22o Πανελλήνιο Ουρολογικό Συνέδριο 2014 Αποτυχία του BCG σε High Risk NMIBC BCG Failure Αλκιβιάδης Γρηγοράκης Επιμελητής Ουρολογικού Τμήματος Γ.Ν.Α. ΄΄Ο ΕΥΑΓΓΕΛΙΣΜΟΣ΄΄ 1884

BCG Failure BCG χρησιμοποιείται σαν συμπληρωματική θεραπεία σε Intermediate και κυρίως High Risk NMIBC (high grade, T1, CIS) Περίπου 40-50% των ασθενών θα υποτροπιάσουν /εξελιχθούν Αυτό ορίζεται γενικά ως «αποτυχία του BCG» -BCG failure

BCG Failure σε T1GIII T1 G3- BCG Failure at 5-yrs Recurrence : ~ 50% Progression : 12-33% MANOHARAN & SOLOWAY. Urol Clin N Am 32 (2005) 133–145

Τοξικότητα BCG SWOG-Trial Recurrence Free surv. Progression Free surv. Overall 5 year surv. “SWOG 3+3+6” Median Recurrence Free Survival: 35,7 months vs. 76,8 months (p<0,0001) Median Progression Free Survival:111,5 m. vs . not estimable (p<0,04) Overall 5 year Survival: 78% vs. 83% (p=0,08) Only 16% of the 243 maintenance cases received all 8 scheduled maintenance courses during 3 years.

Ορισμός BCG failure EAU Σε περίπτωση pT2 νόσου Σε περίπτωση HG NMIBC στους 3 και στους 6 μήνες. Σε υποτροπή στους 3 μήνες νέος κύκλος BCG έχει 50% πλήρη ανταπόκριση Σε οποιαδήποτε επιδείνωση της νόσου , παρά την αρχική ανταπόκριση : ↑ αριθμού όγκων, ↑ στάδιο, ↑ grade, εμφάνιση CIS

Ορισμός BCG failure International Bladder Cancer Group BCG Recurrence: Επανεμφάνιση της νόσου (any grade, T category, or CIS) μετά την ολοκλήρωση της θεραπείας BCG failure: Οποιαδήποτε υποτροπή ή εξέλιξη κατά τη διάρκεια της θεραπείας LammD, et al.Eur Urol Suppl 2008;7:651–66

BCG Failure Herr and Dalbagni J Urol 69: 1706–1708, 2003 BCG-refractory disease (ανίατος) BCG-resistant disease (αντοχή) BCG-relapsing disease (υποτροπή) BCG-intolerant disease (δυσανεξία) failure to achieve a disease-free state by 6 months after initial BCG therapy with either maintenance or retreatment at 3 months recurrence or persistence of disease at 3 months after the induction cycle. It is of lesser degree, stage, or grade, and is no longer present at 6 months from BCG retreatment recurrence of disease after achieving a disease-free status by 6 months . Relapse is further defined by time of recurrence as early (within 12 months), intermediate (12 to 24 months), or late (24months). recurrent disease in setting of inadequate BCG treatment because of drug toxicity

BCG Failure Cystectomy ? Cystectomy ? ? BCG-refractory disease BCG-resistant disease Early BCG-relapsing disease Intermediate, late BCG-intolerant disease Cystectomy ? Cystectomy ? ?

Πρόγνωση BCG failure παράγοντες κινδύνου Γυναικείο φύλο Μεγάλη ηλικία Πολυεστιακοί όγκοι Συνυπάρχον CIS (ιδιαίτερα στη προστατική ουρήθρα) LVI Αρχική υποτροπή στους 3 μήνες (BCG refractory) T1b-c Πρώιμη υποτροπή μετά από αρχική ανταπόκριση (BCG early relapse) Αποτυχία μετά 2 κύκλους BCG Yates D R. et al. Eur. Urol. 62 (2012) 1088-96

