHFcongestive heart failure, CADcoronary artery disease)could be an important side-effect in patients (pts) with RCC treated with tyrosine kinase inhibitors (TKIs). LVEF(Left ventricular ejection fraction)reduction may occur in up to 10% of pts treated with SU and uncontrolled hypertension could worse this side-effect. This complication is reversible with TKI interruption and appropriate antihypertensive therapy. Methods: We have prospectively analyzed patients receiving SU as a first-line treatment for mRCC. Between April 2007 and December 2011,31 consecutive pts, median age 67 yrs (41-80) were treated with SU at the standard dose of 50 mg/day,4 weeks on and 2 weeks off. We recorded for all pts CAD risk factors, preexisting hypertension,rhythm disturbances and heart failure. ECG, echocardiography and cardiology consultation were performed at baseline, and every three months until progression or permanent SU discontinuation. We searched correlations between cardiotoxicity onset and hypertension. Results were assessed with paired Student’s t-test and Chi-square test. Results: At baseline,we found 22 pts (71%) with hypertensive disease (HD). The median duration treatment was 8,3 months(22-0,4).On TKI therapy 6/22 pts (27.2%) worsened the preexisting HD, which was controlled with adequate treatment according to American Heart Association guidelines, without determining treatment discontinuation. Furthermore 6/31 pts (19%) developed this adverse event. In 14/31 pts (45%) we showed a median ≥ 10% LVEF reduction compared to baseline value (p=.001); 13/31 pts were asymptomatic and only one presented symptoms of CHF and discontinued the treatment. In this study, history of HD,worsening of preexisting HD or development of HD are not predictive for >10% LVEF reduction (p=ns). Conclusions: In pts with mRCC receiving SU as a first-line treatment, HD is not predictive for LVEF reduction. Moreover on TKI therapy there is a statistically significant LVEF reduction, but this adverse event does not determine a treatment discontinuation. A cardiovascular monitoring during SU treatment may reduce this event in order to allow an adequate treatment.
Comparative efficacy of sunitinib versus sorafenib as the first-line treatment for patients with metastatic renal cell carcinoma.
Authors: Park Seongjoon , Lee Jae-Lyun , Park Inkeun , Park Kwonoh , Ahn Yongchel , Ahn Jin-Hee , Lee Dae Ho , Song Cheryn , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: March 2020

e15080

Background: Currently, sunitinib has been recommended as the primary treatment in the patients with metastatic renal cell carcinoma (mRCC) among the vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). However, there are no published clinical data that compared directly the efficacy of targeted agents in the first line setting, and first-line treatment in mRCC patients is yet to be determined. Methods: To compare the efficacy and toxicities between sorafenib and sunitinb, clinical database was used to identify all patients with mRCC treated with VEGF TKIs in Asan Medical Center from April 2005 to March 2011. Among 304 patients, we identified 49 and 220 patients who were treated first with sorafenib and sunitinib, respectively. Results: The patients in the sorafenib group were older than those in the sunitinib group (62 vs 56.5 years, p=0.019). Disease control rate (DCR) of 82% was achieved in both groups. After a median follow-up duration of 49 months, progression free survival (PFS) and overall survival (OS) were not significantly different (sorafenib vs sunitinib, PFS; 8.6 months vs 9.9 months, p=0.948, OS; 25.7 months and 22.6 months, p=0.774). The patients treated with sorafenib have required dose reduction due to toxicities less frequently than those treated with sunitinib (37% vs 54%, p=0.034). Hematologic toxicities of grade 3 or 4 were more common in sunitinib group (4.2% vs 44.6%, p<0.001), and also was grade 3 or 4 hypertension, although it was not statistically significant (4.2% vs 13.7%, p=0.06). Age (> 60 years), duration from diagnosis to treatment (less than 1 year), Anemia, Neutrophilia, thorombocytosis, bone and liver metastases were independent prognostic factors affecting OS. Multivariate analysis also showed first-line VEGF TKI did not affect OS [hazard ratio (HR, sorafenib vs sunitinib) = 0.94, p=0.774]. Conclusions: Sorafenib showed comparable efficacy to sunitinb and demonstrated superiority in toxicities in the treatment of mRCC patients.
Sunitinib dosing, toxicity, and outcomes in first-line advanced renal cell carcinoma (aRCC): A U.S. Oncology Network (USON) retrospective study.
Authors: Schnadig Ian D. , Hutson Thomas E. , Chung Hsingwen , Dhanda Rahul , Halm Melissa , Forsyth Michael T. , Vogelzang Nicholas J.
Published: March 2020

