-
1.
Ferumoxytol-Enhanced MR Lymphography for Detection of Metastatic Lymph Nodes in Genitourinary Malignancies: A Prospective Study.
Turkbey, B, Czarniecki, M, Shih, JH, Harmon, SA, Agarwal, PK, Apolo, AB, Citrin, DE, Gulley, JL, Harisinghani, M, Madan, RA, et al
AJR. American journal of roentgenology. 2020;(1):105-113
-
-
Free full text
-
Abstract
OBJECTIVE. The objective of our study was to evaluate the utility of ferumoxytol-enhanced MR lymphography (MRL) in detection of metastatic lymph nodes (LNs) in patients with prostate, bladder, and kidney cancer. SUBJECTS AND METHODS. This phase 2 single-institution study enrolled patients with confirmed prostate (arm 1), bladder (arm 2), and kidney (arm 3) cancer and evidence of suspected LN involvement. Participants underwent ferumoxytol-enhanced MRL 24 and 48 hours after IV injection of 7.5 mg Fe/kg of ferumoxytol. A retrospective quantitative analysis was performed to determine the optimal timing for ferumoxytol-enhanced MRL using percentage change in normalized signal intensity (SI) from baseline to 24 and 48 hours after injection, which were estimated using the linear mixed-effects model in which time (24 vs 48 hours), diseases status, and time and disease status interaction were the fixed-effects independent variables. Differences in normalized SI values between subgroups of lesions were estimated by forming fixed-effects contrasts and tested by the Wald test. RESULTS. Thirty-nine patients (n = 30, arm 1; n = 6, arm 2; n = 3, arm 3) (median age, 65 years) with 145 LNs (metastatic, n = 100; benign, n = 45) were included. LN-based sensitivity, specificity, positive predictive value, and negative predictive value of ferumoxytol-enhanced MRL was 98.0%, 64.4%, 86.0%, and 93.5%, respectively. Sensitivity and specificity of ferumoxytol-enhanced MRL did not vary by LN size. Metastatic LNs showed a significantly higher percentage decrease of normalized SI on MRL at 24 hours after ferumoxytol injection than at 48 hours after ferumoxytol injection (p = 0.023), whereas the normalized SI values for nonmetastatic LNs were similar at both imaging time points (p = 0.260). CONCLUSION. Ferumoxytol-enhanced MRL shows high sensitivity in the detection of metastatic LNs in genitourinary cancers independent of LN size. The SI difference between benign and malignant LNs on ferumoxytol-enhanced MRL appears similar 24 and 48 hours after ferumoxytol injection, suggesting that imaging can be performed safely within 1 or 2 days of injection. Although ferumoxytol-enhanced MRL can be useful in settings without an available targeted PET agent, issues of iron overload and repeatability of ferumoxytol-enhanced MRL remain concerns for this method.
-
2.
An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results.
Packiam, VT, Lamm, DL, Barocas, DA, Trainer, A, Fand, B, Davis, RL, Clark, W, Kroeger, M, Dumbadze, I, Chamie, K, et al
Urologic oncology. 2018;(10):440-447
Abstract
OBJECTIVES CG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising activity in patients with high-grade non-muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy. PATIENTS AND METHODS At interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies. RESULTS Of 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%-62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%-78%), CIS ± Ta/T1 50% (33%-67%), and pure Ta/T1 33% (8%-70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment-related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment-related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment-related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment-related AEs. CONCLUSIONS This phase II study demonstrates that intravesical CG0070 yielded an overall 47% CR rate at 6 months for all patients and 50% for patients with CIS, with an acceptable level of toxicity for patients with high-risk BCG-unresponsive NMIBC. There is a particularly strong response and limited progression in patients with pure CIS.
-
3.
Green-light laser en bloc resection for primary non-muscle-invasive bladder tumor versus transurethral electroresection: A prospective, nonrandomized two-center trial with 36-month follow-up.
Chen, J, Zhao, Y, Wang, S, Jin, X, Sun, P, Zhang, L, Wang, M
Lasers in surgery and medicine. 2016;(9):859-865
Abstract
OBJECTIVES To evaluate the safety and efficacy of LBO laser en bloc resection compared with transurethral electroresection (TURBT) for the treatment of primary non-muscle-invasive bladder tumors. METHODS From September 2010 to February 2012, a prospective, nonrandomized two-center trial was performed. A total of 158 patients (83 underwent laser resection and 75 TURBT) were included in the present study. The preoperative, intraoperative, and postoperative clinical characteristics were recorded and compared in the two groups. RESULTS There were no differences with the preoperative characteristics between the patients in the two groups. The mean operative time was 21.46 ± 10.42 minutes for laser resection and 27.47 ± 15.30 minutes for TURBT (P = 0.004). LBO laser group was also associated with less hemoglobin decrease compared with TURBT group (0.87 ± 0.28 g/ml vs. 1.00 ± 0.33 g/ml, P = 0.009). Obturator nerve reflection was absent during laser resection, whereas was observed in nine patients during TURBT (P = 0.001). Two patients in the TURBT group suffered bladder perforation. Three patients in TURBT group and one patient in LBO laser group experienced urethral stricture. The recurrence-free survival rate did not differ significantly between two groups after 36 months follow-up. CONCLUSIONS The results of our trial have shown that LBO laser en bloc resection is feasible, safe, and effective alternative for the treatment of primary non-muscle-invasive bladder tumors. Besides, it can provide intact specimen for the pathologic diagnosis. Lasers Surg. Med. 48:859-865, 2016. © 2016 Wiley Periodicals, Inc.
-
4.
Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer.
