bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncologic outcomes of radical prostatectomy with neoadjuvant LHRH agonist/estramustine and radiotherapy with neoadjuvant hormonal therapy for high-risk prostate cancer.
Authors: Koie Takuya , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: February 2017

259

Background: To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT). Methods: We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70–76 Gy administered at 2 Gy/fraction. Results: Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival (OS) rates were 98.3% and 92.1% in the RP and RT groups, respectively (P = 0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P = 0.878). Conclusions: Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have important impact on decision making of treatment in high-risk Pca.
Pilot study of focal salvage high-dose rate (HDR) prostate brachytherapy in patients with local recurrence after definitive external-beam radiotherapy (XRT).
Authors: Chung Hans T. , Loblaw D. Andrew , D'Alimonte Laura , Ravi Ananth , Haider Masoom A. , Morton Gerard
Published: February 2017

264

Background: Studies of post-treatment biopsies of the prostate after definitive dose-escalated XRT for intermediate-risk prostate cancer suggest that approximately 20% will be positive. Salvage options include surgery, brachytherapy, cryotherapy or high-frequency ultrasound. However, the complication risk, such as fistula, incontinence or bladder neck contracture, is not insignificant. The objective of this pilot study is to explore the toxicities and efficacy of focal salvage HDR prostate brachytherapy. Methods: This study was approved by the institution’s research ethics board. Eligible patients included those with biopsy-confirmed local recurrence >30 months after completing XRT, MRI of the prostate demonstrating solitary recurrence confined to the prostate, negative metastatic workup, IPSS <15, post-XRT PSA <10ng/mL, prostate volume ≤50cc. Salvage HDR brachytherapy was performed under transrectal ultrasound guidance with a prescription dose of 27Gy divided over two implants separated by 1 week to the target volume (TV) as seen on MRI with dose constraints to the urethra and rectum. Results: Six patients were enrolled in the study. The mean age was 73 years, all had either low- or intermediate-risk disease at presentation, and initial XRT received was 70-78Gy at least 5 years ago. The Gleason score of the local recurrence was 7 and 8-10 in 4 and 2 patients, respectively. The pre-HDR mean PSA was 5.5. The median size of the recurrence on MRI was 9mm and median size of the TV was 5.0cc (2.2-10.2), TV V100% 95.1%, urethral D10% 51.8% and rectal D1cc 39.2%. Four patients have at least 3 months of follow-up, and no acute GU/GI grade 3-5 toxicities were observed, including urinary retention. The most common acute toxicity was frequency and nocturia. Mean IPSS at baseline, 4-weeks, 3-months was 7, 9 and 7. Conclusions: Preliminary data suggests that focal salvage HDR brachytherapy was technically feasible with mild acute toxicities. Clinical trial information: NCT01583920.
Prostate cancer patients' adherence to medication while on abiraterone acetate (AA) therapy.
Authors: Kozma Chris M. , Slaton Terra L , Ellis Lorie , McKenzie R. Scott , Lafeuille Marie-Helene , Grittner Amanda M. , Lefebvre Patrick
Published: February 2017

267

Background: Oral medications have become more widely available for treatment of various cancers, and adherence to dosing/ refill patterns, or medication possession, are important considerations for treatment. Abiraterone acetate (AA), prodrug of aberaterone, is a novel oral androgen biosynthesis inhibitor approved for metastatic castration resistant prostate cancer. This study reports adherence to AA dosing and administration recommendations by prostate cancer (PC) patients as observed in two separate data sources. Methods: PC patients with ≥1 AA prescription fill were identified in two retrospective pharmacy claim data sources: (1) Truven Commercial Claims and Encounters; and (2) Symphony ProMetis. Patients with no evidence of recent chemotherapy (NRC) or with evidence of recent chemotherapy (RC) were identified in the 6 months prior to AA initiation. The average AA daily dose per prescription per patient was reported. To evaluate adherence, the Medication Possession Ratio (MPR), a measure of consistency calculated as the sum of the AA days of supply divided by the total number of days between first and end of last AA fill, was assessed for patients with ≥2 AA fills. Data were summarized by descriptive statistics. Results: In both datasets the mean medication consistency/MPR was greater than 90% and the mean daily dose was within 1% of the recommended daily dose (1,000 mg). Medication consistency and AA daily dose per patient appeared similar between patients with recent chemotherapy and patients without recent chemotherapy (Table). Conclusions: Results from two observational studies representing > 3,700 PC patients reported high levels of AA adherence to AA dosing and administration consistent with prescribing information. Such data support providers’ understanding of the consistency to which AA treated PC patients adhere to AA medication use. [Table: see text]
Novel dosimetric criteria for salvage permanent brachytherapy based on 3D-cancer mapping.
Authors: Okihara Koji , Kobayashi Kana , Kamoi Kazumi , Iwata Tsuyoshi , Miki Tsuneharu
Published: February 2017

