bluuebunny/crossref_metadata_2025 huggingface dataset:
The oral α and β tubulin inhibitor, VERU-111, for the treatment of metastatic castration-resistant and androgen blocking agent-resistant prostate cancer in nonclinical toxicity studies.
Authors: Getzenberg Robert H. , Eisenberger Mario A. , Markowski Mark Christopher , Barnette Gary , Patrick Darryl , Steiner Mitchell S.
Published: March 2019

299

Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.
Prognostic significance of lactate dehydrogenase-5 expression in patients with prostate cancer treated with androgen deprivation therapy and androgen receptor axis-targeted agents.
Authors: Fukuokaya Wataru , Kimura Takahiro , Honda Mariko , Inaba Hiroyuki , Iwatani Kosuke , Keiichiro Mori , Sato Shun , Takahashi Hiroyuki , Egawa Shin
Published: March 2019

300

Background: Evidence suggests that hypoxic zones are prevalent in prostate cancer (PC). Recent clinical data showed that the expression of lactate dehydrogenase-5 (LDH5), a tumor hypoxia marker, affected the outcome of PC treated with radiation therapy. However, the impact of its expression on hormone therapy remains unclear. We investigated the predictive value of LDH5 expression in biopsy specimens from patients with PC treated with hormone therapy. Methods: Baseline data were available from 50 patients with PC treated with both androgen deprivation therapy (ADT) and novel androgen receptor axis-targeted agents (ARATs). LDH5 expression in the biopsy specimens was analyzed using immunohistochemical staining. Patients were stratified according to LDH5 expression in needle biopsy specimens. The relationships between LDH5 expression and baseline data at diagnosis, time to emergence of castration resistance, prostate-specific antigen (PSA) progression, and overall survival from induction of ADT and ARATs were examined. Results: Biopsy specimens from 19 patients highly expressed LDH5. High LDH5 expression was significantly associated with high Gleason scores (≥8) (p = 0.03), high clinical T stage (p = 0.008), and the likelihood of having at least one lymph node (p = 0.019) and metastatic lesion (p = 0.024). In a multivariate logistic regression model, LDH5 expression was significantly associated with high clinical T stage (p = 0.038), the presence of lymph node metastasis (p = 0.013), and high neutrophil-to-lymphocyte ratio (p = 0.016). Multivariate Cox regression analysis showed that high LDH5 expression was a significant predictor of time to emergence of castration resistance (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.12–5.36, p = 0.025) and overall survival (HR 9.3, 95% CI 2.17–39.8, p = 0.003). No significant association was observed between LDH5 expression and time to PSA progression from the induction of ARATs in univariate Cox regression analysis (p = 0.28). Conclusions: The results of this study suggest that LDH5 expression is a predictor of treatment outcomes in patients with PC treated with ADT.
Prostate cancer (PCa) incidence and severity in 821 hypogonadal men with and without testosterone therapy (TTh) in a controlled, observational registry implying more than 7,000 patient-years.
Authors: Haider Ahmad , Haider Karim Sultan
Published: March 2019

304

Background: Guidelines by AUA and EAU state that there is no evidence for an increased PCa risk for testosterone (T) treatment in hypogonadal men. Methods: In a registry study initiated in 2004 in a urology practice, 428 hypogonadal men (T≤350 ng/dL) received T undecanoate 1000 mg every 3 months following an initial 6-month interval for up to 13 years (T-group). 393 hypogonadal men (age range 51-74) opted against TTh (CTRL). Suspicion of or active PCa was excluded by transrectal ultrasound, digital rectal examination and PSA before treatment/observation initiation. Examinations were repeated between one and four times per year. Biopsies were performed when indicated according to EAU Guidelines. Results: In the T-group, 12 (2.8%) , in CTRL, 42 men (10.9%) were diagnosed with PCa. The mean baseline age of PCa patients was 64.9 years in the T-group and 64 in CTRL.In the T-group, the average time span between day of first injection and positive biopsy was 14.2 months (range: 5-18). No patient was diagnosed with PCa beyond 18 months of TTh. In CTRL, PCa was diagnosed at any time during the observation time. In the T-group, radical prostatectomy (RP) was performed in all men. All but 3 patients had Gleason score (GS) ≤6, and all but 1 had a primary GS of 3. Tumor grade was G2 in all 12 (100%), tumor stage T2a in 7 (58%), T2b in 3 (25%), and T2c in 2 (17%) patients. All but 2 patients are back on TTh after an average time of 25 months. In CTRL, RP was performed in all but 6 patients who received radiation therapy (RT). GS was ≤6 in 2 patients, 7 men had a GS of 7, 21 a GS of 8, and 12 a GS of 9. 4 men had a primary Gleason score of 3, 29 had 4, and 9 had 5. Tumor grade was G2 in 9 (21%) and G3 in 33 (79%) patients, tumor stage T2a in 2 (5%), T2c in 1 (2%), T3b in 15 (36%) and T3c in 24 (57%) patients. In CTRL, biochemical recurrence occurred in 11 (26%) patients. These patients received androgen deprivation therapy (ADT). 12 (34%) patients died of whom 7 were on ADT. In the T-group, no biochemical recurrences or deaths occurred during the observation time. Conclusions: Less PCa occurred and severity was lower in testosterone-treated hypogonadal patients compared to untreated hypogonadal controls.
The value of AKR1C3 in predicting the therapeutic efficacy of abiraterone for patients with metastatic castration-resistant prostate cancer.
Authors: Zhao Jinge
Published: March 2019

