bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
How much is reasonable to expect about overall survival (OS) benefit when designing studies with new drugs for patients affected by castration resistant prostate cancer (CRPC)? Meta-analysis of 23 randomized clinical trials (RCT) including 17,640 patients.
Authors: Massari Francesco , Maines Francesca , Pilotto Sara , Porta Camillo , Carlini Paolo , Modena Alessandra , Ciccarese Chiara , Sperduti Isabella , Giannarelli Diana , Tortora Giampaolo , Bria Emilio
Published: March 2020

e16053

Background: Treatment decision making in patients affected by CRPC is difficult because the numerous available therapeutic opportunities can significantly affect OS. To demonstrate that comparing results in absence of head-to-head studies may lead to biased survival estimations, a literature-based meta-analysis was conducted. Methods: Hazard Ratios (HR) with 95% confidence intervals (CI) were extracted and cumulated according to a random-effect model from phase III trials. Sensitivity analyses were performed according to: 1) Treatment Strategy (TS, Chemotherapy versus Hormonal versus Immunotherapy versus Other), 2) Comparison (Chemotherapy versus Placebo versus Other), and 3) Disease setting with regard to treatment with Docetaxel (DOC),. Testing for heterogeneity was performed as well. Results: A significant heterogeneity for the 3 sensitivity analyses was found (p<0.0001). The cumulative HR in favor of (any) experimental arm was 0.91 (95% CI 0.84-0.99, p=0.028). We found a significant interaction according to the chosen TS (p<0.0001), in fact a significant difference in OS was more likely to be detected in RCT evaluating hormonal drugs (HR 0.76, 95% CI 0.64-0.92, p=0.005) versus studies testing immunotherapy (HR 1.16, 95% CI 0.86-1.56, p=0.31). With regard to Comparison, a significant interaction (p<0.0001) was found in favor of RCT having placebo as control (HR 0.86, 95% CI 0.76-0.97, p=0.015), versus studies evaluating chemotherapy (HR 1.00, 95% CI 0.84, 1.19, p=0.99). A significant interaction according to DOC-treatment was also detected (p<0.0001), being the Post-DOC the Setting where a significant OS benefit was more likely to be determined (HR 0.77, 95% CI 0.66-0.90, p=0.001). Conclusions: The cross-trials interpretation in absence of formal direct comparisons may drive biased conclusions with regard to OS estimation. When designing trials to evaluate drugs (or strategies) in CRPC, the expected OS benefit must take into account the comparator, the treatment strategy and the (eventual) pre-treatment with DOC.
Negative association of smoking with PSA and PSA velocity.
Authors: Algotar Amit Mohan , Sokoloff Mitchell , Hsu Chiu-Hsieh , Singh Parminder , Stratton Steven Paul
Published: March 2020

e16060

Background: Smoking and obesity have been implicated in the pathogenesis of various chronic diseases and carcinogenic processes. However, their role in prostate cancer (PCa) & their association with important biomarkers such as prostate specific antigen (PSA) & PSA velocity (rate of PSA change over time) remains unresolved. This study investigates the association of these risk factors with PSA & PSA velocity (PSAV) in men at high risk for PCa. Methods: Data were obtained from 699 men participating in a Phase 3 clinical trial aimed at investigating the effect of selenium supplementation on incidence of PCa. During the course of this trial 73 men were diagnosed with PCa. Multiple linear regressions were used to investigate the association with PSA and mixed effects models were used to investigate the association with PSAV. Results: As compared to non-smokers, smokers demonstrated statistically significant negative association with PSA (8.0 & 6.7ng/ml, p=0.02). This association was more pronounced in men diagnosed with PCa (14.7 & 9.9ng/ml) as compared to those not diagnosed with PCa (4.5 & 3.6ng/ml). As compared to non-obese subjects, obese subjects did not demonstrate a statistically significant association with PSA (6.8 & 7.1ng/ml, p= 0.64) nor do these results change after stratifying the analysis by PCa status. Smoking was associated with statistically significant lower PSAV (p=0.008) whereas obesity was not (p=0.42). Using the standard PSA level of 4ng/ml as a cut off for conducting prostate biopsy, 14.6% of smokers in this study would not have been prescribed a prostate biopsy and thus misclassified as being negative for PCa. Conclusions: The negative association of smoking with PSA and PSA velocity could potentially be due to its negative effect on testosterone. Hence, increased vigilance may be warranted among smokers with borderline PSA to prevent the risk of delayed diagnosis and metastasis thus reducing morbidity and mortality associated with PCa.
Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) refractory to docetaxel (D).
Authors: Peer Avivit , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Boursi Ben , Leibowitz-Amit Raya , Berger Raanan , Neumann Avivit , Kovel Svetlana , Sella Avishay , Pili Roberto , Hammers Hans J. , Sinibaldi Victoria J. , Carducci Michael Anthony , Eisenberger Mario A. , Keizman Daniel
Published: March 2020

