bluuebunny/crossref_metadata_2025 huggingface dataset:
Daily versus weekly prostate cancer image-guided radiotherapy: A phase 3, multicenter, randomized trial.
Authors: de Crevoisier Renaud , Bayar Mohamed-Amine , Pommier Pascal , Muracciole Xavier , Pene Francoise , Dudouet Philippe , Latorzeff Igor , Beckendorf Veronique , Bachaud Jean-Marc , Laplanche Agnes , Supiot Stephane , Chauvet Bruno , N'Guyen TD , Bossi Alberto , Crehange Gilles , Lagrange Jean-Leon
Published: February 2018

4

Background: The optimal frequency of prostate cancer image-guided radiation therapy (IGRT) has not yet been clearly identified. This study sought to compare the safety and efficacy of daily versus weekly IGRT. Methods: This Phase III randomized trial recruited 470 patients with N0 localized prostate cancer, from 21 centers between June 2007 and November 2012. Total IGRT doses ranged from 70 to 80 Gy. Patients were randomly assigned (1:1) to two prostate IGRT control frequency groups: daily or weekly (Days 1, 2, and 3, then weekly). The primary outcome was 5-year recurrence-free survival (RFS). Secondary outcomes included overall survival (OS) and toxicity (CTCAE V.3.0). Post-hoc analyses included biochemical progression-free interval (BPFI), clinical progression-free interval (CPFI) and second cancer-free interval (SCFI). Results: Median follow-up was 4.1 years (Q1 – Q3 = 3.1 – 5.1).There was no statistically-significant difference in RFS between the groups (hazard ratio [HR] = 0.81 [95% CI: 0.52 – 1.25]; p = 0.330). OS was worse in the daily control group versus the weekly control group (HR = 2.12 [95% CI: 1.03 – 4.37]; p = 0.042). Late rectal toxicity (Grade ≥1) incidence was significantly lower in the daily control group (HR = 0.71 [95% CI: 0.53 – 0.96]; p = 0.027). BPFI was better in the daily control group versus the weekly control group (HR = 0.45 [95% CI: 0.25 – 0.80]; p = 0.007). CPFI was better in the daily control group (HR = 0.50 [95% CI: 0.24 – 1.02]; p = 0.057). SCFI was worse in the daily control group versus the weekly control group (HR = 2.21 [95% CI: 1.10 – 4.44]; p = 0.026). Conclusions: Compared to weekly control, daily IGRT control in prostate cancer significantly decreases the risks of recurrence and late rectal toxicity but is associated with an increased risk of second cancer. Clinical trial information: NCT00433706.
Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab (pembro) vs investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC).
Authors: Bellmunt Joaquim , De Wit Ronald , Vaughn David J. , Fradet Yves , Lee Jae-Lyun , Fong Lawrence , Vogelzang Nicholas J. , Climent Miguel A. , Petrylak Daniel Peter , Choueiri Toni K. , Necchi Andrea , Gerritsen Winald , Gurney Howard , Quinn David I. , Culine Stephane , Sternberg Cora N. , Nam Kijoeng , Frenkl Tara L. , Perini Rodolfo F. , Bajorin Dean F.
Published: February 2018

410

Background: Based on interim results from the phase 3 KEYNOTE-045 (NCT02256436) study comparing pembro v investigator’s choice of chemotherapy (chemo), pembro was approved for the treatment of locally advanced or metastatic UC that has progressed during or after a platinum-containing regimen. Updated results after 2 years of follow-up are presented. Methods: Eligible patients (histologically or cytologically confirmed UC, progression after platinum, ECOG PS 0-2, measurable disease per RECIST v1.1, ≤2 lines of systemic therapy) were randomly assigned 1:1 to pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary efficacy end points were OS and PFS (RECIST v1.1, blinded central review). ORR (RECIST v1.1, blinded central review) was a secondary end point. Results: As of Oct 26, 2017, among the 542 enrolled patients (pembro, 270; chemo, 272), median follow-up was 27.7 mo. Median OS was significantly longer with pembro v chemo (10.3 v 7.3 mo; HR, 0.70; P < 0.0002). OS benefit with pembro v chemo was seen in all PD-L1 expression subgroups (HR: combined positive score [CPS] < 1, 0.82; CPS ≥1, 0.58; CPS < 10, 0.75; CPS ≥10, 0.56) and was maintained regardless of age, ECOG PS, prior therapy, liver metastases, baseline hemoglobin, time from last chemo, histology, risk factor group, and choice of chemo. PFS was not different between arms (2.1 v 3.3 mo; HR, 0.96; P = 0.32). ORR was higher with pembro v chemo (21.1% v 11.0%). Median duration of response was longer with pembro (not reached [1.6+–30.3+ mo] v 4.4 mo [1.4+–29.9+ mo]), and a greater proportion of responses lasted ≥12 mo (68% v 35%) as assessed by Kaplan-Meier method. Fewer patients with pembro v chemo experienced a treatment-related adverse event of any grade (62.0% v 90.6%) and a grade ≥3 adverse event (16.5% v 50.2%). Conclusions: Results observed over 2 years of follow-up, including OS benefit and superior safety with pembro v chemo, were consistent with the interim analyses that led to the approval of pembro in locally advanced or metastatic UC that progressed during or after platinum-based chemotherapy. Clinical trial information: NCT02256436.
Nivolumab monotherapy in metastatic urothelial carcinoma: Longer-term efficacy and safety results from the CheckMate 032 study.
Authors: Sharma Padmanee , Callahan Margaret K. , Bono Petri , Kim Joseph W. , Spiliopoulou Pavlina , Calvo Emiliano , Pillai Rathi Narayana , Ott Patrick Alexander , De Braud Filippo G. , Morse Michael , Le Dung T , Taylor Matthew H. , Bendell Johanna C. , Jäger Dirk , Chism David D. , Antonia Scott Joseph , Aanur Nivedita , Yang Lingfeng , Rosenberg Jonathan E.
Published: February 2018

