bluuebunny/crossref_metadata_2025 huggingface dataset:
Secondary rectal malignancy risk reduction with IMRT and rectal balloon placement during radiation therapy.
Authors: Ng John , Burri Ryan J. , Horowitz David Paul , Cesaretti Jamie A. , Kao Johnny , Thompson Dawn , Stephens Talitha , Chao K. S. Clifford , Brenner David J. , Shuryak Igor
Published: March 2020

e15162

Background: The risk of secondary rectal malignancies (SRMs) is a significant concern following radiation therapy for prostate cancer patients. Modern prostate radiotherapy techniques include the use of intensity modulated radiation therapy (IMRT) and rectal balloons to decrease treatment related toxicity. These technologies may also lower the likelihood of radiation-induced SRMs. In this study, a novel biologically-based carcinogenesis model was used to quantify and to compare the predicted risks of SRMs in men treated with or without a rectal balloon in place using either standard 3-D conformal radiotherapy (3D-CRT) or IMRT radiotherapy. Methods: Treatment plans were developed for ten clinically localized prostate cancer patients using CT scans obtained both with and without a rectal balloon in place. Target and normal structures were contoured, and dose-volume histograms (DVHs) for these organs were determined with a planned 3D-CRT dose of 75.6 Gy or with a planned IMRT dose of 81 Gy. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk of SRMs for each plan. These risks were then compared to one another and to the baseline population. Results: Treatment with IMRT and a rectal balloon in place resulted in a significantly lower mean rectal wall dose in all patients compared with treatment with 3D-CRT without a rectal balloon. The average mean rectal wall dose with IMRT and a rectal balloon in place was 31.0 Gy versus 40.1 Gy with 3D-CRT without the rectal balloon (p < 0.001). A significantly higher risk of SRMs was predicted for patients treated with 3-D CRT without rectal balloons when compared with patients treated with IMRT with balloons in place (p < 0.001, relative risk 1.30; 95% confidence interval 1.16-1.44). Conclusions: For prostate cancer patients treated with definitive radiotherapy, the use of IMRT and rectal balloons during radiation, when compared to treatment with 3-D conformal radiotherapy, is associated with a significant reduction in the predicted risk of secondary rectal malignancies.
Assessment of abiraterone (ABI) tumor cell activity via in vitro models of androgen (A)-responsive prostate cancer.
Authors: Hickson Ian , Marien Ann , Derks Maarten , Janssen Marc
Published: March 2020

e15166

Background: Inhibition of CYP17 by abiraterone acetate (AA) blocks A biosynthesis, reduces A levels and results in inhibition of A-dependent tumor growth. AA has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (HR = 0.74) (Scher, ASCO 2011). AA is converted to ABI in vivo. This study investigates whether direct effects of ABI on tumor cells (ie, blockade of intratumoral A synthesis) may contribute to the clinical efficacy of AA using in vitro models. Methods: LNCaP cells (human prostate cancer cell line [HPCCL]) were grown in 2D and 3D cultures, and ABI activity was assessed by reduction of androgen receptor (AR) output in gene expression profiling (Affymetrix microarray), reporter assay, and by immunoblot for A-responsive signals. Using ABI-sensitive LNCaP cells, responses were further characterized in the presence or absence of ligand (dihydrotestosterone [DHT]) and with A-targeting agents TOK-001 and MDV3100. Results: ABI exposure resulted in dose-dependent modulation of A-dependent gene expression in Affymetrix microarray analysis of 2D and 3D cultures. Similar results were seen in an analysis of AR-dependent protein and in an AR-driven reporter assay in 2D LNCaP or VCaP (another HPCCL) cell culture. In LNCaP, AR output was inhibited by low concentrations of ABI (IC50 100-300 nM), comparable to TOK-001 (IC50 30-100 nM) and less potent than MDV3100 (IC50 10-30 nM). Growth inhibition (MTT assay) occurred at concentrations 10-fold higher for all compounds. For ABI and TOK-001, inhibition of AR output was reduced by DHT (30- to 100-fold increase in IC50); with MDV3100, the shift in IC50 was less (10-fold) with agonism of AR output at low nM concentrations. Conclusions: ABI has an inhibitory effect on AR output in LNCaP cells. Partially overcoming this inhibition through addition of DHT implies that CYP17 inhibition and the subsequent A reduction play a role in the intratumoral activity of AA. However, persistent inhibition of AR output in the presence of DHT implies additional anti-A effects of AA in prostate tumor cells. This model may provide a useful tool for the study of AR-targeted therapies, combinations of agents, and resistance to agents targeting A.
VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).
Authors: Eisner Joel Robert , Abbott David H , Bird Ian M , Rafferty Stephen W , Moore William R , Schotzinger Robert J
Published: March 2020

e15167

Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extra-gonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995-2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.
Validity and utility of the University of Texas M. D. Anderson Symptom Inventory (MDASI) among prostate cancer patients: Data from E2Z02: Symptom Outcomes and Practice Patterns (SOAPP).
Authors: Patrick-Miller Linda J. , Zhao Fengmin , Cleeland Charles S. , Wagner Lynne I. , Fisch Michael , Mendoza Tito R.
Published: March 2020