e16068

Background: Abi is a standard treatment (tx) in pts with mCRPC refractory to D. It is a potent and selective CYP 17 inhibitor, that blocks the synthesis of androgens in the testis, adrenal glands, and prostate. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17, there are limited clinical data comparing both agents. Aims: To compare the clinical effectiveness of abi vs keto in pts with mCRPC refractory to D. Methods: Records from 156 mCRPC pts treated with keto 200 - 400 mg 3x day, in 4 centers across the US and Israel, were reviewed retrospectively. 26 pts treated post D were individually matched by clinicopathologic factors to pts treated with abi (selected from a multicenter Israeli database, n=120). We compared the PSA response (decrease ≥50% from baseline), biochemical and radiological progression free survival, and overall survival between the groups. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by Gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), ECOG PS, pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012). Furthermore, they were balanced regarding median age (71 abi vs 69 keto), time from primary tx to disease relapse, time to progression on prior GnRH-a and antiandrogen, PSA response and time to progression on prior D, pre-tx pain score/alkaline phosphatase/hemoglobin/neutrophil to lymphocyte ratio/PSADT/PSA. In the groups of abi vs keto, PSA response was 46% vs 19% (OR 4.4, p=0.043), median biochemical PFS 7 vs 2 months (HR 0.65, p=0.02), median radiological PFS 6 vs 2.5 months (HR 0.63, p=0.016), median overall survival 17 vs 12 months (HR 0.53, p=0.79), and tx interruption d/t adverse events 12% vs 23% (0R 0.6, p=0.023). Conclusions: In mCRPC refractory to D, the outcome of pts treated with abiraterone was superior to ketoconazole.
Comparison of the pharmacokinetics (PK) of galeterone novel oral formulations.
Authors: Kramer William G. , Vince Bradley , McGarry Carolyn
Published: March 2020

e16075

Background: Galeterone (gal) is an orally available steroid analog for the treatment of castration resistant prostate cancer (CRPC). A significant food effect, similar to abiraterone, was found when gal, as powder in capsule (PIC), was dosed in a phase I CRPC trial and confirmed in a PK study in human volunteers.The objective of this study was to assess single-dose PK of gal after reformulation and to evaluate effect of food. Methods: In this single-center open-label study, 24 male subjects were assigned to receive once daily doses of between 100 and 3400 mg in either a 3-treatment, 3-period or 4-treatment, 4-period dose scheme. Treatment periods were separated by 7-day washout intervals. Plasma concentrations were measured over 72 hours to assess PK. Two novel tablet formulations were administered in 100 mg doses under fasted and/or fed condition compared to 2600 mg-PIC administered under fed conditions. Escalating doses of PIC (975 to 2600 mg) and tablet (850 to 3400 mg) formulations were evaluated to assess linearity. Results: Gal was well tolerated. Food effect has been negated with the tablet. Exposure from 1700 mg galeterone tablet (fed or fasted) is comparable to a 2,600 mg dose of PIC (fed) (Table). For tablet, AUC(inf) increased in a dose-related and dose-proportional manner from 6,689 ± 2,602 hxng/mL (850 mg) to 20131 ± 9,930 hxng/mL (2,550 mg). Conclusions: The tablet formulation negates the food effect previously observed. Gal may be dosed either fed or fasted with no difference in absorption, which reduces intra-patient variability in exposure. Tablet has more consistent bioavailability and a linear increase in AUC between escalating doses. [Table: see text]
Quality of life (QoL) of patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel.
Authors: Winquist Eric , Sridhar Srikala S. , Hubay Stacey , Assi Hazem , Berry Scott R. , Alloul Karine , Levesque Eric , Aucoin Nathalie , Czaykowski Piotr , Saad Fred
Published: March 2020

