bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of circulating miR375 and miR371 to differentiate teratoma and viable germ cell tumor in patients with post-chemotherapy residual disease.
Authors: Nappi Lucia , Thi Marisa , Adra Nabil , Leao Ricardo Romao Nazario , Eigl Bernhard J. , Chi Kim N. , Gleave Martin , So Alan , Black Peter C. , Hamilton Robert James , Daneshmand Siamak , Cary Clint , Masterson Timothy A. , Einhorn Lawrence H. , Nichols Craig R. , Kollmannsberger Christian K.
Published: February 2020

414

Background: Viable germ cell tumors (vGCT) express high levels of certain circulating microRNAs, including miR-371a-3p (miR371) that has shown high specificity and sensitivity. However, neither tissue nor serum/plasma from patients with only teratoma are miR371 positive. miR375 is overexpressed in teratoma tissue, but detectability in blood is unknown. Methods: miR371 and miR375 expression was analyzed in 100 patients with various stages and histology of GCT. miR375 expression in teratoma was validated in patients with post-chemotherapy pathologically confirmed teratoma (PCPCT). The miRNAs expression was assessed by RT-PCR and quantified by ΔΔCT method. The optimal cut-off for miR375 expression was estimated by Youden index ( > 20). Spike-in cel-miR-39-3p, miR-451 and miR-30b-5p were used as internal controls. Sensitivity, specificity, AUC of the ROC of miR375 in detecting teratoma was analyzed. Results: In the discovery cohort miR371 and miR375 were measured in 62 pts: 27 CSI NED, 15 chemo-naïve metastatic seminoma and 20 with PCPCT. miR375 was over-expressed in pts with teratoma compared to CSI and seminoma pts (p = 0.002), while miR371 was expressed in the seminoma pts and undetectable in the PCPCT and CSI pts (p < 0.001). In the post-chemotherapy setting, 38 pts were analyzed: 21 PCPCT, 6 vGCT and 11 complete remission (CR). Also in this cohort, miR375 was over-expressed in pts with teratoma compared to the pts presenting vGCT and post-chemotherapy CR (p = 0.01), while miR371 was detectable only in the pts with vGCT (p < 0.001). Overall, sensitivity and specificity of miR375 in identifying teratoma were 78% and 80%, respectively; the AUC was 0.7 (95% CI: 0.5490-0.8186; p < 0.01). Conclusions: Pts with residual post-chemotherapy teratoma present higher plasma levels of miR375 compared to pts with vGCT in whom miR375 is low but miR371 is expressed at high levels. The simultaneous evaluation of miR371 and miR375 may be clinically useful to predict the histology of the GCT components in pts with post-chemotherapy residual disease to inform the best therapeutic options (surgery or chemotherapy). Further validation within larger studies is warranted.
Predictive capacity of miRNA-375 in identifying teratoma in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Kenigsberg Alexander P. , Lafin John T. , Meng Xiaosong , Abe Dreaux , Savalyeva Anna , Singla Nirmish , Woldu Solomon L. , Lotan Yair , Kapur Payal , Margulis Vitaly , Amatruda James F. , Bagrodia Aditya
Published: February 2020

416

Background: Traditional tumor markers for testicular germ cell tumor (TGCT), lactate dehydrogenase (LDH), beta-human chorionic gonadotropin (hCG), and alpha-fetoprotein (AFP), have limited sensitivity in detecting residual tumor on PC-RPLND. Micro-RNAs (miRNA) have emerged as a promising serum markers to predict residual TGCT on RPLND. Previous reports have suggested high levels of miRNA-375 in teratoma. The purpose of this study was to evaluate serum miRNA-375 as a tumor marker for PC-RPLND teratoma. Methods: We prospectively collected pre-surgical serum samples from consecutive GCT patients undergoing PC-RPLND. Serum miRNA-375-3p and -5p expression was validated and quantified by qPCR. Receiver operating characteristic (ROC) analysis and logistic regression were utilized to evaluate test characteristics and predictors of teratoma. Results: 40 patients underwent PC-RPLND. 18 had benign pathology, 2 viable TGCT, 19 teratoma, and 1 embryonal rhabdomyosarcoma. 3 miRNA specimens were excluded as outliers. miRNA-375-5p was undetectable in all samples examined. ROC analysis of miRNA-375-3p revealed an area under the curve of 0.503. Of 19 patients with teratoma, 16 had elevated miRNA-375-3p (84.2% sensitivity). 6/17 with benign pathology had normal mi-RNA-375-3p (35.3% specificity). 16/27 with positive tests harbored teratoma (59.3% positive predictive value). 6/9 with negative miRNA-375-3p had benign disease (66.7% negative predictive value). Univariate analysis demonstrated that clinical stage, pre-RPLND LDH, AFP, hCG, N/L ratio, and miRNA-375-3p were not significant predictors of teratoma. Conclusions: miRNA-375 does not predict teratoma on PC-RPLND. Tissue expression of miRNA-375 did not translate to serum expression in our study. Reliable predictors of teratoma on PC-RPLND remain elusive.
Health-related quality of life in Japanese patients with bladder cancer according to a newly developed Japanese version of the Bladder Cancer Index.
Authors: Osawa Takahiro , Wei John , Abe Takashige , Yamada Shuhei , Frumido Jun , Miyata Haruka , Kikuchi Hiroshi , Matsumoto Ryuji , Sato Yasuyuki , Hirakawa Kazushi , Sasaki Yoshihiro , Tanaka Hiroshi , Kashiwagi Akira , Morita Ken , Takada Norikata , Minami Keita , Harabayashi Toru , Murai Sachiyo , Shinohara Nobuo
Published: February 2020