e15173

Background: Optimal treatment outcomes for patients (pts) with prostate cancer are dependent upon rigorous symptom assessment. The MDSAI, a patient-reported outcome measure of symptoms (sxs) and their impact validated in a sample of patients of diverse cancer types has the potential to inform symptom experience and guide treatment specific to prostate cancer pts. Methods: SOAPP, an Eastern Cooperative Oncology Group (ECOG) study, was conducted at academic and community medical oncology clinics and included pts with prostate cancer of all stages and phases of care. At baseline and 4 weeks, pts completed a measure of symptom severity and functional interference (MDASI). Symptom experiences and psychometric properties of the MDASI in prostate cancer pts (n = 320) were analyzed. Results: The 5 most prevalent moderate/severe sxs reported at baseline were fatigue (34%), disturbed sleep (25%), drowsiness (18%), pain (17%), and dry mouth (15%); moderate/severe nausea (5%) and vomiting (2%) were the least prevalent. At baseline ECOG performance status (PS) was ≥2 in 9% of pts. Pain, sadness, and difficulty remembering things occurred in 17%, 14%, and 13% respectively, and among pts whose PS worsened, severity of these sxs had the highest change scores at follow-up. Internal consistency and test-retest reliability of the MDASI were good, with Cronbach coefficient alphas ≥0.84 and intra-class correlations ≥0.78 for all subscales. Significantly higher scores and moderately large effects for the MDASI severity scale were reported by pts with poorer PS (2.2 vs 1.0, ES=.83) and tumor progression (2.4 vs 1.2, ES=.73) p<.05. Results were similar for the interference scale, demonstrating MDASI known-group validity. Pts whose quality of life declined showed significantly greater increase in severity (1.1 vs .14, p<.01) and interference (1.9 vs .28, p<.004) from baseline to follow-up than pts whose quality of life was unchanged, demonstrating MDASI sensitivity to change. Conclusions: The MDASI is a valid, reliable, and sensitive symptom assessment method for descriptive and clinical studies, and patient care in medical oncology outpatients with prostate cancer.
Detecting circulating tumor cells (CTCs) in patients with high-risk, localized prostate cancer using the CellSearch platform.
Authors: Pal Sumanta Kumar , Lau Clayton , He Miaoling , Twardowski Przemyslaw , Wilson Timothy G. , Kawachi Mark H. , Torres Alejandra , Carmichael Courtney , Yen Yun , Kortylewski Marcin , Jones Jeremy
Published: March 2020

e15178

Background: Enumeration of circulating tumor cells (CTCs) using the CellSearch platform has prognostic value in patients with metastatic castration resistant prostate cancer. However, the prognostic value of CTC enumeration in high-risk, localized prostate cancer (HRLPC) remains undefined. Methods: Patients with HRLPC (defined by ≥1 of the following criteria: ≥ cT3a disease, Gleason score 8-10, or PSA > 20 ng/mL) who have chosen prostatectomy for their definitive management were prospectively identified. Patients were consented to receive 4 sequential 30 mL blood draws, each collected in 3 separate 10 mL EDTA tubes. The first 2 blood draws were conducted 2 weeks prior and immediately prior to surgery, while the second 2 blood draws were conducted 4-6 weeks and 3 months following surgery. Within 4 hrs of blood collection, the white blood cell (WBC) fraction was pooled and Ficoll purified. The WBC fraction was transferred to a CellSave tube, and CTCs were enumerated using the CellSearch system. Expression of CD133 and E-cadherin was characterized using the CellSearch system in patients with detectable CTCs. Results: Within 3 monthsof study initiation in Nov 2011, 19 of a planned 37 patients have been accrued. Median age in the cohort was 65 (range, 51-74), and the number of patients with Gleason score 8-10, ≥ cT3a disease, or PSA > 20 ng/mL was 16, 4, and 2, respectively. The majority of patients (17/19, or 89%) had only one high-risk feature. Mean baseline PSA for the cohort was 11.4 (range, 3.4-37). CTCs were detectable in 67% of patients prior to surgery, 27% of patients at 1 month following surgery and 67% of patients at 3 months following surgery. Amongst those patients with detectable CTCs, the median count was 3 (range, 1-7). Further, in these patients, CD133 and E-cadherin were detected in 44% and 46% of specimens assessed, respectively. Full details of these analyses will be provided at the time of the meeting. Conclusions: Using a modified methodology, CTC enumeration using the CellSearch platform is feasible in patients with HRLPC. Interestingly, markers of epithelial-mesenchymal transition and stem cell lineage are detectable in a proportion of patients with localized disease.
Efficacy of abiraterone acetate in the treatment of castration-resistant prostate cancer: Early results from the German compassionate-use program.
Authors: Ohlmann Carsten Henning , Stöckle Michael , Pfister David A. , Heidenreich Axel , Merseburger Axel S. , Kuczyk Markus , Manka Lukas , Hammerer Peter , Albers Peter , Arsov Christian , Retz Margitta , Gschwend Jürgen E. , Feyerabend Susan , Stenzl Arnulf , Banek Severine , Marin Jan , Gleissner Jochen , Wirth Manfred , Zastrow Stefan , Heck Matthias
Published: March 2020