e15089

Background: Sunitinib is a first-line therapy for patients (pts) with aRCC. As a multitargeted tyrosine kinase inhibitor (TKI), it is associated with toxicities that may impact dosing; dose reductions may result in inferior clinical outcomes (Motzer, 2011 ASCO GU, abstract LBA308). This retrospective study was initiated by USON to evaluate dosing patterns of first-line sunitinib, and its association with toxicities and outcomes in community practices. Methods: Pts with aRCC who started first-line sunitinib between June 1, 2007 and May 31, 2011 at 17 USON practices were identified; clinical data were extracted by chart review from iKnowMed electronic medical records that were linked to USON retail pharmacy database. Pts who were enrolled in clinical trials or receiving care for other primary tumors were excluded. Results: Pt characteristics: N=134; median age = 64 years (range 41–87); ECOG PS 0/1 = 85%; clear cell RCC = 81%; and nephrectomy = 61%. Objective response rate was 16%. Overall survival (OS) was 15.4 months (95% confidence interval 11.9–20.8). Median treatment duration was 4 cycles (range 1–19): 27 pts (20.1%) received only 1 cycle of sunitinib (23 at full dose [50 mg] and 4 at 1 cycle of sunitinib (53 received full dose; 35 started at full dose but were dose-reduced; 14 always received <full dose; 5 started at <full dose but were dose-increased to 50 mg). Overall, 45 pts were dose-reduced, principally (93%) due to toxicities; 67% of all dose reductions occurred in the first 3 cycles. 121 pts discontinued sunitinib after completing at least 1 cycle, mostly due to disease progression (PD; 44%) or toxicities (17%); 74% of all discontinuations occurred within the first 5 cycles. Conclusions: RCC pts in community practices commonly undergo sunitinib dose reductions in the first 3 cycles due to toxicities, and discontinue therapy within the first 5 cycles due to PD. The median number of cycles and OS were lower than those reported in clinical trials (Motzer JCO 2009;27:3584–3590). More selective TKIs are needed to reduce toxicities, optimize dosing, and potentially improve outcomes. Funded by a grant from AVEO Pharmaceuticals, Inc.
Safety and efficacy of pazopanib in heavily pretreated and treatment-naive patients with metastatic renal cell carcinoma (mRCC): A single center experience of the Medical University of Vienna, Austria.
Authors: Schmidinger Manuela , Bojic Marija , Vogl Ursula Maria , Klingler Christoph , Kramer Gero , Zielinski Christoph
Published: March 2020

e15090

Background: Treatment with pazopanib was shown to improve objective response rates (ORR) and progression free survival (PFS) when compared to placebo in treatment-naïve or cytokine-pretreated patients with mRCC. We assessed the efficacy and safety of pazopanib in an unselected group of mRCC-patients at the Medical University of Vienna. Methods: Medical records of all patients who were treated with pazopanib between June 2010 and January 2012 were retrospectively reviewed. Pazopanib was prescribed at a dose of 800 mg daily. Treatment was given until disease progression or unacceptable toxicity. ORR was assessed by RECIST criteria. PFS and overall survival (OS) were calculated from the first day of pazopanib until progression and/or death, respectively. Results: Forty patients with a median age of 69 years (range 47-82) are currently evaluable for this analysis. The majority of patients (61%) presented with an ECOG Performance status of 0 and were classified as intermediate risk (55%) according to the MSKCC risk group classification. All patients had undergone nephrectomy and the majority (75%) had predominantly clear cell tumors. Most of the patients (66%) were diagnosed with three or more metastatic sites. Eighty percent of the patients were heavily pretreated, most commonly with three or more different types of targeted agents. Eight patients (20%) received pazopanib in first-line. Objective remission and disease stabilization were observed in 27% and 30% of the entire population. PFS and OS were 5 months (95%CI 3.07-6.86) and not reached, respectively. The most commonly observed all grade toxicities included fatigue (97%), anorexia (78%), hypertension (82%), diarrhoea (73%), nausea (62%) and vomiting (54%). The most common grade 3 or 4 toxicities were fatigue (68%), hypertension (47%) and diarrhoea (29%). Conclusions: Pazopanib appears effective in the setting of extensively pretreated patients. A later stage of the disease might have led to the unexpected higher incidence of off-target side effects such as fatigue and gastro-intestinal symptoms.
VEGF-VEGFR pathway and its activitation in renal cell carcinoma: Role in sunitinib response.
Authors: Rubio Gustavo , Casado Victoria , Leon Ana , Domine Manuel , Zazo Sandra , Lobo Francisco , Izarzugaza Yann , Arranz Juan Luis , Martin-Valades Jose Ignacio , Serrano Gloria , Carames Cristina , Madoz Juan , Rincon Raul , Canadas Carmen , Perez-Gonzalez Nuria , Fernandez-Acenero Maria Jesus , Cordova Sharon , Campos Angel , Rojo Federico , Garcia-Foncillas Jesus
Published: March 2020