313

Background: AKR1C3 is a multifunctional enzyme playing a significant role in androgen synthesis and metabolism. Previous studies have proved that the activation of AKR1C3 was associated with resistance to abiraterone through increasing the intracrine androgen synthesis. However, clinical validation is still lacking as to the prognostic value of AKR1C3 in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone. Methods: Data of 117 patients with mCRPC between 2016-2018 in our center were retrospectively analyzed. AKR1C3 was detected by the immunohistochemical staining from the 12-core prostate biopsy. Kaplan-Meier curves and COX regression were used to analyze the association between AKR1C3 and the treatment outcomes of abiraterone. The endpoints of this study were PSA progression-free survival (PSA-PFS) and radiograph progression-free survival (rPFS). Results: In total, AKR1V3 was detected in 40/117 (34.2%) cases. The positive AKR1C3 was significantly associated with shorter PSA-PFS for mCRPC patients treated with abiraterone (median PSA-PFS: 6.2 Mo vs. 11.1 Mo, p < 0.001). Those with positive AKR1C3 were also accompanied with obviously poorer rPFS compared to those with negative AKR1C3 staining, despite that the difference was not statistically significant (median rPFS: 11.1 Mo vs. 21.8 Mo, p = 0.250). Multivariate COX regression indicated that, AKR1C3 was an independent prognosticator of rapid PSA progression for the abiraterone treatment (HR,95%CI: 2.612, 1.54-4.44, p < 0.001). Conclusions: This is the first study verifying the adverse prognostic significance of AKR1C3 for mCRPC patients receiving abiraterone treatment. Our results suggested that, AKR1C3 was closely related to early treatment failure of abiraterone, and thus, was worthwhile to be routinely described in pathological report.
Clinical significance of AR amplification from CF DNA among Japanese castration-resistant prostate cancer patients.
Authors: Sakamoto Shinichi , Ando Keisuke , Takeshita Nobushige , Yamamoto Satoshi , Komiya Akira , Nishio Kazuto , Ichikawa Tomohiko , Imamura Yusuke
Published: March 2019

314

Background: We study the prognostic ability of androgen receptor amplification (AR amp) from cf DNA in Japanese castration-resistant prostate cancer (CRPC) patients. Methods: Multiple sets of serums were obtained from 38 castration-resistant prostate cancer patient at Chiba University hospital. Serum cfDNA was purified using a cobas cfDNA Sample Preparation Kit. AR copy number was measured using the QX100 Droplet Digital PCR System. Factors associated with progression-free survival (PFS) and Overall Survival (OS) were statistically studied. Results: The number of patients received Enzalutamide (Enza)/Abiraterone (Abi)/Docetaxel (Doc) were 33/25/11. Regarding PFS, the presence of AR amplification, Bone Scan Index (BSI), PSA was significant factors on univariate analysis. On multivariate analysis, AR amplification was an independent prognostic factor (HR. 8.9, p=0.003). Regarding OS, PSA and AR amp was significant factors. On multivariate analysis, AR amp (HR 4.2, p=0.028) was an independent prognostic factor. AR amp was related to the young age, high bone metastasis, high PSA, while no association was identified related the visceral metastasis. Overall, the presence of AR amp was negatively related to the initial ADT periods (r=-0.28). In contrary, among primary resistance cases (initial treatment periods <1 year), AR amp positively related to the treatment periods (r=0.31). Higher nadir testosterone (>15 ng/dL) was related to the higher AR amp (p=0.0169). AR amp was related to the treatment resistance in Enza (p=0.0216), while no relation was observed in Abi or Doc. Conclusions: AR amp significantly correlated with the poor prognosis. Higher serum testosterone level may predict the presence of AR amp in cf DNA. [Table: see text]
Continuous infusion 5-fluorouracil (5FU) as a novel treatment for heavily pretreated prostate cancer patients: An update.
Authors: Manogue Charlotte , Cotogno Patrick , Moses Marcus Marie , Barata Pedro C. , Layton Jodi Lyn , Sartor A. Oliver , Lewis Brian E.
Published: March 2019

319

Background: Currently patients failing multiple conventional therapies enroll on clinical trials but in many cases, despite a good performance status, patients may not qualify for trial enrollment. CRPC tumor cells typically express prostate specific membrane antigen (PSMA), a folate hydrolase which increases cell folate uptake (Yao et al. Prostate 70:305, 2010). We hypothesize that 5FU, functioning as an anti-folate, antagonizes the downstream effects of PSMA over-expression. Herein we present an update to our 5FU experience in heavily pretreated mCRPC. Methods: Data was retrospectively collected at Tulane Cancer Center for patient treatment history, disease history, performance status and laboratory parameters. All patients were treated with continuous infusion of 5-fluorouracil at a dose of 200mg/m2-day. Results: 24 patients at Tulane Cancer Center were treated with 5FU between Oct/2013 and Oct/2018. The median age was 72, patients had an median of 6 lines of prior therapy, and 37.5% had liver metastatic disease. The 30% and 50% PSA response rates were 41.6% and 29% respectively. Of the PSA responders, 100% had some level of PSA decline after 7 days of therapy with a median time to best PSA response of 2.6 months (95% CI 0.2-5.1). Median time on treatment was 11 weeks for the entire cohort and 18.5 weeks for patients with a ≥30% PSA decline; 20.8% of patients remained progression free by PSA at 4 months. Improvement in performance status as well as transfusion independence were noted in a subset of patients with myelophthistic anemia due to prostate cancer. No grade > 3 AEs were attributable to 5FU. Conclusions: 5FU is a relatively inexpensive and well tolerated therapy that shows benefit in some heavily pretreated patients. Additionally, the ability to quickly assess the potential for response, and lack of > grade 3 adverse events makes it a reasonable option for this population.
Incorporating mpMRI Biopsy data into established pre-RP nomograms: Potential impact of an increasingly common clinical scenario.
Authors: Leong Joon Yau , Chandrasekar Thenappan , Tham Elwin , Teplitsky Seth , Lallas Costas D. , Gomella Leonard G. , Trabulsi Edouard John
Published: March 2019