414

Background: Nivolumab has shown efficacy and acceptable safety in 2 open-label, multicenter studies (CheckMate 032 and 275) and is approved for patients (pts) with metastatic urothelial carcinoma (mUC) after ≥1 platinum-based therapy. Here we report longer-term efficacy and safety results for pts with mUC in the phase 1/2 CheckMate 032 study who received nivolumab monotherapy based on > 2 years of follow-up. Methods: Pts with mUC, regardless of programmed death-1 ligand 1 (PD-L1) expression status, received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Tumor PD-L1 membrane expression was assessed with Dako PD-L1 immunohistochemical staining. Primary endpoint: objective response rate (ORR; RECIST 1.1); other endpoints: safety, progression-free survival (PFS), overall survival (OS), and duration of response. Results: Of 78 treated pts (median age 65.5 years; range, 31-85), 52 (66.7%) had received ≥2 prior therapies. At a minimum follow-up of 24 months, 11 pts (14.1%) remain on treatment. Treatment discontinuation was mainly due to disease progression (52 pts [66.7%]). Tumor PD-L1 expression was evaluable in 68 pts (87.2%); 26 (38.2%) pts had ≥1% and 42 (61.8%) had < 1% expression. The table shows overall efficacy. Updated ORR was 25.6%, with 1 additional complete response (CR) achieved for a CR rate of 8%. Median duration of response was not reached. ORR, 1- and 2-year PFS and OS rates were similar between the PD-L1 < 1% and > 1% subsets. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 22 pts (28.2%); most frequent were ↑lipase (6.4%), ↑amylase (5.1%), and maculopapular rash (3.8%). One pt had a grade 5 TRAE (pneumonitis). Conclusions: Nivolumab showed clinically meaningful, durable efficacy with promising long-term survival regardless of PD-L1 expression, and no new toxicity signals with longer-term follow-up in previously treated pts with mUC. Clinical trial information: NCT01928394. [Table: see text]
Correlation of MECA-79-positive high endothelial venule density with clinical outcomes in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.
Authors: Hashimoto Yasuhiro , Yamamoto Hayato , Yoneyama Tohru , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2018

417

Background: High endothelial venules (HEVs) are present in lymph nodes and tertiary lymphoid organs. It has been reported that low HEV density is associated with the poor prognosis of several carcinomas. MECA-79 antibody recognizes L-selectin ligand (6-sulfosialyl Lewis X glycan) expressed in HEV. In the present study, we examined whether MECA-79 positive HEV density was associated with clinical outcomes of patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Methods: Eighty-eight patients with UTUC who underwent RNU at the Hirosaki University hospital between January 2008 and December 2016 were enrolled. Tissue microarray for MECA-79 was performed, and HEV densities were calculated. HEV density < 1.5/mm2 was defined as HEV (−); HEV density ≥1.5/mm2 was defined as HEV(+). Results: Of 88 patients, 64 (72.7%) were male and 24 (27.2%) were female. The average age was 68.5 years (range, 36–84 years). Fifty-three patients (60.2%) had previously undergone neoadjuvant chemotherapy. The mean observation period was 39.0 months. Twenty-one (23.8%) patients developed recurrence, whereas 16 (33.3%) patients died during follow-up. Five-year cause-specific survival (CSS) rate was 66.1%, and five-year disease-free survival (DFS) rate was 70.7%. In our cohort, 25 (28.4%) patients were found to be HEV(−), whereas 63 (71.5%) were found to be HEV(+). The mean HEV density was 6.3/mm2(0-41.6). The 5-year DFS rates for HEV (+) and HEV (−) patients were 78.0% and 53.9%, respectively, with a statistically significant difference between the groups. (log-rank, p = 0.042). Moreover, the 5-year CSS rates for HEV (+) and HEV (−) patients were 72.5% and 53.4%, respectively, with a statistically significant difference between the groups. (log-rank, p = 0.0036). Conclusions: Low MECA-79-positive HEV density may be associated with poor prognosis of patients with UTUC treated with RNU. Despite the small sample size and preliminary nature of our study, our study provides valuable insights to guide future research.
Quality-of-life (QoL) in RANGE: A phase 3 study of ramucirumab (RAM) plus docetaxel (DOC) versus placebo (P) plus DOC in platinum-refractory locally advanced or metastatic urothelial carcinoma (UC).
Authors: Necchi Andrea , Nishiyama Hiroyuki , Matsubara Nobuaki , Lee Jae-Lyun , Petrylak Daniel Peter , De Wit Ronald , Drakaki Alexandra , Liepa Astra M. , Zimmermann Annamaria , Bell-McGuinn Katherine M. , Powles Thomas
Published: February 2018

