bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter observational study of temsirolimus use records conducted under conditions of routine medical practice.
Authors: Richardet Martin Eduardo , Sala Raul , Fein Luis , Richardet Eduardo Arnoldo 
Published: March 2020

e15610 Background: Sometimes efficacy and toxicity reported in clinical trials differs from what is later found on everyday practice. Temsirolimus was approved in Argentine on 2009. We conducted a study to evaluate the safety profile in advanced renal cancer patients treated with Temsirolimus in everyday practice conditions. Methods: Descriptive, observational, retrospective study of medical records of patients treated with Temsirolimus from 2 Argentinian centers were analyzed at IONC and IOR from April to December 2010. All patients were high risk according to Memorial Sloan Kettering Cancer Center. 50 patients were included, 36% (18) women and 64% (32) men, average age 53.8 years old (20 - 78). Adverse events were assessed based on the NCI CTC v3. Results: No patient showed side effects during or immediately after the infusion, related with the administration of the drug. This study included patients with extensive metastatic disease and multiple factors of adverse prognosis together with short life expectancy. All centers used the standard premedication and dose and no serious adverse events were registered. The most frequent adverse events were anemia, asthenia and mucositis. In all cases adverse events were manageable with support measures or dose reduction. Although more than 80% of patients showed some type of adverse event, the quantity and severity of them were lower than the ones reported in the literature. Disease progression (67.3% of patients) was the most frequent cause of treatment discontinuation. All patients received a dose = 25mg. A total of 52 adverse events were registered. In Terms of efficacy, 46 patients were suitable for analysis. Our rate of clinical benefit (PR 13%+SD 47.8%) is 60.8% , higher than what was reported in the pivotal phase III study (32.1%), this difference could be attributed to our limited sample size. The ORR observed (13%) is similar to the rate reported in the pivotal phase III trial (8.6%. Range 4.8 – 12.4). Conclusions: The treatment with Temsirolimus in patients with advanced renal cancer with poor prognosis factors showed an acceptable safety profile and clinical benefit, taking into account the characteristics of the target population.
Clinical utility of biomarkers of systemic inflammation for patients with metastatic renal cell carcinoma.
Authors: Harris Wayne , Akbashev Mikhail Y. , Kucuk Omer , Liu Yuan , Hsiao Wayland , Osunkoya Adeboya O. , Baumgarten Deborah O. , Master Viraj A. 
Published: March 2020

e15617 Background: The presence or absence of systemic inflammation has been associated with dramatic changes in prognosis for patients with metastatic renal cell carcinoma (mRCC). In this study we define kinetic inflammatory response (KIR) patterns as changes in the intensity of the systemic inflammatory response (SIR) over time as a result of therapeutic intervention or disease progression with the goal of ascertaining whether such patterns have any clinical utility. Methods: A retrospective, single institution study was conducted at the Winship Cancer Institute of Emory University. Inclusion criteria included treatment with a targeted agent for mRCC of any histology and the concurrent assessment of serum CRP and albumin on a minimum of three occasions at least two weeks apart. The modified Glasgow Prognostic Score (mGPS) was used to quantify the intensity of the SIR at each available time point. Results: A cohort of 55 patients was identified from among 635 patients who were evaluated for kidney cancer during the screening period of January 1, 2005 and June 30, 2011. The SIR was assessed a total of 804 times with a median of 14 time points per patient (range 3 to 49). A total of 113 lines of theapy were administered with a median of 2 per patient (range 1 to 5). KIR patterns were categorized as optimal, suboptimal, relapse, refractory and acquired systemic inflamation. Tandem KIR patterns were also observed. The absence or sustained loss of systemic inflammation was associated with responsiveness to therapy and prolonged overall survival (OS) whereas the persistence or acquisition of systemic inflammation was associated with resistance to therapy and shortened OS. In one instance, active surveillance with biomarkers of systemic inflammation led to the discovery of an occult penile metastasis. Conclusions: KIR pattern recognition provides a simple and inexpensive way for clinicians to monitor interactions between the tumor and the innate immune system with the clinical objective of inducing or maintaining an inflammation free state. Biomarkers of systemic inflammation may prove to be particularly useful for active surveillance of patients with fully resected, locally advanced or mRCC.
Patients with advanced-stage germ cell tumors have a high risk of thromboembolic events.
Authors: Gordy Anna Lina-Karin , Brames Mary J. , Einhorn Lawrence H. , Manchanda Naveen 
Published: March 2020