e16088

Background: The effects of cabazitaxel on QoL, pain response and preference/utility data have not been well studied in men with CRPC treated post-docetaxel. As part of a single-arm multicenter Sanofi-funded Early Access Program (EAP) for cabazitaxel, QoL data were collected on Canadian patients. Methods: Between May 2011 and February 2012, 61 patients (pts) were enrolled at 9 centers. QoL was assessed at the start of each cycle using the FACT-P and its subscales, and the EQ 5D-3L. EQ 5D-3L health state index (HIS) data were converted into utility values (Canadian tariff, Bansback 2011). Present pain intensity (PPI) and analgesic scores were assessed using the McGill-Melzack questionnaire. Results: QoL data were evaluable in 55 pts. Baseline pt characteristics were: median age 65 years (range, 42-79), 92.7% of pts were ECOG PS 0 or 1, 87% had bone metastases, and 56% (31/55) received at least 6 cycles of cabazitaxel. Statistically significant changes from baseline in mean QoL scores were observed on FACT-P total score at cycle 2, and prostate cancer specific subscale (PCS) at cycles 1 to 4. As a measure of QoL response, increases were observed and maintained for > 2 consecutive cycles in 9% (>16 points) and 25% (≥10) of pts for FACT-P total score. Improvements to the level of Minimal Important Differences (MID) (Cella 2009) maintained for > 2 consecutive cycles were observed in 36% of pts for FACT-P total score (MID=6), 49% for PCS subscale (MID=2), and 26% for PCS-Pain subscale (MID=2), respectively. The percentage of pts reporting "no problem" in the EQ-5D pain/discomfort domain were above baseline levels at every cycle and improved from baseline to end of treatment from 19% to 29% (p < 0.05). Other EQ-5D dimensions (anxiety/depression, mobility, self-care and usual activities) remained stable over the course of treatment. Improvement from baseline in utility value (HIS) was observed at cycle 4 with a utility value of 0.769 (vs 0.713 at baseline). PPI scores improved despite stable analgesic use and were significantly different from baseline at cycles 2, 4 and 9. Conclusions: Data from this EAP suggest improvements in QoL, pain and prostate cancer specific symptoms with second-line cabazitaxel treatment. Clinical trial information: NCT01254279.
Cost of palliative external beam radiotherapy (EBRT) utilization for bone metastases secondary to prostate cancer (PC).
Authors: Nickman Nancy A. , Ye Xiangyang , Gaffney David K , Barney Reed B. , Biskupiak Joseph E. , Okano Gary J. , Lee Vinson C. , Arellano Jorge
Published: March 2020