419

Background: RAM + DOC in RANGE (NCT02426125) improved progression free survival (hazard ratio [HR] = 0.757) with a higher objective response rate (24.5% vs 14%) and an acceptable safety profile (Petrylak, et al Lancet 2017). QoL was a secondary objective. Methods: Patients (pts) whose UC progressed following platinum-based therapy were randomized to receive RAM (10 mg/kg) + DOC (75 mg/m2) or P + DOC on Day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity with a maximum of 10 cycles for DOC. Pts completed the EORTC QLQ-C30 (v3) prior to each cycle & at the 30-day follow up visit. QoL scales were analyzed for: 1) rates of improved/stable scores (compared with Fisher’s exact test) & 2) time to sustained deterioration (TtD), defined as randomization to first worsening with no subsequent non-worsened assessment (compared with unstratified log-rank test). A ≥10 point change (on 100-point scale) was deemed clinically meaningful. Results: 530 pts were randomized. 254/263 (97%) RAM-DOC & 260/267 (97%) P-DOC pts provided baseline (BL) QoL data & ≥85% for post-BL, on-therapy assessments. Median number of cycles was 4 for RAM-DOC & 3 for P-DOC. Mean BL scores were similar between arms & indicated greatest impairment for global QoL, fatigue, pain, & insomnia. For all scales, rates of improved/stable scores were not different, except for pain at Cycles 4 & 7 where rates were higher for RAM-DOC (p < 0.05). Relative to other QoL scales, pain generally had highest rates of improved scores in both arms (14-25% for RAM-DOC & 8-24% for P-DOC for Cycles 1-4). In a post hoc analysis, Cycles 1-4 rates of improved pain scores were 31-32% for RAM-DOC & 14-26% for P-DOC in tumor responders, but 17-29% for RAM-DOC & 16-28% for P-DOC in pts with stable disease. For TtD, 14/15 QoL scales had HRs < 1, indicating similar or numerically longer TtD in QoL for RAM-DOC (HRs 0.67- 1.06; all 95% confidence intervals included 1). Conclusions: The addition of RAM to DOC for platinum-refractory UC pts did not adversely impact QoL relative to P-DOC. Trends in improved TtD and improved rates of pain associated with tumor response favored RAM-DOC. Clinical trial information: NCT02426125.
German health service research group IQUO present daily routine results of adjuvant instillation therapy for the intermediate risk group NMIBC in out patient office management.
Authors: Luedecke Gerson , Geiges Goetz , Lange Monica , Schulze Matthias ,   Interessenverband zur Qualitätssicherung der Arbeit niedergelassener Urologie-Onkologen in Deutschland e.V. (IQUO)
Published: February 2018

423

Background: The international guidelines for bladder cancer define adjuvant chemo-instillation therapy in intermediate risk NMIBC as standard of care. The health service research foundation IQUO has prospectively checked how strictly German urologists identify and follow the guidelines for intermediate risk BC with adjuvant Mitomycin C indication in daily routine. Methods: Via the Internet based data collection platform of the IQUO uro-oncology specialized office based urologists collected from 2012 to 2015 prospectively adjuvant NMIBC patients treated with Mitomycin C 20mg/20ml in a cohort analysis. Results: 854 patients were included in this study (19% female, 81% male). Median age 73 years, range (30-93). Recurrence risk was classified in 18.7% high-, 33.6% intermediate-, 37.2% low- and 10.5% minimal risk. Progression risk was classified in 3.4% high-, 16.7% intermediate-, 53.3% low- and 26.6% minimal risk. Early instillation was performed in 54% of the patients. The starting point of adjuvant instillation varied form day 1 after TUR to longer than 21 days. The induction phase varied from 4 weeks in minimum (12.9%) to 6 weeks (31.1%), 8 weeks (34%), 12 weeks (4.9%) and 17.1% individually. The maintenance was given in 68.9% of the patients varying from 3 month up to 3 years. Differences in treatment between the genders were not observed. The analysis of accordance to the guidelines in respect to adjuvant instillation in intermediate risk NMIBC showed a 70.7% accordance, an over treatment of 10.5%, and an under treatment of 18.7%. Conclusions: We have found a tremendous heterogeneity in the practiced adjuvant Chemo-Instillation therapy in NMIBC patients. This included early instillation post-operatively, adjuvant onset time point and duration of induction therapy and maintenance. The consequence of this health service research results is that standardization and education is one of our main duties for the near future to ensure consequent, complete and correct adjuvant treatment in intermediate NMIBC patients to ensure effectiveness.
Preoperative chronic kidney disease to predict oncological outcomes after radical cystectomy in patients with muscle-invasive bladder cancer.
Authors: Hatakeyama Shingo , Hamano Itsuto , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Kawaguchi Toshiaki , Ohyama Chikara
Published: February 2018

427

Background: Chronic kidney disease (CKD) is common in elderly patients with bladder cancer. In addition, increasing evidence has suggested that preoperative renal insufficiency indicates poor prognosis in bladder cancer. We aimed to evaluate the impact of CKD on oncologic outcomes in muscle-invasive bladder cancer patients who underwent radical cystectomy. Methods: A total of 581 patients who underwent radical cystectomy at four medical centers between January 1995 and February 2017 were examined retrospectively. We investigated oncologic outcomes, including progression-free, cancer-specific, and overall survival (PFS, CSS, and OS, respectively) stratified by preoperative CKD status (CKD vs. non-CKD). We performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) to evaluate the impact of preoperative CKD on prognosis and developed the prognostic factor-based risk stratification nomogram. Results: Of the 581 patients, 215 (37%) were diagnosed with CKD before radical cystectomy. Before the background adjustment, PFS, CSS, and OS after radical cystectomy were significantly lower in the CKD group compared to the non-CKD group. Background-adjusted IPTW analysis showed that preoperative CKD was significantly associated with poor PFS, CSS, and OS after radical cystectomy. The nomogram for predicting 5-year PFS and OS probability showed significant correlation with actual PFS and OS ( c-index = 0.73 and 0.77, respectively). Conclusions: Muscle-invasive bladder cancer patients with preoperative CKD had a significantly lower survival probability than those without CKD.
Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study.
Authors: Petrylak Daniel Peter , Smith David C. , Flaig Thomas W. , Zhang Jingsong , Sridhar Srikala S. , Ruether Joseph D. , Plimack Elizabeth R. , Merchan Jaime R. , Quinn David I. , Kilari Deepak , Srinivas Sandy , Baranda Joaquina Celebre , Lang Joshua Michael , Milowsky Matthew I. , Galsky Matt D. , Spira Alexander I. , Gartner Elaina M. , Wu Chunzhang , Melhem-Bertrandt Amal , Rosenberg Jonathan E.
Published: February 2018