427

Background: We developed a Japanese version of the Bladder Cancer Index (BCI) to measure HRQOL in Japanese patients treated with various surgical methods. In addition, we performed a cross-cultural comparison of sexual function and bother in bladder cancer patients between the United States and Japan. Methods: The Japanese version of the BCI was developed through a multistage process after a pilot study. Its reliability and validity were examined in Japanese bladder cancer patients via a cross-sectional analysis. The patients were enrolled from August 2016 to March 2018. They also completed the Japanese version of Short Form (SF)-12, the EuroQol five-dimension scale (EQ-5D), and the Functional Assessment of Cancer Therapy-Bladder (FACT-BL). We also compared the Japanese cohort with an American cohort; i.e., the validation cohort used to develop the original version of the English BCI. Results: In total, 371 patients with a median age of 72 years and a median disease duration of 29 months were enrolled. Of these patients, 221 underwent transurethral resection of the bladder tumor, and 150 underwent radical cystectomy. The internal consistency value was ≥0.7 for all subscales, except the bowel function subscale. Each BCI domain was poorly correlated with the SF-12 and EQ-5D, but moderately well correlated with the FACT-BL. The urinary function and bowel function scales exhibited minimal (2.1–9.7%) amounts of missing data, whereas relatively high (≥15%) levels of missing data were seen in items relating to urinary bother, bowel bother, sexual function, or sexual bother. A missing data value of ≥15% was correlated with higher age (p<0.05). Japanese patients were more likely than American patients to report poor sexual function. However, Japanese were less likely than American to be concerned about sexual function. Conclusions: We confirmed the reliability and validity of the Japanese version of the BCI, although it needs to be revised to make it more comprehensible for elderly patients. We found differences between American and Japanese patients with bladder cancer. The BCI can be used for cross-cultural assessments of HRQOL in bladder cancer patients.
Frailty has significant impact on treatment selection in patients with muscle-invasive bladder cancer.
Authors: Iwamura Hiromichi , Hatakeyama Shingo , Fujita Naoki , Okamoto Teppei , Suzuki Yuichiro , Saito Fumitada , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: February 2020

429

Background: Although measuring frailty is important to estimate risks and to aid shared decision making, the impact of frailty on surgical indication in muscle-invasive bladder cancer (MIBC) remain unclear. We aimed to investigate the impact of frailty on treatment modality selection in patients with MIBC. Methods: Between October 2013 and September 2019, we underwent frailty evaluation in 149 patients with localized or locally advanced MIBC (T2-4N0-1M0). Frailty evaluation included modified Frailty index (mFI), Fried phenotype (FP), and frailty discriminant score (FDS). Primary purpose was comparison of frailty between the patients who underwent radical cystectomy (RC group) and trimodal therapy for bladder preservation (TMT group). Optimal cutoff values of frailty between the RC and non-RC groups was defined by receiver operating characteristic curve. Secondary purpose included overall survival (OS) comparison between in patients with frail and non-frail. Overall survival (OS) was compared using Kaplan-Meier method and Cox regression analysis. Results: Of 149, 88 and 61 patients were classified to RC and TMT group, respectively. The median age in the TMT group was significantly older than that in the RC group (80 vs. 68 years). A significantly higher prevalence of frailty was observed in the TMT group than that of the RC group in FP ≥3 (5.7% vs. 61%, P < 0.001), mFI ≥2 (22% vs. 61%, P < 0.001), and FDS ≥2.30 (40% vs. 72%, P < 0.001). Univariate logistic regression analysis showed that frailty was significantly associated with TMT. Frailty was significantly associated with overall survival between the RC and TMT groups in the FP and FDS, whereas it was not the case in mFI. Conclusions: Frailty was significantly associated with indication of RC in patients with MIBC. Measuring frailty is important to estimate risks and to aid shared decision making.
Primary malignant melanoma of the female urethra: Twenty years of surgical and medical management at a tertiary referral center.
Authors: Nichols Paige , Miest Tanner , Montgomery Brian D. , Sharma Vidit , Lightner Deborah , Lomas Derek
Published: February 2020

430

Background: Malignant melanoma of the female urethra accounts for less than 1% of all melanoma and less than 4% of urethral cancer. Due to limited data regarding management and outcomes of this condition, we evaluated the management and outcomes of urethral melanoma in females over the last 20 years at our institution. Methods: Patients were identified via retrospective review of the medical record. Those with metastatic disease at initial diagnosis were excluded. We evaluated primary and adjuvant treatments, disease recurrence and overall survival. Results: Fifteen women (median age 71, range 55, 82) were identified. Majority of masses involved the distal urethra (86.6%). All patients underwent primary surgical resection (60.0% partial urethrectomy, 40.0% radical urethrectomy). Disease recurrence and metastatic spread occurred in 73.3% (median 7 months, IQR 4, 12) and 60% (median 6 months, IQR 3, 9) of patients, respectively. 90.9% of patients with recurrence received adjuvant therapy: 5 chemotherapy and radiation, 4 chemotherapy only, 1 anterior exenteration. Of the 9 patients undergoing chemotherapy, treatment regimens were varied and included checkpoint inhibitors (2/9), platinum-based chemotherapy (3/9), tyrosine kinase inhibitors (2/9), taxels (2/9), and alkylating agents (1/9). Median overall survival was 27 months (IQR 7.5, 57.5). Conclusions: Malignant melanoma of the urethra is locally aggressive with a high likelihood of recurrence and metastases resulting in poor long-term survival. Despite high recurrence rates, our data highlight the lack of consensus adjuvant treatment regimens. Future research is required to identify neoadjuvant, combination, and adjuvant treatment approaches to improve disease outcomes.
The association between allopurinol use and urologic malignancies: A nested case-control study.
Authors: Keizman Daniel , Wolf Ido , Dresler Hadas , Sarid David , Peer Avivit , Rouvinov Keren , Neiman Victoria , Margalit Ofer , Shacham-Shmueli Einat , Mamtani Ronac , Haynes Kevin , Yang Yu-Xiao , Boursi Ben
Published: February 2020

