bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the University of Texas M. D. Anderson Cancer Center.
Authors: Siefker-Radtke Arlene O. , Kamat Ashish M. , Corn Paul G. , Matin Surena F. , Grossman H. Barton , Millikan Randall E. , Dinney Colin P.N.
Published: March 2020

4523

Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to <=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to <= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to <= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 26 months, the 2-year OS and DSS was 78% and 82%, respectively (bladder 2-yr OS and DSS 75%, 78%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in < 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.
Correlation of progression-free survival at 6 months (PFS6) with overall survival at 12 months (OS12) in an analysis of 10 trials of second-line therapy for advanced urothelial carcinoma (UC).
Authors: Maughan Benjamin , Boucher Kenneth M. , Agarwal Neeraj , Choueiri Toni K. , Qu Angela Q. , Vogelzang Nicholas J. , Fougeray Ronan , Niegisch Guenter , Albers Peter , Wong Yu-Ning , Ko Yoo-Joung , Sridhar Srikala S. , Galsky Matt D. , Petrylak Daniel Peter , Vaishampayan Ulka N. , Beer Tomasz M. , Sternberg Cora N. , Rosenberg Jonathan E. , Molins Joaquim Bellmunt , Sonpavde Guru
Published: March 2020

4525

Background: Second-line therapy of advanced UC is a significant unmet need. While phase II trials have relied on response rate (RR) as a primary endpoint, response may not be suitable for assessing cytostatic agents and does not capture duration of benefit. We hypothesized that PFS6 correlates with OS12 and may be a robust intermediate endpoint for phase II trials. Methods: Ten trials with individual patient progression and survival data (n=646) evaluating chemotherapy and/or biologics following chemotherapy were combined. Progression was defined as tumor progression (RECIST 1.0 in 9 trials, WHO in 1 trial), or death from any cause. Unadjusted and adjusted binomial confidence intervals for PFS6, OS12 and response were reported, with adjustment for variability between trials using random effects models. The relationship between PFS6 and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression with larger studies having more influence. The relationship between PFS6 and OS12 at the individual level was assessed using Pearson chi-square test with Yates continuity correction. Statistical analyses employed “R” statistical computing software, version 2.8.0. Results: 59% had visceral metastasis and performance status was 0, 1 and 2 in 50, 39 and 8%, respectively. Median age was 65 years (31-88) and 77% were male. PFS6 was 22% (95% CI: 17-24%), and adjusted PFS6 was 23% (95% CI: 15-34%). The OS12 was 20% (95% CI: 17-24%), and adjusted OS12 was 21% (95% CI: 15-29%). The Pearson correlation between trial level PFS6 and OS12 was 0.66 (p = 0.037). The individual level agreement between PFS6 and OS12 was seen in 82% of patients (kappa = 0.45). Among 560 patients evaluable for response and OS, the RR was 22% (95% CI: 18-25%) and adjusted RR was 21% (95% CI: 13-32%). Trial level Pearson correlation between response and OS12 was 0.37 (p = 0.30), and individual level agreement was seen in 78% (kappa=0.36). Conclusions: PFS6 is associated with OS12 at the trial and individual levels in patients receiving second-line therapy for advanced UC. The association of response with OS was suboptimal. Validation of PFS6 is warranted.
Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive bladder cancer: Results of a multicenter phase II study.
Authors: Plimack Elizabeth R. , Hoffman-Censits Jean H. , Viterbo Rosalia , Greenberg Richard Evan , Chen David , Lallas Costas D. , Trabulsi Edouard John , Wong Yu-Ning , Kutikov Alexander , Lin Jianqing , Duncan Gail , Adair Beth , Cione Charlotte , O'Sullivan Conor , Kilpatrick Deborah , Ross Eric A , Boorjian Stephen A. , Uzzo Robert G. , Kelly William Kevin , Hudes Gary R.
Published: March 2020

4526

Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) demonstrates a survival benefit in the neoadjuvant setting for patients (pts) with muscle invasive bladder cancer (MIBC). Compared with standard MVAC, AMVAC yielded higher response rates with less toxicity in the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with CrCl >=50 and adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) on day 1, with pegfilgrastim 6 mg day 2 or 3, every 2 weeks. Pts with CrCl < 60 could receive cisplatin split over 2 days. Radical cystectomy (RC) with lymph node dissection was performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month period. Median age 64 (range 45-83). Three withdrew from study early and are not evaluable for response (2 physician discretion, 1 withdrawal of consent). An additional 8 are currently receiving treatment on study with toxicity and response data pending. Of the 33 evaluable pts for whom final data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts received < 3 cycles due to grade 3 fatigue (1), low platelets (1), and disease progression precluding RC (1). 32/33 pts underwent RC, all within 8 weeks of last chemotherapy. Median time from start of chemotherapy to RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non muscle invasive disease. For the intent to treat cohort (n=36) 8 pts had grade 3-4 AMVAC related adverse events, the most common being anemia (3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% CI, 20.4-51.8%). All pts will have completed study treatment by April 2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is well tolerated and preliminary results show a pCR rate similar to that reported for standard 12-week MVAC, suggesting that AMVAC for three cycles (6 weeks) is a safe and efficient alternative.
The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumours: A non-cisplatin-based regimen.
Authors: Badreldin Waleed , Chowdhury Simon , Harland Stephen John , Mazhar Danish , Powles Thomas , Wilson Peter , Shamash Jonathan
Published: March 2020