e15094

Background: Activation of VEGFR through its phosphorylation at specific tyrosine residues promotes changes in the microvasculature density. Inhibition of this mechanism targeting kinase activity has demonstrated an impact on clinical benefit in renal cell carcinoma. Methods: Fifty renal cell carcinomas have been assessed to evaluate the role of VEGF-VEGFR pathway and its impact on microvascular density (MVD). In order to identify parameters of potential clinical benefit to sunitinib a control group was included. IHC of VEGF, VEGFR (KDR), phosphorylated VEGFR-Y1175 and microvascular density assessment were performed. Results: All cases show VEGF expression; using a ROC curve a threshold was identified with a statistical significant worse PFS in those cases with higher VEGF expression in the whole series of patients treated with sunitinib (p=0.037) and in the subgroup with clear cell histology only (p=0.011). pKDR was positive in 40%: with an AUC=0.9 and according to this threshold statistical significance was found in PFS in the whole series (p=0.016) and in the clear cell subgroup (p=0.007). Microvascular density showed a statistical significance when was evaluated in terms of PFS in the group including all histologies (p=0.011) and those cases with clear cell subtype only (p=0.005). Conclusions: Our data suggest that VEGF, pKDR-Y1175 and MVD may identify the patients with significant clinical benefit to sunitinib in terms of statistically longer PFS.
Characterization of prostate cancer information available on smartphones.
Authors: Landau Danny , Hajdenberg Julio
Published: March 2020

e15102

Background: When seeking information regarding prostate cancer, patients are often turning to Smartphones. We decided to look at the “top applications” (apps) on the iTunes store to determine the quality of information provided. Methods: In November 2011 on an iPhone the search “Prostate Cancer” was entered. The first page of apps was downloaded and studied (18 in total). They were categorized into apps written at a provider level and apps written for a patient level. The patient apps were then broken into patient support, cancer detection, disease monitoring, advertisements, and patient knowledge. The quality of paid apps was also looked at. Results: Of the 18 apps, two were unrelated to prostate cancer. Of the remaining 16, six were provider apps. Of these six, two were apps for major oncology journals, three were staging guidelines, and one was for a general oncology reference guide. Of the patient directed apps, patient information (general prostate cancer information) apps were four, two were apps to provide support, one was devoted to disease detection which included discussions on prostate specific antigen testing, one for monitoring disease, and one was an advertisement for a radiation technique. One app, once downloaded, required additional payment and personal information prior to giving the promised information. This application was not pursued. Paid apps accounted for eight apps. Two were geared toward providers. Both were prostate cancer staging guidelines. The patient directed paid apps included two apps which provided medically appropriate, level one evidence based information. Two provided information that wasn’t based on accepted medical therapy, including diet advice to prevent cancer and “alternative therapies” including reflexology, roots, and hypnosis as therapies. All free apps that were devoted to prostate cancer were based on level one evidence. Two additional paid apps were unrelated to prostate cancer. Conclusions: The majority of applications available over the iTunes store provide solid evidence and may be a valuable resource to patients and providers. Only the patient directed paid apps provided information that can be deemed questionable.
Augmentation of the cytotoxicity of ibandronate by y-27632, a rho kinase inhibitor, in prostate cancer cells.
Authors: Ata Alper , Ozcimen Ata , Kurt Hakan , Tiftik Nalan , Arican Ali , Buyukafsar Kansu
Published: March 2020

e15104

Background: Bisphosphonates, which have been used for the treatment of breast and prostate cancers (Epplen et al., 2011) inhibit mevalonate pathway that results in the reduction of Ras prenylation, which eventually inhibits tumor growth (Luckman et al., 1998). Rho/Rho kinase signaling has a fundamental role in cancer cell proliferation, migration and metastasis (Vega et al., 2008) Therefore, in this study, we aimed to investigate effects of Y-27632, which inhibits Rho-kinase, ibandronate, which inhibits farnesyl transferase and their combination on cell proliferation in prostate cell lines, PC-3. Methods: The adherent prostate cell line, PC-3 (ATCC) was grown in RPMI-1640 supplemented with 10 % fetal bovine serum, 1 % L-glutamine, 1 % penicillin (10.000U/ml) and streptomycin (10.000 mg/ml) in a humidified atmosphere of 5 % CO2 at 37oC for confluency. The cells were seeded in the wells of E-plates (24,000 cells/well) that allowed a real-time-monitoring of the cell index reflected cell growth and proliferation (xCELLigence, Roche). The cell index was evaluated at the different points of time (post-treatment 12, 24, 36, 48, 60 and 72 h) in the groups of ibandronate, Y-27632, the combination and time-course control. Results: Ibandronate (10-100 mM), Y-27632 (50-100 mM) markedly decreased cell index. The combination of Y-27632 with ibandronate resulted in potentiation of cytotoxicity in PC-3 cells. Conclusions: Rho kinase inhibitors, biphosphonates and their combination may be beneficial for the treatment of prostate cell cancers.
Heterogeneity of treatment effects (HTE) in stage IV prostate cancer (S4PC).
Authors: Mitikiri Nirupama Devi , Reese Emily S , Hussain Arif , Onukwugha Ebere , Mullins C. Daniel ,   University of Maryland
Published: March 2020