32

Background: Current pre-radical prostatectomy (RP) nomograms predicting lymph node involvement (LNI) are based on systematic 12-core prostate biopsies (PBx). With the introduction of mpMRI, cognitive or fusion biopsies have become prevalent, often in the absence of systematic cores. We examine the practical application of MR biopsy data using established pre-RP nomograms and the potential implications on RP intra-operative decision making. Methods: Utilizing a prospectively maintained single institution database, all patients who underwent MRI-based PBx prior to RP were identified. Each patient was assessed using the MSKCC Kattan nomogram and the Briganti nomogram using the following iterations: 1) Targeted [T] (targeted cores alone), 2) Targeted & Systematic [TS] and 3) Targeted Augmented [TA]. The TA iteration utilized targeted core data alone and assumed negative remaining systematic cores for a total 12 core. Nomogram outcomes, specifically risk of LNI, was compared across iterations. Clinically significant impact was defined as a change in risk above or below 2% (Δ2) or 5% (Δ5), based on current guidelines recommendations for lymph node dissection. Results: 69 men met inclusion criteria (6 targeted, 63 systematic + targeted PBx). In the 6 men with targeted only biopsies, using the Kattan and Briganti nomograms, Δ2 occurred in 1 patient (16.7%) and Δ5 in 1-2 patients (16.7-33.3%); in all, TA iteration LNI was lower than the T iteration. In the 58 patients with positive targeted biopsy cores, Δ2 and Δ5 were 8.62-32.76% and 25.86-37.93%, respectively. In the subset of 52 patients with both targeted and systematic biopsies, using their TS nomogram as an internal validation, the TA iteration was a better approximation of their TS outcomes than their T iteration in 48% (Kattan) and 67% (Briganti) of patients. Conclusions: mpMRI-based PBx results, and in particular those from targeted biopsy cores alone, yield significantly different results using established pre-RP nomograms. Therefore, future nomograms must better incorporate MRI biopsy data and provide guidelines on how to account for targeted cores. In the interim, augmenting targeted biopsy data may bridge the gap.
Genomic changes of AR in ctDNA prior to enzalutamide in men with mCRPC after abiraterone acetate.
Authors: Ko Leta , Lilly Michael B. , Hahn Andrew W , Nussenzveig Roberto , Moses Marcus Marie , Ledet Elisa , Manogue Charlotte , Cotogno Patrick , Lewis Brian E. , Layton Jodi Lyn , Agarwal Neeraj , Sartor A. Oliver , Barata Pedro C.
Published: March 2019

320

Background: Approximately 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC) seem to respond to enzalutamide (ENZA) after prior exposure to abiraterone acetate and steroids (AA). The impact of genomic changes in androgen receptor (AR) gene in ctDNA and subsequent response to ENZA after prior AA exposure, is not entirely known. Methods: We performed a retrospective analysis of 28 mCRPC who were treated with ENZA after prior exposure to AA. Patients had NGS testing of ctDNA (Guardant 360) done post-AA and prior to ENZA. AR changes were defined by either amplification (amp; copy number ≥1) and/or mutations (mut; allele fraction ≥0.3%) in the AR gene. The primary endpoint of this study was time to PSA progression on enzalutamide. Correlations between genomic data and clinical outcomes were evaluated. Results: The 28 mCRPC patients had a median age of 67 (47-86), and 66.7% had a Gleason score 8-10. Metastases were found in bone (93%), lymph nodes (35.7%) and viscera (35%). Patients received ENZA after a median of 1 (1-5) treatment for CRPC. Patients were treated with prior AA for a median of 11.0 months (1.2-51.9) and median initial PSA at time of ENZA initiation was 35 ng/mL (1.52-356). The median time from ctDNA testing to ENZA start date was 0.9 months (range 0-5.6). Somatic changes in AR genes were detected in 36% (5/10 AR amp, 4/10 AR mut, 1/10 both). Other common alterations included 39% TP53, 11% DNA repair genes (2/3 BRCA2, 1/3 ATM), 7% PTEN. With a median follow-up of 8.9 months, 32% achieved PSA response (≥50%) and median time to PSA progression was 1.6 months (95% CI 1.0-2.2). On univariate analysis, lower Gleason scores (p = 0.021) and lack of AR changes (p = 0.042) were associated with PSA response to ENZA. Conclusions: In this cohort, responses to ENZA were associated with the absence of AR changes in ctDNA and less aggressive phenotypes. Prospective validation of this genomic association is required.
Clinical outcomes of a Dutch prospective observational registry of metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223 (Ra-223).
Authors: Louhanepessy Rebecca , Badrising Sushil , van der Noort Vincent , Coenen Jules L. L. M. , Hamberg Paul , Beeker Aart , Wagenaar Nils , Lam Marnix G.E.H. , Celik Filiz , Loosveld Olaf , Oostdijk Ad , Zuetenhorst Johanna Maria , Vegt Erik , Zwart Wilbert , Bergman Andre M.
Published: March 2019