435

Background: Oxidative stress may be involved in tumorigenesis processes. Uric acid is an important natural antioxidant that may reduce oxidative stress. Allopurinol is a commonly used uric acid lowering agent. There are conflicting data regarding the association between allopurinol use and cancer incidence. In the present nested case control study, we aimed to evaluated the association between allopurinol use and urologic malignancies in a large western population. Methods: conducted a nested case-control study within a population-representative database from the United Kingdom (THIN). Study cases were defined as individuals with any diagnostic code of prostate cancer, bladder cancer, or renal cell carcinoma. For every case, four eligible controls were matched on age, gender, practice site, time of diagnosis, and duration of follow-up. Exposure of interest was any allopurinol use prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for urologic malignancies were estimated using conditional logistic regression. Adjustment was performed for factors including smoking, BMI, and diabetes. Results: The study population included: for bladder cancer 13440 and 52421 matched controls, prostate cancer 27212 cases and 105940 controls, RCC 1547 cases and 6066 controls. Allopurinol use was associated with a significantly increase of risk for bladder cancer (adjusted OR 1.2, 95%CI 1.09-1.32, p<0.001). prostate cancer (adjusted OR 1.1, 95%CI 1.03-1.,17, p=0.003), RCC (adjusted OR 1.32, 95%CI 1-1..75, p=0.05). In a sensitivity analyses we observed similar associations when alopurinol use was initiated more than two years prior to cancer diagnosis, for bladder cancer (adjusted OR 1.2, 95%CI 1.08-1.33, p=0.001), prostate cancer (adjusted OR 1.09, 95%CI 1.02-1.16, p=0.01), RCC (adjusted OR 1.09, 95%CI 0.78-1.53, p=0.62). Conclusions: Allopurinol use may be associated with an increased risk for urologic malignancies.
Atezolizumab in patients with metastatic urothelial carcinoma who have progressed after first-line chemotherapy: Results of real-life experience.
Authors: Tural Deniz , Olmez Omer Fatih , Sumbul Ahmet Taner , Artac Mehmet , Ozhan Nail , Akar Emre , Cakar Burcu , Kostek Osman , Paksoy Nail , Erman Mustafa , Coskun Hasan Senol , Selcukbiricik Fatih , Keskin Özge , Paksoy Turkoz Fatma , Oruc Kerem , Bayram Selami , Yilmaz Ugur , Bilgetekin Irem , Yildiz Birol , Kilickap Saadettin ,   Turkish Oncology Group (TOG)
Published: February 2020

451

Background: Anti-tumor activity and manageable safety profile of atezolizumab (ATZ) has been demonstrated in the previous clinical trials in patients with locally advanced or metastatic platinum-resistant urothelial carcinoma. In this study, we reported the results of real-life data of urothelial carcinoma patients in Turkey who were treated with ATZ. Methods: Data of the patients with metastatic urothelial carcinoma registered to ATZ Expanded-Access Program and treated with at least one course of ATZ from 36 oncology centers in Turkey were collected. The primary endpoint was the overall response rate (ORR); secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of the ATZ treatment and safety. Results: Data of 115 eligible patients were analyzed. Of the patients, 100 (87%) were male and 13% were female. The median age was 65.3 years (37-86). Most of the patients (92.3%) had received only one chemotherapy regimen prior to ATZ. The median follow-up time was 23.5 months. The complete response rate to ATZ, partial response rate, and ORR were 8.7% (n=10), 20.0% (n=23), and 28.7% (n=33), respectively. The median duration of response was 20.4 months (95% CI 6.47–28.8). Of the thirty-three patients who responded to treatment, 20 (60%) had an ongoing response at the time of the analysis. PFS and OS with ATZ were 3.8 months (95% 2.25–5.49) and 9.8 months (95% 6.7–12.9), respectively. The 12-month PFS rate was 22.3% and the 24-month PFS rate was 16.9%. The 12-month OS rate was 42.2% and the 24-month OS rate was 23.5%, respectively. Sixty-four percent of patients experienced a treatment-related adverse event of any grade, and 24 (20%) of patients had a grade 3–4 treatment-related adverse event. Because of treatment-related side effects, dose reduction was performed in 9 (7.8%) patients and ATZ was discontinued in 8 patients (7.0%). Adverse event that required systemic steroid use was reported in only 7 (6.1%) patients. Four patients (3.5%) died due to treatment-related causes. Conclusions: ATZ is an effective and tolerable treatment for patients with metastatic platinum-resistant urothelial carcinoma.
Real-world evidence of the impact of prior antibiotic exposure on immune checkpoint inhibitor outcomes in patients with metastatic urothelial cancer.
Authors: Hoffman-Censits Jean H. , Harshman Lauren Christine , Metcalf Meredith , Abou Alaiwi Sarah , Meyer Craig S. , Yang Erru , Satram Sacha , Ogale Sarika , Faber Kathleene , Ma Esprit
Published: February 2020