e15108

Background: HTE occurs when patient factors modify a treatment’s effect on health outcomes so patients in the same study have different responses to a specific treatment. Variation in outcomes is caused by interactions between the factors causing HTE and the treatment. HTE may explain some of the heterogeneity in S4PC prognosis. The HTE literature is evolving; hence some factors causing HTE in S4PC are not yet documented. Methods: A systematic literature review (1946-2011) of published trials and observational studies identified evidence of statistically significant factors influencing HTE in S4PC. Inclusion criteria required that articles examine the impact of HTE factors on survival (OS, DSS, PFS) or health-related quality-of-life measures among S4PC patients. Factors that influenced outcomes but were not specifically evaluated in the context of HTE were excluded. Results: Of 398 articles that included key words, 33 met inclusion/exclusion criteria. Treatments included chemotherapy, radiation, hormonal therapy and bone-modifying agents. Both biologic and non-biologic factors (Table) were found to be associated with HTE in S4PC. Evidence was mixed regarding whether HTE in S4PC is influenced by race or by confounding factors correlated with race or both. As no articles examined prognostic factors such as bcl2, PTEN, p53, Pgp and EGFR status in the context of a specific treatment, such factors were excluded. Conclusions: Current evidence reveals diverse factors influencing HTE in S4PC.Ultimately, such knowledge can help oncologists prescribe more personalized medicine, help patients make more informed treatment choices, and aid policy making and treatment coverage decisions. [Table: see text]
The impact of image-guided radiotherapy (IGRT) for prostate cancer (PC) on radiotherapy (RT)-related acute toxicities and prostate-specific antigen (PSA) kinetics.
Authors: Poon Darren M. C. , Leung CM , Chu CM , Lee WY , Lee Louis , Kam Michael K. , Leung Sing Fai , Yu Kwok Hung , Chan Anthony T. C.
Published: March 2020

e15110

Background: IGRT for PC could potentially improve the therapeutic ratio by enhancing accuracy of delivery of radiation to the prostate gland. Our aim is to compare the treatment outcomes in terms of RT-related acute toxicities and PSA kinetics of PC patients (pts) undergoing radical intensity-modulated radiotherapy (IMRT) with or without image-guidance. Methods: A cohort of 21 consecutive pts treated by IGRT (I) from January 2010, when the IGRT system was introduced in our institution, was compared with an immediately precedent cohort of 21 pts receiving IMRT without image-guidance (Non-I). The prescription dose (76Gy in 38 fractions) and the treatment margins were the same between the 2 groups (gps). In the I gp, daily online verification and correction of treatment position was performed with reference to image registration of the daily pre-treatment on-board imaging with the corresponding digitally reconstructed radiographs, based on three-dimensional matching of three intra-prostatic fiducial markers. Androgen deprivation therapy was not used in both gps. Acute toxicities were scored weekly during the course of RT according to the Common Terminology Criteria for Adverse Events Version 4.02. The pre- and the post-RT PSA within 6 months after completion of RT were obtained. The PSA halving time (PSAHT) was calculated by first order kinetics. Results: There was no statistically significant difference regarding the baseline clinical characteristics (age, PSA at diagnosis, Gleason score, T staging) between the gps. No grade 3 or 4 acute genitourinary (GU) or gastrointestinal (GI) toxicities was encountered in either gps. Acute grade 1 or 2 GI toxicities were significantly less frequent in the I gp (23.8% vs 81.0%, p=0.001), and their median duration of such toxicity were also significantly shorter (0.33 week vs 1.38 week, p=0.004).The frequencies of acute grade 1 or 2 GU toxicities were comparable between both gps (66.6% vs 81.0%, p=0.45).The I gp had a shorter median PSAHT than the non-I gp (3.36 week vs 5.49 week, p=0.09). Conclusions: IGRT is effective in reducing acute GI toxicities in treatment of PC, and may have more favorable PSA kinetics.
A cohort compassionate-use program with cabazitaxel plus prednisone for patients with metastatic castration-resistant prostate cancer: Interim results.
Authors: Bavbek Sevil E. , Malik Zafar I , Di Lorenzo Giuseppe , Scholz Hans-Jorg , van Oort Inge M , Ng Siobhan , Ozguroglu Mustafa , Gerritsen Winald R. , Mueller Stefan , Marttila Timo , Antón Aparicio Luis M. , Albers Peter , Gschwend Jürgen E. , Bensfia Samira , Ecstein-Fraïssé Evelyne B , Bracarda Sergio , Heidenreich Axel
Published: March 2020