323

Background: In 2012 the ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit of mCRPC patients treated with Ra-223 over placebo. To date clinical outcomes of Ra-223 treatment in a non-study population have not been prospectively evaluated. Methods: The ROTOR registry aimed to include 300 patients in 20 Dutch hospitals prior to Ra-223 treatment at the physician’s discretion. Clinical parameters collected included: positioning of Ra-223, Adverse Events (AE’s; CTCAE v4.03), Skeletal Related Events (SRE) and survival data. SRE was defined as radiotherapy to a bone metastasis, a new pathological fracture, spinal cord compression and/or bone surgery. Progression-Free Survival (PFS) was defined as survival until radiological or clinical progression, subsequent treatment or death. Results: Between April 2014 and September 2017, 305 patients were included of whom 300 were evaluable. The mean age of patients was 72.6 (range 46.3-91.5) years, 255 (85%) had ≥ 6 bone metastases and 197 (65.5%) were pretreated with taxanes and/or abiraterone or enzalutamide (214 (71.3%)). Two-hundred and ninety (96.7%) patients were treated with Ra-223. Twenty-nine (9.7%), 104 (34.7%), 96 (32%) and 66 (22%) patients received Ra-223 as a first, second, third, ≥ fourth mCRPC treatment line, respectively. Patients received an average of 4.6 (SD 1.8) cycles of Ra-223, while 140 (46.7%) completed all six cycles. After a median follow-up of 13.2 months, PFS was 5.1 (CI 4.5-5.8) months and OS 15.2 (CI 12.8-17.6) months. Eighty-two (27.3%) patients were hospitalized during Ra-223 treatment (Serious AE). Grade ≥ 3 anemia, neutropenia and thrombocytopenia was found in 54 (18.0%), 8 (2.7%) and 11 (3.7%) patients, respectively. Other frequent AE’s (all grades) were nausea (90 (30%)), diarrhea (83 (27.7%)) and fatigue (178 (59.3%)). SREs were observed in 46 (15.3%) patients; 22 (7.3%) received radiotherapy, 6 (2%) developed pathologic fractures, 17 (5.6%) spinal cord compression and 1 (0.3%) received bone surgery during Ra-223 therapy. Conclusions: The non-study ROTOR population had characteristics, all grade AEs and OS comparable with the treatment arm of ALSYMPCA. Clinical trial information: NCT03223597.
Retrospective review of 11C-choline detected thoracic lesions in prostate cancer.
Authors: Rehman Muneeb , Mansfield Aaron Scott
Published: March 2019

325

Background: Prostate cancer recurrence is detected by serum measurements of prostate specific antigen (PSA). Upon PSA elevation, locating sites of recurrence is important to guiding treatment and affecting patient outcomes. The imaging modalities in current practice have varying sensitivities and specificities and often miss early recurrent disease. 11C-choline positron emission tomography (11C-PET) may be able to detect occult disease and guide treatment decisions earlier in the clinical course. We assessed a case series of patients who underwent 11C-PET imaging and were identified to have thoracic disease to estimate the benefit of detection with this modality. Methods: Clinical records were retrospectively reviewed of seventy patients from thoracic oncology teams at Mayo Clinic in Rochester, Minnesota. Patients who had thoracic +/- extra-thoracic metastases on 11C-PET imaging were followed, noting changes in treatment and PSA trends to look for biochemical recurrence of disease. Results: Seventy patients with thoracic metastases discovered on 11C-PET imaging were initially identified. Median time to choline-avid disease from original diagnosis was 82 (IQR: 40-129) months with a median PSA at time of choline of 7.4 (IQR: 3.1-15.7). 11C-PET findings showed 28 patients with metastases limited to the thorax and 42 patients with thoracic and extra-thoracic metastases. After 11C-PET imaging, 1 patient underwent localized therapy only (radiation and surgery), 44 patients underwent systemic therapy only (chemotherapy or hormonal therapy), 19 patients underwent both localized (cryotherapy, radiation, or surgery) and systemic therapy, 3 patients underwent no further treatment, and 3 patients were lost to follow up. After a median follow-up of 36.5 (IQR: 13-52) months, 30 patients had no recurrence and 20 had evidence of biochemical recurrence. For those who underwent local therapy (N=21), 11 had no recurrence of disease. Conclusions: Choline-based imaging may earlier identify metastatic disease that is amenable to local therapy. Further studies are needed to validate the effectiveness of 11C-PET in identifying early, responsive metastatic prostate cancer and its utility in affecting patient outcomes.
Multi-institutional analysis of synchronous prostate and rectosigmoid cancers.
Authors: Jacobs Corbin , Trotter Jacob , Palta Manisha , Wu Yuan , Willett Christopher , Lee W. Robert , Czito Brian G.
Published: March 2019

