bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgen deprivation therapy (ADT) use in Medicare beneficiaries with nonmetastatic (M0) prostate cancer (PC) in the United States.
Authors: Arneson Thomas J. , Cetin Karynsa , Stryker Scott , Liede Alexander , Murray Tom , Li Shuling , Blaes Anne Hudson
Published: March 2020

e15169

Background: ADT is well-established for metastatic PC but is also used in men with less advanced PC. Patterns of ADT use in the M0 PC setting have not been well-described. Methods: Medicare claims in 2005 for men aged ≥66 years (yrs) were assessed for use of gonadotropin-releasing hormone agonists or bilateral orchiectomy. The cohort was limited to men who, during the 15 months (mos) prior to their first 2005 ADT claim, had continuous Parts A + B coverage, a diagnosis code for PC, no claims for metastases (except lymph nodes), and no claims for ADT. Follow-up (f/u) was from ADT initiation to 3 yrs, death, or change in Medicare coverage. Regimen duration was defined by combining claim service count and dosage with FDA label dosing. Because ADT has biologic activity beyond the recommended regimen duration, active dose time was calculated by adding 3 and 6 mos to claims for regimens <6 mos and ≥6 mos, respectively. Interruption was defined as ≥180 days from end of active dose time to next ADT claim. Results: We identified 3246 M0 PC patients aged ≥66 yrs who initiated ADT in 2005 but describe results in the 2161 who had 3 full yrs of f/u (data for the entire cohort were similar). Nearly 70% received only 1 type of ADT agent during f/u (25% had 2 types, 5% had 3 or 4 types), and 73% started on a 3-or 4-month regimen. The distribution of patients by first ADT type (and by type received at any point) was: leuprolide injection: 54% (67%); goserelin implant: 36% (43%); triptorelin injection: 6% (19%); leuprolide implant: 2% (4%); orchiectomy: <1% (1%); and histrelin implant: 0% (3%). Use of >1 type of ADT agent was more common in men who began with goserelin (45%) or triptorelin (53%) versus leuprolide (≤24%). At three years after ADT initiation, 36% received ADT for the entire 36-month period, 15% for 24-35 mos, 17% for 12-23 mos, and 32% for <12 mos. Interruption in active therapy occurred in only 13%. Conclusions: Most elderly men with M0 PC initiating ADT in 2005 started on a 3- or 4-month leuprolide or goserelin regimen. Though these agents remained the most commonly used throughout f/u, switching was common (30% used >1 type during f/u). ADT was continued for at least 2 yrs in nearly half and extended to 3 yrs in over one-third of the cohort.
Lifetime cost-effectiveness of denosumab versus zoledronic for prevention of skeletal-related events (SREs) in patients (pts) with castrate-resistant prostate cancer (CRPC) and bone metastases (BM): United States managed care perspective.
Authors: Rader Michael E. , Danese Mark , Cong Ze , Halperin Marc , Qian Yi , Goessl Carsten Dietrich , Chung Karen
Published: March 2020

e15172

Background: Denosumab (Dmab) is superior to zoledronic acid (ZA) for prevention of SREs in pts with CRPC and BM. As Dmab is not cleared renally, it can be used in pts regardless of renal status or concomitant use of nephrotoxic drugs. Previous economic analyses were limited as the analyses were based on short duration-trial based perspectives and/or did not account for disutility associated with IV vs SC administration of ZA and Dmab, respectively. These analyses assess the lifetime cost-effectiveness of Dmab vs ZA in pts with CRPC and BM from a US managed care perspective, with extensive scenario and sensitivity analyses. Methods: A lifetime Markov model was developed, with efficacy of Dmab vs ZA in SRE prevention from a head-to-head phase 3 trial; clinical practice SRE rate in ZA pts from a large commercial claims database analysis; SRE and mode of administration (IV vs SC) quality adjusted life-year (QALY) decrements estimated using the time trade-off method; and SRE costs estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were also included. Costs and QALYs were discounted at 3% per year. Scenario analyses (including adverse events, drug discontinuation, etc), one-way and multivariate probabilistic sensitivity analyses were conducted. Results: Dmab reduced the number of SREs and increased pts’ QALY vs ZA. In the base case and the scenario analyses, cost per QALY gained was below $50,000, which is commonly considered good value. Cost per SRE avoided was below $9,000. In one-way sensitivity analyses, drug costs and SRE rate were the most influential variables. Probabilistic sensitivity analyses showed the probabilities of Dmab being cost-effective vs ZA were 0.83, 0.94, and 0.98 with willingness-to-pay of $100,000, $150,000 and $200,000 per QALY gained, respectively. Conclusions: Dmab is a cost-effective treatment option in preventing SREs in pts with CRPC and BM compared with ZA from a US managed care perspective. The overall value of Denosumab is based on superior efficacy and more efficient administration.
3T MRI of the prostate correlation to 3D reconstruction of transperineal mapping biopsies.
Authors: Rove Kyle O. , Pshak Thomas J. , Patel Nayana , O'Donnell Colin , Crawford E. David
Published: March 2020