4529

Background: Cisplatin-based chemotherapy with or without high dose chemotherapy remains the standard approach in managing relapsed germ cell tumors (GCT). The feasibility of IPO was first described in 2006.Non cisplatin-based therapies offer the advantage of differing side effect profiles which may be useful to certain patients.Here we describe the outcome of an expanded cohort of these patients. Methods: The results of 72 consecutive patients were reviewed (18% had metastatic mediastinal GCTs). IPO was used either as 2nd line treatment (n=29) of which 20 had HDCT or 3rd line (n=43) of which 32 had HDCT. IPO consisted of oxaliplatin 100mg/m2, irinotecan 200mg/m2 and weekly pac litaxel 80mg/m2 ( IPO) every 3 weeks for 3-4 cycles with the intention of high dose carboplatin , thiotepa and topotecan as consolidation (HDCT). Results: The 2 year PFS and 3 year OS for the whole cohort was 28.4% (95%CI 17.3-40.5%) and 31.6% (95%CI: 20.1-43.8 %) respectively. The overall response was as follows; CR – 3%, m-ve PR 41%, m+ve PR 18%, SD 17%, PD 20%. In the second line setting, the 2 year PFS was 41.8% (95%CI: 21.7-60.8%) and 3y OS 45.8% (95%CI: 24.2-65.1%). The 2 year PFS according to the IGCCCG2 prognostic score was Intermediate = 34%, High risk =50% and very high risk = 30%. In the 3rd line setting the 2 year PFS was 20.9% (95%CI 9.5-35.4%) and 3 year OS was 23.8% (95%CI 11.7-38.2). For HDCT the 2 y PFS was good risk= 52%, Intermediate =29% and poor risk= 0%. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities were as follows (>5%): neutropenia 35%, thrombocytopenia 18%, infection 15%, diarrhea 11%, lethargy 8%. Conclusions: IPO is a safe, non-nephrotoxic day care regimen which produces encouraging responses particularly in high risk cases. Where cisplatin is contra-indicated this is may be a useful alternative.
Sunitinib objective response (OR) in metastatic renal cell carcinoma (mRCC): Analysis of 1,059 patients treated on clinical trials.
Authors: Molina Ana M. , Zhang Jingbo , Lin Xun , Niculescu Liviu , Korytowsky Beata , Matczak Ewa , Wiltshire Robin , Motzer Robert John
Published: March 2020

4542

Background: Sunitinib achieves robust OR and improved progression-free survival (PFS) in mRCC patients (N Engl J Med 2007;356:115). A retrospective analysis was performed to characterize the OR rate with sunitinib treatment (Tx) and OR-associated patient features and survival. Methods: Data from six phase II and III trials were pooled from 1,059 patients who received sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the 1st- (n=783; 74%) and 2nd-line (n=276; 26%) Tx settings. Median PFS and overall survival (OS) were estimated by the Brookmeyer and Crowley method, and compared between responders and nonresponders, and early and late responders (response ≤ and >12 weeks, respectively), by a log-rank test. Baseline characteristics were compared by Fisher-exact Test, T-Test, or Wilcoxon Rank-sum Test. Results: Of 1,059 patients, 398 (38%) had a confirmed investigator-assessed OR by RECIST (including 12 with a complete response), of whom 105 (26%), 243 (61%), 314 (79%), and 342 (86%) had a response by 6, 12, 18, and 24 weeks, respectively. Median (range) time to tumor response (TTR) in all patients was 10.6 (2.7–94.4) weeks, which was similar in the 1st- and 2nd-line Tx settings. Responders had better baseline ECOG scores, more favorable risk factor classification based on published MSKCC data, a longer interval since initial diagnosis, more prior nephrectomy, and less presence of baseline bone metastases (all p<0.05). Early responders had more lung metastases (p<0.01). Median PFS (16.3 vs. 5.3 months) and OS (40.1 vs. 14.5 months) were significantly longer in responders vs. nonresponders (both p<0.001), with similar results regardless of 1st- or 2nd-line Tx setting. Median OS did not differ between early and late responders (p=0.1438). Conclusions: OR was achieved in 38% of 1,059 mRCC patients treated with sunitinib and was predicted by favorable pretreatment prognostic factors. Patients with OR had longer PFS and OS. Median TTR was 10.6 weeks, and characteristics and outcome of early and late responders were similar, except for higher frequency of lung metastases among early responders.
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with renal cell carcinoma (RCC) from a phase I study.
Authors: Puzanov Igor , Sosman Jeffrey Alan , Santoro Armando , Martell Robert E. , Dy Grace K. , Goff Laura Williams , Ma Wen Wee , Fetterly Gerald J. , Michael Shaunita A. , Means-Powell Julie Ann , Chai Feng , Lamar Maria , Strauss Gary M. , Zucali Paolo A. , Chiang Wendy M. , Jarboe Jamie , Schwartz Brian E. , Adjei Alex A.
Published: March 2020