431

Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was < 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999.
T-cell receptor sequencing of bladder tumor infiltrating lymphocytes to reveal a clonal immune response.
Authors: Sankin Alexander , Chand Damini , Schoenberg Mark P. , Zang Xingxing
Published: February 2018

437

Background: High T cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer (Funt et al ASCO 2016). We hypothesized that T cell repertoire is more clonal in tumors than in benign inflammation. Methods: After obtaining IRB approval, we prospectively identified 12 patients with bladder lesions at Montefiore Medical Center/Albert Einstein College of Medicine undergoing transurethral resection of bladder tumor (TURBT). Specimens collected at the time of TURBT were stored at -80C. After DNA extraction, high throughput sequencing of the CDR3 region of the TCR beta chain using the ImmunoSEQ assay (Adaptive Biotechnologies) was performed. Various parameters such as T infiltrating lymphocyte (TIL) percentage, total productive rearrangements, unique productive rearrangements, and maximum frequency of TCR clone were assessed. Results: 9/12 specimens were malignant (UC+) and 3/12 specimens were benign (UC-). There was an even distribution of specimens across all pathologic stages: 3/12 were T0, 3/12 were Ta, 3/12 were T1, and 3/12 were T2 or greater. The median number of T cells sequenced in UC+ and UC- specimens was 5,569 and 25,872 respectively. The median number of unique TCR rearrangements sequenced in UC+ and UC- specimens was 3,069 and 9,680, respectively. The median TIL percentage in UC+ and UC- specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as indicated by maximum productive frequency of up to 17% as opposed to a maximum productive frequency of 2% in UC- specimens. Conclusions: Primary urothelial tumors contain clonally expanded T cell populations that are not present in benign urothelium. Our data supports the hypothesis that bladder tumors induce a clonal T cell host response against tumor derived antigens. In contrast, benign inflammatory response does not appear to demonstrate any T cell clonal dominance. Future studies to identify tumor specific antigens that contribute to clonal expansion and predict therapeutic efficacy of immunotherapy will be of clinical significance.
Efficacy and tolerability of Paclitaxel-Gemcitabine therapy for urothelial carcinoma in patients who have received prior platinum-based chemotherapy.
Authors: Tomisaki Ikko , Minato Akinori , Fujimoto Naohiro
Published: February 2018

443

Background: Although platinum-based chemotherapy is the standard regimen as first line chemotherapy for urothelial carcinoma, the optimal second line regimen has not been yet established. The objective of this study was to evaluate the efficacy and safety of combination chemotherapy with paclitaxel (PTX) and gemcitabine (GEM) (PG therapy) for patients who have received prior platinum-based chemotherapy. Methods: We reviewed consecutive patients with locally advanced or metastatic urothelial carcinoma who received PG therapy after platinum-based chemotherapy. Doses and schedule of PG therapy were as follows; PTX, 200mg/m2on day 1, GEM, 1000/m2 on days 1, 8, 15, repeated every 21 days. Imaging studies to assess the efficacy was repeated every 2 cycles of the therapy. Results: We identified 52 eligible patients. Of 52 patients, complete response (CR), partial response (PR), stable disease and progressive disease were observed in 2 (3.8%), 14 (26.9%), 18 (34.6%) and 18 (34.6%), respectively. With the median follow-up period of 9.8(IQR 5.5-16.3) months, the median progression free survival (PFS) after PG therapy was 4.7 months [95% confidence interval (CI), 3.6-5.8] and median overall survival (OS) after PG therapy was 11.6 months (95%CI:8.6-15.3). The sensitivity to PG therapy differed in disease sites, the response rate (CR+PR) of primary site, metastases in lymph nodes, lung, bone and liver was 8.3%, 48.7%, 29.4%, 0% and 33.3%, respectively. The response (CR or PR) to PG therapy [Hazard ratio (HR);0.42, 95% CI 0.18-0.95, p=0.04] and primary site (upper urinary tract) (HR;2.24, 95% CI 1.09-4.62, p=0.03) were associated with longer and shorter PFS, respectively. The response to PG therapy was also identified as a significant independent predictive factor for longer OS (HR;0.31, 95% CI 0.12-0.77, p=0.01). Myelosuppression was the most common adverse event. Only one patient discontinued the treatment due to an adverse event and there were no therapy-related deaths. Conclusions: PG therapy was safe and effective as second line regimen after platinum-based chemotherapy for urothelial carcinoma, especially in primary, lymph node and lung lesions.
Preliminary results from patients with urothelial carcinoma (UC) in a phase 1A/1B study of bgb-A317, an anti-PD-1 monoclonal antibody.
Authors: Sandhu Shahneen Kaur , Hill Andrew Graham , Gan Hui Kong , Friedlander Michael , Voskoboynik Mark , Barlow Paula , Townsend Amanda Rose , Song James , Zhang Yun , Shen Zhirong , Qi Qinzhou , Desai Jayesh
Published: February 2018