e15176

Background: MRI is new tool in the diagnosis and surveillance of localized prostate cancer. Studies have examined the sensitivity and specificity of MRI for detecting and localizing prostate cancer as compared to radical prostatectomy specimens. We have previously demonstrated excellent correlation between 3-dimensional transperineal mapping biopsies (3DMB) to radical prostatectomy specimens. We hypothesize that MRI does not perform as well detecting smaller lesions of the prostate as larger ones. In this study, we retrospectively compare the correlation of 3DMB to 3T MRI-positive lesions. Methods: Between 2010 and 2011, 34 men with histologically-proven prostate cancer underwent 3T endorectal coil MRI and subsequent template-guided (5-mm grid) 3DMB. Three-dimensional computer models of the mapping biopsies were created using Proview software to identify clusters of positive biopsies likely belonging to a single lesion. MRIs were read by two trained radiologists blinded to 3DMB results. Disagreement between radiologists was settled by consensus. MRI and 3DMB were then compared in a retrospective fashion. Results: Median age and PSA were 65 years (49-76) and 4.3 ng/mL (0.7-15.0). Median prostate volume was 40 cm3 (21-105 cm3). Median total biopsy cores on 3DMB was 60 (26-151), and mean positive cores was 3 (0-13). 3D reconstruction of patient biopsy sets resulted in 58 distinct foci of cancer. MRI identified 64 individual lesions suspicious for cancer. Of these, 66% (n=42) could be correlated to a positive area on 3DMB consisting of one or more positive biopsies, and 34% (n=22) corresponded to negative regions on 3DMB. When two or more biopsies represented a positive lesion on 3DMB, the positive-predictive value of MRI was 100% (n=24). Conversely, only 72% (n=42) of positive 3DMB areas could be correlated to a lesion on MRI, and 28% (n=16) were not seen on MRI.. Conclusions: MRI has vast potential as a less-invasive method in the detection and surveillance of prostate cancer. While MRI does appear to have excellent positive predictive value, the number of false negatives and relevance to clinically-significant lesions require further illumination.
Independent confirmation of the strong early predictive value of modeled PSA clearance in prostate cancer patients treated by radical prostatectomy: Results of the prospective PSAMODEL study.
Authors: Maillet Denis , Ruffion Alain , Perrin Paul , Wilbaux Melanie , Henin Emilie , Freyer Gilles , Tod Michel , You Benoit
Published: March 2020

e15182

Background: Early predictors of relapse after radical prostatectomy are needed. We previously showed that mathematical modeling of PSA kinetics provides a parameter, apparent PSA clearance (CLPSA), which may be a significant early predictor of biochemical relapse [1] (You et al; Prostate 2009;69:1325). Validation of these outcomes in an independent prospective study was warranted. Methods: As required by the initial study, four PSA values were prospectively measured during the first 50 days following radical prostatectomy in 119 patients with localized prostate cancer at our center. PSA values were centrally measured. The bi-compartment model previously reported in 2009 [1] was used to calculate patient CLPSA with NONMEM program. The predicted risk of biochemical relapse based on CLPSA cut-off previously defined (threshold at 0.048 [1]) was assessed using survival univariate and multivariate analyses. The primary endpoint was 3-year biochemical relapse free survival (3 y-bRFS). Results: The data from 119 patients treated with radical prostatectomy were analyzed. Among them 13 experienced a relapse after median 6.5 months. Despite large inter-individual variability, individual PSA decline profiles of patients were well fitted by the model. CLPSA categorized by the same cut-off previously described [1] was a significant predictor of 3 y-bRFS using log-rank test (97% vs 66%, p=0.009). Moreover it had independent significant predictive value when adjusted on other prognostic factors (D’Amico score) using multivariate Cox model (p<0.05). Conclusions: This prospective PSAMODEL studyconfirms modeled CLPSA calculated during the first 50 days after radical prostactectomy is a strong independent reproducible early predictor of biochemical relapse. It may easily be calculated using 4 PSA values after surgery. The potential role of this factor in adjuvant treatment adjustment may be studied. [1] You et al; Prostate 2009;69:1325
Cost-utility of proton therapy in the treatment of localized prostate cancer.
Authors: Goyal Ravi K. , Meyer Anne-Marie , Sheets Nathan Christopher , Federspiel Jerome J , Carpenter William Ruffin , Chen Ronald C. , Biddle Andrea K
Published: March 2020

e15184

Background: Proton therapy (PT) has received much public attention due to its higher costs and lack of evidence of clinical benefit compared to intensity modulated radiation therapy (IMRT) for prostate cancer treatment. In this economic study, we performed a threshold analysis to assess the reduction in toxicity that PT would need to achieve compared with IMRT to be considered cost-effective for the treatment of localized prostate cancer. Methods: SEER-Medicare data was used to identify a cohort, aged 66 years or older, receiving IMRT as definitive radiation therapy (n=4,540). We assumed equal disease control efficacy between IMRT and PT and simulated toxicity outcomes and costs using an incidence-based Markov model. The relative risk of composite toxicity, comparing PT to IMRT, was the efficacy parameter studied. Rates of therapy-induced toxicity associated with IMRT were obtained from SEER-Medicare data. Utility values to calculate quality-adjusted life-years (QALY) and costs (in 2011 US dollars) were obtained from the literature and claims data, respectively. Deterministic threshold analysis using a payer perspective and analytic horizon of 4 years post radiation was performed to determine the relative risk thresholds that would result in incremental cost-effectiveness ratios (ICER) of $50,000 and $100,000/QALY for PT versus IMRT. One-way sensitivity analyses were performed with the lowest and highest treatment costs of PT and IMRT. Results: ComparingPT against IMRT, the threshold values for the relative risk of composite toxicity were 0.318 and 0.588 at cost-effectiveness levels of $50,000/QALY and $100,000/QALY, respectively. Sensitivity analyses showed that the relative risk needed to achieve an ICER of 100,000/QALY ranged from 0.79 and 0.40 for the low and high cost estimates of PT, and from 0.47 to 0.72, for the low and high cost estimates of IMRT. Conclusions: Assuming equal disease control, PT would need to result in a 41% reduction in composite toxicity to be considered cost-effective in the treatment of Medicare beneficiaries with localized prostate cancer at a cost-effectiveness threshold of $100,000/QALY.
Enhancing decision making for treatment options and active surveillance in prostate cancer.
Authors: Gillespie Theresa Wicklin , Rowell Jessica Lauren , Echt Katharina V , Petros John , Lipscomb Joseph , Britan Laura , Herrel Lindsey Allison , Goodman Michael
Published: March 2020