e15112

Background: In the TROPIC trial (NCT00417079), treatment with CbzP produced a statistically significant improvement in overall survival vs mitoxantrone + prednisone (MP) in patients (pts) with mCRPC previously treated with a docetaxel (D)-containing regimen (HR 0.70; p< 0.0001). These results supported the establishment of 2 programs (based on local regulations): a compassionate use (CUP) and an early access program (EAP; NCT01254279). Methods: The aims of the CUP/EAP are to provide drug to pts with mCRPC who may benefit from CbzP prior to commercial availability and further assess CbzP safety profile. Total enrollment for both programs is estimated at 1600 pts from 250 centers globally. Eligible pts receive CbzP (25 mg/m2 Q3W + prednisone 10 mg PO QD) until disease progression, death, unacceptable toxicity or physician/pt decision. Results: Baseline characteristics and safety data are available for the first 399 pts: median age was 68 yrs (range 43–89), with 90.2% ECOG PS 0–1. The median cumulative dose of prior D was 675 mg/m2; prior therapy with MP was permitted. For pts whose disease progressed following D, median time from last dose of D to progression was 4 months; 53.3% of pts experienced disease progression either during or < 3 months after D. 61% of pts had ≥ 2 metastatic sites; the most common were bone (93.2%) and regional lymph nodes (34.4%). At the time of analysis, a median of 4 cycles of CbzP had been administered; 4 pts received ≥ 10 cycles. Median relative dose intensity was 99.2% (range 80.1–104.9). G-CSF was administered to 34.3% of pts in Cycle 1 (6.3% therapeutic, 26.6% prophylactic). Overall, 71.4% of pts had adverse events (AEs; all grades). Most common grade 3-4 AEs were neutropenia 11.3%, febrile neutropenia 6.3%, anemia 2.8%, fatigue 2%, neutropenic sepsis 1.8%, vomiting 1.3% and diarrhea 1%. Eight (2%) treatment-related deaths were reported. Conclusions: The CUP/EAP provides additional safety data for CbzP in a routine clinical practice pt population with heavily pre-treated mCRPC. Treatment with CbzP was tolerable, with a predictable and manageable toxicity profile consistent with data reported for TROPIC and the product labeling.
Effect of immunization with the ii-key modified HER2/neu(776-790) (AE37) peptide vaccine on pre-existent immunity to PSA in HLA-A24+ prostate cancer patients: Association with increased AE37-specific immunologic responses.
Authors: Perez Sonia A. , Anastasopoulou Eleftheria , Pappou Efi , Pistamaltzian Nikolaos Fragkiskos , von Hofe Eric , Papamichail Michael , Baxevanis Constantin N.
Published: March 2020

e15125

Background: In solid tumors such as prostate cancer, novel biomarkers are needed for assessing immunological responses and clinical efficacy. By using dextramers specific for PSA we have retrospectively analyzed CD8+ T cell frequencies in patients with HER-2/neu+ prostate cancer who had received the AE37 vaccine in a phase I study (Perez SA et al Clin. Cancer Res. 2010, 16:3495). AE37 binds to numerous MHC alleles (Perez SA et al Clin. Cancer Res. 2010, 16:3495) (Salazar LG, Clin Cancer Res. 2003, 9:5559) encouraging its use as a therapeutic vaccine for general HER-2/neu+ cancer patients. Methods: CD8+ Dextramer+ T cells were measured, retrospectively, in the blood (which was stored in N2 liquid) of HLA-A24+ (n= 12) and HLA-A2+ (n=12) patients. Blood lymphocytes collected before, during and 6-months post vaccination were all analyzed with the same method involving direct labeling with HLA A24/PSA(153-161)-FITC and PerCP-conjugated anti-CD8 monoclonal antibody. Results: 8 of 12 HLA-A24+ patients had preexistent immunity to PSA as evidenced by the increased percentages of CD8+ HLA-A24/PSA(153-161)+ T cells in pre-vaccination samples. All of these patients had shown increased in vitro (IFNγ-based ELISPOT assay) and in vivo (DTH) immunological responses to the AE37 vaccine in the phase I study (Perez SA et al Clin. Cancer Res. 2010, 16:3495). Importantly, this preexistent immunity was significantly boosted in 5 patients during vaccinations with AE37, was slightly increased in 2 others, whereas in one patient no changes were observed during vaccinations. Conclusions: These results suggest that HLA-A24 expression along with preexistent immunity to PSA(153-164) may represent biomarkers based on which HER-2/neu+ patients can be selected most likely to benefit from vaccination with AE37. A phase II trial is warranted for validating these results. Given the promiscuity of AE37, it would be intriguing to examine if preexistent immunity to other prostate antigens restricted by various MHC alleles exist and to demonstrate an increase in preexistent immunity in association with a positive immunologic response to vaccination with AE37.
Prostate cancer inhibitory activity of a novel dual inhibitor, EL102, in combination with docetaxel, and its effects on MDR1-mediated drug resistance in vitro.
Authors: Glynn Sharon A. , Toner Aidan , Lewis Joe , Sullivan Frank , Breen Laura , Clynes Martin , Giles Francis J.
Published: March 2020