452

Background: Prior research suggests that systemic antibiotic (ABX) exposure may impact gut microbiome and potentially result in suboptimal immune checkpoint inhibitor (ICI) treatment outcomes. A recent real-world analysis demonstrated that cumulative ABX exposure was associated with poorer outcomes across multiple tumor types independent of known prognostic clinical factors. Given the paucity of real-world data, we set out to evaluate the association of prior ABX exposure with ICI treatment outcomes among patients with metastatic urothelial cancer (mUC). Methods: This was a retrospective analysis using Truven Health MarketScan Commercial, Medicare Supplemental, and Coordination of Benefits (Medicare) databases. Patients with mUC, ≥18 years old, who received first line (1L) ICI therapy between 1/1/2016 and 12/31/2018 were analyzed. Prior ABX exposure was defined as any use in the 90 days prior to 1L ICI therapy initiation. Time to treatment discontinuation was used as a proxy to quantify ICI treatment outcomes. Results: Among the 304 ICI treated patients, 128 (42%) had ABX exposure within 90 days prior to ICI initiation. Statistically significant differences in baseline co-morbidities and urinary tract infections (36% vs. 17%; p<0.001) were observed between patients with vs. without ABX exposure. The median time to treatment discontinuation was shorter for patients with ABX exposure (7.9 months) vs. without (9.3 months). In adjusted regression analysis, there was no statistically significant difference in time to treatment discontinuation between patients with vs. without ABX exposure (p=0.95). These findings were consistent in a sensitivity analysis looking at ABX exposure 30 and 60 days prior to 1L ICI initiation. Conclusions: In this real-world analysis of patients with mUC, those with ABX exposure within 90 days prior to 1L ICI initiation demonstrated similar outcomes to those without ABX exposure. While there was a shorter time to treatment discontinuation in the patients with vs. without ABX exposure, findings were not statistically significant. Further research is warranted to investigate the impact of concomitant ABX use on ICI outcomes.
Response to systemic therapy and survival outcomes in de-novo (D1) metastatic castration-sensitive prostate cancer (mCSPC) versus mCSPC with prior local therapy (D0).
Authors: Hahn Andrew W , Kessel Adam , McFarland Taylor Ryan , Swami Umang , Nussenzveig Roberto , Esther John , Goel Divyam , Sirohi Deepika , Maughan Benjamin Louis , Agarwal Neeraj
Published: February 2020

46

Background: A real-world study (n= 436, PMID: 29707790) suggest that D1 mCSPC has worse outcomes than D0 mCSPC. The objective of our study is to validate these findings in a real-world setting, and compare clinical and tumor genomic characteristics associated with D1 vs. D0 mCSPC. Methods: In this retrospective study, eligible patients had mCSPC, received androgen deprivation therapy (ADT) +/- intensification with docetaxel or novel hormonal therapy. D1 mCSPC was diagnosed as those with distant metastasis at the first diagnosis of prostate cancer. Progression-free survival (PFS) was per PCWG2 criteria or clinical progression, and overall survival (OS) was date of death or last follow up from start of ADT for mCSPC. Baseline clinical characteristics were compared using the t test. Survival was compared using the log-rank test with Kaplan-Meier methods. Results: Of 396 eligible patients, 242 had D1 mCSPC. Men with D1 mCSPC were younger, had significantly higher median PSA, Gleason score, and alkaline phosphatase at diagnosis of mCSPC, and had significantly shorter PFS and OS with standard ADT, as well as intensified ADT, compared to men with D0 mCSPC (Table). Conclusions: These findings validate data from a previous real-world study that D1 CSPC is associated with inferior prognosis and outcomes on systemic therapy compared to D0 mCSPC. These data may aid with counseling and treatment selection, as well as patient stratification in future trials in mCSPC. Comparison of comprehensive genomic profiling data, obtained through CLIA certified labs, will be presented at the meeting.[Table: see text]
Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic urothelial carcinoma (mUC).
Authors: Jiang Di Maria , Wong Bryan , Bellmunt Joaquim , Powles Thomas , Morgans Alicia K. , Vaughn David J. , Sridhar Srikala S.
Published: February 2020

467

Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to systematically evaluate QHR in phase III RCTs of mUC. Methods: A comprehensive systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mUC in English between 1985 - 2019. Supplementary material, references and companion publications were reviewed. QHR was quantified using: 1) 2013 CONSORT-PRO extension (CPE), and 2) 2003 Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC). Both scores range from 0-11, with higher scores indicating higher QHR. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if MSC score is 5-7; and “very limited” if MSC score is ≤4. Results: HRQOL data was collected in 7/21 (33%) mUC phase III RCTs. All reported HRQOL data as secondary/exploratory endpoints. Generic instruments included EORTC QLQ-C30 alone (n=3) or combined with EQ-5D (n=2)/McGill pain questionnaire (n=1). Disease-specific FACT-Bl was used in 1 RCT. Both checklists showed strong correlation (Spearman coefficient 0.94, p=0.001). QHR was often limited, however has improved in recent years (Table). No RCT stated HRQOL-specific hypotheses. Only 1 reported instrument validity and mode of administration. Few provided domain specific results (n=2) and statistical methods for handling missing data (n=3). Implications for clinical practice were only discussed in 3 RCTs. Conclusions: QHR has improved over time however many critical methodological deficiencies remain in mUC phase III RCTs. The use of standard checklists are encouraged to further enhance QHR and promote high quality HRQOL research. [Table: see text]
Impact of inflammatory bowel disease on urologic oncology surgical outcomes and costs of care.
Authors: Goldberg Ilana , Chang Steven Lee , Kundu Shilajit , Singer Eric A.
Published: February 2020