e16091

Background: Evaluations of palliative EBRT costs for patients with bone metastases are limited. The objective of this study was to summarize documentation of usual care patterns and episode costs of EBRT to bone in deceased men with metastatic PC treated in a United States specialty cancer hospital. Methods: An Electronic Health Record (EHR)-based retrospective review was used to identify deceased PC (ICD-9 185.xx) patients ≥18 years of age with bone metastases (ICD-9 198.5) treated between 1995 and 2012 with EBRT for metastasis and pain management. Variables of interest encompassed patient-specific demographic and clinical characteristics, including length and number of EBRT treatments and total cost of EBRT usage (standardized to 2011$US).Common Procedural Terminology (CPT) codes related to EBRT and hospital assigned visit numbers were used in an algorithm to identify EBRT episodes of care (defined as all billed professional and technical EBRT services provided between initial and final evaluation by radiation oncologist). Bootstrapping (percentile method) was used to approximate the 95% confidence interval for final EBRT cost estimates. Results: A cohort of 176 men were identified; 19 (10.8%) had metastases in >1 site, and an average (±SD) Charlson Comorbidity Index of 6.4 ± 3.9 at metastasis diagnosis (excluding cancer). An average of 5.1 ± 4.6 years elapsed between PC and bone metastasis diagnoses. Prior to bone metastasis diagnosis, patient-reported symptoms included bone pain (54%). All men received at least 1 episode of EBRT, and 89 (50.6%) received >1 episode (range 1-6, median = 2). The length of first episode of EBRT ranged from 1 - 44 calendar days (average ± SD, 13.4 ± 8.4), with an average cost totaling $7,084 ± $4,028. Approximately 70% of costs were attributable to hospital (technical) charges and 30% to physician (professional) charges. Bootstrapping resulted in a 95% confidence interval of total cost between $6,641 and $7,527. Conclusions: Results suggest thatpalliative EBRT may constitute a significant burden in time and healthcare system costs.
Zoledronic acid for hormone-naive prostate cancer with bone metastasis.
Authors: Nozawa Masahiro , Hara Isao , Nagao Kazuhiro , Matsuyama Hideyasu , Uemura Hirotsugu
Published: March 2020

e16092

Background: The potency of zoledronic acid for hormone-naïve prostate cancer is unclear. We conducted a phase II study to investigate the benefit of administering zoledronic acid concomitant with androgen-deprivation therapy in treatment-naïve prostate cancer patients with bone metastases, in which the primary endpoint was skeleton-related event (SRE)-free survival at 24 months after treatment. Methods: Treatment-naïve male patients with histologically confirmed adenocarcinoma of the prostate and radiologic evidence of bone metastasis were eligible. Treatment consisted of bicalutamide 80 mg administered orally on Day 1 and every day, goserelin acetate 10.8 mg administered subcutaneously on Day 8 and every 12 weeks, and zoledronic acid 4 mg administered intravenously on Day 8 and every four weeks. Results: Between July 2008 and April 2010, a total of 53 patients were enrolled and 52 evaluable. Median age was 72 years (range, 55 - 86). Median primary PSA was 249.4 ng/ml (range, 2.19 –19201). Median follow-up period was 33.3 months. The SRE-free survival rate at 24 months after treatment was 82.7 %. Median time to PSA progression was 25.9 months (95% confidential interval, 17.97-24.43). The score of the extent of bone diseases was stable or decreased in 73 % of the patients at 24 months after treatment. The grade-3 osteonecrosis of the jaw was reported in three patients (5.8 %). Conclusions: Our results suggest the potency of the early introduction of zoledronic acid for prostate cancer patients with bone metastases. Future studies are certainly required to ascertain the most appropriate timing of the commencement of zoledronic acid for patients with bone-metastatic prostate cancer. Clinical trial information: UMIN000007548.
Relation between the disease-free period and body mass index in prostate cancer patients with high-risk prognosis.
Authors: Richardet Eduardo Arnoldo , Laura Perelli , Molina Matias , Brombin Romina , Richardet Martin
Published: March 2020

e16100

Background: To determine, according to BMI, whether overweight and obesity in patients with high risk prognosis in prostate cancer is associated to a shorter disease-free period. Methods: We conducted a retrospective and descriptive study of the population from Instituto Oncológico de Córdoba, in patients with prostate cancer. Prostatectomized, with a high risk according to the College of American Phathologists Consensus Statement served between the year 2000 and 2010, we observed that 52 patients met these characteristics with a average age of 70.16 years, range of 48-87 and those were divided into two groups according to their BMI in equal or greater value than 26 and in another group those in equal or smaller than 25. Results: From the 52 patients, 27 (51.92%) had a BMI equal or greater than 26, those who experienced relapse, in average, at 25.33 months; while 25 patients (48,08%) had a BMI equal or smaller than 25, with an average relapse time of 28.35 months, presenting a p=0.11 Conclusions: We observed that patients with overweight and obesity had a tendency towards relapse before patients with a normal BMI. Further sample size would be needed to establish statistically significant differences.
Liver metastases in carcinoma of the prostate as an indicator of aggressive subtype refractory to hormonal therapy and duration of response to docetaxel monotherapy: A single institution experience.
Authors: Singh Arsh , Kafeel Muhammad I. , Shakil Shams A. , Gulmi Frederick , Mooppan Unni , Wang Jen C.
Published: March 2020