269

Background: Salvage permanent brachytherapy (SPB) is one of treatment options in recurred men after external beam radiation therapy (EBRT). The accurate 3D correspondence between recurred cancer focus and location of seed implants using transrectal sonography (TRUS) is indispensable to design excellent dosimetry. The application of MRI-TRUS fusion targeted/systematic biopsy (Fusion-B) has enabled us to draw 3D recurred-cancer mapping. We have started SPB in men who recurred 3D-conformal EBRT using 3D-cancer mapping from Fusion-B. We introduce the novel dosimetric criteria for SPB-based on 3D cancer mapping. Methods: The patients with PSA failure (defined by Pheonix criteria) and without lymphnode/distant metastasis were enrolled in this study. In men who had suspicious recurrent focus/foci in MRI, we performed Fuision-B (ultrasound equipment: Image fusion: Koelis in France, and Biopsy: Medison in South Korea). We classified the three dosimetric patterns as follows: (1) Focal pattern: one core positive from target biopsy alone within hemilobe and GS less than 8. (2) Hemi-lobe pattern: positive cores within hemi-lobe from target/ systematic biopsies and GS less than 8. (3) Whole / focused gland pattern c/w hormonal therapy: Positive core(s) with GS greater than seven was identified regardless of positive biopsies location, or positive cores with GS less than eight from bilateral lobes. Prescribed dose to the target lesion, rV100 and uD90 were planned greater than 160Gy, 0% and less than 165Gy respectively. Results: Since August 2012, SPB has underwent in nine cases (PSA range prior to SPB: 2.22- 4.97ng/ml, age 61 to 77). In those cases, prescription dose at the 3D-conformal EBRT was 72 Gy and the duration between the 3D-conformal EBRT and SPB ranged from 41 to 107 months. The biopsy GS (-7/8-) obtained from Fuison-B distributed in 6/3 cases. Biopsy revealed single focus obtained from target biopsy in two cases. Focal and hemi-lobe pattern were chosen in two and one case, respectively. For the present, there is no re-PSA failure and G3-4 GI and GU comorbidities. Conclusions: To reduce the incidence of co-morbidity and maintain reasonable oncological outcome, it is informative to apply the 3D Cancer mapping for the SPB candidates. It is necessary to assess this criteria with the further follow-up.
An indirect treatment comparison (ITC) and cost-effectiveness analysis of abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy.
Authors: Li Tracy , Thompson Melissa , Todd Mary Beth , Yu Margaret K. , Kheoh Thian San , He Jianming , Saadi Ryan
Published: February 2017

270

Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are two new agents indicated for the treatment of patients with mCRPC. Presently, there is a high level of interest in understanding the relative clinical and economic value of these therapies. The objective of this study was to determine the comparative effectiveness and cost-effectiveness of AA vs. ENZ. Methods: The PICO (population, intervention, comparison, and outcomes) construct was used to assess the comparability of Study COU-AA-301 for AA and the AFFIRM trial for ENZ, and an ITC was conducted using the Bucher method and Bayesian statistics. A survival-based Markov cohort model with three health states (progression-free, progressed, and death) was developed to project cost-effectiveness over a life time horizon. Since only the US price of ENZ was publicly available at the time of analysis, US drug acquisition costs were used. Average wholesale prices for 30-day supplies of AA and ENZ were $7,674 and $8,940, respectively. One-way sensitivity analyses were performed for all probability, utility, and cost values incorporated into the model. Results: The ITC result on overall survival (OS) was HR = 0.95 (95% CI: 0.71-1.26) for AA vs. ENZ on the risk of mortality, after accounting for important differences in comparators and background treatments. In the base case of the economic analysis, AA was found to provide a substantial cost savings of $13,322 per patient vs. ENZ, primarily due to higher acquisition costs. Quality adjusted life years gained were comparable for AA and ENZ. These results were supported by sensitivity analyses. Conclusions: While benefits are similar for OS, AA is cost-saving compared with ENZ for the treatment of patients with mCRPC following treatment with docetaxel.
Allegheny General Hospital experience with LDR prostate brachytherapy comparing Pd-103 with I-125.
Authors: Hall Michael William , Horn Jeffrey , Fuhrer Russell
Published: February 2017

274

Background: To report a retrospective review of a single institution’s experience treating patients with localized adenocarcinoma of the prostate with low-dose rate brachytherapy (LDR-BT) comparing clinical outcomes at 5 years of patients treated with Pd-103 vs. I-125. Methods: 332 hormone-naïve patients with localized adenocarcinoma of the prostate were treated with LDR-BT without androgen deprivation therapy (ADT) between 1998-2008 at Allegheny General Hospital. 300 patients had more than 12 months of follow-up and were included in the statistical analysis. 40 patients (13%) were treated with Pd-103 and 260 (87%) were treated with I-125. The decision to treat with Pd-103 was based on physician preference and pretreatment urinary AUA score. Both treatment groups (Pd-103 vs. I-125) were otherwise stratified similarly with regards to median patient age (65 vs. 65), NCCN low-risk category (87.5% vs. 89.9%), Gleason score 6 (92.5% vs. 88.1%), Clinical T1c (85% vs. 79.9%), pretreatment median PSA (5.9 vs. 5.6), and pretreatment mean AUA score (8 vs. 6.5). All pathology was reviewed by a single genitourinary pathologist. All prostate seed implants were performed by a single radiation oncologist. Results: Median follow-up was 67 months for Pd-103 patients and 80 months for I-125 patients. Mean D90 for the Pd-103 group was 140.7 Gy versus 170.9 Gy in the I-125 group. There was one biochemical failure in the Pd-103 group and 21 biochemical failures in the I-125 group. 5-year biochemical failure free-survival rates were 95.7% for the Pd-103 group and 90.1% for the I-125 group (p=0.13). Conclusions: Prior studies have shown no difference in outcomes between patients treated with Pd-103 and I-125 for early stage prostate cancer. Therefore the choice of isotope in LDR-BT is based on urologist and/or radiation oncologist preference and patient clinical presentation (AUA score). Our institution’s experience indicates a trend towards increased rates of biochemical failure in a homogenous group of patients treated with I-125 compared to Pd-103. Due to the retrospective nature of our study as well as the limited number of patients, this requires validation in a prospective trial.
Quality of life after high-dose rate brachytherapy monotherapy for prostate cancer.
Authors: Contreras Jessika , Wilder Richard , Mellon Eric Albert , Strom Tobin Joel Crill , Fernandez Daniel Celestino , Biagioli Matthew C.
Published: February 2017