e15195

Background: Abiraterone acetate (AA) plus prednisone (P) has demonstrated an improved survival of patients with castration-resistant prostate cancer (CRPC) compared to placebo plus P in a large phase III trial. In Germany, patients were able to receive AA within a compassionate-use program (CUP). Here, we report the first results of the program. Methods: Patients were eligible for the CUP if they progressed on or after at least one cytotoxic chemotherapy regimens. For CUP entry, patients were considered to have disease progression if they had radiographic evidence of disease progression in soft tissue or bone with or without PSA-progression and ongoing androgen deprivation. Patients received AA 1000mg daily plus prednisone 5mg BID until progression of disease or unacceptable toxicity. Results: Between 02-05/2011, 398 patients were registered for the CUP in Germany. Data from 191/350 (47.9%) of the patients treated at 10 different sites were available for evaluation of efficacy. Median age was 70.72yrs (52.35-87.61) and patients received a median of 1 (1-4) chemotherapy lines prior to CUP entry. Median PSA at baseline was 220.5 ng/ml (0.47-4245); 168 (88%) of patients presented with bone metastasis. With regard to efficacy, 64/191 (33.5%) of the patients showed an unconfirmed PSA-response ≥50%. At a median follow-up of 5.3 months, 51/191 (26.7%) patients had died, resulting in a median PSA-progression free and overall survival of 8.3 and 10.61 months, respectively. In a subset of patients (71/191, 37.2%) data regarding objective response was available with 25/71 (35.2%) achieving an objective response. Data from 114 pts. revealed fatigue (20.3%), hot flushes (15.8%), edema (10.6%), elevated liver enzymes (8.0%) and asthenia (7.9%) being the most frequent toxicities (any grade). Conclusions: Treatment of CRPC patients with AA outside controlled clinical trials leads to considerable PSA- and objective response rates with a favourable toxicity profile, comparable to the results from COU-AA-301 registration trial. Due to the short median follow-up, conclusions regarding PSA-progression free and overall survival may not be drawn.
Risk of skeletal-related events (SREs) in patients with prostate cancer (PC) and newly diagnosed metastases to bone.
Authors: Glass Andrew , Lamerato Lois , Edelsberg John , Richert-Boe Kathryn E. , Taneja Charu , Wolff Greg G. , Czapski Natalie , Chung Karen , Richhariya Akshara , Oster Gerry
Published: March 2020

e15197

Background: Bone is a common site of metastatic involvement in patients (pts) with PC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large U.S. Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary PC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study for evidence of first SRE. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 420 men with primary PC and newly diagnosed bone mets; 42 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 378 pts, mean (SD) age was 72.7 yrs (9.8 yrs); 38% were Caucasian and 58% were African-American. Median duration of follow-up after diagnosis of bone mets was 17.1 months (mos). At 12 mos, cumulative incidence of SREs was 31.6% (SCC, 6.1%; PF, 15.0%; SCC and/or PF, 19.1%; SB, 3.9%; RT, 24.4%) (Table). Corresponding figures at 24 mos were 45.3% (SCC, 12.5%; PF, 22.2%; SCC and/or PF, 30.2%; SB, 6.2%; RT, 34.9%). Relatively few pts (14.6%) received intravenous bisphosphonates prior to SRE. Conclusions: Pts with PC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
Initial experience with sipuleucel-T (sip-T) in the immediate post-approval setting: The University of Washington (UW) experience.
Authors: Dean James P. , Yu Evan Y. , Beauchene Suzanne , Hall Suzanne P , Higano Celestia S.
Published: March 2020

e15206

Background: UW has participated in clinical trials of sip-T for over 15 years. After sip-T administration in the 3 phase III trials, patients (pts) did not receive additional therapy until objective progression. However, the course of treatment after administration of sip-T outside the setting of a clinical trial is not defined. In order to better understand our own practices in response to this new clinical scenario, we evaluated our institutional experience with commercial sip-T after FDA approval. Methods: Charts of all pts treated with sip-T at UW with at least 3 mos follow-up were retrospectively reviewed. Pt characteristics and treatments administered during the first 3 mos after sip-T infusion were collected. The institutional review board approved this study. Results: Between June 2010 and Nov 2011, 36 pts with mCRPC were treated with commercial sip-T by 3 different MDs. There were 31 Caucasian, 3 African American, and 2 Asian pts. At diagnosis, Gleason score (# pts) was 3+3 (2), 3+4 (5), 4+3 (7), 4+4 (4), 4+5 (16), 5+5 (2); initial therapy was watchful waiting (1), ADT with brachytherapy [BT] (1), BT with XRT (4), ADT/XRT (6), radical prostatectomy [RP] (9), ADT/RP (1). At the time of sip-T therapy, median age 67.8 yrs (44.2 to 84.5), median PSA 56.0, LDH 179.5, alk phos 77, Hgb 12.7, CTC 2. 3 pts had prior chemotherapy for metastatic disease. 34, 2, and 1 pts received 3, 2, and 1 sip-T infusion(s) respectively. Within the first 3 mos after the last sip-T dose, 29 pts had no significant symptoms and received no additional therapy other than ADT +/- ongoing zoledronic acid or denosumab (27), ketoconazole (1), or nilutamide (1); 7 developed pain and received docetaxel [D] (1), XRT and D (3), XRT (1), nilutatmide/D (1), or cabozantinib (1). 6 pts died a median of 10 months after sip-T; none had received chemotherapy before sip-T therapy. Conclusions: The majority of UW pts (80%) received no additional therapy in the first 3 mos after sip-T while 20% developed pain and were treated with docetaxel or other systemic therapy. What treatments should be given and at what interval after sip-T remains unclear. It is likely that new agents will impact the treatment paradigm after sip-T.
Association of expression of ERG oncoprotein with development of disease recurrence and prostate cancer-specific mortality.
Authors: Johnston Richard , Spencer Elysia Sophia , Qu Xiaoyu , Himmetoglu Ussakli Cigdem , Gordon Ryan Robert , Vakar-Lopez Funda , Lewinshtein Daniel , Lucas Jared , Dobi Albert , Mcleod David G. , Fang Min , Srivastava Shiv , Nelson Peter , Porter Christopher R.
Published: March 2020