33

Background: Synchronous prostate cancer (PC) and rectosigmoid (RS) cancer (RSC) is a challenging clinical situation. Methods: A retrospective review of Duke University and Durham VA charts was performed for men with adenocarcinomas of the prostate and RS colon from 1988-2017. Synchronous presentation was defined as symptoms, diagnosis (dx), or treatment (tx) of PC/RSC within 12 months. The primary endpoint was overall survival (OS), calculated from latest dx date. Univariate and multivariate (MVA) Cox regression was performed using STATA 15.1. Results: Among 31,883 men with PC identified, 330 (1%) also had RSC. 54 (16%) were considered synchronous (median age 67, IQR 62-72). PC was more commonly the first dx (59%), and 15 (28%) underwent prostatectomy (n=13) or radiotherapy (RT, n=2) before a dx of synchronous RSC. 26%, 57%, and 17% had stage I, II-III, and IV RSC, respectively. Prostatectomy, LAR, APR, and combined surgery for both PC/RSC was performed in 17 (31%), 24 (44%), 10 (19%), and 2 (4%) men, respectively. 35 (65%) received RT with median RS dose of 50.4 Gy (IQR 50.4-54 Gy) and prostate boost to 66 Gy (IQR 61-72 Gy). 34 (63%) received 5-FU based chemotherapy, 23 (43%) received ADT, and 9 (17%) received no PC-specific tx. After a median follow up of 43 (IQR 21-93) months, there were 34 deaths: 18 (53%) due to RSC, 2 (6%) due to PC, 3 (9%) due to grade 5 toxicity, 7 (21%) due to another malignancy, and 4 (12%) due to unknown cause without recurrence. Grade 5 toxicities resulted from sequential hepatectomy/LAR, combined prostatectomy/APR, and myocardial infarction while on ADT. Crude late grade ≥3 toxicities include 9 (17%) GI and 6 (11%) GU. Two anastomotic leaks <2.3 years after LAR occurred in men who received neoadjuvant prostate RT boost of 70.6-76.4 Gy. Stages II-III (HR 4.3, p=0.02) and IV (HR 16, p<0.01) for RSC but only stage IV (HR 31, p<0.01) for PC were significantly associated with OS on MVA. Among 30 men with stage II-III RSC and non-metastatic PC, 5-FU based chemotherapy (HR 0.34, p=0.04) but no PC-specific tx was significantly associated with OS on MVA. Conclusions: Synchronous RSC is a greater contributor to mortality than PC. Men aged ≥50 with localized PC should undergo colorectal cancer screening prior to tx to evaluate for synchronous RSC.
Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Hwang Wei-Ting , Smith Andrew , Abdalla Ahmed , William Hany , Baumann Brian Christopher
Published: March 2019

351

Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before & after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) & late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT & 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) & 15 months for PORT (range 5-70). There were 2 local failures for PORT & none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) & 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) & 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) & 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS & OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local & distant disease. Clinical trial information: 01734798.
Evaluation of submicron particle docetaxel directly injected into uro-oncologic xenografts.
Authors: Dizerega Gere , Maulhardt Holly , Peterson Lauren M , Frost Michael , Tornio Ashley , Dafoe Sara , Drummond Leanne
Published: March 2019

360

Background: We evaluated intratumoral (IT) injection of submicron particles of pure docetaxel (NanoDoce) into clear cell renal carcinoma (768-O [R]), transitional cell bladder carcinoma (UM-UC-3 [B]) and prostate carcinoma (PC-3 [P]) xenografts implanted into immunocompromised rats and mice. Methods: Animals received IT NanoDoce and IV docetaxel per Table. Treatments were 7 days apart. Animals were followed up to 60 days post-treatment initiation. Tumor size, clinical signs and body weight were assessed 2-3 times per week. In the 786-O and UM-UC-3 studies, tumor site tissues were analyzed for docetaxel levels and H&E and IHC (CD11b, CD45r) was evaluated. Results: Tumor volume decreases with 2 and 3 doses of NanoDoce were significantly greater than (R, B) or similar (P) to IV docetaxel and better than vehicle (p < 0.05). High tissue levels of docetaxel were detected in all NanoDoce-treated animals with evaluable tumor tissue. In these animals, histology confirmed tumor volume findings; IHC showed (peri)tumor-infiltrating immune cells in all NanoDoce-treated animals. Comparators exhibited limited to no infiltration. NanoDoce-treated UM-UC-3 tumor injection sites were typically cleared of tumor and contained lymphoid structures. No lymphoid structures were seen in comparators and all had residual tumor. Conclusions: Local presence of persistent, therapeutic levels of docetaxel from IT NanoDoce creates a unique disruption of the tumor microenvironment. IT injection of NanoDoce may kill tumor cells through direct and indirect means. NanoDoce directly inhibits tumor cell mitosis, and in reducing tumor burden, indirectly promotes immune cell-mediated tumor clearance. Clinical testing of NanoDoce in urogenital tumors is underway. [Table: see text]
Economic burden of select adverse events (AEs) in patients (Pts) with advanced urothelial cancer (aUC) treated with first-line (1L) systemic therapy.
Authors: Grivas Petros , Laliberté François , Doleh Yunes , O'Connor Cristi , Duh Mei Sheng , Shenolikar Rahul
Published: March 2019