278

Background: There is little information in the literature on health-related quality-of-life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy monotherapy for prostate cancer. Methods: We conducted a prospective study of HRQOL changes due to HDR brachytherapy monotherapy for low risk or favorable intermediate risk prostate cancer. Forty-nine of 84 (58%) patients who were treated between February 2011 and April 2013 completed 50 questions comprising the Expanded Prostate Cancer Index Composite (EPIC) before treatment and 6 and/or 12 months after treatment. Results: Six months after treatment, there was a significant decrease (p<0.05) in EPIC urinary, bowel, and sexual scores, including urinary overall, urinary function, urinary bother, urinary irritative, bowel overall, bowel bother, sexual overall, and sexual bother scores. By one year after treatment, all EPIC scores had increased and were not significantly different from baseline values. Conclusions: HDR brachytherapy monotherapy is well-tolerated in patients with low and favorable intermediate risk prostate cancer. Urinary, bowel, and sexual domain scores returned to close to baseline 12 months after treatment.
Optimizing a risk stratification for local-regional failure after radical cystectomy using the SWOG 8710 cohort.
Authors: Baumann Brian C. , He Jiwei , Hwang Wei-Ting , Tucker Kai , Lerner Seth P. , Tangen Catherine M. , Herr Harry W. , Guzzo Thomas J. , Malkowicz S. Bruce , Christodouleas John Paul
Published: February 2017

297

Background: Trials of adjuvant radiation (RT) after radical cystectomy + pelvic node dissection (RC) are in development, but patient selection criteria have not been clearly identified. We evaluated a published model predicting the risk of local-regional failure (LF) by applying the model to a multi-center patient cohort. We also assessed the model’s ability to stratify overall survival (OS) and isolated distant metastases (DM). Methods: The original LF risk model was derived from 442 patients who had a RC +/- chemotherapy at the University of Pennsylvania (PENN). Analysis identified 3 subgroups with significantly different LF risk based on pathologic stage (pT) and number of nodes dissected (<10 vs ≥10). This risk rubric was then applied to 264 patients in the multi-center SWOG 8710 trial randomized to RC +/- neoadjuvant chemotherapy. SWOG patients differed significantly from PENN patients in mean age, pT stage, number of nodes removed, surgical margin status, and use of neoadjuvant chemotherapy. In both cohorts, LF was any pelvic failure detected before or within 3 months of DM. Secondary endpoints were OS and DM. Competing risk analysis was used. Results: The original risk stratification was not fully validated in the SWOG cohort. Regression analysis of the SWOG data found margin status was more predictive of LF than number of nodes dissected. A revised risk stratification model combining pT stage, margin status, and number of nodes removed identified 3 subgroups in both the SWOG and PENN cohorts with significantly different LF risks: low (≤pT2), intermediate (≥pT3 with negative margins AND ≥10 nodes removed), and high (≥pT3 with positive margins OR <10 nodes removed) with 5 year LF rates of 8%, 20%, and 41% in the SWOG group and 8%, 19%, and 41% in the PENN cohort. The 3 subgroups also differed significantly in OS within both cohorts with 5 year OS of 62%, 39%, and 7% for SWOG and 60%, 31%, and 10% for PENN. The model did not stratify with respect to isolated DM. Conclusions: The revised risk model combining pT stage, margin status, and number of nodes excised provides a simple rubric to stratify LF risk in two significantly different bladder cancer populations and may inform the design of adjuvant RT trials.
Multi-institutional quality care initiative (QCI) to improve the care of patients with invasive bladder cancer (BlCa).
Authors: Bochner Bernard H. , Feifer Andrew , Sperling Dahlia , Mashni Joseph W , Bajorin Dean F. , Shah Jay Bakul , Kamat Ashish M. , Steinberg Gary D. , Stadler Walter Michael , Grubb Robert L. , Kibel Adam S. , Schoenberg Mark , Black Peter C. , Zlotta Alexandre , Kassouf Wassim , Lerner Seth P. , Lotan Yair ,   Collaborators of the BCAN Quality of Care Initiative Consortium
Published: February 2017