e15621 Background: Thromboembolism (TE) accounts for significant morbidity and mortality in cancer patients. Rates of TE have been reported from 0.9%-28.0%, depending on the population. Patients with germ cell tumors have a 4.0-8.4% risk of TE following platin chemotherapy. Our patients are high-risk, many with advanced disease receiving high-dose chemotherapy and peripheral blood stem cell rescue. We sought to more completely understand TE events in advanced germ cell tumor patients. Methods: Forty-four consecutive patients visiting our germ cell tumor clinic between 11/05/2012 and 1/22/2013 were selected. Data were collected by retrospective chart review from tumor diagnosis until TE (ranging from TE on diagnosis to 20 years later). A logistic regression model was fitted to determine variables that predispose patients to TE. Results: In our patient series, seven (15.9%) had venous TE and none had arterial events. Five patients (11.4%) had TE within 16 weeks of chemotherapy, and 2 at 10 and 19 years after diagnosis, respectively. Two had bilateral pulmonary emboli (PE) (4.5%), 3 had upper or lower extremity DVTs, or both, and 1 had bilateral PE and DVTs. Five patients with TE had nonseminomatous tumors, 2 had non-testis primaries, 4 had relapsed disease, 2 with late relapse (>7 years), 6 had metastatic disease, 3 had retroperitoneal lymph node dissection, and all 7 received platin chemotherapy. In logistic regression analysis, significant risk factors for TE included relapse (P= .016), bulky retroperitoneal lymphadenopathy (P= .006), alpha-fetoprotein >10,000 (P= .047) beta-HCG > 1,000 (P= .020), chemotherapy (P= .031), platin-refractory disease (P= .055), and poor risk disease compared to good risk disease (P=.020). Conclusions: Germ cell tumor patients have a high risk of venous TE. Those with relapsed disease, bulky retroperitoneal lymphadenopathy, platin chemotherapy, platin-refractory, or poor risk disease are at increased risk. Our estimates are higher than previously reported and in contrast to earlier studies, do not include arterial TE. To confirm our findings, we will extend this study to 100 patients. If confirmed, this pattern of TE events may be a consequence of advanced stage disease in our patients.
Phase I/II clinical trials of dendritic cell-based immunotherapy in patients with the biochemical relapse of the prostate cancer.
Authors: Spisek Radek , Podrazil Michal , Babjuk Marek , Jarolim Ladislav , Fucikova Jitka , Fialova Anna , Minarik Ivo , Hromadkova Hana , Bartunkova Jirina 
Published: March 2020

e16002 Background: In order to have the highest impact on the control of tumor growth, cancer immunotherapy should be initiated as early in the disease course as possible. In prostate cancer, the effect of cancer immunotherapy at the minimal residual disease stage can be evaluated in patients with the biochemical relapse detected by ultrasensitive PSA measurements. We performed a Phase I/II clinical trial of dendritic cell based immunotherapy in patients with the biochemical relaps of the prostate cancer. Methods: Patients with the prostate cancer in the biochemical failure after radical prostatectomy or primary radiotherapy were enrolled in the study. Study medication consisted of 12 doses of 1x107 dendritic cells pulsed with killed prostate cancer cell line LNCap (DCVAC/PCa), injected s.c. in 4 weeks intervals. Primary goal of the study was to assess the safety. Secondary goals were PSA kinetics and presence of tumor antigen specific immune response in the peripheral blood. Study is registered as EudraCT 2009-017259-91. Results: Twenty patients were enrolled in the study and evaluated after receiving complete treatment cycle of DCVAC/PCa. Administration of DCVAC/PCa did not lead to any significant side effects. Continuous cancer immunotherapy by DCVAC/PCa significantly prolonged the PSA doubling time (PSA-DT) in all treated patients, on average there was a 3,43-fold increase of PSA-DT after the completion of the treatment. Seven of 20 patients had stable PSA levels during the treatment duration. Mean PSA-DT increased from 8,15 months before the initiation of cancer immunotherapy to 52,64 months at the completion of 12 doses, p<0.0015. Sustained T cells responses against PSA, NY-ESO1, MAGE A1 and MAGE A3 were detected in the peripheral blood of enrolled patients. Conclusions: This study indicates that the continuous cancer immunotherapy with dendritic cells loaded with killed LNCAP cell line represents efficient treatment modality for prostate cancer patients with biochemical relapse. This study supports the use of immunotherapy early in the course of the disease, provided that relevant surrogate endpoints predictive of improved prognosis of early stage patients will be identified. Clinical trial information: 2009-017259-91.
Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy.
Authors: DiPippo Vincent A. , Magargal Wells W. , Moorji Sameer M. , Murga Jose D. , Olson William C. 
Published: March 2020