e15207

Background: ETS-Related Gene (ERG) protein is present in approximately half of prostate cancer (PCa) specimens and correlates with TMPRSS2-ERG rearrangement. ERG oncogenic activation is believed to be a causal genomic alteration in a significant portion of PCa, its prognostic value in disease progression remains uncertain. This study evaluated ERG levels at radical prostatectomy (RP) to determine if it was predictive of earlier relapse or prostate cancer-specific mortality (PCSM). Methods: From 1954-1997, 1004 consecutive patients underwent RP at Virginia Mason Medical Center in Seattle. Recurrence was confirmed by tissue diagnosis or radiographic signs. Death certificates confirmed PCSM. Patients without tissue were excluded. 34 patients with metastases or PCSM were matched to patients without recurrence at a 1:2 ratio. Paraffin embedded tissue was stained with two anti-ERG monoclonal antibodies, clone 9FY (Furustao et al., PCPD, 2010) and clone EPR3864 (Epitomics, Burlingame, CA). A pathologist evaluated the nuclear expression intensity using a 4-point scale. Statistical analysis was performed on SAS. Results: Mean follow up was 10.26 yrs.Antibody 9FY detected ERG in 10/16 (62.5%) PCSM and 24/44 (54.6%) no recurrence patients. Cancer expression intensity was higher from patients that developed recurrent disease, 0.99 vs 1.59 (p = 0.0265) and PCSM 2.09 (p = 0.0002). Antibody EPR3864 detected ERG in 11/17 (64.7%) PCSM and 26/48 (52.1%) no recurrence patients. Cancer expression intensity was higher from patients that developed recurrent disease, 0.97 vs 1.64 (p = 0.011) and PCSM, 2.30 (p < 0.0001). The two antibodies were independent of PSA and grade and were highly correlated with each other (p < 0.0001). Conclusions: ERG expression at time of surgery was prognostic for the development of disease recurrence and PCSM. Previous studies have shown an increased lifetime risk of PCSM with ERG expression in a surveillance cohort. This is the first report linking PCSM to ERG expression in men treated with surgery. ERG scoring may be a useful metric to identify patients who would benefit from adjuvant treatment or closer follow-up, allowing more accurate individual patient treatment plans.
Oral low-dose cyclophosphamide, as a second-line agent, in patients with primary docetaxel refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shapiro Daniela , Symanowski James Thomas , Vogelzang Nicholas J. , Goodman Oscar B.
Published: March 2020

e15210

Background: Docetaxel is the standard of care for treatment in mCRPC, yet docetaxel resistance is universal, presenting as primary refractoriness or developing after an initial response. While abiraterone and cabazitaxel are FDA approved after docetaxel failure, multiple other agents, including oral low dose cyclophosphamide (OLDC), have also been utilized with some clinical success. We have witnessed several remarkable responses to OLDC and sought to define clinical predictors of such responses. Methods: Twenty-one patients progressing on docetaxel were classified according to initial docetaxel response as either docetaxel non-responsive (DNR) or docetaxel responsive (DR). Patients were classified as DNR if an initial response to docetaxel by prostate specific antigen (PSA) working group-2 and RECIST criteria was absent, or if circulating tumor cells (CTC) numbers remained >5 at all assessed time points. Otherwise patients were classified as DR. All patients initiated OLDC (50-150 mg/day), and subsequent response to OLDC was determined by decrease in CTC, PSA and/or radiologically. Results: Of the DR patients 1/10(10%) responded, while for DNR patients the response rate was 7/11 (63.4%), p= 0.024 between the two groups. The median survival from the date of initial treatment with docetaxel was 84 weeks in initial responders, and 115 weeks in refractory patients (p=0.495). Conclusions: The data suggest that patients who are DNR have higher rates of response to OLDC compared DR patients and may benefit from second line OLDC. A study prospectively evaluating the role of initial response to docetaxel in predicting response to OLDC is warranted, as are additional molecular analyses of DNR patients.
Sipuleucel-T immunotherapy in clinical practice: Patient characteristics, tolerability, and survival.
Authors: O'Shaughnessy Matthew , Warlick Christopher , Ziegelmann Matthew , Konety Badrinath , Jha Gautam Gopalji
Published: March 2020

e15211

Background: Sipuleucel-T has been shown to provide survival benefit to men with minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In the 18 months following FDA approval of sipuleucel-T, we sought to characterize patients referred for consideration of sipuleucel-T, determine the tolerability of therapy, and evaluate survival outcomes in clinical practice. Methods: We reviewed the records of patients referred to our institution for consideration of sipuleucel-T. Clinical characteristics, disease characteristics, and previous treatments were identified. Tolerability and adverse events were characterized. Results: Patients with minimally symptomatic mCRPC were offered sipuleucel-T (n=90), whereas patients with ECOG>1, progressive disease, or lack of metastases were not (n=11). Post chemotherapy patients started sipuleucel-T if their CD4 count was >400 at least 3 weeks following chemotherapy. Treatments were well tolerated, with 96% completing an entire series. Three patients did not complete treatment due to disease progression. The biggest challenge with sipuleucel-T therapy was disease control immediately before, during and post therapy. Androgen receptor blockade with nilutamide or high dose bicalutamide was used to control the disease during this time. Mean patient age was 69.8±9.7 years and all had ECOG status of 0-1. 40% of patients had minimal metastases, while 36% and 19% had moderate or extensive metastases. Median survival time (MST) for men >65 years who received sipuleucel-T was 17.6 months, whereas MST for men ≤65 years was not reached. There was no significant difference in overall survival (OS) between these groups (p=0.27). When stratified by disease burden, we found that OS of patients with extensive disease was shorter than men with mild or moderate disease burden (p=0.002 and p=0.04), with MST of 6.0 months. MST was not reached for men with mild and moderate disease burden. Conclusions: Sipuleucel-T is well tolerated in clinical practice for well-selected patients with asymptomatic or minimally symptomatic mCRPC. Patients with extensive metastatic disease, even when minimally symptomatic, did not appear to benefit from sipuleucel-T.
Salvage focal versus salvage total cryoablation for radio-recurrent prostate cancer: Seven years experience.
Authors: Ukimura Osamu , Abreu Andre Luis de Castro , Leslie Scott , Sohji Sunao , Silverman Paul , Gill Inderbir S , Bahn Duke
Published: March 2020