470

Background: Recent studies suggest an association between genitourinary malignancies and inflammatory bowel disease (IBD). Our objective was to investigate clinical and financial impacts of IBD on common major urologic cancer surgeries: radical prostatectomy (RP), radical cystectomy (RC), radical nephrectomy (RN), and partial nephrectomy (PN). Methods: Using ICD9 codes, the Premier Hospital Database was queried for patients who underwent one of four surgeries: RP, RC, RN, or PN from 2003 to 2015. The cohort was segregated into IBD patients and non-IBD patients. Multivariable logistic regression models were used to determine the independent impact of IBD on complication rates (by Clavien-Dindo classification and organ system) and readmission rates. Hospital cost differences between the two cohorts, adjusted to 2016 US dollars, were examined with multivariable quantile regression models. Results: Our study population included 220,192 patients with urological malignancies, 5165 (0.4%) of whom had IBD. After controlling for clinicodemographic variables, there were significantly higher odds for any complication (Clavien ≥1) for IBD patients compared to non-IBD controls for RC (Odds ratio [OR]: 3.04, 95% confidence interval [CI]: 1.25-7.43), RN (OR: 1.57, 95% CI: 1.1-2.23), and PN (OR: 1.5, 95% CI: 1.02-2.22). Specifically, IBD patients had significantly more gastrointestinal, infectious, and soft tissue complications. Readmission rates were significantly higher for IBD patients who underwent RC (OR: 2.50, 95% CI: 1.17-5.35) and PN (OR: 1.81, 95% CI: 1.17-2.80). Hospital costs were significantly elevated for IBD patients, ranging from +$893 (95% CI: 108-1677) to +$6261 (95% CI: 1861-10660). Conclusions: There was a significantly higher overall complication rate for IBD patients undergoing RC, RN, or PN compared to the non-IBD cohort. Hospital readmission rates were significantly higher for the IBD cohort who underwent RC and PN. Hospital costs associated with surgery were also increased for IBD patients. These findings may be important when counseling IBD patients about surgical outcomes and during development of enhanced recovery pathways or bundled payment programs.
Real-world survival improvements in patients with newly diagnosed metastatic prostate cancer treated in the United States.
Authors: Cattrini Carlo , Zanardi Elisa , Rubagotti Alessandra , Zinoli Linda , Capaia Matteo , Barboro Paola , Boccardo Francesco
Published: February 2020

48

Background: New drugs have become available for the treatment of metastatic prostate cancer (mPCa) during the last two decades. Here, we explored the clinical outcomes of de novo mPCa in 3 large cohorts of patients diagnosed in 3 treatment eras: pre-docetaxel 2000-2003 (T1), docetaxel 2004-2010 (T2) and new androgen-receptor signalling inhibitors (ARSi) + cabazitaxel 2011-2016 (T3). Methods: The USA Surveillance Epidemiology and End Results (SEER) Incidence Data were investigated using the SEER*Stat software. We used the Kaplan – Meier method, log-rank test, Cox regression, hazard ratio (HR) and confidence intervals (CI) to analyse overall survival (OS) and cancer-specific survival (CSS). The maximum follow-up time point was 5 years. Results: A total 34.034 patients with de novo mPCa were analysed for OS, of these 6.621 T1, 12.711 T2 and 14.702 T3. Median OS was 29 months (mo) [95% CI: 28.5-29.5], 28 mo [27.0-28.9], 28 mo [27.3-28.7] and 31 mo [30.2-31.8] in whole, T1, T2 and T3 cohorts, respectively. In the multivariable model, adjusted for age and race, T3 patients showed better OS compared to T1 and T2 patients (HR: 0,92 [95% CI: 0,88-0,95] and 0,92 [0,89 to 0,95], respectively, p<0.001). A total of 33.641 patients were analysed for CSS, of these 6.514 T1, 12.540 T2 and 14.587 T3. Median CSS was 36 mo [35.3-36.7], 34 mo [32.6-35.3], 34 mo [33.0-35.0] and 38 mo [36.9-39.1] in whole, T1, T2, T3 cohorts, respectively. T3 patients had better CSS compared to T1 and T2 patients (HR: 0,93 [0,89-0,97] and 0,92 [0,89 to 0,96], respectively, p<0.001). No difference in OS or CSS was found between T1 and T2 cohorts. Conclusions: The prognosis of patients with de novo mPCa remains poor, with a median CSS of 3 years and a 5-year CSS of 35%. Approximately 8% decrease in the risk of death was found in the era of ARSi and cabazitaxel. The recent intensification of therapy in metastatic hormone-sensitive setting might lead to better outcomes in the next years.[Table: see text]
Type, timing, and risk factors associated with immune-related adverse event development in patients with advanced genitourinary cancers treated with immune checkpoint inhibitor.
Authors: Qin Qian , Patel Vaibhav G. , Mellgard George , Parikh Anish B. , Wang Bo , Alerasool Parissa , Garcia Philip , Jaladanki Suraj , Leiter Amanda , Carroll Emily , Brooks Danielle , Shimol Jennifer Ben , Eisenberg Elliot , Gallagher Emily J. , Galsky Matt D. , Oh William K. , Tsao Che-Kai
Published: February 2020