e15187

Background: Prostate cancer (PCa), the most common malignancy among U.S. males, ranks second in tumor-specific mortality. African-Americans (AA) experience the highest rates of PCa mortality of any group. Many screen-detected PCa represent low-risk disease, and active surveillance (AS) may be a viable option in those cases; however, few men pursue AS. In December 2011, the NIH convened a State-of-the-Science Conference on the role of AS and issued a Draft Statement, highlighting knowledge gaps in treatment decision-making (DM) about AS. The purpose of this study was to determine strategies to enhance DM by men and their significant others (SO) about AS and other PCa therapies. Methods: This mixed methods design study (N=402, enrolled 2010-2011) investigated DM by men (N=204; 68% AA) with normal screening PSA and their SO (N=181; 65% AA) from 5 sites nationwide-51% from rural areas. Each site hosted 6 male and 6 SO focus groups. Data reported here include participant ranking of preferred source(s) for information about PCa therapies, including AS, and desired amount of treatment DM guidance. Results are from quantitative questionnaires analyzed using Fisher’s exact test, accompanied by two-sided p values, and qualitative data analysis utilizing Nvivo8. Results: A greater proportion of participants who were AA (62% vs 36%, p<0.0001), those with lower health literacy (60% vs 47%, p=0.0144), and those self-identifying as having lower income levels (55% vs 43%, p=0.0372) preferred the primary care physician (PCP) vs. specialists or other health care providers as the main resource for DM related to AS and PCa. Qualitatively, PCPs were compared to “quarterbacks” who can solicit and coordinate information from the “whole team”. Over 90% of respondents overall indicated they would prefer major DM guidance (4/5 on scale of 1 to 5) from providers. Acceptance of AS as a treatment strategy was accompanied by themes of worry, insufficient provider-specific information, uncertainty, and need for care coordination. Conclusions: Men and their SO have important needs and preferences related to PCa DM in general, but AS in particular. Critical to better informed DM is more effective communication with providers, coordinated by an engaged PCP.
Cost-effectiveness of denosumab (D) versus zoledronic acid (Z) for skeletal-related event (SRE) reduction in bone-metastatic prostate cancer (mPC) in the United Kingdom.
Authors: Botteman Marc , Carter John A. , Fishman Peter , Chandiwana David , Bains Manjinder , Snedecor Sonya J.
Published: March 2020

e15189

Background: D reduced SREs vs Z in a phase III trial, but no significant differences in overall survival, disease progression, or serious adverse events were reported. The cost-effectiveness of D vs Z in mPC was assessed from a UK payer perspective. Methods: A literature-based Markov model estimated quality-adjusted life-years (QALYs), number and costs of SREs, and drug/administration costs for mPC pts receiving D or Z for 27 mo (trial timeframe) and 60 mo (extended lifetime analysis). Current list prices/injection (£309.86 for D; £174.14 for Z) were used in the base case. As the model’s analytical horizon starts June 2012 and extends beyond generic Z availability in May 2013, a generic Z price (53% < list price, per data for other now-generic bisphosphonates) was used beyond May 2013 in scenario analysis. In other analyses, discounted prices (–30%) were used for both D and Z to assess the effect of price reductions on cost/QALY. Clinical inputs were selected to reproduce trial outcomes. QALYs were estimated by assigning utility weights to time spent in health states (no SRE; SRE; post-SRE; death). SRE costs were £250 to ≥ £6,000/event. Results: Although D may result in fewer SREs, higher QALYs, and lower SRE-related costs (Table), higher acquisition cost of D results in substantially higher costs and may be cost-ineffective in every pricing scenario. Similar results were found for the 27-mo analysis. Conclusions: The incremental cost/QALY gained with D vs Z ranged from £50,000 to £215,000 (> traditional £30,000 threshold), thus raising important questions about D’s value in mPC. [Table: see text]
Risk of adverse cardiovascular events (CVE) and incident diabetes mellitus (DM) in patients (pts) with prostate cancer (PC) treated with androgen deprivation therapy (ADT): A meta-analysis of adjusted observational results.
Authors: D'Ambrosio Lorenzo , Brusa Federica , D'Ascenzo Fabrizio , Cavallero Erica , Biondi-Zoccai Giuseppe , Boccone Paola , Bironzo Paolo , Levin Glenn N , Eckel Robert H , Milani Richard V , Sagalowsky Arthur I. , Gasparini Mauro , Grignani Giovanni , Gaita Fiorenzo , Ciuffreda Libero , Aglietta Massimo
Published: March 2020