e15212

Background: Salvage cryoablation (SC) of the whole prostate is a curative option for radio (RT)-recurrent prostate cancer (PCa). Focal SC has emerged as an option for minimizing morbidity. We present our 7-year experience of oncological and functional outcomes of Salvage Focal (SFC) and Salvage Total (STC) Cryoablation (CRYO) for RT-recurrent PCa. Methods: From Dec 2003 to Aug 2010, 50 men underwent SFC (n=25) or STC (n=25) for RT-recurrent PCa. SFC patients had biopsy-proven unilateral PCa and underwent a hemi-CRYO of the prostate. STC patients underwent CRYO of the whole prostate gland. All patients were evaluated to exclude metastases prior to treatment. Two freeze-thaw cycles were used to perform transperineal prostate CRYO under TRUS guidance. Follow up was assessed by PSA, TRUS, biopsy and questionnaires at 3, 6, 12, 24 and 36 mth. Results: Median (range) age, PSA and Gleason score for the SFC group were 71 y (59-81); 2.8 ng/ml (0-8.2) and 7 (6-8), while those for STC were 73 y (57-83), 3.9 ng/ml (0.1-12) and 7 (6-9), respectively. Oncological outcomes: Within one year after SC, the median percent PSA-decrease was 89% for SFC and 98% for STC. The median (range) follow up was 31 mth (4-90) for SFC and 53 mth (12-92) for STC. No patient died. One patient treated with STC developed bone metastases. Using the Phoenix criteria (PSA nadir + 2 ng/ml), 8 SFC and 3 STC patients had biochemical failure (BF), and the 5-year biochemical free survival (BFS) was 54% and 86% respectively (p=0.05). In those patients with no BF, the median PSA remained stable, ranging from 0.2 to 0.6 ng/ml for SFC and 0.1 to 0.1 ng/ml for STC during the follow up period. Follow up biopsy-proven cancer occurred in 2 patients in the SFC group (both on the untreated side), and in 1 patient in the STC group. Functional outcomes: New onset urinary incontinence occurred in none (0) of the SFC vs 3 (13%) of the STC patients. One (4%) patient in the STC group developed a recto-urethral fistula. Conclusions: Salvage Focal and Total CRYO after RT-failure are feasible and safe. Although STC had a favorable BFS compared with SFC, there was no significant difference in disease specific or overall survival between groups. SFC offered comparable cancer control to STC with lower morbidity.
Overall survival (OS) prognostic factors in metastatic castrate-resistant prostate cancer (mCRPC) patients retreated with docetaxel (D).
Authors: Shah Shilpa Rashmikant , Albany Costantine , Hahn Noah M.
Published: March 2020

e15213

Background: Until recently, few post-D treatment options existed for mCRPC patients (pts). In pts taken off of first-line D for reasons other than progressive disease (PD), retreatment with D at the time of PD was a commonly used strategy. While several prognostic nomograms have been developed for mCRPC patients, none have exclusively examined prognostic factors in D retreated patients. In the present study, we aimed to characterize baseline clinical factors associated with OS outcomes in D retreated mCRPC pts. Methods: Between 1/2007 and 10/2010, all mCRPC pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the IRB approved biorepository protocol. Participants completed a demographic and clinical questionnaire and provided a blood sample. Only mCRPC pts retreated with D with confirmed dates for D first-line completion, D retreatment, and OS were included in this analysis. At D retreatment, patient age, Gleason Grade (GG), presence of pain, time to progression after first-line D therapy, visceral metastases, ECOG performance status, PSA, and PSA doubling time (PSAdt) were examined by Cox proportional hazards model for significant associations (p < 0.05) with OS outcomes. Results: 30 mCRPC pts retreated with D were identified. Complete data were available on 22 pts which formed the analysis cohort. Demographics included: mean age – 69.1 yrs, Caucasian/African-American – 21/1, median GG 8, 55% pain present at baseline, median time from first-line D – 8.6 mo., 30% visceral mets, ECOG 0/1/2 – 3/17/2, mean baseline PSA – 536 ng/ml, mean baseline PSAdt – 2.7 mo. By Cox proportional hazards model, baseline PSA (p = 0.006) was significantly associated with D-retreatment OS with a trend toward significance in patients with pain at baseline (p = 0.059). No other significant associations were identified. Conclusions: Baseline PSA levels were significantly associated with OS outcomes in mCRPC pts retreated with D. Validation and examination of additional clinical variables is warranted in larger datasets.
Expression and the prognostic relevance of p53, Bcl-2, Bax, and Ki-67 in uterine leiomyosarcoma.
Authors: Gagua Irina Rezo
Published: March 2020