298

Background: Level 1 evidence supports a survival benefit for BlCa pts that receive periop cisplatin chemotherapy in addition to radical cystectomy (RC). Underutilization of multimodal therapy has been reported nationally. We instituted a multicenter QCI to improve the use of periop chemotherapy. Methods: A two phase effort was initiated at 16 academic institutions. Phase 1 was initiated in 2010 and designed to evaluate baseline patterns of periop chemotherapy use for T2-4N0M0 BlCa pts that underwent RC between 2003-2008. Phase 2 was a prospective QCI. The quality indicators included (1) referral to medical oncology for consideration of multimodality therapy, (2) neoadjuvant, if recommended, be cisplatin based and at least 3 cycles, (3) adjuvant, if recommended, be cisplatin based and at least 3 cycles, (4) all treatment be completed within 6 months. Data on all eligible pts were collected prospectively for 12 months on a web-based survey system. Results: All 16 centers participated in phase 1. Of 4,344 pts on whom data was available, 34% received periop chemotherapy. Neoadjuvant and adjuvant therapy use was 14% and 20%, respectively. 65% of pts receiving periop chemotherapy were treated with a cisplatin-based regimen. Of those treated neoadjuvantly, cisplatin was received in 70% of cases. Nine of the 16 institutions completed phase 2 data collection. Over 700 pts that underwent RC were evaluated. 395 pts with T2-4N0M0 disease were deemed eligible for data entry. Fifty-six percent of eligible pts received periop systemic chemotherapy. Of this 56%, 47% received neoadjuvant cisplatin chemotherapy and 9% received adjuvant cisplatin chemotherapy. This represented a 64.7% increase in the use of any periop chemotherapy and a 3.4 fold increase in neoadjuvant chemotherapy compared to baseline data. Conclusions: We have successfully completed a multi-institutional QCI to improve the use of periop chemotherapy in pts undergoing RC for resectable, non-metastatic bladder cancer. Our data demonstrates that significant improvements can be achieved in not only overall use of periop chemotherapy but most notably in the use of neoadjuvant chemotherapy.
Peptide vaccines with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive castration resistant prostate cancer: A randomized phase II study.
Authors: Uemura Hirotsugu , Kimura Takahiro , Minami Takafumi , Yoshimura Kazuhiro , Nozawa Masahiro , Egawa Shin , Fujimoto Hiroyuki , Yamada Akira , Itoh Kyogo
Published: February 2017

3

Background: We previously developed MHC class I restricted peptide vaccines for prostate cancer and carried out a phase 1 trial for castration resistant prostate cancer (CRPC) patients to assess safety and immunological evaluation. In the present study, we conducted a randomized phase 2 trial to evaluate the efficacy of peptide vaccination therapy for chemotherapy-naive CRPC patients. Methods: Early-stage CRPC (PSA<10ng/ml) patients positive for HLA-A02 or A24 or A3 super family were randomized into two treatment groups; peptide vaccine with low dose (1mg/day) dexamethasone (Dx) versus low dose Dx alone. Patients were vaccinated subcutaneously with 3 mg of selected peptides (max. 4 kinds) 6 times at two weeks interval. Dx 1mg/day p.o. was started on the first day of peptide vaccination. Toxicity was assessed monthly, and immunological responses such as cytotoxic T lymphocyte activity and clinical responses were evaluated every 3 months. The primary endpoint of this study is progression-free survival including serum PSA. Secondary endpoints are overall survival and safety. Results: A total of 83 chemotherapy-naive CRPC patients were selected for this trial. Of these 10 patients were excluded due to HLA type mismatch and exclusion criteria. 73 patients were enrolled and randomized; 37 in the vaccine treatment group and 36 in the Dx group. One patient in the Dx group self-withdrew from the study immediate after the randomization. Median time to PSA failure in the vaccine group was significant longer than the Dx group; 602 days vs 210 days, p<0.001 (Table). Conclusions: These findings suggest that combination therapy of peptide vaccines and low dose dexamethasone may be a promising tool for chemotherapy-naive CRPC patients. Clinical trial information: UMIN000000959.[Table: see text]
Using adjuvant radiotherapy to improve cancer-specific survival in patients with highly aggressive prostate cancer: Examining recently released criteria.
Authors: Abdollah Firas , Gandaglia Giorgio , Briganti Alberto , Trinh Quoc-Dien , Nguyen Paul Linh , Hu Jim C. , Montorsi Francesco , Perrotte Paul , Karakiewicz Pierre I. , Sun Maxine
Published: February 2017

30

Background: Although adjuvant radiotherapy (aRT) after radical prostatectomy (RP) improves biochemical recurrence (BCR)-free survival rates, its effect on cancer-specific mortality (CSM) in patients with prostate cancer (PCa) is still controversial. The aim of our study was to test the effect of aRT on CSM according to a risk score based on the number and nature of adverse pathological characteristics (Gleason score 8-10; pT3b/4, lymph node invasion [LNI]). Methods: Overall, 7,616 patients with pT3/4 N0/1 PCa treated with RP between 1995 and 2009 within the Surveillance Epidemiology and End Results Medicare-linked database were included in the study. Patients were stratified according to the risk score (less than 2 vs. 2 or more adverse characteristics), and the impact of aRT on CSM was examined in each sub-group. Additionally, to evaluate the effectiveness of aRT, we calculated the number needed to treat (NNT), defined as the average number of patients who must be treated to prevent one detrimental outcome. Subsequently, competing-risks regression models were used to test the effect of aRT on CSM rates in the overall population and after stratifying patients according to their risk score (less than 2 vs. 2 or more). Results: The risk score was associated with increasing 10-year CSM rates (P<0.001). When focusing on patients with a risk score 2 or more, 10-year CSM rates were significantly lower for individuals undergoing aRT compared to their counterpart not receiving aRT (6.9 vs. 16.2%, respectively; P=0.002). The corresponding NNT to prevent one death from PCa was 10. Adjuvant RT was not associated with lower CSM rates overall and in patients with a risk score less than 2. This was confirmed in multivariable analyses, where aRT decreased the risk of CSM only in patients with a risk score 2 or more (P≤0.02). Conclusions: Our findings confirm the validity of the previously reported risk score in selecting the most optimal candidates for aRT after surgery in a large contemporary population-based cohort of patients with pT3/4 N0/1 PCa. Patients with two or more adverse pathological characteristics at RP might benefit the most from aRT in terms of reduced CSM.
Using exon-capture, deep sequencing of high-grade bladder urothelial carcinoma to identify recurrent genetic alterations and potential therapeutic targets.
Authors: Kim Philip H. , Sfakianos John P. , Scott Sasinya N. , Iyer Gopa , Cha Eugene K. , Al-Ahmadie Hikmat , Sun Arony J. , Garcia-Grossman Ilana Rebecca , Bambury Richard Martin , Dalbagni Guido , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Solit David B. , Bochner Bernard H.
Published: February 2017