e16007 Background: Recent approvals of four new prostate cancer (PCa) drugs and a growing number of pipeline agents have created opportunities for designing rational drug combinations. Potent antiandrogens such as enzalutamide and abiraterone affect expression of a host of androgen-regulated molecules, including those that represent targets for therapy. One such target is PSMA, a well-characterized cell-surface antigen abundant on prostate cancer cells. PSMA ADC is a PSMA-targeted antibody-drug conjugate currently in phase II clinical testing, comprised of a fully human IgG1 mAb conjugated to vcMMAE (valine-citrulline monomethylauristatin E). Here we examined the kinetics and reversibility of PSMA induction by potent antiandrogens and their associated effects on the preclinical activity of PSMA ADC. Methods: Androgen-dependent and -independent PCa cell lines with varying basal levels of PSMA expression were cultured for up to one month in the presence of enzalutamide or abiraterone, followed by drug washout. Cells were tested for PSMA expression over time and for susceptibility to cytotoxicity by PSMA ADC. Potential drug synergy or antagonism was evaluated using the combination index method. Results: Enzalutamide (1 mM) increased PSMA expression by approximately 2.5-fold in LNCaP (androgen-dependent) and C4-2 (androgen-independent) cells, with maximal expression observed after approximately 4 weeks’ culture. PSMA expression returned to basal levels within days following removal of enzalutamide from the culture. Enzalutamide and PSMA ADC exhibited synergistic antitumor activity in LNCaP and C4-2 cells (P < 0.05). Similar results were observed for abiraterone in C4-2 cells. Less induction of PSMA expression by antiandrogens and modest effects on cytotoxicity were observed using 22Rv1 cells, an androgen-independent cell line with low basal expression of PSMA. Conclusions: Enzalutamide and abiraterone significantly and reversibly augmented PSMA expression and potentiated the activity of PSMA ADC in PCa cell lines in vitro. The findings support clinical exploration of regimens that combine potent antiandrogens and PSMA-targeted therapies.
Qualitative assessment of the brief pain inventory (BPI) “pain at its worst in the last 24 hours” item to support assessment of pain as a clinical trial endpoint in metastatic castrate resistant prostate cancer (mCRPC) per FDA labeling standards.
Authors: Bennett Antonia V. , Atkinson Thomas Michael , Heon Narre , O'Keeffe Bridget , Scheffold Christian , Schimmoller Frauke , Basch Ethan M. 
Published: March 2020