445

Background: Monoclonal antibodies (mAb) against programmed cell death-1 (PD-1) have demonstrated antitumor activity across multiple malignancies. BGB-A317 is a humanized IgG4 mAb with high affinity and binding specificity for PD-1. Previous reports from an ongoing Phase 1A/1B study (NCT02407990) in patients with advanced solid tumors suggested that BGB-A317 was generally well tolerated and had antitumor activity in multiple tumor types. Here, we present the preliminary results from a subset of patients with UC enrolled in this study. Methods: Patients with UC received intravenous BGB-A317 at doses of 2, 5, 10 mg/kg Q2W or Q3W and 200 mg Q3W. Tumor cell (TC) and immune cell (IC) PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Safety and tolerability was assessed by monitoring adverse events (AEs) and antitumor effects were assessed by RECIST v1.1 criteria. Results: As of 8 June 2017, 15 patients with UC (median age, 72 yr [range: 39–79]) received BGB-A317 during phases 1A (n = 8) and 1B (n = 7). All patients were Caucasian and 13 patients were male; the median number of prior systemic anticancer therapies was 1 (range: 0–4). Median duration of treatment was 115 d (range: 27–476); 6 patients remain on treatment. The most common treatment-related AEs (TRAEs) were fatigue (n = 5) and rash (n = 3); grade ≥3 TRAEs included fatigue (n = 1), and hyperglycemia and type 1 diabetes mellitus (T1DM; n = 1). Serious TRAEs occurred in 2 patients (infusion-related reaction [n = 1]; hyperglycemia and T1DM [n = 1]). All patients were evaluable for response assessment. Confirmed complete and partial responses occurred in 1 and 3 patients, respectively, for a response rate of 27%; the disease control rate (CR+PR+SD) was 53%. Nine samples were available for PD-L1 evaluation. Responses were observed in 3 of 6 patients with PD-L1+ tumors (defined as ≥25% TC or IC expressing PD-L1 by IHC) while 1 in 3 patients with PD-L1– tumors responded. Conclusions: BGB-A317 was generally well tolerated in patients with UC and objective responses were observed in both PD-L1+ and PD-L1– diseases. BGB-A317 is currently being investigated in China as monotherapy for patients with PD-L1+ UC (CTR20170071). Clinical trial information: NCT02407990.
Identifying high surgical risk in muscle-invasive bladder cancer (MIBC) patients undergoing radical cystectomy (RC).
Authors: Marqueen Kathryn E. , Waingankar Nikhil , Sfakianos John , Mehrazin Reza , Niglio Scot Anthony , Audenet François , Jia Rachel , Mazumdar Madhu , Ferket Bart , Galsky Matt D.
Published: February 2018

460

Background: Although RC is the standard treatment for MIBC, it is associated with non-negligible morbidity and mortality. Given the advanced age and prevalence of comorbidities in MIBC patients, many are suboptimal RC candidates. We sought to develop a prediction rule for determining high surgical risk using routinely available pre-surgical variables. Methods: We identified N=8,634 patients with MIBC (cT2-T4aN0M0) who underwent RC, without perioperative chemotherapy, within the National Cancer Database (2003-2012). Using multi-state modeling, we calculated time spent in 3 health states: hospitalized, discharged and death over 90 days post-RC. Predictors were selected in a stepwise manner. Cross validation was performed leaving one of 6 geographic regions out to assess model performance. Time spent in each state was weighted by utility (0=death, 1=full health) to determine 90d quality-adjusted survival (QAS) as a composite of morbidity and mortality. Results: Median age: 69y (IQR 62-78), mean length of stay: 10±12d, and 90d mortality: 654/8,634 (7.6%). Increasing age, cT stage, Charlson comorbidity index (CCI) and lower hospital RC volume were associated with greater 90d mortality (Table). C-statistics of 0.57-0.73 and calibration slopes of 0.54-1.37 (1=perfect) were sufficient across the regions. Our model predicted 25% of patients had a 90d mortality >10%; observed 90d mortality in this group was 14.0% (95% CI 12.5-15.5). Mean QAS was 63d (range 43-68). Conclusions: We developed a multi-state model to identify high post-RC risk that may ultimately help to identify patients for ‘prehabilitation’ strategies and/or inform standard definitions of ‘cystectomy ineligibility’ for clinical trials. [Table: see text]
Combination therapy of low-dose gemcitabine and paclitaxel in every 4 weeks for patients with platinum-resistant urothelial cancer whose performance status is 2 or 3.
Authors: Matsuo Tomohiro , Miyata Yasuyoshi , Sagara Yuji , Ohba Kojiro , Sakai Hideki
Published: February 2018