308

Background: Urothelial carcinoma (UC) is highly lethal malignancy with limited therapeutic options in the advanced setting. Using a targeted, deep sequencing approach, we analyzed high grade bladder tumors to determine the prevalence of known cancer genes and to identify potential targets for therapy. Methods: High-grade bladder UC frozen tumor and matched germline blood was obtained from 109 patients (pts) undergoing transurethral resection or cystectomy. Tumor and normal DNA were analyzed using IMPACT (Integrated Molecular Profiling of Actionable Cancer Targets), a next generation, exon-capture targeted deep sequencing assay designed to identify point mutations, indels, and copy number alterations in the coding regions of 300 cancer-associated genes. Results: Median age was 68 and 82 pts (75%) were male. Mean target coverage for all sequenced exons was 579X. The most commonly mutated gene was TP53 (63 pts, 58%). Alterations in genes regulating cell cycle were also prevalent, including mutations in Rb (25 pts, 23%), and copy number gains of CCND1 (19 pts, 17%) and CCNE1 (8 patients, 7%). Mutations in several chromatin remodeling genes were also highly prevalent, including KDM6A (46 pts, 42%), MLL2 (34 pts, 31%), and ARID1A (31 pts, 28%). Alterations within recognized cancer-related signaling pathways were common. PI3K pathway alterations were prevalent, with PIK3CA mutations found in 25 pts (23%), 23 of which were recurrent missense mutations. Six pts (6%) had mutations in PTEN. Mutations in TSC1 were also found in six pts (6%). Alterations in select MAPK pathway genes were common, including FGFR3 (21 pts, 19%) and ERBB2(15 pts, 14%). Conclusions: High-grade bladder UC is a genetically heterogenous disease. However, over half of the tumors analyzed in this study harbor alterations in genes that have been targeted for therapeutic benefit in other cancers. Results from our targeted exon-sequencing analysis therefore provide a compelling case for clinical trials using novel agents in UC. Moreover, this deep sequencing assay may be used clinically to prospectively identify pts for trials enriched for patients with specific alterations.
Changes in relative conditional survival (RCS) in de novometastatic urothelial carcinoma (mUC): A Surveillance, Epidemiology, and End Results (SEER) database analysis.
Authors: Pal Sumanta Kumar , Vogelzang Nicholas J. , Nelson Rebecca A.
Published: February 2017

314

Background: Currently, no agents are FDA approved for second-line treatment of mUC. Still, many patients receive second-line treatment, with data from phase II studies used as justification for payors. While this practice may not prolong disease-specific survival (DSS) for all mUC patients, assessing RCS may better account for benefit from 2nd line treatment. Methods: The SEER database was queried to compare DSS and 1-year RCS rates in de novo mUC patients diagnosed from 1994-2000 (T1) to those diagnosed from 2001-2009 (T2). The cut-off at 2000 was chosen to account for treatment variations stemming from phase II second-line trials published subequent to this date. DSS rates for T1 and T2 were modeled using Kaplan-Meier methods and compared using the log-rank test. 1-year RCS was computed annually from diagnosis through 5-years post diagnosis. The results were age standardized and compared across time periods using the z-test statistic, with 95% confidence intervals calculated using the log(log()) transformation. Multivariate Cox proportional hazard models were used to assess independent prognostic factors of DSS. Results: A total of 4,465 mUC patients were included, with 1,155 diagnosed during T1 and 3,310 diagnosed during T2. Mean age of the overall cohort was 70, and the majority of patients had poorly differentiated or undifferentiated tumors. Median DSS was 6 months for both T1 and T2 groups (P=NS). 1-year RCS rates at 1, 2, and 3 years post diagnosis, were 46%, 71%, and 76% for T1 patients compared to 39%, 68% and 78% for T2 patients (P=NS for each comparison). On MVA, older age (>65) and undifferentiated histology were independently associated with shorter DSS, while use of radiation and surgery were associated with longer DSS. Time period of diagnosis (T1 vs T2), however, had no impact on DSS. Conclusions: Multiple published phase II studies emerging over the past decade have been used to justify use of post second-line therapies for mUC to payors. In contrast to DSS, our assessment of RCS should better account for the impact of these therapies. The lack of improvement in RCS calls into question the impact post first-line therapies have on the natural history of mUC.
NOTCH2 inhibition on tumor growth and metastasis in bladder cancer.
Authors: Hayashi Tetsutaro , Gust Kilian , Jaeger Wolfgang , Awrey Shannon , Li Na , Altamirano-Dimas Manuel , Buttyan Ralph , Fazli Ladan , Matsubara Akio , Black Peter C.
Published: February 2017

