New Therapies for Non-muscle-Invasive Bladder Cancer

8/8/2019 New Therapies for Non-muscle-Invasive Bladder Cancer

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Dr. K. Sholay Meitei(M.Ch. student)


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Introduc tiony T he initial treatment for non-muscle-invasive bladder

cancer (NMIBC) is transurethral resection of all visible

tumors.y 70% of bladder tumors recur and 10 20% of those that

recur progress to muscle-invasive diseasey High-grade T 1 and carcinoma in situ (CIS) tumors are

at higher risk for recurrence and progressiony T he major challenge in the management of bladder

cancer is the prevention of recurrence and progressionof disease


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y Intravesical bacillus Calmette Guerin (BCG) has beenshown to be the most effective intravesical agent forNMIBC and is currently standard therapy for adjuvanttreatment in high-risk patients, particularly CIS.

y Intravesical chemotherapeutic agents such as mitomycin C,doxorubicin and thiotepa have been used to treat NMIBC. Although intravesical chemotherapy has been shown to

reduce the recurrence rate in the short term by an averageof 14%, there is no evidence that it reduces the long-termincidence of recurrence or the risk of progression tomuscle-invasive disease .

y Clearly, there is a need for novel strategies and therapies toaddress the shortcomings of current standard therapy. A number of new options have been developed for themanagement of NMIBC in recent years. T hese new optionsare aimed not just towards BCG failures but also at novel ways to inhibit or eradicate bladder cancer cells.


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Me thodsy A PubMed database search was performed for articles

published between 1980 and 2009 investigating theuse of new or novel therapies, intravesical agents,immunotherapies, gene therapies, chemotherapeutics,device-assisted deliveries, thermotherapies, vaccines,biological therapies and other therapies for treatingnon-muscle-invasive bladder cancer. T he review

process also included review articles, meta-analyses,search of the reference lists in trial publications andreview articles, and annual meeting abstracts in the Journal of Urology and European Urology.


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Immunoth e rapyy Mycobacterial cell wall-DNA complex (MCC) is a new

immunostimulant prepared from Mycobacterium phlei,and contains a mixture of immunostimulatory

mycobacterial DNA attached to antigenic cell wall extracty Mycobacterial cell wall extract was used to treat 61 patients with CIS, at 4 mg once weekly for 6 weeks and thenmonthly for 1 year. T his resulted in recurrence-free survivalof 62.5% at 12, 49.3% at 24 and 41.1% of patients at 60 weeksafter therapy, and with minimal toxicity. T his study alsosuggested that MCC was efficacious as first-line therapy inBCG-nave patients (69% complete or partial response) andin BCG failures (52% complete or partial response).


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y O rally administered lactobacillus casei (LC) preparationhas been reported to suppress recurrence aftertransurethral bladder tumor resection .

y Naito et al. recently reported a prospective randomized,controlled study where patients with superficial bladdercancer were treated with transurethral resection followed

by one single instillation of epirubicin within the first 2 hand another instillation 1 week after transurethralresection. 102 patients received a further six instillations of epirubicin (30 mg/80 ml) and another 100 patientsunderwent the same instillation schedule with the additionof oral administration of LC preparation for 1 year. T heepirubicin plus Lactobacillus casei group had asignificantly higher 3-year recurrence-free survival ratecompared to the epirubicin alone group (74.6 vs. 59.9%), with no significant difference in side effects.


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y T he efficacy of the combination of BCG and interferon-

(IFN ) for patients who have failed prior BCG therapy hasbeen reported to be from 27 to 66%, based on several smallseries and a phase 2 multicenter trial of 1007 NMIBC patients,467 of whom had BCG failure

y In a phase 2 trial, first-line BCG IFN achieved a disease-free

rate of 59% at a median of 24 months follow-up, compared to45% in those who had previously failed BCG. However, BCGIFN was not compared to BCG monotherapy in that study.

y Immunotherapy for the treatment of bladder cancer usingDNA vaccines has been described in pre-clinical studies. Inone study, Lee et al. reported that in mice withsubcutaneously implanted bladder cancer cells, treatment with recombinant BCG DNA (poly-rBCG) and murineinterleukin (IL)-12 (mIL-12) vaccine achieved significantly

higher survival than those treated with either vaccine alone orcontrol mice.


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Ch e moth e rap e utic ag e ntsy T he role of intravesical chemotherapy in decreasing

NMIBC recurrence is well established. However, its

inability to reduce disease progression and cancerrelated mortality has limited its success.Chemotherapeutic agents are usually reserved forpatients who have failed BCG therapy. Severalchemotherapeutic agents have been investigated asintravesical treatment options.