462

Background: Platinum-based regimens are standard therapy for advanced urothelial cancer (UC). However, second-line chemotherapy is still not established. Therefore, best supportive care is often selected in patients with poor performance status (PS). In our hospital, combination therapy of low-dose gemcitabine and paclitaxel every 4 weeks is administered as second-line therapy for platinum-resistant patients with PS 2 or 3. We investigated the quality of life (QoL) and safety of our regimen in these patients. Methods: Forty-two advanced UC patients were treated with gemcitabine (700 mg/m2 on day 1) and paclitaxel (70 mg/m2 on day 1) every 4 weeks (experimental group). The QoL was evaluated using the short-form survey (SF)-36, and the data were collected on the day before the first cycle was started and 8 weeks after starting the therapy. In addition, survival analysis was performed between these patients and 30 patients who received no second-line therapy (control group). Results: In experimental group, one patient showed grade 3 anemia after the treatment. However, this patient also had severe hematuria before staring of the therapy. No patient had severe adverse events (grade 3 and higher) because of this therapy. The QoL score decreased after the therapy; however, the difference was not significant. With regard to efficacy, partial response was found in two patients, and the mean/SD survival period of the experimental group was 9.2/7.2 months. This period was significantly (P < 0.01) longer than that in the control group (5.8/2.4 months). In addition, 13 (31.0%) and 6 patients (14.3%) survived over 12 and 18 months, respectively. Conclusions: Combined therapy of low-dose gemcitabine and paclitaxel every 4 weeks was well tolerated, and the patient’s QoL was maintained after treatment. Some patients showed relatively long survival periods. We suggest that this treatment regimen is worthy of consideration as second-line therapy for patients with advanced UC with PS 2 or 3.
Evaluation of a 29 gene classifier for basal/non basal prediction in muscle-invasive bladder cancer FFPE samples.
Authors: Allory Yves , Sirab Nanor , Drubay Damien , Gentien David , De ReyniÃ¨s AurÃ©lien , Albaud Benoit , Kamoun Aurélie , Soyeux Pascale , Maille Pascale , Lebret Thierry , Benhamou Simone , Paoletti Xavier , Radvanyi Francois
Published: February 2018

467

Background: Recent and independent muscle-invasive bladder cancer (MIBC) molecular classifications identified the basal / squamous-like (BASQ) tumours as an intrinsic and robust subtype, with a poor outcome and possible chemosensitivity to cisplatin based regimen, making mandatory the development of a diagnostic tool for their identification in routine samples. Our study aimed to evaluate the diagnostic accuracy of a Nanostring classifier for tumor subtype prediction on FPPE specimens. Methods: Two series of MIBC were used (CIT n = 51 & Stransky n = 22) for which BASQ tumours were identified previously using Affymetrix transcriptome data obtained from frozen samples (Rebouissou, Science Trans Med 2014). 29 genes were selected to predict the basal subtype, RNA expression of matched frozen and FFPE samples was studied using Nanostring technology. To define the classifiers for Affymetrix, frozen and FFPE Nanostring expression matrix on CIT samples the centroid of each cluster was calculated using the expression of 29 genes. Internal validation used leave-one-out cross-validation to train and test the prediction accuracy of the new classifier. For external validation, the CIT samples were used as training set and the Stransky samples as validation set. Predictive accuracy expressed as percentage of correctly classified samples is provided. Results: Correlations between Affymetrix, frozen and FFPE Nanostring data set were checked for gene expression and samples. Using CIT samples as train and test set, the predictive accuracy for BASQ tumour identification was for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers, 90.20% [78.59%; 96.74%], 88.24% [76.13%; 95.56%] and 92.16% [81.12%; 97.82%], respectively. Using training on CIT samples and test on Stransky samples, this predictive accuracy was 90.91% [70.84%; 98.88%] both for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers. Conclusions: The 29 gene expression Nanostring codeset was able to identify reliably basal / squamous like tumours on FFPE samples from MIBC in comparison with the gold standard approach based on transcriptomic profile, appearing as a promising diagnostic tool.
Application-based perioperative management of the radical cystectomy patient.
Authors: Metcalf Meredith , Hamilton-Reeves Jill , DeRuyter Martin , Bishop David , Hand Lauren , Holzbeierlein Jeffrey M. , Lee Eugene
Published: February 2018

480

Background: Radical cystectomy patients are a vulnerable population, with up to 65% suffering complications and 26% readmitted within 90 days. Perioperative education, early identification of patients at risk, and discharge transitions remain central to improving outcomes. This project aimed to examine the feasibility of using LifeScience Technologies tablet-based application (LST app) for perioperative patient education, transition care communications, and post-discharge monitoring. Methods: We initiated a prospective feasibility pilot trial (NCT NCT02942121) in 20 patients undergoing radical cystectomy. Participants were provided an iPad preloaded with the LST app and equipment to measure vital signs during the study. Patient education videos tailored to each individual based on gender and diversion type were sent via the app for viewing preoperatively. Postoperatively participants were asked to log medication compliance and vital signs. Vital equipment was wirelessly transmittable, and the study team was alerted to any abnormal patient data. Compliance with watching videos and recording vital signs was the primary aim of the study. Results: Twenty patients were enrolled between 2/2017 and 10/2017. Two patients discontinued due to difficulty with electronics, two due to oncologic restaging, and two await surgery. Patients watched 155/235 (66%) of assigned education videos. On average, each video was viewed 2.1 times (range 0-3.7), and 16/18 (89%) of all videos were watched more than once. Excluding the patients who did not complete the trial, compliance in video watching was 143/193 (74%). Complete vital signs were logged on 181/227 (70%) of patient study days. Excluding patients who did not complete the trial, compliance in vital sign recording was 175/216 (81%). Conclusions: Tablet-based applications are emerging as adjuncts to traditional clinical practice. This protocol demonstrates patient compliance with assigned tasks and was feasible for extending educational content beyond the office while allowing for repetition of viewing, vital for improving comprehension and recall. Additionally, patients were compliant with recording vitals while at home, demonstrating feasibility of this novel technology. Clinical trial information: NCT02942121.
Association of stromal lymphocyte infiltration with tumor invasion depth and high-grade T1 bladder cancer.
Authors: Rouanne Mathieu , Betari Reem , Radulescu Camélia , Signolle Nicolas , Allory Yves , Marabelle Aurelien , Adam Julien , Lebret Thierry
Published: February 2018