315

Background: Notch is a family of cell surface receptors that has been demonstrated in several malignancies to regulate differentiation, proliferation, and metastasis. We have investigated the role of Notch signaling in bladder cancer and report here effects of modulating Notch2 in preclinical models of bladder cancer. Methods: Notch2 staining was examined in cystectomy patients by immunohistochemistry (IHC). The high NOTCH2 expressing UM-UC3 and UM-UC13 bladder cancer cells were stably transduced with either Notch2 specific or control shRNA. The low Notch2 expressing RT4V6 and RT112 cells were transduced with NOTCH2 intracellular domain or empty vector. A Notch2 inactivating antibody, NRR2Mab, was provided by Genentech, Inc. (San Francisco, CA). The effects of NOTCH2 overexpression and inhibition were assessed for changes in proliferation under both adherent (AH) and anchorage independent conditions (AI), and invasive activities in vitro, as well as for expression of markers of epithelial to mesenchymal transition (EMT) and stem cell markers. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. Results: NOTCH2 overexpression in IHC correlated with higher grade and stage. Both NOTCH2 overexpressing cells showed spindle shaped morphology and increased cell growth in AH and AI and invasion compared to mock cells. This was associated with cell cycle progression and increased expression of EMT and stem cell markers. Stable NOTCH2 knockdown cells and cells treated with NRR2Mab demonstrated decreased growth in AI and invasion, and this was associated with decreased expression of EMT and stem cell markers. In vivo, RT4V6 NOTCH2 overexpression increased xenograft tumor growth and NOTCH2 overexpression increased ki67 positive cells and promoted EMT in IHC. Stable Notch2 knockdown inhibited xenograft tumor growth in UM-UC3 and UM-UC13. NRR2Mab treatment also inhibited UM-UC13 xenograft tumor growth and lymph node metastasis. Conclusions: NOTCH2 plays a crucial role in growth, self-renewal and invasion in bladder cancer. These results provide pre-clinical proof of principle that Notch2 inhibition may be a rational treatment for bladder cancer.
Treatment target development in muscle-invasive bladder cancer.
Authors: Brown Mick D. , Robinson Richard , Hart Claire , Clarke Noel W.
Published: February 2017

328

Background: Outcome for many patients with high-grade muscle invasive bladder cancer (MIBC) remains poor despite aggressive therapy. This study used novel marker approaches to evaluate putative treatment targets, correlating cell line models of bladder cancer with a large scale MIBC tissue microarray (TMA) linked to long-term post-treatment outcomes. Methods: The TMA was constructed from 497 cystectomy specimens from patients with comprehensively documented disease outcome (minimum 5 years follow-up). TMA sections were stained for putative targets using DAB-based IHC. Cellular expression of CYR61 and CTGF was quantified (after targets had been identified using the genetic search programme, Oncomine) using Definiens automated image-analysis (AIA) software. Putative TMA based-targets studied were also evaluated in J82 and T24 bladder cancer cell-lines by siRNA knockdown during proliferation, time course stimulation and Boyden chamber MatrigelÒ invasion assays. Results: CTGF was increased significantly in both cell lines following stimulation with the cMET ligand HGF. siRNA knockdown of CTGF and CYR61 reduced cell proliferation and invasion towards HGF and FCS significantly (p<0.01). AIA demonstrated high sensitivity and specificity (82.5% and 99.8% respectively) for identifying tumour cells. There was no intra-observer variability (ICC=1). CYR61 was associated with significantly improved survival following cystectomy, median 15.2 versus 40.0 months for intermediate/high versus negative/low expression respectively (p=0.004). Conclusions: AIA is robust tool for use in IHC based research. CTGF is an important component of the cMET axis in MIBC. CTGF and in particular CYR61 are promising treatment targets and warrant further investigation in the management of this disease.
Adjuvant chemotherapy for upper-tract urothelial carcinoma: A systematic review and meta-analysis of available studies.
Authors: Leow Jeffrey J. , Chang Steven L. , Choueiri Toni K. , Bellmunt Joaquim
Published: February 2017

330

Background: Upper-tract urothelial carcinoma (UTUC) accounts for less than 5% of all urothelial cancers. Adjuvant chemotherapy (AC) for UTUC may improve survival outcomes, but currently available evidence is limited. Methods: A comprehensive literature review was performed to identify all studies comparing AC with control for patients with UTUC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to June 2013. An updated systematic review and meta-analysis was performed. Results: A total of 9 retrospective cohort studies were identified (Table). For disease-specific survival, 6 studies had sufficient data (AC: n=406, control: n=1,227), with a pooled hazard ratio of 0.64 in favor of AC over control (95% CI: 0.41 to 0.99; p=0.047). Between-trial heterogeneity was not significant based on the Cochran Q statistic (p=0.14) and I2 = 40% (95% CI=0-76). Four studies had sufficient data for overall survival (AC: n=228, control: n=685), with a pooled hazard ratio of 1.06 (95% CI: 0.52 to 2.13; p=0.88). Between-trial heterogeneity was observed based on the Cochran Q statistic (p=0.03) and I2(68%, 95% CI: 7-89). There were no randomized trials investigating the role of AC for UTUC. Conclusions: There appears to be a significant benefit in disease-specific survival, but not overall survival, for AC in UTUC. While limited by the retrospective nature of studies and relatively small sample size, this analysis may be helpful in guiding the oncologic management of UTUC. [Table: see text]
Comparison of oncologic outcomes following systemic neoadjuvant chemotherapy and radical cystectomy in patients with mixed histologic variants and pure urothelial carcinoma of the bladder.
Authors: Sverrisson Einar Freyr , Espiritu Patrick , Kim Timothy , Gupta Shilpa , Poch Michael Adam , Spiess Philippe E. , Pow-Sang Julio , Sexton Wade Jeffers
Published: February 2017