480

Background: Immune related adverse events (IRAEs) with immune checkpoint inhibitor (ICI) therapy are well recognized, but predictors for IRAEs are not well defined. We aim to characterize the type, timing, and clinical risk factors associated with (w/) IRAEs in ICI-treated, advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC) patients (pts). Methods: We retrospectively reviewed charts of pts w/ advanced UC and RCC who received at least 2 ICI doses at our institution from 1/1/10 to 10/31/18. Patient baseline characteristics, treatment course, and clinical outcomes were collected. IRAEs were identified and graded (GR) based on CTCAE (v.4.0). Fisher’s exact test was used to study the differences between pts w/ versus without IRAE. Results: Of the 71 pts identified (UC n = 53; RCC n = 18), 27 pts (38%) developed IRAEs with 42 total events (38% GR1, 60% GR2, and 2% GR≥3) [table]. The majority of pts with dermatitis (70%) also developed a secondary, systemic IRAE(s). Systemic steroid (SS) was required in 17 events. The median time to any IRAE was 17.5 weeks (w, range 1-93). ECOG ≤ 1 predicted IRAE development (p < 0.05). No other characteristics (demographics, co-morbidities, metastatic sites, ICI type, line of therapy, and duration of ICI > 12w) were associated with IRAE. Conclusions: In our study, good function status is associated with the development of IRAE. Time to IRAE ranged from immediately to 93w after initiating ICI. Clinical validation with additional datasets will be needed to confirm these findings. [Table: see text]
Conditional immune adverse event rate in urothelial and renal cell carcinoma patients treated with immune checkpoint inhibitors.
Authors: Nuzzo Pier Vitale , Pond Gregory Russell , Abou Alaiwi Sarah , Nassar Amin , Flippot Ronan , Curran Catherine , Kilbridge Kerry L. , Wei Xiao X. , McGregor Bradley Alexander , Harshman Lauren Christine , Choueiri Toni K. , Sonpavde Guru
Published: February 2020

481

Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). While the incidence and prevalence of irAEs have been well characterized in the literature, much less is known about the cumulative incidence (CI) rate of irAEs. We sought to evaluate the CI of irAEs in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC) patients (pts) treated with ICIs. Methods: We identified a cohort of mUC and mRCC pts who received ICIs at DFCI. irAEs were classified using CTCAE v.5.0 guidelines. The CI rate was a defined measure that accounted for elapsed time since treatment initiation and estimated the risk of irAE development conditioned on time elapsed without experiencing an irAE, accounting for the competing risk of death. Incidence and CI of irAEs at each monthly landmark time was calculated. Prognostic factors of irAE were assessed using the Fine and Gray method. Results: A total of 470 pts was treated with ICIs between July 2013 and October 2018 [mUC: 199 (42.3%); mRCC: 271 (57.7%)]. 341 (72.6%) pts received ICI monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received a combination of two ICIs. Overall, 186 pts (39.5%) experienced any irAE at any time point. Common irAEs included hypothyroidism (n=42 [22.6%]), skin (n=36 [19.4%]), colitis (n=35 [18.8%]), transaminitis (n=32 [17.2%]), and pneumonitis (n=14 [7.5%]). The risk of developing an irAE over time was as follows: 33.5% if no irAE within the 1st month(mo), 27.3% if no irAE in 3mo, 18.8% if no irAE in 6mo, and 16.4% if no irAE by 12mo. No difference was observed in CI based on type of cancer (mUC vs mRCC) or agent (PD1 vs. PD-L1). Multivariable analysis showed that ICI combined with ICI or other agents vs. ICI monotherapy (p<0.001), firstline therapy (p=0.013) and PD-1 vs. PD-L1 inhibitors (p=0.008) were statistically correlated with the development of irAEs. Conclusions: This study quantitates the incidence of developing irAEs with ICI conditioned on time elapsed without irAE development. Although the incidence of irAEs decreased over time on therapy, irAEs require continuous vigilant monitoring because of the long tail in its incidence.
Characterizing patterns of disease progression in patients with genitourinary cancers treated with immune checkpoint inhibitors.
Authors: Patel Vaibhav G. , Qin Qian , Mellgard George , Parikh Anish B. , Wang Bo , Alerasool Parissa , Garcia Philip , Jaladanki Suraj , Leiter Amanda , Carroll Emily , Brooks Danielle , Shimol Jennifer Ben , Eisenberg Elliot , Gallagher Emily J. , Galsky Matt D. , Oh William K. , Tsao Che-Kai
Published: February 2020

482

Background: Despite the widespread use of immune checkpoint inhibitors (ICIs), patterns of disease progression (POD) are poorly characterized. We aim to define these characteristics in patients (pts) with advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC) treated with ICIs. Methods: We retrospectively reviewed charts of pts with advanced UC and RCC who received at least 2 ICI doses at our institution from 12/1/10 – 10/31/18. Demographics, medical history, ICI course, toxicity, and outcomes were recorded. Characteristics at the time of radiographic POD including location of metastases (mets), symptoms (sx), and hospitalization details were collected. Fisher’s exact test was used to study differences in pts with and without hospitalization at POD. Results: Of the 71 pts identified (UC N=53; RCC N=18), 59 pts had POD. At POD, 19 (32.2%) pts had new sites of disease involvement, while the remaining pts (N=40, 67.8%) had progression only at previously known sites of disease. Fourty-six (78.0%) pts had sx at POD: 1 sx (N=19, 32.2%), 2 sx (N=13, 22.0%), 3+ sx (N=14, 23.7%). Pain was the most common sx at POD (N=32, 54.2%), followed by loss of energy (N=18, 30.5%), and loss of appetite (N=14, 23.7%). Twenty-five (42.4%) pts were hospitalized at POD, most commonly for sepsis (N=8, 32%). No clinical factors were identified to predict for pts being hospitalized at POD. Conclusions: In our review of GU cancer patients on ICIs, a large proportion of pts reported clinical sx at POD, pain being the most frequent. Furthermore, a substantial number of pts were hospitalized at POD, most commonly for sepsis. Thus, further studies are warranted to confirm these findings, and potentially identify strategies to optimize patients’ quality-of-life and reduce rates of hospitalizations at the time of POD on ICIs.
Outcomes of patients with high-risk non-muscle invasive bladder cancer (NMIBC) who undergo radical cystectomy after BCG and subsequent salvage intravesical therapy.
Authors: Packiam Vignesh T. , Labbate Craig V. , Boorjian Stephen A. , Tarrell Robert F. , Adamic Brittany , Mahmoud Mohammad , Tsivian Matvey , Avulova Svetlana , Cheville John , Karnes R. Jeffrey , Tollefson Matthew K. , Werntz Ryan P. , Steinberg Gary D. , Frank Igor
Published: February 2020