e15126

Background: EL102 is a dual-action drug promoting apoptosis and inhibiting angiogenesis. It exerts its action though the inhibition of Hif1a induced hypoxic signalling and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity in normoxia and hypoxia indicating it may be equally active in these different tumor compartments. We tested its ability to circumvent chemotherapeutic drug resistance. Methods: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and motility in vitro, calculating IC50s for CWR22, 22Rv2, PC3 and DU145 prostate cancer cell lines, comparing sensitivity between androgen dependent, androgen independent and metastatic prostate cancer. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine CWR22 xenografts. The ability to overcome MDR1 and BCRP mediated drug resistance was also tested using DLKP drug resistant variants which exhibit 200 fold resistance to doxorubicin, docetaxel, paclitaxel and vincristine. Results: We found that prostate cancer cell lines are sensitive to EL102 with IC50s in the region of 10-50nM. Of particular interest was the identical sensitivity of the androgen independent 22Rv1 and its androgen dependent parent CWR22, suggesting ability to overcome hormone refractory prostate cancer. Additionally we demonstrate dose response for inhibition of cell motility in metastatic DU145. In CWR22 murine mouse models treatment with EL102 resulted in decreased tumor volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumor growth than EL102 or docetaxel alone. The lung cancer cell line DLKP, its drug resistant variants DLKPA (MDR1 overexpressing) and DLKPMitox (BCRP overexpressing) were equally sensitive to EL102 indicating that EL102 is not a substrate for MDR1 or BCRP. Conclusions: EL102 is a potential therapeutic for the treatment of prostate cancer, in particular in combination with docetaxel, and exhbibits the potential to overcome drug resistane. Future studies will include the efficacy of this drug in prostate cancer metastatic mouse models.
Increased cardiovascular risks associated with primary androgen deprivation therapy versus radical prostatectomy among patients with localized prostate cancer.
Authors: Liu Jinan , Shi Lizheng , Sartor A. Oliver , Culbertson Richard
Published: March 2020

e15130

Background: We examined whether primary androgen deprivation therapy (PADT), as compared to radical prostatectomy (RP), was associated with cardiovascular disease and death. Methods: Male patients with localized prostate cancer were identified in the SEER-Medicare (01/1998-12/2007). PADT patients were matched to the RP patients via propensity score. Cardiovascular risks ((i.e., ischemic heart disease (IHD), congestive heart failure (CHF), or cerebrovascular disease) were examined by Cox (PH) model; cardiovascular death by Fine & Gray competing risk. Important independent variables were controlled for. Results: The baseline variables were comparable. For the sample without cardiovascular disease (CVD) history, significantly increased risks for IHD, CHF, and aggregate risk of CVD were found in PADT group (all p-values <0.05), and the risks for cerebrovascular disease and cardiovascular death were also increased but not significantly (both p-values>0.05); for the sample with CVD history, all the risks aforementioned were significantly increased in PADT group (all p-values <0.05). Conclusions: In this retrospective study, PADT was associated with increased cardiovascular disease and death when compared with RP, especially in the sample with history of CVD. [Table: see text] [Table: see text]
Efficacy of low-dose ketoconazole in the treatment of castration-resistant prostate cancer (CRPC): A single-institution experience.
Authors: Ortega Cinzia , Ruatta Fiorella , Prati Veronica , Ballatore Valentina , Capaldi Antonio , Garibaldi Elisabetta , Gabriele Pietro , Muto Giovanni , Aglietta Massimo
Published: March 2020