e15192

Background: ADT is a mainstay treatment in pts with PC and is supposedly associated to an unfavorable metabolic and cardiovascular profile. Recently, a meta-analysis of randomized controlled trials (RCT) found no association between ADT and increased risk of CVE (JAMA 2011). However, no conclusive data were available about ADT association with metabolic changes and adverse CVE or DM because of pts selection in RCT. Therefore, we performed a meta-analysis of adjusted observational results in order to look for DM and CVE onset in an ADT unselected population. Methods: Medline, Cochrane Library and Biomed Central were searched for articles addressing adverse events related to ADT in patients with PC. Selection criteria were: not RCT, pts assigned to ADT or not, adjusted risk of CVE and DM according to ADT. Exclusion criteria were: duplicate publication, comparison of two different strategies of ADT (different drugs or duration). Cardiovascular death was the primary endpoint; non-fatal myocardial infarction (MI), stroke/transient ischemic attack (TIA) and new DM onset were secondary endpoints. Random effects model with generic inverse variance weighting was used to estimate adjusted risks as odds ratios (OR) with 99% confidence interval (CI). Results: We selected 12/2100 screened studies. We included 208643 pts of which 102177 received ADT. At a follow up of 5 years (4-7.5), ADT did not result as an independent risk factor for cardiovascular death (OR= 1.04; 99% CI= 0.94-1.14). No increased risk of MI (OR= 1.13; CI= 0.86-1.48) or of stroke/TIA (OR= 1.11; CI= 0.78-1.57) were detected. Incident DM was more frequent among ADT pts (OR= 1.32; CI= 1.14-1-53). Even in 7205 pts with previous CVE (2450 received ADT), ADT was not associated with an increased risk of overall death (OR= 1.23; CI= 0.87-1.75). Meta-regression analysis showed no significant interactions between duration of ADT and cardiovascular death or incident DM. Conclusions: In non-selected pts,ADT appears to increase the risk of incident DM, but not of CVE or stroke/TIA. Moreover, overall mortality is not increased in pts with a history of CVE.
Patterns of second-line chemotherapy for metastatic prostate cancer in the United States.
Authors: Wang Hongwei , Liao Laura , Obi-Tabot Eliot , Sands Robert , Rose Mathieu , Zhang Quanwu
Published: March 2020

e15193

Background: Patients with prostate cancer progressing from first-line (1L) docetaxel have limited approved treatment options available. Study is to evaluate patterns of second-line (2L) chemotherapy in a US managed care between 2004 and 2010. Methods: Patients with metastatic prostate cancer (mPC) and treated with docetaxel as 1L chemotherapy after July 1, 2004 were ascertained from the OptumInsight database. We evaluated type and timing of chemotherapy and relationships between patient characteristics, physician specialty, healthcare costs and geographic region, 6 months prior to 1L docetaxel and choice of 2L chemotherapy. Results: Patients (N=1,173) were on average 71 yrs old at onset of 1L docetaxel. During a mean follow-up period of 18 months, 38% of patients received 2L treatment. Out of the patients received 2L therapy, 32% received mitoxantrone (MITO), 24% with docetaxel rechallenge (RECH), 14% carboplatin (CARB), and 12% paclitaxel (PAC), plus 11% on Combo therapy. Examination of the 2L treatment groups showed that during the 6 months prior to 1L docetaxel, the RECH group (n=101) was older (73yrs), had fewer hospital admissions (12%), lower comorbidity burden [Charlson Comorbidity Index (CCI)=7.4], lower total healthcare costs ($10,083), and 78% seeing an oncologist; relative to MITO group (n=143) with 70 yrs, 16% hospital admissions, CCI of 7.5, total healthcare costs of $12,074, and 80% seeing an oncologist. The combo group (n=52) was 66 years old, with 19% hospital admissions, CCI of 8, total healthcare costs of $20,505, and 92% seeing an oncologist. Median time to MITO from the start of 1L docetaxel was 184 days, 309 days to RECH and 223 days to Combo therapy. Midwest (36%) and West (37%) were more frequently using MITO than Northeast (26%) and South (31%), while RECH was more frequently used in Northeast. Conclusions: Patients with mPC in US were most frequently treated with MITO or RECH as 2L chemotherapy after 1L docetaxel. MITO was also given sooner than RECH, hence a valid comparator for comparative effectiveness evaluation on new 2L therapy. Rechallenge with docetaxel increased with time and was given to patients with lower disease burden and healthcare costs than the MITO or Combo group.
Survey on management of metastatic hormone-refractory prostate cancer upon progression during or following first-line chemotherapy in five European countries.
Authors: Auziere Sebastien , Flinois Alain , Obi-Tabot Eliot , Rose Mathieu , Parnaby Adam
Published: March 2020

e15198

Background: In Europe, docetaxel is the standard first-line chemotherapy (1L) for patients with metastatic hormone-refractory prostate cancer (mHRPC). Upon progression, either during or after 1L chemotherapy, treatment options are limited. This study evaluated how patients who progressed during or after 1L docetaxel between Oct 2009 and Jun 2010 were managed. Methods: A representative sample of 349 physicians (oncologists, urologists) who managed patients with mHRPC selected from Germany, France, UK, Spain and Italy were surveyed. Information on the treatments used at the time of progression (during or within the first 6 months following 1L treatment with docetaxel was provided. Results: Information on a total of 2,870 mHRPC patients was provided of which 2,670 (94 %) had received docetaxel in 1L. 1,389 (52%) patients progressed during 1L docetaxel or within 6 months following treatment; of these, 615 (44 %) received as 2L chemotherapy (Table). Conclusions: In this study, mitoxantrone was the most commonly used chemotherapy agent for 2L treatment of patients with mHRPC who progressed during treatment or within the first 6 months following the end of 1L. Docetaxel rechallenge was uncommon for patients experiencing progression early, during or after the end of 1L. [Table: see text]
Prelinical evaluation of selective inhibitors of nuclear export (SINE) CRM1 (XPO1) inhibitors in prostate cancer (PrCa).
Authors: Shacham Sharon , Gravina Giovanni Luca , Ricevuto Enrico , Mancini Andrea , Chin Lynda , Shechter Sharon , Sandanayaka Vincent , McCauley Dilara , Kauffman Michael , Draetta Giulio Francesco , Festiccia Claudio
Published: March 2020

