Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what

Peyton, Charles C.; Chipollini, Juan; Azizi, Mounsif; Kamat, Ashish M.; Gilbert, Scott M.; Spiess, Phillippe E.

doi:10.1007/s00345-018-2591-1

Cited by 38 publications

(35 citation statements)

References 78 publications

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“…Unfortunately, only 16% of the participants of this study were able to tolerate the full dose-schedule of BCG maintenance regimen due to substantial toxicity. In addition, about 20-40% of patients treated primarily with BCG will show recurrent disease at the first follow up evaluation 3 months after instillation [9][10][11]. These findings emphasize the need for new effective agents with a reduced toxicity profile that will allow continuous and long-term administration.…”

Section: Introductionmentioning

confidence: 98%

Halofuginone: a novel oral and intravesical agent for the treatment of non-muscle invasive bladder cancer

2018

J. Mol. Clin. Med.

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Background: Non-muscle invasive form (NMIBC) is a chronic disease with a high recurrence rate and requires lifelong surveillance. Various intravesical agents were shown to reduce tumor recurrence but unfortunately, none of these agents proved to be of benefit in long-term prevention of local recurrence or disease progression. Aim of Research: Previous studies have shown that Halofuginone (HF), an antiprotozoal agent, exerts anti-neoplastic activity in various cancer models. Our aim was to evaluate the in vivo activity of oral and intravesical HF treatment in an experimental mouse model harboring NMIBC. Methods: Initially, 60 mice were divided into six treatment groups to evaluate the toxicity of this anti-parasitic agent on the bladder mucosa. The second stage included 126 mice which underwent intravesical implantation with Mouse Bladder Tumor cells (MBT-2): Group 1 (n = 30) received no treatment, group 2 (n = 32) received 6 intravesical instillations of PBS, group 3 (n = 32) received 6 doses of 250 µg oral HF, whereas group 4 (n = 32) received 6 intravesical instillations of 250 µg HF. Results: The average weight of bladders, which reflects the anti-neoplastic activity, differed significantly between the control and treated groups: 88.8 mg ± 15.58 SEM and 81.2 mg ± 13.79 SEM for untreated and PBS-treated mice, respectively, versus 38.0 mg ± 4.02 SEM and 39.6 mg ± 5.97 SEM for animals treated with oral and intravesical HF, respectively. Conclusions: HF exerted a significant anti-neoplastic activity in mice bearing NMIBC upon oral as well as intravesical administration. These results may constitute the basis for the maintenance of oral treatment with HF in patients with NMIBC.

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Section: Introductionmentioning

confidence: 98%

Halofuginone: a novel oral and intravesical agent for the treatment of non-muscle invasive bladder cancer

2018

J. Mol. Clin. Med.

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“…In the absence of any adjuvant treatment, up to the 90% may recur after transurethral resection (TURBT) and about half of patients’ progress to MIBC 2 . The recommended treatment of high risk NMIBC is a six weekly induction course with intravesical instillations of bacillus Calmette‐Guérin (BCG) followed by maintenance courses 3 . BCG fails in up to 50% of patients and it may be associated with local or systemic adverse events in approximately 70% of them 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Thus, there is a rising need for bladder‐sparing alternatives. In the last decade several new agents, which can be delivered more safely and efficiently to the bladder, have been investigating 3,8 . Unfortunately, development of new drugs in this disease space has been hampered by the heterogeneity in patient population, poor definition of disease status, uncontrolled studies, and consensus on outcome definition.…”

Section: Introductionmentioning

confidence: 99%

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

et al. 2020

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Background There is an unmet alternative medical therapy for BCG unresponsive patients. Objective To report efficacy of intravesical gemcitabine in NMIBC patients, who failed a previous course of BCG, or intolerant, and unwilling to undergo radical cystectomy (RC). Material and methods This is an open‐label, single‐arm study, which enrolled patients showing a failure or were intolerant to BCG and unwilling to undergo the RC. Intravesical gemcitabine was administered once a week for six consecutive weeks and once a month for 12 months. The primary outcome was DFS defined as the lack of a tumor on cystoscopy and negative urine cytology. Secondary endpoint was safety defined according a grading of side effects. OS, PFS, and DFS were described with Kaplan–Meier method at 12 and 24 months. Results and limitations Overall 36 patients were enrolled. The median follow‐up was 27 months. The DFS was 68.75% at the end of induction phase and 44.44% and 31.66% at 12 and 24 months of, respectively. The PFS was 43.75%. The OS and CSS were 77.9% (95% CI 58.78%‐88.92%) and 80.68% (95% CI 61.49%‐90.96%), respectively. There was no life threatening event or treatment‐related death (grade 4 or 5). The most common mild and moderate adverse events reported were urinary symptoms (LUTS) and fatigue (G1‐G2). Conclusion Patients who presented an unresponsive‐BCG recurrent NMIBC and unwilling to receive a RC, could benefit from intravesical gemcitabine as salvage organ‐sparing treatment.

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“…Although studies proved IL-2 to also be effective against NMIBC [ 41 , 42 , 43 , 44 , 45 , 46 ], owing to severe side effects and the necessary expertise of highly specialized centers, this cytokine-based therapy has limited usability [ 33 ]. Besides the transurethral removement, most commonly, the adjuvant Bacillus Calmette-Guerin (BCG) intravesical installation immunotherapy has become, and still is [ 47 , 48 , 49 ], the gold standard for high risk NMIBC worldwide [ 50 , 51 ].…”

Section: Introductionmentioning

confidence: 99%

The Impact of a New Interleukin-2-Based Immunotherapy Candidate on Urothelial Cells to Support Use for Intravesical Drug Delivery

Schmitz

Berdien²,

Huland³

et al. 2020

Life

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(1) Background: The intravesical instillation of interleukin-2 (IL-2) has been shown to be very well tolerated and promising in patients with bladder malignancies. This study aims to confirm the use of a new IL-2 containing immunotherapy candidate as safe for intravesical application. IL-2, produced in mammalian cells, is glycosylated, because of its unique solubility and stability optimized for intravesical use. (2) Materials and Methods: Urothelial cells and fibroblasts were generated out of porcine bladder and cultured until they reached second passage. Afterwards, they were cultivated in renal epithelial medium (REM) and Dulbecco’s modified Eagles medium (DMEM) with the IL-2 candidate (IMS-Research) and three more types of human interleukin-2 immunotherapy products (IMS-Pure, Natural IL-2, Aldesleukin) in four different concentrations (100, 250, 500, 1000 IU/mL). Cell proliferation was analyzed by water soluble tetrazolium (WST) proliferation assay after 0, 3, and 6 days for single cell culture and co-culture. (3) Results: Proliferation assays showed that all IL-2 products induced very similar cultivation results and none of the IL-2 variants had a negative impact on the proliferation of urothelial cells and fibroblast in either concentration. (4) Conclusion: Human recombinant glycosylated IL-2 as well as human non-glycosylated IL-2 have no negative influence on the tissue cell proliferation of porcine urothelial cells and fibroblasts in vitro and represent a promising and innovative potential intravesical therapy candidate for patients in high need.

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Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what

Cited by 38 publications

References 78 publications

Halofuginone: a novel oral and intravesical agent for the treatment of non-muscle invasive bladder cancer

Halofuginone: a novel oral and intravesical agent for the treatment of non-muscle invasive bladder cancer

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

The Impact of a New Interleukin-2-Based Immunotherapy Candidate on Urothelial Cells to Support Use for Intravesical Drug Delivery

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