488

Background: Morphological assessment of tumor-infiltrating lymphocytes (TIL) has been shown to provide prognostic and potentially predictive significance in many different tumor types. Large studies investigating TIL in urothelial carcinoma are lacking. We investigated in a homogenous population of patients with high-grade T1 (HGT1) bladder cancer the association of TIL with clinico-pathological parameters and clinical outcomes. Methods: Pretreatment index tumors were collected between 2000 and 2015 from 147 patients with primary high-grade cT1N0M0 bladder cancer. The density of stromal TIL was evaluated using hematoxylin and eosin (H&E)-based staining on whole tissue sections. Stromal TIL density was scored as percentage of stromal area infiltrated by mononuclear cells. Inter-reader assessment and stromal TIL correlation with a subset of CD3+ stained sections were evaluated. The main endpoint was correlation with overall survival (OS). Hazard ratios (HRs) and 95% CIs associated with stromal TIL were estimated through a multivariable Cox model. Results: Median follow-up was 8.2 years (6.1-9.5). Induction BCG therapy was followed by 126 patients (86%). Recurrence and progression were respectively observed in 67 patients (46%) and 40 patients (27%). Stromal TIL density was high (≥10%) in 82 tumors (56%). The overall agreement was good between the two readers (κ = 0.75). Correlation between stromal TIL density analyzed on H&E-sections and CD3+ IHC staining was high (ρ = 0.71, p < 1.10-5). Stromal TIL were positively associated with variant histology (p = 0.01) and tumor invasion depth (p = 0.03). For the OS analysis, intense (≥10%) vs. non-intense ( < 10%) stromal TIL unadjusted HR (95% CI, p) was 1.30 (0.75-2.24, p = 0.34) and adjusted HR was 1.25 (0.72-2.16, p = 0.43). Conclusions: Density of stromal TIL was associated with tumor invasion depth and variant histology, but not with prognosis of patients with HGT1 bladder cancer. These data suggest that tumor progression is associated with an increased adaptive immune response but other factors may influence outcome of patients. Characterization of TIL subpopulations may be required to identify immune-related prognostic factors.
Is radical radiotherapy effective for elderly patients with muscle invasive bladder cancer?
Authors: Price James , Sivanandan Mayuran , Elmusharaf Rania , Chakraborti Prabir R , Smith-Howell Mike , Das Prantik
Published: February 2018

506

Background: Radical radiotherapy (RT) is a curative option for muscle-invasive bladder cancer (MIBC), and offers the chance of bladder preservation. RT and radical cystectomy have not been compared in an RCT, but landmark trials of RT +/- concurrent systemic therapy have demonstrated outcomes comparable to surgery. In clinical practice, patients are often older and less fit compared to trials, and consequently may not be fit for concurrent chemotherapy which may impact treatment outcomes. Methods: A retrospective review of all patients aged 70 years or older treated with radical RT for MIBC from January 2010 – October 2016. Minimum 12 months follow-up. iSOFT manager for used for clinical data and MOSAIQ for radiotherapy parameters. Statistical analysis performed using Stata version 11.2. Results: 71 patients were identified. Male: female ratio 3:1 and median age 79 (range 71 – 93). Median performance status (PS) 1. 81.7% of patients had pT2 disease or greater, 77.5% of patients underwent TURBT prior to RT and 97.2% had transitional cell-carcinoma histology. 38 patients were treated to 60-64Gy/30-32 fractions and 33 patients to 52.5-55Gy/20 fractions. 6 patients (8.5%) received neoadjuvant chemotherapy and 15 (21.1%) received concurrent chemotherapy. Of the 53 patients who did not receive chemotherapy, all were deemed not suitable. 23 of 71 patients (32.4%) developed a loco-regional relapse, either in the bladder (n = 18), pelvic lymph nodes (n = 4), or on cytology alone (n = 1). 24 patients (33.8%) developed distant metastases, only 7 of these were fit for palliative chemotherapy. The median progression-free survival (PFS) was 17 months (95% C.I. 10 – 34 months). Neoadjuvant and concurrent chemotherapy use was not associated with an increased PFS (p = 0.99 and p = 0.97, log rank). The median overall survival was 18 months (95% C.I. 14 – 27 months). Conclusions: Our data demonstrate RT produces favourable outcomes for elderly patients and reasonably well tolerated without significant toxicities. Use of concurrent systemic therapy did not significantly improve outcomes, but numbers were small.
The impact of neoadjuvant chemotherapy (NAC) on conditional survival (CS) among patients with muscle-invasive bladder cancer (MIBC).
Authors: Waingankar Nikhil , Jia Rachel , Ferket Bart , Audenet François , Mehrazin Reza , Sfakianos John , Mazumdar Madhu , Galsky Matt D.
Published: February 2018

520

Background: Achieving a pathologic complete response (pCR) with NAC for MIBC is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Whether the difference in prognosis of patients with pCR and pRD is sustained over time has not been explored. Methods: We queried the National Cancer Database for patients who received NAC and RC for clinically localized MIBC (cT2-T4aN0M0) between 2002-2010. We identified patients with pCR (</= pTis) and pRD. Using Kaplan-Meier analysis, we assessed CS up to 5 years given survivorship of 0-4 years using log-rank test with multiple comparison adjustment. Results: The cohort comprised 1,554 patients (pCR: 314, pRD: 1,240). The median follow up was 2.38 (0.04-9.60) and 2.76 (0.01-9.97) years for pCR and pRD, respectively. Patients with pCR had lower stage (cT2= 79% vs. 72%; cT3= 14% vs. 18%; cT4= 7% vs. 10%), more recent diagnosis (2010: 31% vs. 19%), and were more often treated at a high-volume center (>15 RC/year: 61% vs. 49%). Patients with pCR had improved CS relative to those with pRD with survivorship up to 3 years, but the benefit associated with pCR becomes attenuated from 4 years post-RC (Table). Conclusions: MIBC patients with pRD after NAC have worse CS up to years 3 post-RC, but this difference diminishes after 4 years. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD, and are subject to confirmation with a forthcoming multivariable analysis. Probability of surviving to X years (95% CI). [Table: see text]
Pre-operative chemotherapy (ctx) in plasmacytoid urothelial carcinoma (PUC).
Authors: Teo Min Yuen , Al-Ahmadie Hikmat , Seier Kenneth , Ostrovnaya Irina , Regazzi Ashley Marie , Dalbagni Guido , Bochner Bernard H. , Funt Samuel , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E.
Published: February 2018