e16101

Background: Prostate cancer exhibits distinct pattern of metastasis with bone being the most common site of involvement. Liver is an uncommon site of metastasis and is associated with poor prognosis. Very few data is available on treatment with hormone including LHRH agonist (LA) and abiraterone (Ab) and chemotherapy. We retrospectively reviewed data of patients with liver metastasis with the primary objective of determining their clinical characteristics and treatment outcome from a single institution experience. Methods: Data of 5 patients with prostate cancer who developed liver metastases during the course of their disease was collected between 2007 and 2013. Four out of five patients had histological confirmation of prostatic origin adenocarcinoma while one had radiological confirmation. All patients except one had received prior LA and all were chemotherapy naïve prior to development of liver metastases. Objective biochemical response was defined as >50% decrease in PSA value following therapy. Results: Gleason score was >8 in 4/5 patients and unknown in one. Three out of five patients who progressed on LA received docetaxel, and despite achieving a more than 50% objective PSA response in all patients, it was of short duration, the mean duration of response was only 6 months. Two patients received Ab, after chemotherapy with docetaxel ,did not show any response and another two patients received LA therapy also failed ( one patient who presented with lung metastases developed liver metastases in <6 months; one patient who presented with liver metastases expired in <3 months despite LA therapy). Thus, four of five patients in this small series did not respond to hormone therapy. Conclusions: From this small series of study, it suggests that liver metastases in carcinoma of prostate represent an aggressive subset that does not respond to hormonal therapy including the LHRH agonist and abiraterone. Although they responded to docetaxel chemotherapy, the responses were of short duration. An alternative regimen should be explored for this particular subset of patients.
Fecal and urinary incontinence impairing social functioning and quality of life among survivors of gynecologic cancers.
Authors: Pushpalatha Kameshwarachari , Sharma Dayanand , Kumar Sunesh , Julka Pramod Kumar
Published: March 2020

e16511

Background: Fecal and urinary incontinence are late side effects of pelvic radiotherapy and are termed as most bothersome causes for distress and detachment among survivors of gynecological cancers. The present study was conducted to find out the impact of fecal and urinary incontinence on quality of life with regard to psychological, social and sexual functions. Methods: A cross-sectional study was conducted between June 2010 - June 2011 on cohort of 100 advanced cervical cancer patients treated with pelvic radiation of 50.4 Gy in 28 fractions over 5.5 weeks and concurrent cisplatin, followed by intracavitary boost of 15 Gy. By using a questionnaire addressing social, psychological, sexual concerns, data was collected with respect to loss of interest in social parties, travelling, domestic performance, sexual life, personality changes. Results: Fecal incontinence was seen in 17% and urinary incontinence in 28% which affected quality of life (58%). The impact of these symptoms reflected on refraining from participation in social gatherings (20%) and travelling (18%), decreased performance in domestic activities (32%), fear of losing support of spouse and children especially owing to malodour of urine and feces (35%), lack of interest in pursuing sexual intimacy (25%), apathy (18%), fear of disease recurrence (35%), fear of death (42%). Conclusions: Although psychosocial and sexual issues are less openly addressed in the clinics, structured patient-doctor discussion to envisage and demystify longstanding misconceptions concerning sexual function, psychological education by psychotherapists coupled with social support by system-wide dissemination of awareness in the form of pamphlets, books, videos, websites and other visual aids to patients can maintain the quality of life in such patients. Satisfaction regarding discussions on these issues may also vary depending on oncologic specialty clinic, age of the patient and the gender of her oncologist. Timely intervention to minimize these problems would result in significant increase in the followup rates and prolong the survival of the cancer patients.
Combination chemotherapy with temsirolimus and trabectedin in patients with heavily pretreated clear cell carcinoma of the ovary.
Authors: Takano Masashi , Kouta Hiroko , Sasaki Naoki , Kudoh Kazuya , Kita Tsunekazu , Kikuchi Ryoko , Oda Katsutoshi , Goto Tomoko , Furuya Kenichi , Kikuchi Yoshihiro
Published: March 2020