333

Background: Neoadjuvant chemotherapy (CT) is recommended prior to radical cystectomy (RC) in patients with muscle invasive urothelial carcinoma of the bladder (UCB), and has been shown to have modest survival benefit in clinical trials. The purpose of our study was to investigate the response and survival rates in patients with histologic variants (HV) and compare oncologic outcomes to patients with pure UCB. Methods: We performed a retrospective review of 163 patients treated with neoadjuvant CT prior to RC. Twenty-four patients with HV and 139 with pure UCB were identified. Numerous patient demographics, clinical and pathologic characteristics were evaluated including; clinical and pathologic stage, HV, lymphovascular invasion (LVI), margin status, node counts, concomitant carcinoma in situ (CIS), previous intravesical treatments, prior pelvic radiation, completeness of bladder tumor resection (TURBT), and CT regimens. Results: Patients with HV were younger (66.5 versus 71 years, p=0.04) but otherwise there were no significant differences noted between the two groups comparing previous treatments, clinical staging, margin status, node counts, CT regimens, # of neoadjuvant CT cycles, or rates of adjuvant CT administration. Of the 24 HV patients, 11 (47.8%) were downstaged to < pT2 compared to 50 (64.1%) of 139 patients with pure UCB (P=0.37). pT0 rates for HV and pure UCB were 16.7% and 23%, respectively (p=0.60). Twelve (50%) of the HV group compared to 65 (46.8%) of the pure UCB patients (p=0.83), had no evidence of disease at a mean follow up after RC of 19.5 (HV) and 22 (UCB) months. Eight (33.3%) patients with HV died of disease compared to 44 (31.7%) in the UCB group, (p=1.0). There was no significant difference noted in CSS and OS between the 2 groups, although there was a trend towards higher rates of node positive disease (p=0.086) and inferior CSS (p=0.09) in patients with HV compared to patients with pure UCB. Conclusions: Our results indicate that patients with HV experience similar oncologic outcomes from neoadjuvant systemic CT compared to patients with pure UCB.
Comparative effectiveness of radical cystectomy versus bladder-sparing treatment for muscle-invasive urothelial carcinoma: A population-based report.
Authors: Sun Maxine , Gandaglia Giorgio , Karakiewicz Pierre I. , Hu Jim C. , Kim Simon P. , Nguyen Paul Linh , Choueiri Toni K. , Abdollah Firas , Trinh Quoc-Dien
Published: February 2017

334

Background: Radical cystectomy (RC) represents the standard of care for patients with muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Alternative organ-conserving treatments such as chemotherapy and/or radiotherapy have gained interest. We sought to compare survival outcomes of patients according to treatment modalities, in a stage-for-stage analysis. Methods: We relied on the Surveillance, Epidemiology, and End Results Medicare-linked database to identify 12,950 patients diagnosed with T2–T4a N0/x M0 UCUB between years 1992 and 2009. Treatment types include RC (n=5207), chemotherapy/radiation (n=2,669), and surveillance (n=5,074). Following instrumental variable analysis, Cox- and competing-risks regression analyses were performed for prediction of overall survival (OS) and cancer-specific mortality (CSM), respectively. All analyses were stratified according to disease stage (T2, T3, T4a). Results: After adjusting for potential confounders, OS was more favorable for RC relative to chemotherapy/radiation (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.02–2.40) or surveillance (HR: 1.82, 95% CI: 1.20–2.78) in patients with T2 UCUB. For the same stage, CSM rates were lower in the surgery group compared to chemotherapy/radiation (HR: 2.05, 95% CI: 1.14–3.67) or surveillance (HR: 1.95, 95% CI: 1.09–3.48). When analyses focused on individuals with more advanced disease (T3–T4a), no statistically significant difference was observed between chemotherapy/radiation relative to RC for both OS and CSM. Conclusions: In the current retrospective population-based cohort, RC was associated with improved survival outcomes relative to its alternative treatment counterparts. However, this effect was only observable in patients with T2 disease. Conversely, no difference between chemotherapy/radiation vs. surgery was noted in patients with more advanced disease stage.
Predictive and prognostic significance of early positron emission tomography/computed tomography (PET/CT) in advanced transitional cell carcinoma.
Authors: Giannatempo Patrizia , Alessi Alessandra , Miceli Rosalba , Raggi Daniele , Farè Elena , Nicolai Nicola , Serafini Gianluca , Padovano Barbara , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Maffezzini Massimo , Mariani Luigi , Gianni Alessandro M. , Sonpavde Guru , Salvioni Roberto , Crippa Flavio , Necchi Andrea
Published: February 2017