e15200

Background: CRM1 (XPO1) is the sole exportin mediating transport of multiple tumor suppressor proteins (TSP) including p53, pRB, FOXO, APC and NPM1 out of the nucleus, abrograting their function. Many tumor types show overexpression of CRM1, thus extinguishing TSP function. CRM1 inhibition forces nuclear accumulation of TSPs inducing apoptosis in cancer cells. Methods: MSKCC PrCa gene database was used for mRNA analyses. Inhibition of CRM1 mediated NE was determined by IHC. MTT assays were used to determine cytotoxicity across divergent PrCa lines: LAPC-4 (p53wt, AR+, low Akt/mTOR); LnCaP (p53wt, AR+, high Akt/mTOR); LnCaP-C81 and LnCaP-C4-2B (p53wt, AR+, androgen independent, high Akt/mTOR); 22rv1 (p53wt, AR+, androgen independent, low Akt/mTOR); PC3 (p53-del, AR–, high Akt/mTOR), DU145 (p53mut, AR–, low Akt/mTOR). BPH1 and prostatic epithelial line EPN were used as non-neoplastic controls. 22rv1 xenografts were initiated in the flanks of SCID mice and treatment begun when tumors reached ~150mm3. Results: Analyses of nuclear pore complex (NPC)-related mRNA levels shows coordinate regulation of transcripts and allow PrCa to be segregated into high and low NPC expression. Low NPC expressing tumors tended to have reduced AR expression; APC, NPM1, and RB1 mRNA levels were also low (p<10e-12) and p16INK4A levels were elevated. As NE is dysregulated in PrCa, we assessed the effects of SINE, irreversible CRM1 inhibitors, across PrCa cell lines. SINE block CRM1 mediated nuclear export of TSPs with IC50 values <100 nM in all tested cell lines. SINE are selectively cytotoxic for neoplastic (EC50 10-1000nM) versus non-neoplastic lines (EC 50 >5-20µM). SINE cytotoxic effects are independent all tested genetic alterations. In the aggressive, androgen independent 22rv1 xenograft, oral SINE KPT-251 showed dose-dependent inhibition of tumor growth and synergy with cisplatin. Conclusions: These data show that PrCa shows coordinate NPC regulation, and that selective blockade of CRM1 dependent NE represents a completely novel, neoplasia-selective and well-tolerated target for use as single agent or in combination with chemotherapy for PrCa.
Retrospective mathematical analysis of serial prostate specific antigen (PSA) measurements for patients with M0 prostate cancer treated with intermittent androgen suppression (IAS).
Authors: Higano Celestia S. , Hirata Yoshito , Akakura Koichiro , Bruchovsky Nicholas , Aihara Kazuyuki
Published: March 2020

e15201

Background: Recently a phase III trial demonstrated that IAS was non-inferior to continuous AS in men with M0 disease after primary or salvage radiation and quality of life was better in the intermittent arm (Crook ASCO 2011). In that trial, men were treated with 8 months of AS followed by a variable time off AS driven by the absolute PSA value. The Hirata mathematical model describes the dynamics of prostate cancer treated with IAS (Hirata et al, J of Theoretical Biol 2010). In the model, there are three classes of cancer cells: a class of androgen dependent (AD) cells and two classes of androgen independent (AI:X1 and AI:X2) cells. During AS, AD cells will change to the two AI classes, and during the off treatment period, AI:X1 cells will revert to AD cells whereas AI:X2 cells cannot revert to either AD or AI:X1 cells. Methods: After IRB approval, we applied the Hirata model using serial monthly PSAs from men with M0 disease treated with IAS from Japan, Canada, and the United States. The proportions of men from each country who fell into the 3 categories of patients previously defined by the Hirata model were compared. Results: Serial PSAs from 26 men from Japan, 72 from Canada, and 79 from US were put into the model. The 3 categories of patients from the model include: (i) those with disease that will remain androgen sensitive and will respond to IAS without development of castration resistance (CRPC) (ii) those who will benefit from IAS but will develop CRPC sooner than those in group (i), (iii) those for whom continuous AS is superior to IAS. The datasets from each country show a similar distribution among the categories, and overall there were 42%, 51%, and 7% falling into groups i, ii, and iii respectively. Conclusions: This retrospective analysis shows that men with M0 disease treated with IAS fall into the 3 categories predicted by the Hirata model in similar proportions, regardless of country of origin. The ability to apply this model to the individual patient in the clinic is currently under development. The model may ultimately be able to optimize both the on and off treatment durations of IAS and to predict those patients who will most benefit from this approach.
NF-κB p65 as a prognostic tool in prostate cancer: An immunohistochemical study from biopsy samples.
Authors: Labouba Ingrid , Gannon Philippe O. , Forest Valerie , Le Page Cécile , Storoz Cristina , Lessard Laurent , Mes-Masson Anne-Marie , Saad Fred
Published: March 2020