e15506

Background: Uterine leiomyosarcomas (LMS) are rare, aggressive gynecological malignancies of the female reproductive tract. They represent less than 2-5% of all uterine malignancies. Despite the advanced modern treatment modalities, according to our data 5 year overall and disease - free survival of patients with LMS is 48,5± 4,2% and 44.3 ± 4.3 %, respectively. One of the challenging directions in advancing the prognosis and optimization of treatment tactics in LMS is investigating the expression of molecular-biological markers in tumor tissue. So, the aim of our study was to evaluate the expression of p53, Bcl-2, Bax, and Ki-67 and their prognostic relevance. Methods: A retrospective chart review was done to 198 patients with LMS treated at the N.N. Blokhin Russian Cancer Research Center from 1971 to 2009. Immunohistochemical (IHC) staining for 20 patients was performed for p53, Bcl-2, Bax and Ki-67. Negative and positive IHC staining was scored for each marker. Survival was determined from the time of initial diagnosis to last follow-up. Results: Ten (50%) patients with LMS expressed p53. P53+ patients mostly had multiple metastases, compared to p53– patients with solitar metastases (60% against 20%) (g<0,05). Eleven (55%) patients expressed Bcl-2 and 4 (20%) expressed Bax. In Bcl-2 + patients distant metastases were observed in 45,5%, compared to Bcl-2 – patients were we observed metastatic disease in 77,8% (p=0,068). Expression of ki-67 was observed in 15 patients (75%). Conclusions: LMS patients with p53 expression had a poorer survival compared to LMS patients with negative expression (g53+ — 26,7±18,4% and g53– — 80,0±12,6%) (g<0,05). On opposite, the disease-free survivla is better in bcl-2+ patients, compared to patients, who don’t express bcl-2 (47,2±19,6% and 28,1±18,0%, respectevly (g>0,05). We didn’t observe statistical significant difference in survival depending on Bax expression. LMS patients with Ki-67 expression had a poorer survival compared to LMS patients with negative expression (34,9±13,1% and 60,0±20,7% , respectively) (g>0,05). Our study indicates that p53 expression may serve as a prognostic marker for LMS patients.
Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for treatment of metastatic or recurrent uterine leiomyosarcoma.
Authors: Pant Alok , Lurain John Robert , Schink Julian C.
Published: March 2020

e15523

Background: Metastatic or recurrent uterine leiomyosarcoma is often treated with chemotherapy. There are a limited number of viable regimens that are effective and well tolerated. Our objective was to evaluate the efficacy and toxicity of the MAID chemotherapy regimen in women with advanced uterine leiomyosarcoma. Methods: We conducted a retrospective analysis of 18 patients who received MAID chemotherapy for metastatic or recurrent uterine leiomyosarcoma between 1998 and 2010. Ten patients had received prior radiation therapy (3) and/or gemcitabine-docetaxel chemotherapy (8). The MAID regimen was administered intravenously in the hospital every three weeks as follows: mesna 120 mg/m2 prior to ifosfamide day 1 and 1.2 mg/m2 infusion over 8 hours starting immediately after the ifosfamide d 1-3, doxorubicin 15 mg/m2 d 1-3, ifosfamide 1.2 gm/m2 d 1-3, and dacarbazine 200 mg/m2 d 1-3. Disease response was evaluated by physical exam and imaging studies. Toxicity was assessed using NCI Common Toxicity Criteria. Results: Response to MAID chemotherapy was observed in 7 (39%) of 18 patients: 2 (11%) complete responses and 5 (28%) partial responses. Stable disease was noted in 8 patients (44%) and disease progression occurred in 3 patients (17%). There was no difference in response rates between patients who had received prior chemotherapy (3/8, 38%) and patients who had not received prior chemotherapy (4/10, 40%). A total of 90 cycles of chemotherapy were administered with a median of 5.5 (range 1-9) cycles per patient. Grades 3 and 4 toxicity requiring dose reduction of treatment delay complicated only 4 cycles (4.4%), including only one admission for neutropenic fever. There were no reported cases of cardiac dysfunction, hemorrhagic cystitis, or encephalopathy. The median progression-free survival was 10 (range 6-152) months for responders, 7.5 (range 3-120) months for those with stable disease, and 0 months for those with progressive disease. Conclusions: This is the largest series of uterine leiomyosarcoma patients treated with MAID chemotherapy. MAID chemotherapy in the dosage schedule utilized is a well-tolerated and effective regimen.
Patient surveillance after curative-intent treatment for ovarian cancer: What motivates clinicians?
Authors: Jamaluddin Nimah , Virgo Katherine S. , Gao Feng , Mutch David Gardner , Johnson Frank E.
Published: March 2020

e15528

Background: In the US, ovarian cancer is diagnosed in > 20,000 women and causes >13,000 deaths each year. After curative-intent initial treatment, surveillance is common. Marked variation in surveillance intensity has been documented, suggesting overuse and/or underuse of resources. We sought to determine what factors motivate gynecologic oncologists as they design their surveillance strategies. Methods: A survey about ovarian cancer surveillance after initial treatment was mailed to all 943 members of the Society of Gynecologic Oncologists. The survey included 14 questions about putative motivating factors. Responses were submitted on a 10-level Likert scale. Motivating factors were ranked by the percent of responses for each of the ten levels. Results: 323 of the 943 (34%) responded; 283 responses were evaluable. “Current literature documents significant survival benefits” was the weakest motivating factor. Conclusions: The table below is consistent with the lack of evidence that any particular surveillance strategy confers any survival benefit. This is the first empirical evidence concerning factors that may motivate gynecologic oncologists in designing their surveillance strategies. Understanding motivating factors may be useful in devising methods to diminish the marked variation in strategies. [Table: see text]
Benign cystic ovarian neoplasms and procoagulant potential.
Authors: Iqbal Omer M. , Ersahin Cagatay , Hu Zhihong , Duan Xiuzhen , Hoppensteadt Debra
Published: March 2020