4545

Background: Inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptor are standard therapy for RCC, and the MET signaling pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Previously, dose escalation established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with RCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts received treatment at the RP2D (n = 19) or tivantinib 360 mg BID plus sorafenib 200 mg BID (n = 1). 4 pts are still on study. 16 pts (13 with clear cell RCC) received ≥ 1 previous systemic therapy (median, 2; range, 0-4) including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common (≥ 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus (25% each). Best response was partial response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts with SD had ≥ 10% tumor size reduction. The overall response rate (ORR) and disease control rate (DCR; PR + SD) were 15% and 90%, respectively. Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination therapy with tivantinib plus sorafenib was well tolerated and exhibited preliminary anticancer activity in pts with RCC, including pts pretreated with VEGF inhibitors.
Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial.
Authors: Armstrong Andrew J. , Haggman Michael , Stadler Walter Michael , Gingrich Jeffrey R. , Assikis Vasily J. , Polikoff Jonathan , Denmeade Samuel R. , George Daniel J. , Andreou Cal , Clark William R. , Sieber Paul , Agajanian Richy , Belkoff Laurence , Damber Jan-Erik , Nordle Orjan , Forsberg Goran , Carducci Michael Anthony , Pili Roberto
Published: March 2020

4550

Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that binds S100A9 protein and has preclinical anti-angiogenic and anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P)) men with metastatic CRPC were randomized and received treatment once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4 weeks. Placebo patients could cross over to T after 6 months or at disease progression. The primary endpoint of improved PCWG2 criteria-defined progression at 6 months was met (69 vs. 37% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P1 with acceptable toxicity. This abstract provides the first analysis on symptomatic progression, overall survival (OS) as well as a multivariate analysis for PFS and OS. Methods: Survival data were collected between June 2011 and January 2012 with a median time to censoring of 32 months. Survival data was also evaluated in an exploratory multivariate model of known prognostic factors in CRPC. Results: An imbalance of several baseline prognostic criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO 2011;20:4022). Time to symptomatic progression was longer in T treated patients (p=0.039, HR=0.42). Record of death (97 events) or survival >13 months was documented in 182 patients. Median time to death was 34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2 bone-metastatic subgroup (N=92/44) was 34.2 vs. 25.6 months. A multivariate analysis of known prognostic factors including PSA, LDH, PSA kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54 (95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total population and 0.63 (95% CI 0.37,1.07, n=136) in the bone-metastatic group. Conclusions: OS observed after tasquinimod treatment is longer than previously reported in this patient population. The current exploratory data indicates that the prolongation in PFS observed with tasquinimod treatment may lead to a survival advantage in men with metastatic CRPC. A phase III placebo-controlled study (NCT01234311) is ongoing in men with bone-metastatic CRPC powered to detect an OS improvement.
Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with ketoconazole (keto): Association with outcome and predictive model.
Authors: Sella Avishay , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Neumann Avivit , Peer Avivit , Rosenbaum Eli , Kovel Svetlana , Sinibaldi Victoria J. , Hammers Hans J. , Carducci Michael Anthony , Eisenberger Mario A. , Keizman Daniel
Published: March 2020