e16018 Background: Pain is common in men with mCRPC and can substantially impair function and quality of life. For assessment of pain as a clinical trial endpoint, substantial validation work has been conducted on the BPI “pain at its worst in the last 24 hours” item, but additional qualitative study of patient understanding of this item is necessary to fully meet FDA labeling standards. Methods: Twenty-six patients with mCRPC in a non-randomized expansion cohort (N=144) of phase II study XL184-203 were interviewed to confirm their comprehension of the BPI “pain at its worst in the last 24 hours” item, and elicit their interpretation of points on the 0-10 response scale to establish levels of intra-patient pain rating consistency. Patient descriptions were evaluated and further compared with previously identified associations between pain severity and pain interference ratings. Results: Patients (median age = 68; range 44-81) had ECOG performance status of 0 (38%) and 1 (62%). Nearly all patients answered the question as intended – by considering the past 24 hours (72%; 18% did not specify); including non-cancer related pain (96%); and reporting pain experienced with analgesia (100%). Patients described pain of “2” as relatively mild, noticeable, and not limiting; pain of “5” as moderate and limiting activity; and pain of “8” as severe and more or less incapacitating. Interpretation of the response scale was highly consistent both among patients and in comparison to levels of pain severity and interference identified in previous large statistical analyses. Conclusions: This study provides important qualitative support for the use of the BPI “pain at its worst in the last 24 hours” item to assess pain per FDA labeling standards in men with mCRPC. Consistent with prior qualitative work, these results confirm this item is well understood by patients. The interpretation of the response scale is remarkably consistent among patients, as well as with results from large statistical analyses, demonstrating the reliability of this item to assess patient-reported pain in cancer trials.
Inhibition of the IGF pathway in metastatic castrate resistant prostate cancer (CRPC): Results from a phase II study of OSI-906 (linsitinib).
Authors: Garcia Jorge A. , Elson Paul , Cooney Matthew M. , Tyler Allison Janine , Rezash Victoria , Borden Ernest C. , Dreicer Robert 
Published: March 2020

e16022 Background: AR ligand independent pathways are responsible for the development of CRPC. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. Linsitinib is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of linsitinib in men with CRPC a Simon two-stage phase II study was conducted. Methods: Men with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received linsitinib at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of linsitinib on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs. Results: Eighteen pts were enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted (8/18), seventeen pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolonged QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway. Conclusions: Treatment with linsitinib is safe however no PCa activity was seen. No changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. Linsitinib plus an AA might provide synergistic activity in this setting. Clinical trial information: NCT01533246.
Serum insulin to predict time to castration-resistant progression and overall survival in metastatic androgen-dependent prostate cancer (mADPCa).
Authors: Dayyani Farshid , Nogueras-Gonzalez Graciela M. , Slack Rebecca , Millikan Randall E. , Zurita Amado J. , Araujo John C. , Gallick Gary E. , Logothetis Christopher , Corn Paul Gettys 
Published: March 2020

e16038 Background: Duration of response to androgen-deprivation therapy (ADT) is highly variable in patients with mADPC and prognostic markers are needed. Insulin resistance and hyperinsulinemia may contribute to prostate cancer progression. We hypothesized that pretreatment serum insulin levels would predict time to castration-resistant progression (PFS) and overall survival (OS). Methods: Sera from men treated on a randomized phase 3 trial of first line ADT vs. ADT plus chemotherapy were retrospectively analyzed using a multiplex ELISA for cytokines and angiogenic factors (CAFs). Univariate and multivariate Cox proportional hazards regression models were used to identify associations between CAFs and PFS/OS. Results: 66 pts were evaluable, 86% Caucasian, median age 72 yrs, median PSA 31.5ng/mL, 77% Gleason score of ≥8, and 53% high volume metastatic disease (HVM). Thirty-five pts received ADT; 31 pts received ADT+chemo. In univariate analysis, higher pretreatment insulin and C-peptide were positively correlated with PFS, whereas higher hepatocyte-growth factor (HGF), osteopontin (OPN) and HVM were negatively correlated with PFS. In multivariate analysis, only higher insulin was associated with longer PFS (HR=0.72, 95%CI 1.32 -0.87; p<0.001), whereas higher HGF and OPN were associated with reduced PFS (HR=1.82, 95%CI 0.59-2.83, p<0.01 and HR=1.81, 95%CI 1.18-2.47, p<0.001, respectively). Higher Insulin and Program Death 1 (PD1) were associated with longer OS on multivariate analysis (HR=0.78 p<0.02 and HR=0.55 p<0.02, respectively), whereas HVM and higher OPN were associated with reduced OS (HR=2.28 p<0.01 and HR=1.60 p<0.02). Using low insulin, high HGF and high OPN as 3 independent risk factors (RF), 3 distinct risk groups could predict PFS: good (zero RF), intermediate (1 or 2 RF) and poor risk (3 RF), with median PFS of 6.90, 1.97, and 0.86 years, respectively (p<0.001). Conclusions: Higher pretreatment insulin was associated with prolonged PFS and OS in men with mADPC treated with ADT. Our data suggest that insulin levels are a biomarker for sensitivity to ADT and highlight the complex interactions between metabolism and PCa progression.
Impact of skeletal related events (SREs) on health-related quality of life (HRQoL) and healthcare resource utilization (HRU) in prostate cancer patients with bone metastases (BM).
Authors: Arellano Jorge , Chen Kristina S , Atchison Carolyn , Rider Alex , Worsfold Andrew , Collins Helen 
Published: March 2020