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Background: PUC is characterized by E-cadherin loss, diffuse growth pattern and aggressive natural history. Management of this entity is controversial. This retrospective study aims to evaluate the impact of PUC histology on clinical outcomes with ctx compared to UC-NOS. Methods: Consecutive cases of nonmetastatic PUC were identified as either (1) localized disease (LD: cT2-3 cN0) or (2) locally-advanced (LA: fixed bladder or radiographic nodal disease). All cases were reviewed by a GU pathologist to confirm PUC histology per WHO classification (2016). A separate cohort of neoadjuvant(NAC)-treated UC-NOS (Tully et al, ASCO GU 2014) served as comparator for clinical outcomes. Kaplan-Meier estimates and logrank test were used for analysis of recurrence free (RFS) and overall survival (OS) defined from date of cystectomy (RC). Results: Between 2000 and 2017, eighty one PUC were identified, with median age of 65 years (range: 22 - 84) and 65% male. Thirty patients (pts) had up-front RC; 51 pts had ctx. In the former group, all pts had LD but upstaging was seen on post-op pathology: 63% pT3, 17% pT4 and 37% pN+. Among ctx pts, 33/51(65%) were LD and had NAC: 70% had ctx doublet and 24% triplet; 82% had 4 cycles and 18% had up to 6 cycles. Response ( < pT2 pN0) was seen in 7/33(22%), four (12%) of which had no residual disease (pCR). Six RC were aborted after NAC for pT4b disease. NAC response was not associated superior RFS (NR vs. 17.3 months; HR 0.52 95% CI 0.18 – 1.47, p = .218) or OS (41.3 vs. 25.5 months; HR 0.65 95% CI 0.23 – 1.87, p = .428). Compared to UC-NOS, PUC responders had significantly inferior outcomes (table). In LA cohort, majority had triplet chemotherapy (72%) and up to 6 cycles (89%). Response was seen in 4/18(22%) pts, with two pCR (11%). Five RC were aborted for pT4b disease. Median RFS and OS were 5.8 and 10.5 months, respectively, with 19% alive at 2-years. Most common sites of recurrence/progression for PUC were peritoneal (42%) and locoregional invasion (26%). Conclusions: Outcomes for PUC are poor with conventional NAC-RC approach. [Table: see text]
An analysis of multiple biomarkers to better predict prostate cancer metastasis and death after radical prostatectomy.
Authors: Zhang Alison Yan , Chiam Karen , Haupt Ygal , Fox Stephen B. , Birch Simone , Tilley Wayne , Butler Lisa , Knudsen Karen E. , Cornstock Christopher , Rasiah Krishan , Grogan Judith , Mahon Kate Lynette , Bianco-Miotto Tina , Bohm Maret , Henshall Susan M. , Delprado Warick , Stricker Phillip , Horvath Lisa , Kench James
Published: February 2018

54

Background: Identification of potentially lethal disease at the time of diagnosis with localized prostate cancer (PCa) remains a significant clinical issue despite a plethora of candidate biomarkers. This study evaluates a range of biomarkers previously associated with biochemical relapse (BR) in localized PCa to determine whether a combined expression model can improve detection of clinically significant cases. Methods: The Australian PCa Research Centre NSW has completed 23 studies of molecular biomarkers associated with BR in a well-described localized PCa cohort (n=324, median followup 16 years). 12 studies were excluded due to missing data. Each biomarker was analyzed as a marker for metastatic-free survival (MFS) and prostate cancer specific survival (PCSS) and then used to develop a prognostic model for clinical outcomes incorporating clinico-pathological factors. This model is currently being validated in an independent cohort. Results: The PCa cohort experienced 39 metastatic relapses (12%) and 23 PCa deaths (7%). Of 12 biomarkers (AR, AZPG1, C0S, Cyclin D1a, Cyclin D1b, E6AP, H3K18Ac, H3K4me2, Ki67, p53, PML, SGTA) assessed, only AZGP1 and Ki67 were associated with MFS (HR 2.9, 95% CI, 1.4-5.6; P=0.002, and HR 1.2, 95% CI, 1.0-1.4; P=0.03, respectively) and PCSS (HR 4.2, 95% CI, 1.7-10.5; P=0.002; and HR 1.2, 95% CI, 1.0-1.5; P=0.04, respectively). The combined panel of AZGP1 and Ki67 was an independent predictor of MFS (HR 1.9, 95% CI, 1.1-3.2; P=0.01), and PCSS (HR 3.3, 95% CI, 1.5-7.3; P=0.002) when modeled with known clinicopathological variables. The panel was more robust in predicting MFS and PCSS compared to the individual biomarkers alone and superior to other prognostic models (See table). Data from the validation cohort will be available for the meeting. Conclusions: Our novel signature of AZPG1 and Ki67 improves existing prognostication tools in predicting PCa metastasis and death. [Table: see text]