4564

Background: The CYP17 inhibitor keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited vs extensive). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. Results: From 1999-2011, 156 mCRPR pts (median age 69) were treated with keto. 78/156 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-144). Excluded from the analysis were 23 pts without available data on pre-tx NLR, and those with recent (≤1 mos) health event or tx (surgery, steroids, radiation) associated with a change of blood counts. 133 pts were included in the analysis. 62 (47%) had an elevated pre-tx NLR >3. Risk factors associated with PFS (table) were pre-tx NLR >3, prior response to GnRH-a <24 mos and to antiandrogen (AA) <6 mos, and pre-tx PSADT <3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text]
PIK3CA gene alterations in bladder cancer: Analysis of correlative series of transurethral resection (TUR)—Correlation with grade histology and tumor size.
Authors: Castellano Daniel E. , Sepulveda Juan , Martinez-Fernandez Monica , Dueñas Porto Marta , Garcia Escudero Ramon , Villacampa Felipe , de la Rosa Federico , Duarte Jose , Martinez Victor , Paramio Jesus
Published: March 2020

4584

Background: PI3K pathway involvement in bladder cancer is well documented and activating mutations of the gene have been identified, particularly in tumors of low grade and stage. We have analyzed hot spot mutations and copy number in PIK3CA gene as well as mRNA expression levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent normal tissue was collected. All pts signed an informed consent and basic demoghrapics data were collected. Histology confirmation of UCC was required. PIK3CA alterations were analyzed by quantative-PCR. Results: Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences were observed. 13% normal tissue and 51,8% tumor samples harbored alterations in PIK3CA gene, including alterations affecting the helical domain (mutations 65%, amplifications 60%, both 21%). According to T stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p<0.05). When analyzing factors related to tumor recurrence, it was found that PIK3CA gene mutations in E542 or E545 had a lower recurrence risk (p-value ²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) showed that tumors bearing altered PIK3CA gene are more similar to non-tumoral samples comparing with tumors bearing wtPIK3CA gene. Moreover, overexpressed genes in mutant samples are mainly involved in G-protein and Wnt signaling, whereas underexpressed genes are involved in cell morphogenesis and cell polarity. Conclusions: We observed that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, and more frequently found in larger tumor stages. These data support that PIK3CA status may constitute a good prognostic tool, as well as a therapeutic target in stratified groups for bladder cancer.
External validation of somatic copy number alteration (SCNA) at chromosome 1q23.3 in advanced urothelial carcinoma (UC).
Authors: Riester Markus , Werner Lillian , Molins Joaquim Bellmunt , Selvarajah Shamini , Weir Barbara , Stack Edward C. , Park Rachel S. , O'Brien Robert , Schutz Fabio Augusto Barros , Choueiri Toni K. , Signoretti Sabina , Gallardo Enrique , Rojo Federico , Lloreta Trull Josep , Marchionni Luigi , Hahn William C , Berman David Monty , Kantoff Philip W. , Michor Franziska , Rosenberg Jonathan E.
Published: March 2020

4585

Background: Advanced UC is associated with multiple SNCAs. To identify SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We obtained DNA copy number data from bladder cancer patients in two independent cohorts [Spanish cohort (n= 93, Agilent aCGH 180k array) and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n = 48, Affymetrix OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired copy number information from 30 primary tumors and 33 metastases. For 12 patients, both primary and matched metastases were available. The GISTIC method was used on GLAD segmented data to identify driver copy number lesions, and the NBC algorithm to identify recurrent breakpoints. Cox proportional hazards models were used to estimate the effect of the identified SCNAs on overall survival, defined as time from start of chemotherapy for metastatic disease (Spanish) or from metastatic recurrence (BW/DF). Copy numbers were incorporated in the Cox models as continuous measures. Statistical significance of optimal cutpoints was estimated with permutation tests. Copy number profiles of primary tumors and metastases were compared with hierarchical clustering. Results: Amplification of 1q23.3 was independently associated with overall survival in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p < 0.03; C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84-21.4; p < 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at 22q12.2 were enriched in patients who developed metastasis (p < 0.05). A breakpoint analysis identified possible truncations of ITPR1 (Spanish: 15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large numbers of samples. For primary tumors with matched metastases, we observed that metastases clustered together with their primary tumors. Conclusions: External validation of the 1q23.3 amplification demonstrates the association of this SCNA with poor outcomes in advanced UC; the identification of the target of this copy number gain is ongoing. Gene truncations and their biological significance require further experimental investigation.
Utilization and predictors of neoadjuvant chemotherapy for muscle-invasive bladder cancer in the Veterans Health Administration.
Authors: Sandhu Gurdarshan Singh , Luo Suhong , Zeringue Angelique , Carson Kenneth Robert , Nepple Kenneth Gerard , Strope Seth A. , Hudson M'Liss A. , Grubb Robert L.
Published: March 2020