Birkhäuser, FD, Studer, UE, Froehlich, JM, Triantafyllou, M, Bains, LJ, Petralia, G, Vermathen, P, Fleischmann, A, Thoeny, HC
European urology. 2013;(6):953-60
Abstract
BACKGROUND Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer patients. OBJECTIVE To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS Examinations with 3-Tesla MRI 24-36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO-DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed. RESULTS AND LIMITATIONS At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17-68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3-26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. CONCLUSIONS Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time.
-
5.
Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma.
Wong, YN, Litwin, S, Vaughn, D, Cohen, S, Plimack, ER, Lee, J, Song, W, Dabrow, M, Brody, M, Tuttle, H, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;(28):3545-51
-
-
Free full text
-
Abstract
PURPOSE The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. PATIENTS AND METHODS Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m(2) with or without paclitaxel 80 mg/m(2) per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. RESULTS We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). CONCLUSION Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.
-
6.
Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study.
Jarmalaite, S, Andrekute, R, Scesnaite, A, Suziedelis, K, Husgafvel-Pursiainen, K, Jankevicius, F
Journal of cancer research and clinical oncology. 2010;(6):847-54
Abstract
PURPOSE Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2. METHODS After complete TURB, patients with multifocal superficial BC were treated with five daily intravesical instillations of IL-2. Promoter hypermethylation in six TSGs and the TP53 gene mutations were prospectively assessed by methylation-specific PCR and automated capillary single-strand conformation polymorphism in 21 primary bladder cancer specimens and ten bladder wall biopsies collected during follow-up. RESULTS After IL-2 treatment, 9 out of 21 (43%) patients did not develop recurrent tumour within the 1 year of follow-up period. The mean duration of recurrence-free survival in the rest of the study group was 112 days. In the current pilot study, BC with p16 gene hypermethylation had a lower risk of recurrence after treatment with IL-2, as compared to IL-2 treated BC without p16 hypermethylation (p = 0.02). Significant associations were observed between tumour grade and the mean methylation index (p = 0.003), as well as the hypermethylation of the RARbeta gene (p = 0.048). CONCLUSION Our preliminary data suggest that DNA methylation biomarkers may assist in selection of BC patients for efficient IL-2 therapy.
-
7.
AdCD40L immunogene therapy for bladder carcinoma--the first phase I/IIa trial.
Malmström, PU, Loskog, AS, Lindqvist, CA, Mangsbo, SM, Fransson, M, Wanders, A, Gårdmark, T, Tötterman, TH
Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;(12):3279-87
Abstract
PURPOSE Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease. EXPERIMENTAL DESIGN Patients with invasive bladder cancer scheduled for cystectomy or patients with T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored. RESULTS All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells. CONCLUSIONS To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.
-
8.
Arsenic trioxide in recurrent urothelial cancer: a cancer and leukemia group B phase II trial (CALGB 99903).
Bajorin, DF, Halabi, S, Small, E
Clinical genitourinary cancer. 2009;(3):E66-70
Abstract
BACKGROUND Arsenic trioxide is highly active in patients with acute promyelocytic leukemia. There are also preclinical data to suggest that this drug might be active in nonhematopoietic malignancies, and transitional cell carcinoma cell lines are particularly sensitive to this agent. PATIENTS AND METHODS Twelve evaluable patients with metastatic urothelial cancer were treated with arsenic trioxide in a phase II trial conducted by the Cancer and Leukemia Group B. Eligible patients were required to have measurable urothelial cancer and a maximum of 1 previous chemotherapy regimen. Arsenic trioxide was given at a dose of 0.3 mg/kg daily for 5 days every 28 days. RESULTS No major responses were observed; 4 patients achieved stable disease. The median survival was 6.5 months (95% CI, 3.9-13.4 months). The most commonly observed toxicities included fatigue and malaise, anemia, nausea, emesis, and constipation. CONCLUSION Arsenic trioxide at this dose and schedule does not have significant activity in previously treated urothelial cancer and has substantial toxicity in this patient population.
-
9.
Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group.
Dreicer, R, Li, H, Stein, M, DiPaola, R, Eleff, M, Roth, BJ, Wilding, G
Cancer. 2009;(18):4090-5
-
-
Free full text
-
Abstract
BACKGROUND There is no effective second-line systemic chemotherapy for patients with disease progression after cisplatin-based chemotherapy. A phase 2 trial of sorafenib was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen. METHODS Twenty-seven patients with advanced urothelial carcinoma were treated with sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity. RESULTS There were no objective responses observed. The 4-month progression-free survival (PFS) rate was 9.5%; median overall survival of the group was 6.8 months. There were no therapy-related deaths, and common grade 3 toxicities included fatigue and hand-foot syndrome. CONCLUSIONS Although sorafenib as a single agent has minimal activity in patients with advanced urothelial cancer in the second-line setting, further investigation of tyrosine kinase inhibitors using different trial designs with PFS endpoints is warranted.
-
10.
Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium.
Hutson, TE, Vukelja, S, Atienza, D, Awasthi, S, Delaune, R, Deutsch, M, Dien, PY, Gregory, TF, Kolodziej, MJ, Muscato, JJ, et al
Investigational new drugs. 2008;(2):151-8
Abstract
OBJECTIVES Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P+G in patients with metastatic TCC. METHODS Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800-1,000 mg/m2 on days 1 and 15; P 400-500 mg/m2 on day 15; and C 50-70 mg/m2 on day 1. All patients received folic acid, vitamin B12, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. RESULTS Fifteen patients registered: 13/15 white males; median age 70 years (range, 53-82); 11/15 had KPS>or=90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed<1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3-4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). CONCLUSION Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.