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Ge mcitabin ey Gemcitabine-shown to be efficacious in advanced bladder

cancer, with a low incidence of side effects. Currently, itsintravesical use for treating NMIBC is being investigated.

y

Dalbagni et al. reported a phase I study of intravesicalgemcitabine for BCG-refractory NMIBC patients usingdoses up to 2,000 mg in a twice a week for 3 weeks followedby a second cycle after a week of rest schedule. In thisstudy, intravesical gemcitabine was shown to be well-tolerated with minimal bladder-related symptoms andacceptable myelosuppression. Complete response (CR),defined by a negative post-treatment biopsy and cytology was seen in 39% (7/18) of patients.

y Intravesical gemcitabine up to 2,000 mg dose was well-tolerated with minimal systemic absorption and toxicity.


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Taxan e sy docetaxel and paclitaxel are cytotoxic chemotherapeutic agents

that inhibit microtubule depolymerizationy In a recent phase 1 trial of NMIBC patients who failed standard

intravesical therapy, intravesical doxcetaxel had shown nosystemic absorption and no grade 3 or 4 dose-limiting toxicitiesin patients

y T he usage of paclitaxel for intravesical therapy has been limiteddue to its high lipid solubility and poor efficiency in intravesicaldelivery. To overcome this difficulty, several approaches such as

sustained-release bioadhesive paclitaxel microspheres, rapid-release paclitaxel-loaded gelatin nanoparticles, and sustained-release paclitaxel incorporated in hydrophobically derivatizedhyperbranched polyglycerols have been used. In vivo studieshave shown promise for these novel approaches to intravesicalpaclitaxel therapy.


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Suraminy block the binding of the epidermal growth factor

(EGF) to its receptor (EGFR).y

Phase 1 studies of intravesical suramin havedemonstrated low systemic absorption and lowtoxicity


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Me glumin e gamma-linol e nic acid ( Me GLA)y essential fatty acid with cytotoxic effects when applied

topically for prolonged periodsy

Intravesical MeGLA produced a 13% CR and 30%partial response in a phase 2 study of patients withrecurrent NMIBC


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Apaziquon e (EO9), y apaziquone was cytotoxic to transitional cell

carcinomas at concentrations 6 78 times lower

compared to mitomcyin Cy In a recent phase 2 marker lesion study of intravesical

apaziquone on low-intermediate risk NMIBC patients,six instillations of 4 mg/40 ml of apaziquone achieved

a 67% (30/45) histologically proven CR within 4 weeksafter completion of the therapy, while maintaining aside effect profile comparable to other commonchemotherapeutic agents


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Improv e d or d e vice -assist e d ag e ntd e live ry

y to increase efficacy of treatment of NIMBC is toincrease the bladder wall penetration of the

therapeutic agent, thereby increasing the amount of exposure of the agent to the urotheliumy T he use of intravesical microwave to induce

thermotherapy around 42 43C to enhance

effectiveness of chemotherapy drugs locally, have beeninvestigated


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y Electromotive drug administration ( EMDA) is alsoanother method of enhancing drug delivery throughthe urothelial barrier of the bladder, by creating anelectrical gradient between the intravesical agent andthe bladder wall.

y Ph otodynamic t h erapy ( P DT) is another devise-assisted approach that uses photosensitizers toselectively bind tumors targeted to be ablated by anintravesical light source


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y Magnetic targeted carriers ( MTC) to effect site-specific delivery of intravesical doxorubicin has beenexplored in normal swine bladder

y B ioad h esive microsp h eres , drug-loaded gelatinnanoparticles , and drugs incorporated inh ydrop h obically derivatized h yperbranc h edpolyglycerols


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Ge n e th e rapyy Gene therapy is an emerging modality of treatment as

new vectors for transfection are being developed and

more bladder cancer-associated genes are beingidentified. T he use of synthetic nucleic acids such asantisense oligonucleotide (AS O DN) and smallinterfering RNAs (SiRNAs) technology to target genesthat play important roles in the recurrences andprogression of bladder cancer has been explored.