4594

Background: The survival benefit with neoadjuvant chemotherapy for bladder cancer was established in 2003. However, adoption of this paradigm in clinical practice has been slow. We explored the use of neoadjuvant chemotherapy and identified predictors of its use in a contemporary cohort in the Veterans Health Administration (VA). Methods: Using the national VA Clinical Cancer Registry, all patients diagnosed with clinical stage T2-4, N0 or Nx, M0 bladder cancer from 1997 to 2007 were stratified into surgically (radical cystectomy [RC], n=1,211) and nonsurgically managed groups (n=2,125). Receipt of neoadjuvant chemotherapy was defined as chemotherapy treatment up to 6 months before RC as well as initial treatment only with chemotherapy (without subsequent surgery or radiation) in the nonsurgical group. Temporal trends in neoadjuvant chemotherapy use were evaluated with a chi square test. Predictors of neoadjuvant chemotherapy were examined using a multivariable logistic regression model incorporating demographic, socioeconomic, comorbid, pathologic and hospital factors. Results: 6.3% and 8.3% of patients received neoadjuvant chemotherapy in the surgical and non-surgical group, respectively. Analysis of temporal trends in chemotherapy use demonstrated an increase in neoadjuvant chemotherapy use over time (p<0.0001); from 3% (2003 and before) to 14% annually (2007). On multivariable analysis of both groups, older age and more recent diagnosis were predictive of neoadjuvant chemotherapy use (Table). Other covariates did not predict receipt of neoadjuvant chemotherapy. Conclusions: While overall use of neoadjuvant chemotherapy in the VA population with bladder cancer remains low, use thereof is slowly increasing, with a more recent diagnosis most strongly predicting its use. [Table: see text]
Genetic determinants of long-term response to rapalog therapy in advanced renal cell carcinoma (RCC).
Authors: Voss Martin Henner , Hakimi Abraham A. , Scott Sasinya N. , Takeda Shugaku , Liu Han , Chen Yingbei , Motzer Robert John , Berger Michael F. , Hsieh James
Published: March 2020

4604

Background: Temsirolimus (T) and everolimus (E) are rapalog inhibitors of the mammalian target of rapamycin (mTOR) with efficacy in advanced RCC [NEJM;356(22):227-81; Lancet;372(9637):449-56]. With reported median progression-free survival (PFS) of 5.5 and 4.9 months (mo), respectively, benefit is typically modest, yet a subset of patients (pts) achieves long-term disease control evident by extended PFS. The oncogenomic background for this is unclear. Methods: We analyzed frozen specimens of tumor and adjacent normal kidney from pts with advanced RCC and documented long-term response to T or E, defined as PFS of ≥ 20mo. Samples from pts with PFS ≤ 2mo served as comparators. Specimens were subjected to whole exome sequencing; a targeted next-generation sequencing platform was used for deep sequencing and investigation of copy number variations (CNV) in 230 genes of interest. Results: In 5 pts with long-term response to T [n=3] or E [n=2], histologic subtypes were clear cell [n=3] and unclassified [n=2] RCC. Median number of prior treatments was 2 (1-3). Two pts remain on therapy, 3 have stopped drug for disease progression; treatment duration was 20, 25+, 27, 28, and 28+ mo. Three control pts progressed after 1, 2, and 2 mo on therapy. Mean target coverage was 86x for whole exome and 443x for targeted sequencing. Three of 5 long-term responders harbored acquired somatic mutations and/or CNV in genes encoding for members of the Phosphoinositide 3-Kinase (PI3K) / mTOR pathway. Effects on amino acid sequence and gene function suggest a hyperactive pathway in all 3. For the other 2 long-term responders genomic changes with possible indirect link to the pathway, but no apparent determinants of treatment response were seen. In 3 control patients with rapid disease progression no genomic alterations suggesting hyperactivation of the pathway were seen. Conclusions: In this retrospective discovery set of RCC pts with unusually long response to rapalog therapy, next generation sequencing using pre-treatment tissue specimens revealed plausible oncogenomic determinants of treatment benefit in 3 of 5 cases. These findings provide basis for further biomarker development and studies in a larger sample set are ongoing.
Evolving trends in non-clear cell renal cell cancer (RCC) epidemiology: A large registry analysis of 4,483 patients.
Authors: Pai Ashok P. , Brown Monica , Pan Chong-xian , Lara Primo
Published: March 2020