e15133

Background: The management of rising PSA in CRPC remains controversial. Secondary hormonal manipulations are commonly used before starting chemotherapy. Ketoconazole, an antimycotic that affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This retrospective study describes our experience with low doses of ketoconazole and prednisone treatment for CRPC. Methods: From 4/2007 to 12/2011, 65 patients with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally bid with orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Performance status of all patients was ECOG0. Overall, 34/65 (52.3%) patients had only bone metastases, 12/65 (18.5%) had nodal metastases, 17/65 (26.2%) both and only 2/65 (3.1%) had bone plus lung mets. All patients had low tumor burden and PSADT >6 months. Thirty-six out of 53 patients with bone mets received concomitant zoledronic acid. PSA response was defined as a >50% fall in PSA from baseline and PSA nadir was calculated. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Patients were monitored clinically and with serial PSA measurements every 1-month. Results: Median age was 74.05 (range: 52.8-84.4) years; median baseline PSA was 29.95 (range: 1.18-1348.8) ng/ml; median duration of the treatment was 5.87 (range: 0.57-52.4) months. All pts were evaluable for PSA response. At a median F.U.of 15.4 mos. 19/65 patients (29.2%) showed a decrease in PSA >50%, with a median TTP of 17.23 mos for responders. Overall TTP was 5.86 mos and it was not affected by metastatic sites (p= 0.71).Toxicity was mild and no patients discontinued therapy because of side-effects. Five out of 65 patients had G2 (CTC.AE 4) nausea and moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Our data confirm that low-dose ketoconazole is an effective and well-tolerated treatment in patients with CRPC and should be considered in the subset of patients with low-volume disease and a rising PSA level despite maximal androgen blockade.
Clinical experience with oral vinorelbine (NVBO) plus prednisone as first- or second-line chemotherapy of metastatic hormone-refractory prostate cancer (HRPC).
Authors: Cervera Grau Jose Manuel , Beltran Miguel , Garcia Carbonero Iciar , Girones Regina , Gonzalez del Alba Aranzazu , Calderero Veronica , Gonzalvez Maria Luisa , Domenech Montserrat , Diaz Nieves , Jimenez Paula , Juan Vidal Oscar , Saenz Alberto , Perez Francisco Javier
Published: March 2020

e15144

Background: IV NVB plus hydrocortisone (HC) compared with HC alone resulted in improved clinical benefit, progression-free survival (PFS) and PSA response rate in HRPC. The oral formulation of NVB avoids the side effects associated with the IV injection, may reduce administration and toxicity-related costs and is easy to administer. Due to these advantages, single agent NVBO treatment could be considered as an optimal option for patients (p) with HRPC previously treated with a taxane or as first-line treatment when a taxane is not indicated. We retrospectively evaluated efficacy and toxicity or NVBO administered as single agent as first or second-line chemotherapy of metastatic HRPC. Methods: Retrospectively data was collected from p with metastatic HRPC treated with NVBO 80 mg/m2 on days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the 1st cycle (cy), plus prednisone 10 mg/day. Patients had received either a taxane as 1st-line treatment or had a documented contraindication to receiving docetaxel. 1 cy was equivalent to a 3-week period. Results: Data on 67 p treated in 13 Spanish centres were included. Median age 73 years (range 54-86). ECOG PS 0, 16.4%; 1, 56.7%; 2, 11.9%. Median PSA 88.9 ng/mL. Prior chemotherapy, 58.2%. Median number of cy was 4 (range 1-6). 56.9% of p could escalate NVBO to 80 mg/m2. 265 cy were performed, 9.1% were delayed and 2.3% had a dose reduction. Grade 3-4 events were infrequent and mainly hematological: neutropenia (6% of p), anemia (4.5%), pain (3%), infection (1.5%), asthenia (3%), respiratory (1.5%), cystitis (1.5%), rectal bleeding (1.5%), febrile syndrome (1.5%), renal (1.5%). No febrile neutropenia was reported. PSA response rate 16.1%, PSA stable was reported in 41.9%. 39 p were evaluable for measurable disease; among them, PR 17.9%, SD 48.7%. Median follow-up, 7.1 months. Median overall survival, 11 months [95% CI: 7.3-14.7]. Median PFS, 2.9 months [95% CI: 2.2-3.6]. Conclusions: NVBO is a safe and active regimen in previous chemotherapy treated HRPC. For those p who cannot receive a taxane as first-line therapy, NVBO can also be considered as an effective first-line treatment.
Correlation of biologic recurrence after radical prostatectomy and a positive surgical margin with the predominant Gleason pattern on the specimen.
Authors: Neuzillet Yann , Pichon Audrey , Lebret Thierry , Raynaud Jean-Pierre , Botto Henry
Published: March 2020