e16519

Background: Clear cell carcinoma (CCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. An inhibitor against the mammalian target of rapamycin (mTOR), temsirolimus, has been reported to be effective in renal CCC. Additionally, a marine natural product, trabectedin, had activity against recurrent ovarian cancers. We evaluated the effect of combination therapy with temsirolimus and trabectedin for patients with recurrent/refractory CCC of the ovary. Methods: Patients with recurrent/refractory CCC of the ovary were treated with weekly regimen using two drugs: 10mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest) with written informed consents. Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. Responses were evaluated by RECIST criteria, and adverse effects were analyzed by NCI-CTCAE v4.0. Results: A total of 12 patients treated with the regimen, and there were no cases that discontinued the therapy due to toxicities. Median age was 60 years (range: 42-69), and median number of previous chemotherapy was 3 (range: 1-5). All cases were assessable by RECIST and CTCAE. One patient (8%) had a complete response (CR), and another (8%) achieved a partial response (PR), and 4 patients (33%) had stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD>3month) of 50%. Median response duration in CBR case was 3.5 months (range: 3-12+). There were no cases that developed toxicities more than grade2. Conclusions: The present preliminary study demonstrated combination therapy with temsirolimus and trabectedin was effective in patients with recurrent/refractory CCC of the ovary. These results warrant further study in such clinical settings.
Impact of comorbidities on recurrence rates and survival in patients with endometrial cancer.
Authors: Kucukoztas Nadire , Dizdar Omer , Rahatli Samed , Tarhan Cagla , Haberal Nihan , Dursun Polat , Yalcin Selim , Ozen Ozlem , Yildiz Ferah , Altundag Ozden , Ayhan Ali
Published: March 2020

e16528

Background: The aim was to determine the clinical characteristics, comorbidities, tumor features, and survival outcomes in patients with uterine carcinoma treated in our institution. Methods: Charecteristics of 410 patients underwent initial abdominal surgery for primary endometrial cancer in our institution between 2006 and 2012 were reviewed. Demographic features, histologic types, stage, type of surgery, comorbidities, treatment modalities and patient outcomes in terms of relapse-free survival (RFS) and overall survival (OS) were assessed. Results: Patient characteristics are shown in the Table. Nearly all patients (97%) were initially treated surgically with comprehensive staging, i.e. total abdominal hysterectomy, bilateral salphingooopherectomy, bilateral pelvic and paraaortic lymph node dissection and omentectomy. Median follow up was 26 mos. 3 year RFS was 90%. 3 year RFS was 97% at stage 1, 80% at stage 2, 62% at stage 3 and 4. 3 year OS was 91%. 3 year OS was 96% at stage 1, 85% at stage 2, 64% at stage 3-4. The only significant independent predictor of RFS was disease stage (HR 5.7, 95% CI 2.1-15.3, p<0.0001) while histologic grade also bordered significance (HR 2.3, 95% CI ,8-6.4, p=0.085). Independent predictors of OS was age (HR 4.5, 95% CI 1.5-13.7, p<0.007), presence of diabetes mellitus (HR 4.5, 95% CI %1.1-6.7, p=0.019) and stage (HR 5.2, 95% CI 2.2-12.6, p<0.0001). Conclusions: Our data shows that older age (>60 years) and advanced stage patients with endometrial cancer have significantly decreased overall survival. Presence of diabetes mellitus is not associated with recurrence rates but is associated with worse overall survival. Stage and grade are considered independent risk factors for recurrence [Table: see text]