4607

Background: Non-clear cell (ncc) RCC is uncommon but includes a heterogeneous group of histologic subtypes such as papillary, chromophobe (Chr), medullary (Med), and collecting duct (CD) cancers. We used a large cancer registry to define nccRCC clinical features and outcomes, identify prognostic variables, and to generate hypotheses for further study. Methods: Invasive RCC tumors in the California Cancer Registry from 1998-2009 among adults > 18 years of age (n=38,251) were analyzed. Baseline clinical and tumor variables were collected. Primary outcome measures were 3-year cause-specific (CSS) and overall survival (OS). Uni- and multivariate survival analysis were used to identify predictors of CSS and OS. Results: Of 38,251 RCC cases, 19,149 (50%) were of clear cell type; 14,619 (38.2%) were “unclassified.” Thus, 4,483 (11.7%) nccRCC cases were identified and included in this analysis. Of these, 3,304 (73.7%) were diagnosed in 2004-09, suggesting a shift to more precise coding of histologic subtypes starting in the early 2000s. Histology distribution (n, %): papillary - 2,863 (63.9%); Chr - 1,507 (33.6%); and other including Med and CD - 113 (2.5%). Variables associated with significantly better OS and CSS (univariate analysis) were Chr histology, female sex, and higher socioeconomic status (SES). Significantly worse OS and CSS were seen in Med+CD, age > 65 yrs, no nephrectomy (Nx), and higher stage. Non-hispanic blacks had significantly worse OS and CSS, while the “targeted therapy era” (2004-2009) was associated with better OS. Multivariate analysis showed the following to be independently associated with outcomes (all p <0.001; Hazard Ratios [HR] shown for CSS and OS): Chr histology (0.48, 0.56), Med+CD histology (2.99, 2.42), no Nx (2.84, 3.18), regional stage (5.84, 1.98), distant stage (25.7, 7.67); and non-hispanic blacks (1.5,2 p=0.006; 1.25, p=0.03). Age > 65 yrs (HR 1.78, p<0.001) and high SES (HR 0.88, p=0.001) were associated with OS but not CSS. Conclusions: This is among the largest registry analyses of nccRCC ever performed, showing emerging trends in this uncommon RCC subset. Clinical variables associated with CSS and OS were identified that can inform the design of future clinical trials in nccRCC.
Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies.
Authors: Hall Philip S , Witteles Ronald , Srinivas Sandy , Harshman Lauren Christine
Published: March 2020

4610

Background: Almost all patients with advanced RCC are treated with therapies targeting the hypoxia inducible factor axis. The potential for these agents to cause cardiovascular (CV) toxicity has been increasingly recognized but the overall incidence and extent have not been well described. We sought to identify and characterize the incidence and severity of CV toxicity among RCC patients treated with targeted therapies. Methods: Between 2004 and 2011, all RCC patients treated with targeted therapies directed against the VEGF or mTOR axes were identified at our institution. The incidence of hypertension, left ventricular (LV) dysfunction, changes in serum markers of CV toxicity (e.g., troponin I, NT-proBNP) and heart failure were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.4.0). Results: Cardiovascular toxicity developed in 116 of 159 patients (73%). Excluding hypertension, 52 of 159 (33%) developed cardiovascular toxicity. Cardiac toxicity ranged from asymptomatic drops in LV ejection fraction (LVEF) to rises in NT-proBNP to severe heart failure. Asymptomatic cardiotoxicity as defined by decrease in LVEF or increase in NT-proBNP occurred in 43 patients (27%). Symptomatic heart failure (grade 2-3) and grade 3-4 decrease in LVEF each occurred in 4%. Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well. The mTOR inhibitors elicited significantly less CV toxicity, but sample sizes were small. Conclusions: Cardiovascular toxicity is an important adverse event related to targeted therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.
Circulating mir-21 and mir-378 are predictive of progression-free survival (PFS) in patients treated with everolimus in metastatic renal cell cancer (mRCC).
Authors: Chen James Lin , Rathmell Kimryn , McDermott David F. , Stadler Walter Michael
Published: March 2020

4617

Background: The oral mTOR inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and modestly delays RCC progression. We hypothesized that circulating microRNAs, which have been associated with renal cancer and inflammation, may serve as predictive biomarkers to help better define a population more sensitive to treatment. Methods: Plasma from mRCC pts refractory to VEGF inhibition were obtained prior to treatment with standard dose everolimus as part of a clinical trial examining FDG-PET as a potential predictive biomarker. As we were specifically interested in tumor response to drug, only pts who died, remained on trial, or had radiographic progression by RECIST criteria were profiled. Pts who were unable to tolerate drug were excluded. MicroRNAs were extracted and profiled without pre-amplification using Exiqon LNA PCR panels. Crossing point (Cp) values within 5 of the negative control were removed. MicroRNAs must have been present in >90% of samples and varied at least p > 0.10 from mean to be further analyzed. Cox-proportional hazards model and Kaplan-Meier analyses were performed. Results: 28 patients had available plasma and met criteria for profiling. Pt characteristics included: 20 (71%) clear cell histology, median age 57.7 (43 – 76), median number of prior systemic therapies 2 (1 – 3). 103 microRNAs were expressed in at least 90% of all samples. Mir-21 and mir-378 were independently correlated with PFS (FDR: 0.02 and 0.06, respectively). Low circulating plasma mir-21 and mir-378 levels resulted in a median PFS prolongation of 370d vs. 101d (p=0.027) and 368d vs. 106d (p=0.001). Analysis of the clear cell cohort for mir-21 and mir-378 also demonstrated a significant median PFS difference of 350d vs. 173d (p=0.045) and 345d vs. 147d (p=0.004). Conclusions: Elevated levels of circulating mir-21 and mir-378 have been associated with systemic inflammatory states, and in our study are correlated with decreased PFS in mRCC pts undergoing everolimus therapy. Further prospective studies will be required to validate these exploratory results for their potential role as prognostic or predictive biomarkers.
Evaluation with DCE-US of antiangiogenic treatments in 539 patients allowing the selection of one surrogate marker correlated to overall survival.
Authors: Lassau Nathalie , Vilgrain Valérie , Taieb Sophie , Lacroix Joëlle , Aziza Richard , Cuinet Marie , Soria Jean-Charles , Chapotot Louis , Koscielny Serge
Published: March 2020