e15202

Background: Our previous immunohistochemical studies of NF-κB p65 in prostate cancer (PCa) highlight its clinical potential as a prognostic marker in different cohorts of Canadian and European men. However these studies are essentially based on tissue microarrays (TMAs) built from samples obtained from radical prostatectomy specimens where other prognostic parameters, such as pathologic stage, Gleason score, and margin status are also available. However, limited prognostic parameters are available to clinicians at the time of diagnosis. The current study aims to assess whether the immunohistochemical staining of p65 could offer prognostic information at the time of diagnosis and help risk stratify patients. Methods: Prostatebiopsies were obtained from a cohort of 328 prostate cancer patients who were further treated by radical prostatectomy. NF-κB p65 was stained by immunochemistry on biopsy samples containing malignant tissue. The nuclear frequency was quantified as a percentage of positive p65 nuclear cells. Results: Our first statistical analyses revealed that the nuclear frequency of NF-κB p65 on biopsy samples was correlated with clinical paramaters as final Gleason score and BCR. Patients with Gleason score post-prostatectomy of 7 or more had a higher NF-κB p65 nuclear frequency in biopsy samples (p<0.05, Student test). NF-κB p65 nuclear frequency was also higher in patients developing a BCR and bone metastasis (p<0.05, Student test). Conclusions: These preliminary results show an association between NF-κB p65 nuclear distribution in biopsy samples and PCa aggressivity. We showed that NF-κB p65 immunohistochemical staining on biopsies was predictive of BCR. NFkB p65 may be prognostic marker at the time of diagnosis and could eventually be useful in clinical decision making.
Targeting mTOR and VEGF in CRPC: Preliminary results of a phase I/II trial of temsirolimus (T) and bevacizumab (B) in docetaxel-refractory metastatic CRPC.
Authors: Garcia Jorge A. , Elson Paul , Cooney Matthew M. , Tyler Allison Janine , Dreicer Robert
Published: March 2020

e15208

Background: Despite the availability of novel agents in the docetaxel-refractory setting, their activity is often short lived as all pts eventually progress. Activation of the PI3K/AKT/mTOR/VEGF/CXCR6 pathway regulates proliferation, differentiation, and malignant transformation in PCa progression. mTOR inhibition inhibits CXCL16, IL8/VEGF levels and other CXCR6 targets including CD44 and matrix metalloproteinase 3. Combination strategies capable of blocking the CXCR6/VEGF/AKT/mTOR signaling pathway could become a more effective therapeutic strategy for CRPC. Methods: Eligible docetaxel-refractory CRPC pts had serologic or objective PD after 1 or 2 prior chemotherapies. Pts with CNS metastases or active spinal cord compression were excluded. A staged-cohort design to study primarily safety of the combination was undertaken. Once the MTD was established a two-stage phase 2 trial was implemented. An underlying ORR >20% was deemed sufficient to warrant further study, whereas an ORR rate <5% would not. Starting doses of T and B were 15mg wk and 5mg/kg e/2 wk. Exploratory endpoints included CTCs, VEGF levels and Th1 cytokine production. Results: To date 22 of a total planned 28 pts are enrolled, median age was 64 and half of the pts were ECOG 1. Most pts had bone disease and the median PSA was 205 ng/mL. Pts have received a median of 4 cycles of treatment (range: 1-12). All pts have discontinued therapy; 48% PD, 38% AEs and 5% consent withdrawal. PSA reductions were observed in 30% of pts. No RECIST defined PR was seen. The most common AEs included anorexia (67%), mucositis (53%), fatigue (57%) and myelosuppression in over 60% of pts. CTC analysis and VEGF/TOR and cytokine levels are currently underway. Conclusions: The combination of T and B demonstrated significant toxicity in a heavily pretreated CRPC pt population. Minimal antitumor activity was observed. Exploratory studies and their correlation with clinical outcome are underway.
The incidence of vascular, genitourinary, and intestinal tract injuries in gynecologic oncology: An extensive, single institutional experience.
Authors: Rettenmaier Christopher , Rettenmaier Nicholas , Abaid Lisa , Mendivil Alberto , Brown John V. , Micha John P. , Lopez Katrina , Wojciechowski Tomasz , Goldstein Bram
Published: March 2020

e15500

Background: Iatrogenic vascular, genitourinary, and intestinal tract injuries are an unfortunate consequence in gynecologic surgery because the uterus and ovaries are adjacent to critical pelvic structures. The incidence of these complications in general gynecology reportedly varies from 0.3-8.0%; conversely, in gynecologic oncology, the rate is presumably higher although the outcomes are not well documented. Methods: We reviewed the charts of gynecologic oncology patients treated at a single medical institution from January 2003 to February 2011. The following study variables were noted for evaluation: patient characteristics (age, body mass index (BMI)), medical history, cancer origin (e.g., ovarian, uterine), disease pathology, previous pelvic surgery, injury type (genitourinary, vascular or intestinal tract) and injury diagnosis (intra- or post-operative). Descriptive analyses were initially employed, followed by further evaluation of the clinicopathologic parameters via logistic regression, ANOVA and Cox proportional-hazard ratios. Results: In the current, retrospective investigation, 810 gynecologic cancer patients were identified; from this group, there were 25 (3.1%) intestinal tract, 10 (1.2%) genitourinary and 20 (2.5%) vascular injuries encountered. The logistic regression model classified correctly 84% of the injuries. Moreover, a Cox proportional hazard model revealed that cancer origin (p=0.023), previous pelvic surgery (p=.003), BMI (p=0.002) and disease stage (p < 0.01) were surrogate markers for operative injury occurrence. Conclusions: The incidence of vascular, genitourinary and intestinal tract injuries in this large group of gynecologic oncology patients was quite reasonable. Fortunately, when these conditions arise, gynecologic oncologists have extensive surgical experience and are well prepared to address them. Additional study of the clinicopathologic factors that may predispose these cancer patients to a surgical complication is necessary.
Recurrence patterns in patients with stage IIIC1 versus IIIC2 endometrial adenocarcinoma.
Authors: Bevan Catherine , Nagel Christa Irene , Boren Todd Patrtick , Miller David Scott , Kehoe Siobhan Marie , Richardson Debra L. , Lea Jayanthi
Published: March 2020