341

Background: A risk-adapted treatment for TCC may guide new trial designs for early-recognized unresponsive patients (pts). We aimed to prospectively identify early fluorodeoxyglucose (FDG)-PET/CT as a predictor of response and outcome. Methods: Pts with newly-diagnosed advanced/metastatic TCC receiving first-line chemotherapy underwent CT and FDG-PET/CT at baseline, a restaging with PET/CT after 2 cycles only (PET2), and a CT (± FDG-PET/CT) at the end of treatment and during follow up. The endpoints were PET2 metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox models were fitted. Prespecified variables were presence of visceral metastases, nodal or soft tissue disease, and PET2 response. Results: In the time-frame 05/2010-10/2012, 31 pts with ECOG-PS 0 received a modified MVAC regimen according to Institutional protocol, every 3 weeks. After 2 cycles of MVAC, 6 patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR) (74% total responders; 95% CI, 55.4-88.1%), 4 had stable disease (SD), 4 progressed. Metabolic response (CR + PR) was associated with final CT response (p=0.007 at Fisher exact test). Metabolic CR was followed by a RECIST CR in all but one cases and metabolic progression at PET2 corresponded to a RECIST PD in all four patients and they all switched to second line chemotherapy. Median follow up was 18 months (IQR: 10-47). Those with metabolic response had a median (95% CI) PFS of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). PET2 responders had a significant benefit in 8-month PFS (p<0.001) and 15-month OS (p=0.016 at Klein test). A significant association was observed between PET2 response and longer PFS in both UVA and MVA (p=0.027 and p=0.023, respectively). Results are limited by small numbers. Conclusions: PET2 response might confer an independent prognostic impact on PFS and OS. Results warrant a validation series, a comparison with the impact of early RECIST response as well as a detailed cost-efficacy analysis prior to devise a new strategy of first-line treatment.
Clinical evaluation of cisplatin sensitivity germ line polymorphisms in neoadjuvant chemotherapy (NAC) for urothelial cancer (UC).
Authors: O'Donnell Peter H. , Garcia-Grossman Ilana Rebecca , Cao Hongyuan , Ostrovnaya Irina , Plimack Elizabeth R. , Stratton Kelly Lynn , Manschreck Christopher , Smith Norm D. , Steinberg Gary D. , Joseph Vijai , Offit Kenneth , Stadler Walter Michael , Bajorin Dean F.
Published: February 2017

342

Background: Cisplatin-based NAC in UC confers a survival benefit, but prediction of which patients (pts) will benefit is not possible. We attempted to validate pharmacogenomic (PGx) markers of cisplatin sensitivity derived from a cell-based model and previously associated with response in a population of pts receiving NAC. Methods: Three germline single nucleotide polymorphisms (SNPs) were previously associated with pathologic response at cystectomy in a single-institution discovery set of 59 cT2 UC pts. These SNPs were tested for association with NAC response in a prospectively-identified, multi-institution, independent cohort. The primary analysis tested for association between rs244898 and rs7937567 and pathologic complete response (pT0). A replication set of 134 pts would provide 80% power to detect effects of both SNPs at p=0.05 independently using a multivariate logistic model. Results: N=146 pts with ≥cT2 N0 disease were identified from three institutions. All pts received ≥3 cycles of cisplatin-based NAC and underwent definitive surgery. Rates of pT0 and 5 odds ratio of effect on pT0 in the discovery set, neither was associated with achievement of pT0 in the replication set. The third SNP (rs10964552) which was associated with pathologic downstaging in the discovery set, also failed to replicate. All three SNPs were in Hardy-Weinberg equilibrium, and minor allele frequencies were similar between discovery and validation. Conclusions: Three germline SNPs previously associated with platinum sensitivity in pre-clinical and clinical models were not associated with NAC response in a large replication cohort of UC pts. Reasons for failure may include unmeasured clinical differences between the pt cohorts, a higher proportion of MVAC use in the replication set compared to gemcitabine/cisplatin in discovery pts, or simply spurious association in the discovery cohort. These results emphasize the need for replication when evaluating PGx markers, and demonstrate that multi-institutional efforts are feasible and will likely be necessary to achieve advances in UC PGx.
C-reactive protein prior to cystectomy: An external validation of the TNR-C score.
Authors: Kramer Mario W. , Heinisch Annika , Wegener Gerd , Abbas Mahmoud , Peters Inga , von Klot Christoph A. J. , Tezval Hossein , Herrmann Thomas R. W. , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

344

Background: Systemic inflammation has been described as a common reaction to cancer progression. Besides other malignancies, elevated serum CRP levels have been sparsely reported in bladder cancer patients prior to treatment. The aim of this study was to analyze whether our patient cohort showed association of CRP levels and survival after radical cystectomy as well as for external validation of the recently described TNR-C score. Methods: We retrospectively reviewed charts of patients undergoing radical cystectomy and bilateral pelvic lymphadenectomy between 1996 and 2005 identifying 279 patients of which 194 had preoperative CRP levels and no concomitant infection. CRP levels were defined as elevated if they were >5 mg/l. Cancer-specific outcome was predicted based on the aforementioned CRP-based scoring model (T=T-stage; N=N-stage; R=residual tumor; C=CRP). The mean follow-up was 29 months (0-131). Results: Elevated serum CRP levels were found in 89 (45.9%) patients preoperatively. These patients were more likely to have advanced tumor stages (pT3-4; p<0.01), positive resection margins (p<0.01) and positive lymph nodes (p<0.05). Cancer specific survival was decreased by approx. 17% after 12, 36, and 60 months. In multivariate analysis, CRP was identified as an independent prognostic indicator for poor cancer-specific survival. The 3-year CSS in patients with a TNR-score in the ranges 0-2, 3-6, and 7-10 was 74.0%, 33.3%, and 4.0%, respectively (p<0.001) with a concordance index of 0,833 (p<0.001). Conclusions: Elevated preoperative CRP levels might be used in nomograms to predict poor survival after radical cystectomy. The prognostic impact of the TNR-C score could be validated. However, more evidence, especially from prospective studies is needed.