363

Background: Limited information on costs related to incident AEs in pts with aUC in the real-world setting is available. Methods: Pts with aUC treated with 1L systemic therapy (94% chemotherapy, 6% immune checkpoint inhibitor) between 1/2012-9/2017 (first therapy administration defined the index date) were identified using IQVIA Real-World Data Adjudicated Claims – US database. Pts with continuous enrollment for ≥6 months pre- and ≥3 months post-index and ≥1 UC diagnosis code were included. Proportions of pts with febrile neutropenia (FN), dehydration, acute kidney injury (AKI), sepsis, colitis, hepatitis, adrenal insufficiency, and pneumonitis (select AEs), and per-pt-per month (PPPM) healthcare costs were assessed. Incident AEs during 1L therapy were identified using outpatient/inpatient claims and a subgroup of severe AEs (identified using only inpatient claims) was analyzed separately. Incremental costs of AEs were calculated as cost differences (CDs) between pts with and without AEs using multivariate linear regression to adjust for baseline differences. Results: Pts with (n = 666) and without (n = 569) select AEs had similar median age of 62 years; pts with select AE had more women (34.4% vs. 29.0%) and chemotherapy-treated pts than pts without select AEs (96.1% vs. 91.0%) (both p < 0.05). Baseline characteristics were similar in pts with (n = 290) and without (n = 1,290) severe AEs. FN (28.0%; severe 6.3%), dehydration (26.5%; severe 8.3%), AKI (11.3%; severe 8.8%), and sepsis (8.8%; severe 8.0%) occurred most frequently during 1L therapy (median duration: 15 weeks). Adjusted PPPM CDs between pts with and without AEs were $1,716 overall and $6,130 for severe AEs, with the greatest CDs observed for pneumonitis ($14,400; severe $20,242), sepsis ($8,581; severe $9,490) and AKI ($7,977; severe $8,843) (all p < 0.05). Inpatient costs had the largest impact on CDs. Conclusions: Costs of AEs, especially severe, during 1L treatment of aUC can cause substantial burden to healthcare system. Biomarker-based therapy selection, education/awareness early recognition and management of AEs may reduce hospitalizations and healthcare costs, and may impact care quality.
Bladder-preserving therapy using a real-time tumor-tracking radiotherapy system for muscle-invasive bladder cancer.
Authors: Miyata Haruka , Osawa Takahiro , Frumido Jun , Kikuchi Hiroshi , Matsumoto Ryuji , Abe Takashige , Maruyama Satoru , Nishioka Kentaro , Shimizu Shinichi , Hashimoto Takayuki , Shirato Hiroki , Shinohara Nobuo
Published: March 2019

364

Background: Bladder-preserving therapy with a real-time tumor-tracking radiotherapy system (RTRT system) has been used for muscle-invasive bladder cancer (MIBC) since 1998 in our institution. We evaluate long term outcomes of this therapy. Methods: From 1998 to 2016, 38 patients with a T2-T4N0M0 bladder cancer who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection (TUR) and 40 Gy irradiation to the whole bladder was followed by TUR of the tumor bed (1st Evaluation) and endoscopic implantation of fiducial markers in the bladder wall around the primary tumor. Then, a boost of 25 Gy was made to the primary tumor using RTRT system. Protocol TUR of the tumor bed was performed 6 months later (2nd Evaluation). Patients with adequate renal function (CCR>45ml/min) received concurrent chemoradiotherapy with nedaplatin (cisplatin analog made in Japan, 70mg/m2 intravenously, day1, day22, day50). Results: Median follow-up for surviving patients was 6 yr. 5- and 10-yr OS were 55%, 40%, and 5- and 10-yr PFS were 55% and 39%, respectively. The CR rate at 1st evaluation was 66%, in those patients 5- and 10-yr OS rates were 70% and 61%. Among the patients with non-CR at 1st evaluation, CR rate at 2nd evaluation was 31%. Local recurrence occurred in 13 patients. One of them was performed cystectomy and 9 were performed TUR and/or bladder injection therapy. 11 patients experienced distant recurrence, 2 of those was performed chemotherapy. In univariate analysis, male (OS; HR: 0.33, 95% CI: 0.12-0.92, PFS; HR:0.25, 95% CI: 0.09-0.69) and PS0-1 (OS; HR: 0.26, 95% CI: 0.09-0.79, PFS; HR: 0.29, 95% CI: 0.10-0.85) were significantly associated with good OS and PFS (shown in Table). In multivariate analysis, the both of these covariates were also significantly associated with good OS and PFS (male; OS; HR: 0.31, 95% CI: 0.11-0.88, PFS; HR: 0.21, 95% CI: 0.07-0.62, PS0-1; OS; HR: 0.25, 95% CI: 0.08-0.76, PFS; HR: 0.24, 95%CI: 0.09-0.75). Conclusions: Bladder-preserving therapy is a considerable option in patients medically unfit for or not desiring cystectomy.
Interim analysis of ibrutinib plus paclitaxel for patients with metastatic urothelial carcinoma previously treated with platinum-based chemotherapy.
Authors: Castellano Daniel E. , Morales-Barrera Rafael , Duran Ignacio , Keam Bhumsuk , Chung Ik Joo , Arkenau Tobias , Vaishampayan Ulka N. , Tuthill Mark , Gajate Pablo , Shin Sang Joon , Dang S. Paul , Ju Chia-Hsin , Lin Jennifer , Cole George , James Danelle Frances , Reig Torras Oscar
Published: March 2019