e16046 Background: Advanced prostate cancer often leads to the development of BM and as a result SREs. Treatment and management of SREs, as well as the underlying disease, influences the patient’s HRQoL and HRU. We evaluated the impact of SREs on HRQoL (FACT-P) and HRU in patients with BM. Methods: Data were extracted from the Adelphi Prostate Cancer Disease-Specific Programme (DSP), a cross-sectional survey of 150 urologists and oncologists and their prostate cancer patients conducted from March to June 2012 in the US. Each specialist completed comprehensive record forms on 12 of their patients being treated for prostate cancer. Patients were invited to complete a questionnaire, which included the FACT-P HRQoL instrument. Patients were stratified by SRE experience to assess the impact of SRE on patients with BM. SRE was defined as an event of bone radiation, bone surgery, fracture, or spinal cord compression. Results: Data were collected from 1,749 prostate cancer patients, of which 941 were identified with BM; SRE status was recorded in 499 BM patients (Table). HRQoL was significantly lower in patients experiencing SREs, while the rate of consultations and likelihood of being hospitalized was significantly higher. Conclusions: SREs result in a significant economic burden on the healthcare system and negative impact on HRQoL in prostate cancer patients with BM. [Table: see text]
The sequential use of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: Experience from Birmingham, United Kingdom.
Authors: Stevenson Robert , Ford Daniel , Zarkar Anjali M , Glaholm John , Porfiri Emilio , Tew Alice , El-Modir Ahmed , James Nicholas David 
Published: March 2020

e16048 Background: Phase III studies have demonstrated survival benefits from abiraterone1 (Abi), and Enzalutamide2 (MDV3100; Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enzalutamide (Enz) is available, via early access scheme, for progressive disease post docetaxel, regardless of prior Abi exposure. There has been no randomised trial on sequential usage of Enz post Abi. We therefore report our experience. Methods: We searched our pharmacy database for patients who have received Enz and identified 51 patients who started treatment between the 2nd August 2012 and 10thJanuary 2013. A detailed notes review was carried out of these patients. Results: Median age was 76 (range 55-87) years. All patients had received androgen deprivation therapy and Docetaxel. 46 patients had received previous Abi, 38 of patients’ receiving Abi as the last treatment prior to Enz. At the time of submission 10 patients had stopped Enz due to PSA progression with a mean TTP of 15 weeks (range 7-22) and 6 patients had died; 2 from disease progression (mean TTP 3.5 weeks). For the 30 patients still on Enz, the mean duration of treatment was 16.47 weeks (range 4-27). 33 patients didn't report any significant side effects associated with Enz treatment. The most common side effect was fatigue (23.6%); 3 patients (6%) experiencing G3 fatigue. Other reported side effects included diarrhoea (4%), nausea (6%), confusion (6%), anxiety (6%), depression (6%), hallucinations (2%) and insomnia (2%). 3 patients (6%) had Enz stopped due to G3 fatigue. Conclusions: The AFFIRM study demonstrated TTP of 8.3 months (36 weeks) in patients post-docetaxel2. In this audit the TTP of patients receiving Enz post-Abi was 15 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. However, longer follow-up of the 30 patients currently taking Enz is required. The number of patients experiencing G3 fatigue was the same as reported in AFFIRM, but there were a surprising number of patients experiencing psychiatric side-effects.