e15501

Background: To identify differences in recurrence patterns between stage IIIC1 and IIIC2 endometrial adenocarcinomas. Methods: A retrospective review was performed with IRB approval of all patients treated for stage IIIC1 and IIIC2 endometrial adenocarcinoma at our institution from 1989-2011. Patients were required to have comprehensive surgical staging including total abdominal hysterectomy, bilateral salpingo-ophorectomy, pelvic and paraaortic lymph node dissection. Descriptive statistics were performed using Microsoft Excel 2011 and Fischer’s exact test, Kaplan-Meier analyses were used to compare disease free (DFS) and overall survival (OS). Results: Eighty-seven patients with stage IIIC endometrial adenocarcinoma were identified, of which 69 were evaluable. The mean age was 59 years and the mean follow up was 32 months. There were 31 patients with stage IIIC1 and 38 patients with stage IIIC2 disease. There was no statistical difference in histology between the two groups: 47 endometrioid, 11 papillary serous, and 11 with other types of adenocarcinoma. Patients with stage IIIC1 disease were more likely to receive pelvic radiation (p=0.0004) and patients with IIIC2 disease were more likely to receive chemotherapy (p=0.014). Median DFS was 28.9 months (range 0-112) and 15.0 months (range 0-166) (p=0.017) and median OS was 31.9 months (range 0-134) and 18.0 months (range 0-166) (p=0.061) for the IIIC1 and IIIC2 groups respectively. Seven of 31 (23%) patients with stage IIIC1 disease recurred: 1 (14%) at the vaginal cuff and 6 (86%) distant. The patient who recurred locally was initially treated with chemotherapy alone. Of the 6 patients with distant recurrences only 1 received chemotherapy. Twelve of the 38 (32%) patients with stage IIIC2 experienced a recurrence: 6 (50%) vaginal/pelvic and 6 (50%) distant. There was a difference between the rates of local versus distant recurrence in patients with IIIC1 and IIIC2 endometrial cancer. Conclusions: IIIC1 patients were less likely to receive systemic chemotherapy and more likely to recur distantly. Our findings suggest a role for adjuvant chemotherapy and radiation in the frontline treatment of both IIIC1 and IIIC2 endometrial cancer.
Hormone receptor expression and risk of recurrence in patients with high-risk endometrial carcinoma treated with chemotherapy.
Authors: Barrett Olivia Claire , Burnett Omer L. , Conner Michael G. , Li Yufeng , Estes Jacob Michael , De Los Santos Jennifer F.
Published: March 2020

e15502

Background: Poor long-term survival in high-risk endometrial cancer patients attests to a need for new therapeutic strategies. The prevalence of estrogen (ER) and progesterone receptors (PR) among high-risk endometrial carcinomas has not been systematically studied and is a target to which individualized therapies may be tailored. Methods: 41 women with high grade, stage III/IV and/or aggressive histology endometrial cancer who received post-hysterectomy chemotherapy were identified. Patient, tumor and treatment characteristics were recorded. Immunohistochemical staining of ER and PR was scored on a 0-4 scale incorporating intensity and extent of expression. Receptor-positivity was defined as a score of >= 2. Univariate and multivariate logistic regression analysesand the Cox proportional hazards model were performed to examine hormone receptor expression and recurrence risk. Results: Median age at surgery was 59 years (range 34-79). Median follow up time was 39 months (range 1-82). Recurrence occurred in 21 women (51%) with median time to first recurrence of 19 months (range 1-71). 22 cancers (54%) were ER+ and 21 (51%) PR+. Median ER and PR expression was 2 and 2, respectively (range 0-4). While ER and PR were not independent factors for recurrence, on multivariate logistic regression analysis ER and PR as continuous values showed recurrence associated with greater ER expression (p = 0.0836) and lesser PR expression (p = 0.0986). Cox proportional hazards model supported the association between increasing ER and decreasing PR with shorter recurrence free survival (p=0.0034, p = 0.0021). An increase in ER score of 1 corresponded to a hazard ratio (HR) of 2.647 (95% CI 1.38-5.08); an increase in PR score of 1 corresponded to a HR of 0.362 (0.19-0.693). Conclusions: More than 50% of high-risk endometrial cancers in this small retrospective cohort receiving cytotoxic chemotherapy expressed positive hormone receptors. Multivariate analyses of hormone receptors suggest increased recurrence with discordant expression of ER and PR. Further investigation is warranted to verify whether differential hormone receptor expression predicts poorer response to cytotoxic systemic therapy.
Prediction of major surgical complications by comprehensive geriatric assessment in elderly patients with gynecologic cancers: A prospective cohort study.
Authors: Kim Jae Weon , Suh Dong-Hoon , Kim Jae Hoon
Published: March 2020