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Background: In patients (pts) with advanced urothelial carcinoma (aUC) who progressed after platinum-based chemotherapy (CT), median overall survival (OS) is ~6 mo with CT and 8-10 mo with novel immune checkpoint inhibitors (ICIs). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton’s tyrosine kinase (BTK) with immunomodulatory properties, plus paclitaxel (pac) may be an effective treatment (tx) for pts with UC. Methods: One cohort in this phase 1b/2 study assessed ibr + pac in pts who had 1-2 prior tx (≥1 platinum-based and/or ICIs) with aUC. Recommended phase 2 dose per Phase 1b was ibr 840 mg/d + weekly pac 80 mg/m2 in 21-d cycles; starting ibr dose: 560 mg/d. Preliminary BTK/other kinase assessment in baseline tumor biopsies was done by NanoString gene expression assay. Results: Based on interim analysis of the first 29 pts treated (ibr 840/560 mg/d, n = 25/4), median time on study/ tx was 7.2/2.3 mo (max tx: 11.5 mo). Median age was 67 y; 52% had 2 prior regimens (prior PDL-1 inhibitors, 100%). Unconfirmed ORR was 41% (complete/partial response: 10%/31%) and disease control rate was 62%. ORR was 71% for subset of 7 pts with only lymph node metastases, and 36% for 14 pts with 1 prior tx and 47% for 15 with 2 prior tx. Median duration of response was 4.2 mo (90% CI: 1.9, 7.1). Median PFS was 3.6 mo (90% CI: 1.6, 5.4) and median OS was 14.7 mo (90% CI: 7.7, 15.9). Follow-up for durability/survival is ongoing with 6 pts alive without progression, with 4 still on ibr tx. 76% of pts had grade ≥3 adverse events (AEs); 4 discontinued ibr + pac due to AEs and 1 had major hemorrhage. Pac exposure was not impacted by ibr; pac geometric mean Cmax (2066 ng/mL) and AUC0-∞ (3813 ng.h/mL) were consistent with historical data. Preliminary tumor biopsy data showed a non-significant trend of higher BTK/ITK/BMX expression in responders; analyses are ongoing for ibr-targeted kinases. Conclusions: These results indicate that ibr + pac shows promising results for ORR and OS in pts with aUC previously treated with platinum-based CT and ICIs. There were no unexpected safety signals; ibr + pac seemed tolerable. Follow up of these and additional pts will support the efficacy and safety of ibr + pac in this study. Clinical trial information: NCT02599324.
Comparing costs of radical cystectomy versus trimodal therapy for patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Ray-Zack Mohamed Danny , Shan Yong , Kerr Preston , Kosarek Christopher David , Hudgins Hogan K , Jazzar Usama , Tyler Douglas S. , Freedland Stephen J. , Swanson Todd A. , Baillargeon Jacques G. , Hu Jim C. , Kaul Sapna , Kamat Ashish M. , Gore John L. , Mehta Hemalkumar B , Williams Stephen Bentley
Published: March 2019

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Background: Studies on the cost of muscle-invasive bladder cancer treatments lack granularity and are limited to 180 days. This study aimed to compare the one-year costs of trimodal therapy versus radical cystectomy, accounting for survival and intensity effects on total costs. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we included a total of 2,963 patients aged ≥66 years diagnosed with clinical stage T2-4a bladder cancer between 2002 and 2011. We compared total Medicare costs within one year of diagnosis among patients following radical cystectomy or trimodal therapy using inverse probability of treatment weighted (IPTW) propensity score models, which included a two-part estimator to account for intrinsic selection bias. Results: Median total costs were significantly higher for trimodal therapy than radical cystectomy in 90 days ($83,754 vs. $68,692; median difference $11,805, 95% CI $7,745 to $15,864), 180 days ($187,162 vs. $109,078; median difference $62,370, 95% CI $55,581 to $69,160), and 365 days ($289,142 vs. $148,757; median difference $109,027, 95% CI $98,692 to $119,363), respectively. Outpatient, radiology, pharmacy and pathology/laboratory costs contributed largely to the significantly higher costs associated with trimodal therapy. On IPTW-adjusted analyses, patients undergoing trimodal therapy had $142,337 (95% CI $117,423-$175,300) higher costs compared with radical cystectomy one year after treatment (Table). Conclusions: Compared to radical cystectomy, trimodal therapy was associated with higher costs among patients with muscle-invasive bladder cancer. Extrapolating cost figures to the total US population resulted in excess spending of $853 million for trimodal therapy compared with radical cystectomy for patients diagnosed in 2018. [Table: see text]
Prognostic significance of history of nonmuscle invasive bladder cancer in patients with muscle invasive bladder cancer treated with neoadjuvant chemotherapy followed by surgery.
Authors: Lee Yongjune , Kim Young Seok , Hong Bumsik , Cho Yong Mee , Lee Jae-Lyun
Published: March 2019

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Background: Efficacy of cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) for T2-4aN1M0 muscle-invasive bladder cancer (MIBC) was proved by randomize controlled trials. Recent retrospective studies suggested that MIBC patients who had a history of non-muscle invasive bladder cancer (NMIBC) had lower pathologic complete response and worse overall survival rate to NAC and RC. This study aimed to compare clinical outcomes between MIBC that progressed from NMIBC (secondary MIBC) and primary MIBC. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received neoadjuvant chemotherapy from January 2011 and December 2017 in Asan Medical Center was conducted. Clinicopathologic outcomes were compared between 187 patients with primary MIBC and 38 patients with secondary MIBC. Results: Baseline characteristics are well balanced between the groups. Downstaging rate ( < ypT2 and no N upstaging) are 46.7% for secondary MIBC group, 55.6% for primary MIBC group (p = 0.390), and positive pathologic metastatic nodes (ypN1+) are observed in 23.3% for secondary MIBC group, 18.3% for primary MIBC group (p = 0.523). There were no differences in overall survival (OS) (3 year OS 69.3% for secondary MIBC, 70.3% for primary MIBC, p = 0.420), disease-free survival (DFS) (3 year DFS 57.7% vs 56.6%, p = 0.880) between the groups. History of NMIBC is not independent prognostic factor for OS on multivariable analysis. Conclusions: Patients with secondary MIBC treated with NAC showed no differences in NAC response, pathologic downstaging rate, OS, DFS compared to patients with primary MIBC. Prospective or larger cohort study are required in the future. Genomic analysis is ongoing to identify genetic differences between two groups.
Comparing clinical outcomes between patients with urothelial carcinoma who treated neoadjuvant chemotherapy by gemcitabine-cisplatin and dose-dense MVAC.
Authors: Lee Yongjune , Kim Young Seok , Hong Bumsik , Cho Yong Mee , Lee Jae-Lyun
Published: March 2019