4618

Background: A prospective study of dynamic contrast-enhanced ultrasound (DCE-US) with quantification for the evaluation of antiangiogenic treatments was launched (19 centers), supported by the French National Cancer Institute. The objectives were the diffusion of the standardized method, a cost evaluation and the identification of perfusion parameters predicting tumor response. Methods: All patients had DCE-US at baseline, D7, D14, D30, D60 and every two months. Each examination included a bolus injection of sonovue (Bracco) and 3 minutes of raw linear data with an Aplio (Toshiba). Raw data were analyzed with a mathematical model (patent PCT/IB2006/003742) to evaluate 7 parameters characterizing the tumor perfusion curve. Response to treatment was evaluated every 2 months with RECIST criteria. In order to have sufficient follow-up data, the statistical analysis has to be performed more than 6 months after the inclusion of the last analyzed patient. Inclusions were closed in March 2010. Results: A total of 539 patients have been included (mainly RCC (157) and HCC (107)); more than 2 000 DCE-US and 1700 CT-scan were performed. A follow-up more than 12 months showed that 3 parameters have a strong significant difference (p<0.0003) according to the response at 6 months. The decrease of more than 40% of AUC at one month is correlated to the TTP (p< 001) and OS (p< 0.04). Conclusions: Final results confirm the usefulness of this tool to monitor anti-angiogenic treatments. The criteria: the decrease of more than 40% of AUC at one month is predictive of response.
Use of bisphosphonates (Bis) combined with sunitinib (Su) to improve the response rate (RR), progression-free survival (PFS), and overall survival (OS) of patients (pts) with bone metastases (mets) from renal cell carcinoma (RCC).
Authors: Peer Avivit , Ish-Shalom Maya , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Pili Roberto , Maimon Natalie , Gottfried Maya , Hayat Henry , Kovel Svetlana , Sella Avishay , Neumann Avivit , Boursi Ben , Berger Raanan , Carducci Michael Anthony , Keizman Daniel
Published: March 2020

4619

Background: Bis are used to prevent skeletal events of bone mets, and may exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a RR, PFS, and OS benefit to pts with bone mets from RCC that are treated with Su. Methods: We performed an international multicenter retrospective study of pts with bone mets from RCC who were treated with Su. Pts were divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on RR, PFS and OS, was tested with adjustment for known prognostic factors using a chisquare test from contingency table and partial likelihood test from Cox regression model. Results: Between 2004-2011, 244 pts with metastatic RCC were treated with Su. 92 pts had bone mets, 41 group 1 and 51 group 2. The groups were balanced regarding the following known prognostic factors: past nephrectomy, clear cell vs non clear cell histology, initial diagnosis to sunitinib treatment (tx) time, presence of ≥ 2 mets sites, presence of lung/liver mets, ECOG performance status, anemia, calcium level > 10 mg/dL, elevated alkaline phosphatase (AP), pre-tx neutrophil to lymphocyte ratio (NLR) >3, sunitinib induced HTN, and the use of angiotensin system inhibitors. They were also balanced with regard to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective response was partial response/stable disease 85% (n=35) vs 71% (n=36), and progressive disease 15% (n=6) vs 29% (n=15) (OR 3.287, p=0.07) in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 0.433, p=0.035), and median OS not reached with a median folloup time of 43 mos vs 12 months (HR 0.398, p=0.003), in favor of group 1. In multivariate analysis of the entire pt cohort (n=92), factors associated with PFS were Bis use (HR 0.433, p=0.035), pre-tx NLR ≤3 (HR 0.405, p=0.016), and elevated AP (HR=3.63, p=0.012). Factors associated with OS were Bis use (HR 0.32, p=0.003), elevated AP (HR 3.18, p=0.002), and Su induced HTN (HR 0.193, p< 0.001). Conclusions: Bis may improve the outcome of Su tx in RCC with bone mets. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Prognostic role of body composition parameters in renal cell carcinoma (RCC).
Authors: Lanoy Emilie , Antoun Sami , Iacovelli Roberto , Albiges Laurence , Loriot Yohann , Merad Mansouriah , Fizazi Karim , Di Palma Mario , Baracos Vickie E. , Escudier Bernard J.
Published: March 2020