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y A number of chemical modifications have been made to

the AS O DN in the effort to improve the stability, bindingaffinity and increased inhibition of the target genes.Currently, a number of pre-clinical studies using AS O DNand SiRNA have explored targeting various antiapoptoticgenes (Bcl-2, clusterin, Bcl-xl, XIAP, surviving), angiogenicfactor genes (VEGF, basic fibroblast growth factor),oncogenes (Ha-ras, c-myc), growth factor genes ( T GF-beta1, insulin-like growth factor-1 receptor, Protein kinaseC , EphB4) and other genes (telomerase, Ki-67, Polo-like

kinase-1, human telomerase reverse transcriptase) that areinvolved in bladder cancer recurrence and progression, andshowing varying success in bladder cancer cells in vitro andin vivo


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y More recently, an in vivo study combination AS O DN

and SiRNA therapy targeting a number of target geneshave been reported. T he authors showed thatsimultaneous inhibition of two of the selectedtranscripts significantly reduced cell viability

compared to the controls and that both syntheticnucleic acids were biocompatible in vivo. Furthermore,synthetic nucleic acids have also been found toenhance chemotherapeutic efficacy

y

Kamada et al. reported that targeting Heat shockprotein 27 (Hsp27) using AD O DN (O GX-427) andHsp27 siRNA treatment induced apoptosis andenhanced sensitivity to paclitaxel in UM-UC-3 cells


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y Intravesical adenovirus-CD40L transfection has been

shown to significantly increase interleukin-12 expressionand cured 60% of mice in an orthotopic murine bladdercancer model. Another study reported that intravesicaladenovirus delivery of interferon- 2b (IFN) can increaseinterferon concentration in bladder tissue and urinecompared to recombinant IFN alone. It also showed thatthe gene transfer ability of adenovirus was increased by agene enhancing agent Syn3. Tao et al.further reported that 1single instillation of adenovirus-IFN at 10 10 -1011 particles/ml with Syn 3 was highly effective in reducingthe size of human tumors in a orthotopic nude mice model.Currently, a dose escalation phase 1 gene therapy clinicaltrial using single dose of Adenovirus-IFN with Syn 3 onNMIBC BCG refractory patients, with re-dosing at 90 daysif CR is achieved, is ongoing at the University of Texas MD Anderson Cancer Center.


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y Interest in non-viral gene therapy approaches has beengenerated due to the concern for potential toxicity from inadvertent systemic absorption of viral vectorsfrom the bladder. In our laboratory, we have used anovel cationic liposome N -[1-(2,3-dioleoyloxyl)propyl]- N , N , N trimethylammoniummethyl sulfate andmethyl-beta-cyclodextrin-solubilized cholesterol totransfect plasmids containing IFN-alpha1 andgranulocyte macrophage colony-stimulating factor,

and have demonstrated that successful inhibition of tumor cell growth could be obtained with cytokinegene therapy in an immunocompetentorthotopicmouse bladder cancer model.


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y A phase 1 liposomal cytokine gene therapy clinical trialfor high-risk NMIBC patients is currently beingplanned at our institution. Cationic liposomes havealso been used to transfect bladder cancer withintravesical siRNA.

y In one study, Nogowa et al. reported that PLK-1 siRNA was successfully transfected intravesically usingcationic liposomes and produced inhibition of cancergrowth in an orthotopic murine bladder cancer model.


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y Sidi et al. recently reported a phase 1/2 study of 18

NMIBC patients where escalating doses of intravesicalBC-819 DNA plasmid (causing Diptheria toxin A expression) complexed with polyethyleneimine (in vivo-jetPEI , Polyplus-transfection Inc. , NY) were

well-tolerated and resulted in 44% (8/18) of patientsachieving either complete marker tumor ablation or a50% reduction of the marker lesion


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CONCLUSIONy Prevention of recurrence and progression remains the key goals in the treatment of NMIBC

y A number of new developments in NMIBC therapy haveemerged in the recent years, with many showingencouraging results. However, due to the fact that asignificant proportion of these therapies are still in eitherpre-clinical investigation phase or require further clinicalevaluation and validation, their exact clinical role inNMIBC cannot be defined.

y Newer immunostimulants such as MCC and LC, having theadvantage of lower toxicity, may possibly emerge to bealternative (either as monotherapy or in combination withchemotherapy) therapies to BCG


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y T he combination of BCG and IFN can be used to treatBCG relapses or BCG failures, but its role at first-linetherapy for NMIBC is still controversial. Intravesicalgemcitabine is likely to be a viable alternative to currentstandard intravesical chemotherapy or for BCG failures.

y

O ther chemotherapeutics such as intravesical doxcetaxeland apaziquone still requires further evaluationy T he use of thermochemotherapy and electromotive drug

adminstration for chemoenhancement has potential use inBCG failures but requires further evaluation and validation.

y T he gene therapy approach to treating NMIBC is promisingbut requires further investigation.


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New Therapies for Non-muscle-Invasive Bladder Cancer

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