Progressed Invasive Ca BCG FAILURE Early vs. delayed cystectomy H. HERR AND P.C. SOGANI, J Urol.2001 ; 166: 1296–1299 Vs. Mortality: 2,5% Morbidity: 28% pT0: Early 29pts, delayed 15pts DOD: Early 6 pts, Delayed 40 pts pT0: Early 33pts, Delayed 11pts DOD: Early 15 pts, Delayed 31 pts Recurrent SBC pT0: Early 24pts, Delayed 5pts DOD: Early 2 pts, Delayed 4 pts Progressed Invasive Ca pT0: Early 9pts, Delayed 6pts DOD: Early 13 pts, Delayed 27 pts

BCG FAILURE Early vs. delayed cystectomy 5-yrs CSS: Early C/my: 80% vs. Delayed:69% 10 yrs CSS: Early C/my: 76-78% vs. Delayed: 51-61% 3-yrs CSS: Pts progressing to ≥ T2 after BCG: 37% vs. primary muscle-invasive disease: 67% Herr HW, et al. J Urol. 2001;166:1296–9. Thalmann GN, et al. Urol 2004;172:70–5. Denzinger S, et al. Eur Urol 2008;53:146–52.

BCG failure Bladder Preservation Therapies

BCG failure INF-a /BCG A national multicentre randomised phase 2 trial, involving 1007 pts. BCG failure pts: INF-a (50 million U) + reduced-dose BCG: 2 yrs DFS: 45% BCG naïve pts: INF-a (50 million U) + full dose BCG: 2 yrs DFS: 59% Best results: when BCG failure > 1 yr after BCG treatment Bad results: when BCG failure < 1 yr after BCG treatment or after 2 cycles of BCG treatment Gallagher BL,et al. Urology 2008;71:297–301. Joudi FN, et al. Urol Oncol 2006;24:344–8.

BCG failure Gemcitabine Dose scheme : 2000 mg/100ml every week x 6 weeks Συμπερασματικά: Η Gemsitabine αποτελεί εναλλκτική θεραπεία σε BCG faikure αλλά η μακροχρόνια επίδραση της στην αναστολή της εξέλιξης της νόσου δεν έχει αποδειχθεί

Thermotherapy/Synergo BCG failure Thermotherapy/Synergo

BCG failure Thermotherapy/Synergo 80mg MMC: TC weekly x6-8 weeks ,maintenance x4-6 sessions every 6-8 weeks In a recent systematic review : TC 59% relative reduction in NMIBC recurrence compared with MMC alone, with a bladder preservation rate of 87.6%, Lammers RJM, et al. Eur Urol 2011;60:81–93. UK bladder cancer trial (HYMN, ClinicalTrials.gov identifier NCT01094964) Phase 3 trial : TC +MMC vs. 2nd course of BCG in NMIBC with BCG failure

BCG failure Taxanes Dose scheme: 6 weeks + /- maintenance x 9 months Mucoadhesive Nanoparticulate Docetaxel Paclitaxel-Hyaluronic Acid Bioconjugate(ONCOFID-P-B) Nanoparticle Albumin-bound Paclitaxel (Abraxane)

BCG failure Photodynamic therapy Per os:5-aminolevulinic acid (5-ALA) Complications: high incidence of haemodynamic instability in patients with preexisting cardiovascular comorbidity  Recurrence Rate Currently: PDT is not a realistic option for BCG-failure patients

BCG failure MMC + Gemcitabine Dose scheme: MMC (40 mg) + Gemcitabine (1000 mg) x 6-wk + maintenance x 1yr/monthly

BCG failure Εν δυνάμει νέες θεραπείες EMDA MMC

BCG failure Εν δυνάμει νέες θεραπείες EMDA MMC RPT: 108 high risk BCG –naïve NMIBC pts. EMDA MMC MMC BCG p value CR 3 months 53% 28% 56% 0.036 CR 6 months 58% 31% 64% 0.012 Time to Rec./months 35 19,5 26 0.013 Peak plasma concentrations of MMC: 5.5 times higher (43 ng/ml vs 8 ng/ml) in EMDA MMC Di Stasi SM, et al. J Urol 2003;170:777–82