4621

Background: Previous studies have shown that body component i.e. muscle tissue (MT) and adipose tissue (AT) are linked to overall survival (OS) and progression free survival (PFS). The aim of our study is to analyze whether MT and AT have a prognostic role in metastatic RCC treated with targeted therapy. Methods: We investigated body mass index (BMI), MT and AT in RCC pts. Analysis of CT image was used to evaluate cross-sectional areas (cm2) of total AT (TAT), MT, and the grey level image (GLI) of MT, reflecting physical properties of the scanned tissue and used as a proxy to describe the quality of muscle. The 3rd lumbar vertebra (L3) was chosen as a landmark since L3 and whole-body measurements are linearly related. Images were analyzed using Slice-O-Matic software V4.3 (Tomovision). Indexed on height MT (cm2/m2), indexed on height TAT (cm2/m2) and mean GLI of MT were computed and described stratified on sex. For each measurement, population was divided in two groups: patients with values < or >= median observed in patient of the same gender and OS and PFS were estimated using Kaplan-Meier method and compared with the log-rank test. Multivariable Cox proportional hazards model were adjusted for modified MSKCC risk group and treatment (active versus placebo). Results: There were 113 men aged of 60 (interquartile range=52-56) years with BMI of 26 (24-29) kg2/m2 and 36 women aged of 58 (54-65) years with BMI of 23 (20-26) kg2/m2. After adjustment for MSKCC (OS and PFS) and active treatment (PFS), GLI of MT over the median was associated with longer OS (HR=1.85, 95%CI=[1.22;2.82], p=.004) and PFS (HR=1.81, 95%CI=[1.22;2.65], p=.002) Conclusions: Quality of muscular tissue is independently associated with better outcome in RCC. Surprisingly, adipose tissue as well as BMI is not associated with survival in this study. [Table: see text]
Impact of maximum standardized uptake value (SUVmax) evaluated by 18-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) on survival for patients with advanced renal cell carcinoma.
Authors: Nakaigawa Noboru , Yao Masahiro , Tateishi Ukihide , Minamimoto Ryogo , Uemura Hiroji , Inoue Tomio , Kubota Yoshinobu
Published: March 2020

4626

Background: In this era of molecular targeting therapy when various systematic treatments can be selected, prognostic biomarkers are required for the purpose of risk-directed therapy selection. Numerous reports of various malignancies have revealed that 18-Fluoro-2-deoxy-D-glucose (18F-FDG) accumulation, as evaluated by positron emission tomography, can be used to predict the prognosis of patients. The purpose of this study was to evaluate the impact of the maximum standardized uptake value (SUVmax) from 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) on survival for patients with advanced renal cell carcinoma (RCC). Methods: A total of 67 patients with advanced or metastatic RCC were enrolled in this study. The FDG uptake of all RCC lesions diagnosed by conventional CT was evaluated by FDG PET/CT. The impact of SUVmax on patient survival was analyzed prospectively. Results: The mean duration of observation was 461 days (range, 7-1229 days). The SUVmax before treatment of 67 patients ranged between undetectable level and 16.6 (mean 7.6±3.6). The patients with RCC tumors showing high SUVmax before treatment demonstrated poor prognosis (p<0.001 hazard ratio 1.289, 95% CI 1.161-1.430). The median survival time of 36 patients with RCC showing SUVmax less or 7.0 was 1229±991 days, that of 21 patients with RCC showing SUVmax between 7.0 and 12.0 was 446±202 days, and that of 10 patients RCC showing SUVmax higher than 12.0 was 95±43 days (≤7.0 vs. 7.0< ≤12.0 p=0.0052, 7.0< ≤12.0 vs. 12.0<:p=0.0169, log-rank test). SUVmax demonstrated a tendency to predict the survival compared with the Memorial Sloan-Kettering Cancer Center classification (p =0.015 vs 0.315, multivariate Cox analyses). Conclusions: The survival of patients with advanced RCC can be predicted by evaluating their SUVmax using FDG PET/CT. FDG PET/CT has potency as an “imaging biomarker” to provide helpful information for the clinical decision-making.