e15538

Background: Ovarian cancer is one of the leading causes of increased morbidity and mortality worldwide. The fluid content of the cystic ovarian tumors has never been thoroughly analyzed. It is hypothesized that the fluid contents of the ovarian cystic tumors have procoagulant effects. Methods: Under an institutionally approved protocol, cystic fluids from ovarian neoplasms were collected (n=28) and analyzed to determine their procoagulant potential. Assays such as Thrombelastography (TEG, Helige, Germany), Platelet aggregometry (BioData, Horsham, PA), Fibrinopeptide A (FPA, Dade Behring, Marburg, Germany), Thrombin Antithrombin Complex (TAT, Dade Behring), and Zymuphen Platelet Microparticle Activity Assay (Hyphen BioMed, Neuville-Sur-Oise, France). Cerebral Array II (Randox, Crumlin, CO) was used to determine the levels of C-reactive protein (CRP), D-Dimer, Neuron Specific Enolase (NSE), Neutrophil Gelatinase-Associated Lipocalin (NGAL), soluble Tumor Necrosis Factor Receptor I (TNFRI) and Thrombomodulin. Results: The TEG parameters such as r- time, rk-time, k-time, MA, and angle were measured to be 17 , 22 , 5 , 54 mm, 55° with clear cell carcinoma, 18 , 24 , 6 , 58 , 54° with benign serous cyst compared to saline control values of 23 , 30 , 7 , 41 mm and 48° respectively. Platelet aggregometry showed increased aggregations when cystic fluids were supplemented in donor platelet rich plasma. The levels of Fibrinopeptide A were in the range of 24.1 and 56.6 ng/ml compared to a control value of 1.8 ng/ml. The TAT complexes were in the range of 6.7- 175 µg/ml compared to a control value of 0.7 ug/ml. The platelet microparticle measurements were markedly increased and were in the range of 10-45 nM for benign and malignant cystic fluids, compared to control values in the range of 2.3-6.6 nM. The results of CRP, D-Dimer, NSE, NGAL, TNFRI and TM were 9.28 mg/m (Normal=5.03) , >2000 ng/ml (N=227.34) , >120 ng/ml (N=10.50), >1229 ng/ml (N=228.16), 3.98 ng/ml (5.91) and 13.55 ng/ml (N=13.55) respectively. Conclusions: Benign ovarian tumors have prothrombogenic activity as much as the malignant tumors. Early surgical evaluation of clinically silent benign ovarian tumors should be considered.
Estrogen receptor α phosphorylated at Ser167: Distribution and prognostic implications in endometrial cancer.
Authors: Yoshida Yoshio
Published: March 2020

e15539

Background: Both ligand-dependent and ligand-independent activation of estrogen receptor (ER)α is modulated by receptor phosphorylation, which is enhanced by ligand binding. Similar to Akt, ERα is activated through phosphorylation at Ser167, resulting in activation of the ERα-dependent pathways that are involved in endometrioid endometrial cancer (EEC) pathogenesis. It is known that the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) and mitogen-activated protein kinase (MAPK)/p90 ribosomal S6 kinase (RSK) signaling pathways coordinately regulate phosphorylated- (p-) ERα. The purpose of this study was to determine the importance of Ser167 phosphorylation in EEC progression. Methods: Immunohistochemical staining of primary EEC surgical specimens (n=103) was carried out using antibodies specific for p-ERα and for p-Akt, p-mTOR/S6K1 and p-MAPK/RSK. and for p-Akt, p-mTOR/S6K1 and p-MAPK/RSK. Results: Patients positive for nuclear Ser167 phosphorylation had significantly shorter relapse free survival. Althoughthe result was not significant, levels of nuclear p- tended to be higher in advanced-stage ECC patients. Nuclear p-ERα was significantly positively correlated with p-MAPK and p-S6K1. Conclusions: The amount of nuclear ERa Ser167 phosphorylation is associated with p-MAPK and p-S6K1, and may be important in EEC progression and outcome.
Comparison of serum CYFRA 21-1 and ROMA in distinguishing ovarian cancer from benign pelvic masses.
Authors: Li Zhong-Qian , Smalley Robert J , Glover Curtis L , Raju Savitha , Falcone Katherine , Fegely Maryellen , He Kuanglin , Radwan Rachel R , Kettlety Timothy R
Published: March 2020