BCG failure Εν δυνάμει νέες θεραπείες Sequential BCG+EMDA MMC RPT: 212 high risk BCG –naïve NMIBC pts./fu 88 months EMDA MMC+ BCG BCG p value Dis.Free/months 69 21 0.00012 Rec.Rate 42% 58% 0.0012 Pogr. Rate 9,3% 22% 0.004 DSM 5,6% 16,2% 0.01 OM 21,5% 32,4% 0.045 Di Stasi SM, et al. Lancet Oncol 2006;7:43–51 Di Stasi SM, et al. World J Urol 2009;27:325–30

BCG failure Εν δυνάμει νέες θεραπείες

BCG failure Second-line intravesical therapy 2nd line BCG (response: 50%) BCG+INF-A2b Optimization of intavesical chemotherapy Local microwave hyperthermia + MMC (Synergo) Photodynamic Therapy (5-ALA) Intravesical Gemcitabine, Docetaxel “Oncologically inferior than RC” EAU Guidelines 2013

ευχαριστώ

Interferon-a/bacillus Calmette-Gue΄rin. Interferon-a (INF-a) is a naturally occurring cell-signalling cytokine that is produced by the immune system in response to insults such as tumour cell growth. Gemcitabine. Gemcitabine is a standard first-line systemic chemotherapeutic agent used in the neoadjuvant, adjuvant, and palliative treatment of UC. It is a nucleoside analogue that causes defective DNA replication, leading to apoptosis of tumour cells. Thermochemotherapy. Bladder-wall hyperthermia used in combination with intravesical MMC is referred to as thermochemotherapy (TC) and is otherwise known as the Synergo system. Inducing temperatures of approximately 42 8C in the bladder wall (using a thermocoupled catheter and microwave equipment) significantly improves the absorption of sequentially administered intravesical MMC compared with conventional MMC alone

Taxane chemotherapy agents. Docetaxel (Taxotere) is a semisynthetic microtubule depolymerisation inhibitor that belongs to the taxane group of chemotherapy agents. Paclitaxel (Taxol), which was first described in 1967 and is an extract of the rare Pacific yew tree, is another taxanetype chemotherapy agent that has benefited from binding to albumin (gelatin nanoparticles) to increase its neoplastic activity. Excitation of photosensitised bladder tumour cells with a specific wavelength of intravesical light can cause tumour cell destruction and is referred to as photodynamic therapy (PDT). Efficacy and Safety Evaluation of EN3348 (Mycobacterial Cell Wall-DNA Complex [MCC]) as Compared With Mitomycin C in the Intravesical Treatment of Subjects With BCG Recurrent/Refractory Non-muscle Invasive Bladder Cancer (EMBARC-RF)

Abraxane=paclixatel RAD001=everolimus  DTA-H19, is a doubled stranded DNA plasmid that carries the gene for the diphtheria toxin A (DT-A) chain under the regulation of the H19 promoter sequence.  This is a Patient-Oriented, Targeted Therapy as DT-A chain expression is triggered by the presence of H19 transcription factors that are upregulated in tumor cells. The selective initiation of toxin expression results in selective tumor cell destruction via inhibition of protein synthesis in the tumor cell, enabling highly targeted cancer treatment. Lenalidomide (also known as Revlimid ®) is used to treat people with myeloma, which is a type of cancer that affects the plasma cells found inside bone marrow.

Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer (BOND) recombinant adenovirus-interferon SCH 721015   A replication-deficient recombinant adenovirus encoding human interferon alpha-2b with potential antineoplastic activity. Upon intravesical administration, recombinant adenovirus-interferon SCH 721015 infects nearby tumor cells and expresses INF alpha-2b intracellularly which activates the transcription and translation of genes whose products mediate antiviral, antiproliferative, antitumor, and immune-modulating effects The use of a designed viral vector that can destroy cancer cells while leaving normal cells largely unharmed. The virus also stimulates an immunological response by producing a special factor (GM-CSF) to attract and promote the development of dendritic and T effector cells. It forms the hypothesis that this regimen may be used for people who have failed current forms of treatment and are recommended for cystectomy. 

Urocanic acid (UCA; 3-(1H-imidazol-4-yl)prop-2-enoic acid) is an endogenous compound in the mammalian skin. trans-UCA, synthesized enzymatically from histidine and located in the upper epidermis, is photo-isomerized to cis-UCA by exposure to UV radiation. It has been well documented that cis-UCA is able to induce immunosuppression