e15503

Background: To evaluate the ability of a preoperative comprehensive geriatric assessment (CGA) to predict the risk of postoperative complications in elderly patients who underwent primary surgery for gynecologic cancers. Methods: Fifty-six consecutive patients (24 ovarian, 15 cervical, 6 endometrial, 5 uterine sarcoma, 4 vulvar, and 2 metastatic cancers) older than 70 years scheduled to take surgery electively for gynecologic cancer were preoperatively assessed by CGA. Every category of CGA was evaluated for in-hospital postoperative complications and mortality within 30 days of surgery. Major complication included any complication of 2 or higher grade according to Memorial Sloan-Kettering Surgical Complication Criteria 12/99. Results: Mean age was 73.5±3.5 years (range 70-85). Overall postoperative complication rate was 28.6% (16/56) with 7 (12.5%) and 6 (10.7%) being major and multiple complications, respectively. Mean hospital stay was 18.7±13.6 days (range 3-81), during which in-hospital mortality was 2 (3.6%). There was no postoperative complication that occurred after discharge within 30 days of surgery. Dependent instrumental activity of daily living (IADL) was associated with high incidence of postoperative complication, especially for multiple complications. However, poor performance status (PS) was associated only with major and multiple complications. Multivariate regression analysis revealed that only poor PS was associated with postoperative in-hospital mortality (p=0.006). Conclusions: IADL and PS were useful to predict postoperative complication, in particular, major and multiple complications, in elderly patients with gynecologic cancers. Major and multiple postoperative complications can be prevented by identifying the elderly patients with gynecologic cancers who showed dependent IADL and poor PS in CGA.
Evaluation of the overall survival rates in locally advanced cervix cancer patients treated with radiotherapy alone and chemoradiation: A Brazilian experience.
Authors: Campos Conceicao Souza , Salvajoli Joao Victor , Novaes Paulo Eduardo , da Silva Marcelo Gurgel
Published: March 2020

e15509

Background: Locally advanced cervical cancer is a major worldwide health problem. The treatment might include radiotherapy and few trials evaluate the timing of pelvic external irradiation (RT) and high dose rate brachytherapy (HDR) in local control and survival rates of these patients as well as the addition of chemotherapy. The objective were to evaluate the overall survival rates in locally advanced cervix cancer patients and determine the clinical and treatment prognostic factors for local control and overall survival rates. Methods: A retrospective cohort study was carried out with 261 patients stage IIIB, 164 patients received 54 Gy RT to the pelvis and 30 Gy HDR without chemotherapy and 97 patients received 54 Gy RT to the pelvis and 30 Gy HDR with weekly cisplatin 40mg/m2 IV (CDDP) from August 1998 to June 2004 in Hospital Haroldo Juacaba, a Brazilian northeastern hospital. The mean follow-up time was 50 months (2-185 months) and the Kaplan-Meier method was used to calculate survival curves. The Cox regression was used to evaluate multivariate analysis and p values =<0.05 was considered significant. Results: Local control and 5-year survival rates were 39.6% and 38.4% for exclusively radiation and 50.5% and 47.4% for chemoradiation (p = 0.19 and p = 0.36, respectively). The mean treatment time was 61 days. Both local control and overall survival rates were affected by age, parametrial involvement and the timing of brachytherapy (p<0.05). The overall treatment time did not influence survival or local control rates (p>0.05). But less than six cycles of chemotherapy improved local control rates better than six or more cycles (55.1% versus 44.9% p = 0.02). Conclusions: The study is a nonsuperiority one where the addition of weekly chemotherapy with six cycles of CDDP 40mg/m2 during the irradiation did not improve overall survival rates. Further prospective studies would be useful to evaluate the benefit of adding weekly chemotherapy to the standard radiotherapy treatment as well as the financial impact of the adoption of this international guideline in patients with advanced lesions from developing countries.
Proteomics of the ascitic fluid for the differentiation of advanced ovarian cancer.
Authors: Hariprasad Gururao , Hariprasad Roopa , Kumar Lalit , Kaushik Amit , Srinivasan Alagiri
Published: March 2020

e15510

Background: Ovarian cancers are classified as primary, if it arises in the ovary and secondary or metastatic, if the origin is from other parts of the body. The clinical manifestations of these cancers in the advanced stage are very similar making it difficult to distinguish clinically, hiostopathologically and radiologicaly. The therapeutics and management of the primary and secondary malignancies are completely different. While, the advanced primary malignancies are treated by cytoreduction followed by chemotherapy, the metastatic tumors are treated mainly with palliative chemotherapy. The prognosis is better for primary than secondary ovarian cancer making their diagnosis very crucial for patient care. Methods: 1D and 2D-gel based proteomic approaches were used to study the differentially expressed proteins in the ascitic fluid of patients (10 primary and 4 secondary) with advanced ovarian cancer. The relative ratios of the protein expression were estimated by densitometric analysis. The bands/spots with more than three fold difference were subjected to in-gel trypsin digestion and identified by mass spectrometric analysis. The differential expression of one of the proteins was further validated by western blot experiments and ELISA. Results: Programmed Cell Death 1-Ligand 2 and apolipoprotein A1 were seen to be up regulated in the advanced primary ovarian cancer while apolipoprotein A4, and chain L, humanized version of the anti-human fas antibody Hfe7a were seen to be up regulated in the metastatic variant. Validation for the expression of apolipoprotein A1 shows that a 61.8ng/ml cut off is ideal to differentiate the primary and secondary advanced ovarian cancers. The assay has 100% sensitivity, 75% specificity, positive predictive value of 90.9%, negative predictive value of 100%, accuracy of 92.85% and a pre-test odds positive of 2.5. Conclusions: Proteomics of ascitic fluid is useful for the differentiation of advanced ovarian cancers. There are proteins which are differentially expressed in the ascitic fluid of patients with primary and secondary ovarian cancer. Apolipoprotein A1 is a potential biomarker that can be used to differentiate the closely mimicking clinical scenarios of advanced ovarian cancer.