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Background: Prospective randomized trials demonstrated efficacy of MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC). In metastatic setting urothelial cell carcinoma (UCC), clinical trials showed no difference in oncologic outcomes between Gemcitabine-Cisplatin (GC) and MVAC, and another prospective trial proved dose-dense (dd) MVAC had significantly better overall survival (OS) and response rate then MVAC. Comparative data between GC and ddMVAC are limited in neoadjuvant setting. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received NAC from January 2011 and December 2017 in Asan Medical Center was conducted. Patients who received GC were compared to patients received ddMVAC in terms of outcomes including downstaging ( < ypT2 and no N upstaging), pathologic complete response (pCR, ypT0N0), disease-free survival (DFS), and overall survival (OS) and tolerability. Results: In a total of 277 patients, 176 patients received NAC with GC and 41 patients with dose-dense MVAC. The median chemotherapy cycle is 4 (IQR 3-4) cycles for GC group, 4 (IQR 3-5.5) cycles for dose-dense MVAC group. With an exception of age; GC group is associated with younger age (p = 0.002), other baseline characteristics are well balanced between groups. Downstaging rate are 50.8% in GC group, 58.1% in dose-dense MVAC group (p = 0.47). The rates of achieving ypT0 (28.7% vs 22.6%, p = 0.68), ypN0 (78.3% vs 81.5%, p = 0.39). There were no differences in overall survival (OS) at 3 year (72.2% vs 73.2%, p = 0.58), disease-free survival (DFS) at 3 years (54.9% vs 63.3%, p = 0.21) according to chemotherapy regimens. ddMVAC with prophylactic G-CSF are associated with higher incidence of febrile neutropenia (p = 0.004) than GC. NAC regimen is not independent prognostic factor for OS on multivariable analysis. Conclusions: GC regimen had no significant difference in oncologic outcomes compare to ddMVAC as NAC in UCC.
Mature results from EV-101: A phase I study of enfortumab vedotin in patients with metastatic urothelial cancer (mUC).
Authors: Rosenberg Jonathan E. , Sridhar Srikala S. , Zhang Jingsong , Smith David C. , Ruether Joseph D. , Flaig Thomas W. , Baranda Joaquina Celebre , Lang Joshua Michael , Plimack Elizabeth R. , Sangha Randeep S. , Heath Elisabeth I. , Merchan Jaime R. , Quinn David I. , Srinivas Sandy , Milowsky Matthew I. , Wu Chunzhang , Gartner Elaina M , Melhem-Bertrandt Amal , Petrylak Daniel Peter
Published: March 2019

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Background: Enfortumab vedotin (EV) is an antibodydrug conjugate that delivers MMAE, a microtubule disrupting agent, to tumors expressing Nectin-4, a protein found on most urothelial cancers. Preliminary results of the EV-101 study (NCT02091999) suggest EV is active and tolerable. Methods: Patients with mUC treated with ≥1 prior chemotherapy, or those ineligible for cisplatin, received EV 1.25 mg/kg on Day 1, 8, and 15 every 28 day cycle. The primary objective was tolerability; antitumor activity (ORR per RECIST v1.1), assessed every 8 wk, was a secondary objective. Results: As of14 Sept 2018,112 pts with mUC received EV with a median follow up of 13.4 mo. Bladder was the primary tumor site in 86 pts (77%) and 33 (29.5%) had liver metastases (LM). Nearly all pts received prior platinum chemotherapy; 89 (79.5%) received prior anti-PD(L)1. EV was well tolerated; fatigue (53%), alopecia (46%), and decreased appetite (42%) were the most commonly reported treatment-related AEs (TRAEs). Anemia (8%), hyponatremia (7%), UTI (7%), and hyperglycemia (6%) were the grade ≥3 AEs reported in ≥5% of pts regardless of attribution; 4 fatal TRAEs were reported (respiratory failure, urinary tract obstruction, diabetic ketoacidosis, multi-organ failure). Confirmed ORR was 42% (CR, n = 5; PR, n = 42). Among responders, median duration of response was 7.7 mo (95% CI 5.6, 9.6) and 23.4% of responses were ongoing with a median follow up of 11.3 mo. Estimated median PFS and OS were 5.4 mo (95% CI 5.1, 6.3) and 12.5 mo (95% CI 9.3, 16.1), respectively; OS at 1 yr was 51.8%. Similar results were seen in pts with prior anti-PD(L)1 and with LM (Table). Conclusions: Single-agent EV was generally well tolerated and provided encouraging response and survival data in a population with an unmet medical need including pts with LM, which is associated with poor prognosis. Phase 2 and 3 monotherapy studies as well as evaluation of combination therapies are ongoing. Clinical trial information: NCT02091999. [Table: see text]