483

Background: We evaluate the impact of salvage intravesical therapy on survival in patients with NMIBC previously treated with BCG who ultimately underwent radical cystectomy (RC). Methods: We retrospectively identified patients with NMIBC who received at least 1 complete induction course of BCG and subsequently underwent RC for bladder cancer between 2000-2018. Patients were stratified by receipt of salvage intravesical therapy following BCG prior to RC. Oncologic outcomes were compared using Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: We identified 371 patients who underwent RC after receiving BCG, of whom 55 (15%) received salvage intravesical therapy, most commonly Mitomycin C (n = 26), Valrubicin (n = 8), Gemcitabine (n = 7), and CG0070 (n = 6). Median follow-up among survivors was 1.1 (IQR 0-4.3) years. Patients who received salvage intravesical therapy were more likely to initially present with CIS (27% vs 17%) and less likely to present with T1 disease (33% vs 50%, both p < 0.05). Receipt of salvage intravesical therapy was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (33% vs 41%, p = 0.27). Furthermore, on Kaplan-Meier analysis, receipt of salvage intravesical therapy was not associated with cancer-specific or overall survival. On multivariable Cox proportional hazards regression, clinical stage prior to RC, but not receipt of salvage intravesical therapy, was associated with inferior cancer-specific survival and overall survival. Conclusions: Our results suggest that RC following carefully managed salvage intravesical therapy after BCG is not associated with inferior oncologic outcomes, which can improve patient counseling. [Table: see text]
FORT-1: Phase II/III study of rogaratinib versus chemotherapy (CT) in patients (pts) with locally advanced or metastatic urothelial carcinoma (UC) selected based on FGFR1/3 mRNA expression.
Authors: Quinn David I. , Petrylak Daniel Peter , Bellmunt Joaquim , Necchi Andrea , Gurney Howard , Lee Jae-Lyun , Van Der Heijden Michiel Simon , Rosenbaum Eli , Penel Nicolas , Pang See-Tong , Li Jian-Ri , Garcia del Muro Xavier , Joly Florence , Papai Zsuzsanna , Ellinghaus Peter , Lu Chengxing , Nakajima Keiko , Ishida Tatiane , Nishiyama Hiroyuki , Sternberg Cora N.
Published: February 2020

489

Background: Aberrant activation of fibroblast growth receptor (FGFR) signaling plays a role in UC. Rogaratinib, a pan-FGFR1-4 inhibitor, has promising efficacy and safety in pts with advanced muscle-invasive UC, selected based on FGFR1-3 mRNA overexpression and/or FGFR3-activating mutations/translocations. This Phase II/III, randomized, open-label study evaluated the efficacy of rogaratinib vs CT in pts with FGFR-positive advanced or metastatic UC who received prior platinum CT. We present an ORR analysis for rogaratinib vs CT. Methods: FGFR1/3 mRNA was tested by in situ hybridization of archival tissue. Pts were randomized 1:1 to 800 mg rogaratinib p.o. BID continuously or CT Q3W (i.v., docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2), and stratified by PIK3CA/ RAS-activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. Results: 87 pts were assigned to rogaratinib and 88 to CT. Overall, 82.9% were male, median age was 69.0 yrs (range: 36-89), 96.6% had stage IV disease, and 2.3% were stage IIIB. PIK3CA/ RAS-activating mutations were present in 11.4% of pts. ORRs of 19.5% and 19.3% (1-sided p=0.56) and disease control rates of 49.4% and 55.7% (p=0.84) were observed for rogaratinib and CT, respectively; median progression-free survival was 2.7 months (95% CI 1.6, 4.2) and 2.9 months (95% CI 2.6, 4.2). Grade 3-4 treatment-emergent adverse events occurred in 40/86 pts (47%) treated with rogaratinib and 46/82 pts (56%) with CT, most commonly anemia (3% vs 15%), neutropenia (1% vs 17%), asthenia (9% vs 1%), lipase increase (8% vs 2%), fatigue (2% vs 6%), and urinary tract infection (2% vs 6%). Exploratory analysis of pts with FGFR3 DNA alterations (4 spot mutations and fusions) showed ORRs of 52.4% with rogaratinib and 26.7% with CT. Conclusions: In pts with FGFR1/3 tumor mRNA-positive UC, rogaratinib had efficacy comparable with standard CT and an acceptable safety profile. Subgroup analysis suggests rogaratinib may be more active in pts with an FGFR3 DNA alteration. Sensitivity analysis of biomarker subgroups is ongoing. Clinical trial information: NCT03410693.
Clinical criteria predicting an overall survival benefit to platinum rechallenge (PR) in metastatic urothelial cancer (mUC).
Authors: Mussat Elodie , Jouinot Anne , Saldana Carolina , Joly Charlotte , Allory Yves , Nourieh Maya , Vordos Dimitri , Salomon Laurent , de la TAILLE Alexandre , Tournigand Christophe , Rousseau Benoit
Published: February 2020