e15145

Background: The risk of biological recurrence following radical prostatectomy depends, among other factors, on surgical margins status. This study compared the prognosis of prostate cancer patients with positive surgical margins according to the predominant Gleason pattern (PrdGP). Methods: Prospective study of 247 consecutive prostate cancer patients, who underwent radical prostatectomy (RP) from 3/2007 to 12/2009, and were followed up in our institution. Pathological stage and Gleason score were determined in RP specimens by a pathological reference. Biological recurrence was defined as two consecutive values of PSA > 0.2 ng/mL. The median overall follow-up was 33 months (2 to 54 months). Biological recurrence-free survival was estimated and compared using Kaplan-Meier plots and Log rank test. A multivariate logistic regression model was done with PrdGP4, and two other predictive variables (pT≥3a, preoperative PSA level) entered as statistically significant independent predictors of biological recurrence. Results: Forty-eight patients (19.4%) had a positive surgical margins, 26 patients have PrdGP3 (54%) and 22 have PrdGP4 (46%). Whereas 7 biological recurrences were observed in PrdGP4 patients, none occurred in PrdGP3 patients. Biological recurrence-free survivals were significantly different (Log rank p=0.001). In multivariate analysis, PrdGP4 was a predictor of biological recurrence (p<0.0001, OR= 9.023, 95% CI [3.161–25.757]). Conclusions: This study demonstrates that biological recurrence after positive surgical margin are correlated with the predominant Gleason pattern assessed on radical prostatectomy specimen which s more easily evaluable than accurate margins features. Adjuvant treatment, specifically external beam radiotherapy, should be indicated in accordance to this result. [Table: see text]
The relations between age and androgen deprivation therapy use among men receiving radiation therapy for prostate cancer in the Medicare population.
Authors: Quon Jennifer L. , Yu James B. , Soulos Pamela R. , Gross Cary P.
Published: March 2020

e15150

Background: For older men with prostate cancer who are undergoing radiotherapy, the benefit of neoadjuvant and concurrent androgen deprivation therapy (ncADT) varies according to tumor characteristics and life expectancy (LE). National Comprehensive Cancer Network (NCCN) guidelines recommend ncADT for men with high-risk cancer characteristics, but not for men with low-risk cancer, or for men with LE < 5 years. Although older patients with shorter LE have the lowest likelihood of benefit, it is unclear whether ncADT is used less frequently in this group. Methods: We used the Surveillance, Epidemiology, and End Results-Medicare database to assess patterns of ncADT use among men diagnosed with prostate cancer during 2004 through 2007 who received external beam radiation. Men were stratified according to NCCN guidelines into low- (T1-T2a/N0/M0 and Gleason 2-6 and PSA< 10 ng/mL), intermediate- (T2b-T2c or Gleason 7 or PSA 10-20 ng/mL), and high- (Gleason >7 or PSA> 20 ng/mL) risk groups. Men were further stratified according to LE, which was calculated based on age and comorbid illness. We used logistic regression to identify patient and clinical factors associated with ncADT use within each risk group. Results: There were 11,080 men in the sample (mean age= 74.2 years; 83.5% white). The use of ncADT was highest in the high-risk group (80.7%). However, a considerable number of men in the intermediate- (54.1%) and low-risk (27.8%) groups also received ncADT. Compared to men with longer LE, men with LE < 5 years had higher rates of ncADT use in all risk groups. For instance, in the low-risk group 32.7% men with LE < 5 years received ncADT compared to 26.5% men with LE ≥ 10 years. Similarly, within each risk group, advancing age was associated with a higher likelihood of receiving ncADT (OR for men aged 80-84 compared to 67-69 = 1.93(95% CI 1.37-2.70); 1.51(95% CI 1.22-1.87); and 1.71, (95% CI 1.14-2.57) for high-, intermediate-, and low-risk groups, respectively). Conclusions: The use of ncADT in actual practice is not consistent with guideline recommendations and is used more frequently among men who are older, have a shorter LE, and are less likely to benefit from therapy.
A phase I trial of AEZS-108 in castration- and taxane-resistant prostate cancer.
Authors: Liu Stephen V. , Schally Andrew V , Dorff Tanya B. , Tsao-Wei Denice , Groshen Susan G. , Hawes Debra , Xiong Shigang , Quinn David I. , Tai Yu-Chong , Block Norman L. , Engel Juergen , Pinski Jacek K.
Published: March 2020

e15153

Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH), which is highly expressed on prostate cancer cells. AEZS-108 is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of LHRH receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide enumeration of CTCs and results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs. Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Due to potential cardiotoxicity, patients with an ejection fraction < 50% or prior exposure to doxorubicin or mitoxantrone were excluded. Pituitary function was closely monitored. Patients received AEZS-108 every 21 days for up to 6 cycles until progression or unacceptable toxicity. The primary endpoint was safety. Results: Enrollment began in November 2010 and is ongoing. Currently, 13 patients have been enrolled. The first two planned dose levels had no dose-limiting toxicities observed. Two patients on the third dose level experienced a dose limiting toxicity. The second dose level has been reopened for expansion. There have been no cardiac or pituitary toxicities. At the time of submission, a decrease in PSA was noted in 6 of the 13 patients. Final results detailing safety, response and the suggested dose for the phase II portion will be reported. All correlative studies will also be reported. Conclusions: In general, AEZS-108 has been well tolerated. The phase II portion of the study will begin once the MTD is established.