e15565

Background: CYFRA 21-1 is a known lung cancer biomarker. In subjects with ovarian cancer (OC) versus those with benign gynecological diseases, serum CYFRA 21-1 was reported sensitivities (SN) of 44% and 41% at specificity (SP) of 95% for OC detection using an ELISA assay by Hasholzner U (1994) and Tempfer C (1998), respectively. Nolen B (2010) reported a SN of 84.1% and 85.8% and a SP of 85% and 79.3% with a combination of CYFRA 21-1, CA 125 and HE4 using a multiplex bead-based immunoassay in a training and validation set, respectively. We carried out a cohort study to evaluate the serum CYFRA 21-1 as an ovarian cancer biomarker and compared it with ROMA (Risk of Ovarian Malignancy Algorithm), an FDA-cleared ovarian cancer algorithm. Methods: ARCHITECT CYFRA 21-1 assay was used to measure the levels of serum CYFRA 21-1. Single point serum samples from 170 female subjects with a pelvic mass were randomly selected from an archive cohort of female subjects. Among the 170 subjects, 47 had OC (42 with epithelial OC and 5 with low malignant potential tumor) and 123 with benign gynecological diseases. ROMA values were obtained with HE4 EIA and ARCHITECT CA 125 II. Results: For ARCHITECT CYFRA 21-1, the ROC-AUC, cut-off, SN, SP, PPV and NPV were 86%, 1.8 ng/mL, 70.2% (95% CI: 55.1% to 82.7%), 95.1% (95% CI: 89.7% to 98.2%), 84.6% and 89.3%, repectively. For ROMA algorithm, the ROC-AUC, cut-off, SN, SP, PPV and NPV were 92%, 2.44, 89.4% (95% CI: 76.9% to 96.5%), 84.6% (95% CI: 76.9% to 90.4%), 68.9% and 95.4%, repectively. Chi-square test showed an SN for ROMA was significantly higher than that of ARCHITECT CYFRA 21-1 (p < 0.05), and SP for ARCHITECT CYFRA 21-1 was significantly higher than that of ROMA (p < 0.01). Conclusions: In distinguishing OC from benign gynecological diseases, ROMA algorithm appears to be more sensitive than serum ARCHITECT CYFRA 21-1 (p < 0.05), and serum ARCHITECT CYFRA 21-1 appears to be more specific than (p < 0.01) in this cohort study.
Neoadjuvant chemotherapy for locally advanced cervical cancer: Experience at the Instituto Oncologico Nacional SOLCA Guayaquil.
Authors: Paulson Guillermo , Garcia Katherine , Santacruz Mayra , Engracia Ruth Ginger , Mendoza Jose Francisco
Published: March 2020

e15571

Background: Cervical cancer is the most common malignancy of women in Ecuador. The main problem of concomitant chemo-radiotherapy (CRT) is the delay in starting radiation therapy, economic and logistical problems for high demand in radiotherapy. It has been neoadjuvant chemotherapy (NACT) followed by CRT the main treatment at our center in order to find an alternative to long waits before the start of radiotherapy. The aim of this study was to determine the response to NACT followed by CRT in terms progression-free survival (PFS) and overall survival (OS). Methods: diagnosed with invasive cervical cancer locally advanced stage II-III were analyzed retrospectively reviewed clinical records of pre-existing data from 2008 to 2010. Results: after meeting the criteria of exclusion, leaving 116 cases. The median age: 49 years (range: 28-82 years). The histology was 73% (85) squamous cell carcinoma, 26% (30) adenocarcinoma and 0.9% (1) not specified. Patients with stage IIB: 81.9% (95), IIIA: 10.3% (12), IIIB: 7.8% (9). Of the 116 patients 69% (80) received NACT. The main NACT was paclitaxel 175mg/m2 + Cisplatin 75mg/m2 every 3 weeks 63.8% (74), the remaining group received another protocol, the median number of cycles of NACT was 5 (1 - 8 cycles), the start of radiotherapy since the conclusion of NACT was 53 days on average (1 to 285 days) and the main regimen of CRT concomitant was cisplatin 40mg/m2 weekly 47.5% (38). In the 49 patients who underwent NACT followed by CRT, a radiological study showed, complete response (CR) 38.8% (19), 18.4% partial response (PR) (9), disease progression (DP) 12.2% (6), stable disease (SD) 8.2% (4) and the end of treatment evaluation gynecological was performed and CR was obtained in 59.2% (29). Persistent or progressive disease after treatment was 22.4% (11), recurrence was 12.2% (6), local recurrence 2.0% (1), distant metastasis 10.2% (5). OS of NACT followed by CRT was 93.9% (46) and PFS was 65.3% (32), OS after CR was 96% (25 / 1) and then 91.7% PR (24 / 2) with p: 0.439. Conclusions: NACT followed by CRT is a valid option because it improves disease-related symptoms, but OS did not improve significantly even after CR.
Retrospective analysis of stage IC uterine cancer patients: A single center experience.
Authors: Kucukoztas Nadire , Yalcin Selim , Rahatli Samed , Ozen Ozlem , Haberal Nihan , Tarhan Cagla , Dursun Polat , Dizdar Omer , Yildiz Ferah , Altundag Ozden , Ayhan Ali
Published: March 2020

e15573

Background: Stage IC patients are at an increased risk of recurrence and overall worse prognosis compared with stage IA and IB patients. Adjuvant chemoherapy is utilized based on specific pathologic factors. The objective of this study is to evaluate treatment outcomes at a single institution in patients with 1988 FIGO stage IC endometrial adenocarcinoma. Methods: Records of the patients with FIGO stage IB (formerly IC) endometrial cancer were retrospectively evaluated. All patients were initially treated surgically with comprehensive staging lymphadenectomy. Results: A total of 85 patients were included. Patient and tumor characteristics are shown in the table. Median age of the patients was 60 (range 27-95). Fifty-nine patients had at least one co-morbid disease. Complete surgical staging including pelvic and paraaortic lymph node dissection was performed in all the patients. Sixteen patients (19%) received adjuvant chemotherapy, including 6 patients with serous cancer and one patient with small cell cancer. Paclitaxel/carboplatin was the preferred regimen in Median follow up was 30 months (range 10-61 months). Seven patients (8%) relapsed and 4 patients (5%) died on follow up. 5 year disease free survival was 89% and overall survival was 95%. One of the 16 patients (6.2%) who received chemotherapy and 6 of the 69 patients (8.7%) who did not receive relapsed/died on follow up. Survival analysis was not performed because of the low number of events in both groups. Conclusions: We found similar rates of recurrence and death with previous studies in stage IC endometrial cancer. Complete surgical staging is the mainstay of treatment. Marginally lower recurrence rate in chemotherapy treated patients delineate the need for prospective randomized data addressing the role of adjuvant systemic therapy in early-stage patients with endometrial adenocarcinoma. [Table: see text]