490

Background: In mUC, 2nd line treatments after platinum-based regimen have limited efficacy, such as vinca-alkaloid, taxan or immune checkpoint inhibitors. PR is proposed by ESMO guidelines if progression occurs >12 months after initial exposure with low level of evidence. Our objectives were to assess if PR was associated with better outcomes compared to other regimens and to identify parameters predicting its benefit in mUC. Methods: From a large monocentric cohort of mUC pts pretreated by 1st line platinum-based regimen, we retrospectively included pts who received a second line (PR, other cytotoxic drugs, immunotherapy). The primary end point was overall survival (OS). Survival analyses were performed using Cox models, weighted on a propension score to ensure groups comparability. Results: Among 155 consecutive pts firstly treated between 2006 and 2017, 55 pts were then treated by PR and 45 pts treated by other chemotherapy (n=37), immunotherapy (n=6) or targeted therapy (n=2). As PR is used in pts who benefited from platinum therapy, we restricted the analyses to pts who did not progressed during 1st line, resulting in 43 PR pts and 25 pts treated by other regimens. Univariate analyses identified main factors impairing OS at 2nd line initiation: time from prior chemotherapy <6 months, non-complete response to 1st line treatment and 2nd line treatment without platinum. These factors were subsequently used in a propension score to weigh survival analyses. PR was significantly associated with better OS than other regimens (HR=0.57, CI95% [0.37-0 .88], p=0.011). Median OS, median PFS and ORR were 16.5 vs 9.0 months (P=0.012), 5.8 vs 2.4 months (P=0.012) and 45 vs 15% (P=0.048) for PR and other regimens respectively. The most common grade 3 to 4 adverse events were hematologic toxicities: 54% for PR vs 22% for other treatments. ROC curve analysis of the best delay for PR since the end of 1st line was 5.7 months (sensitivity 60%, specificity 84%). Conclusions: PR is feasible and associated with significant OS improvement in second line treatment of mUC in pts that benefited initially from 1st line platinum and with Platinum-free interval >6 months. These results should be confirmed prospectively.
Interim results of PEANUT: pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).
Authors: Necchi Andrea , Raggi Daniele , Bandini Marco , Farè Elena , Giannatempo Patrizia , Colecchia Maurizio , Pederzoli Filippo , Gallina Andrea , Marandino Laura , Calareso Giuseppina , Madison Russell , Briganti Alberto , Ross Jeffrey S. , Montorsi Francesco
Published: February 2020

494

Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel (nPtx) demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigate their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts receive 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nPtx on D1 and D8, every 3 weeks, until disease progression (PD) or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response is evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers include PD-L1 expression with the combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 08/2019, PEANUT enrolled 46 pts evaluable for the study endpoint: 26% female, median age 66 y (range 43-78); 70% had failed 1 prior systemic therapy vs 30% 2 prior therapies; 24% had ECOG-performance status 1; 28% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up of 5 months, 18 pts have relapsed (39%). The projected median PFS was 7 months (95%CI: 4-not achieved). The confirmed objective response-rate (ORR) was 47.8% (95%CI: 32.9-63.1): 18 partial responses and 4 complete responses (8.7%). Grade 3 treatment-related adverse events (TRAE) were seen in 6 pts (13%). Most common any-grade TRAE included alopecia (91%), asthenia (21.7%), and neutropenia (15%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. 7/8 pts with PI3KCA mutations in matched tumor/blood samples had an objective response (87.5%). Conclusions: Preliminary results from PEANUT study demonstrated a promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. Updated data, including mature PFS, duration of response and biomarkers will be presented. Clinical trial information: NCT03464734.
The role of previous radical local treatment (RLT) on the outcome of immune checkpoint inhibitors (ICI) in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Morales-Barrera Rafael , Vidal Casinello Natalia , Domenech Montserrat , Bonfill Teresa , Puente Javier , Figols Mariona , Joaquin Julia Giner , Gonzalez Macarena , Lozano Fernando , Lopez Hector , Galante Isabel , Mast Richard , Serra Hernandez Ester , Semidey Maria Eugenia , Serrano Cesar , Gallardo Diaz Enrique , Suarez Rodriguez Cristina , Maldonado Xavier , Morote Juan , Carles Joan
Published: February 2020

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Background: There is a growing interest in local treatment for metastatic solid tumors. Recently, retrospective studies have reported the potential benefit of RLT to primary bladder cancer in pts with metastatic disease. We tested the impact of previous RLT in pts with mUC treated with ICI. Methods: Data from pts with mUC treated with ICI collected between May 2013 and May 2019 using a multi-institutional database was evaluated. Stratification was made according to previous RLT with ICI versus no RLT with ICI. We defined RLT as radical surgery (RS) or ≥50 Gy of radiotherapy (RT) delivered to the bladder. The X2 test was used to determine differences in rates. Overall survival (OS) between previous RLT plus ICI (group A) versus no RLT plus ICI (group B) generated using Kaplan-Meier method was compared by log-rank test. OS was calculated from the date of initiation of ICI to the date of death. Analyses were performed using SPSS v21. Results: A total of 115 pts with mUC were treated with ICI, 62 (53.9%) previously were treated with RS, 7(6.1%) RT and 46 (40%) no received RLT. ICI prescribed were atezolizumab (55.7%), pembrolizumab (16.5%), durvalumab (11.3%), durvalumab/tremelimumab (7.8%), nivolumab (5.2%) and avelumab (3.5%). The disease control rate (CR [6.9%] +PR [9.6%] +SD [14.1%]) was higher for pts with previous RLT compared to those pts who did not receive RLT (CR [3.2%] + PR [5.8%] + SD [6.4%](P=0.325). Median OS was 11.23 mo (95% CI; 6.02-16.44) and 7.95 mo (95%IC; 5.15-10.75) for group A and group B, respectively (P=0.481). Conclusions: This multicenter cohort suggests that previous RLT might play an impact for control disease in pts with mUC treated with ICI. Although this is hypothesis generating, the true value of this approach remains to be demonstrated in prospective studies.