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

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Παρουσίαση με θέμα: "22o Πανελλήνιο Ουρολογικό Συνέδριο 2014 Αλκιβιάδης Γρηγοράκης Επιμελητής Ουρολογικού Τμήματος Γ.Ν.Α. ΄΄Ο ΕΥΑΓΓΕΛΙΣΜΟΣ΄΄ 1884 Αποτυχία του BCG σε High Risk."— Μεταγράφημα παρουσίασης:

1 22o Πανελλήνιο Ουρολογικό Συνέδριο 2014 Αλκιβιάδης Γρηγοράκης Επιμελητής Ουρολογικού Τμήματος Γ.Ν.Α. ΄΄Ο ΕΥΑΓΓΕΛΙΣΜΟΣ΄΄ 1884 Αποτυχία του BCG σε High Risk NMIBC BCG Failure

2 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

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

4 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. Τοξικότητα BCG SWOG-Trial

5 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

6 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 Ορισμός BCG failure International Bladder Cancer Group LammD, et al.Eur Urol Suppl 2008;7:651–66

7 BCG-refractory disease (ανίατος) BCG-resistant disease (αντοχή) BCG-relapsing disease (υποτροπή) BCG-intolerant disease (δυσανεξία) BCG Failure Herr and Dalbagni J Urol 69: 1706–1708, 2003 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

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

9 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)

10 BCG FAILURE Early vs. delayed cystectomy H. HERR AND P.C. SOGANI, J Urol.2001 ; 166: 1296–1299 pT0: Early 33pts, Delayed 11pts DOD: Early 15 pts, Delayed 31 pts pT0: Early 29pts, delayed 15pts DOD: Early 6 pts, Delayed 40 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 Vs. Mortality: 2,5% Morbidity: 28%

11 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.

12 BCG failure Bladder Preservation Therapies

13 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 INF-a /BCG

14 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

15 BCG failure Thermotherapy/Synergo

16 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 NCT ) Phase 3 trial : TC +MMC vs. 2 nd course of BCG in NMIBC with BCG failure

17 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)

18 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

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

20 BCG failure Εν δυνάμει νέες θεραπείες EMDA MMC

21 EMDA MMCMMCBCGp value CR 3 months53%28%56%0.036 CR 6 months58%31%64% Time to Rec./months 3519, RPT: 108 high risk BCG –naïve NMIBC pts. 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

22 EMDA MMC+ BCG BCGp value Dis.Free/months Rec.Rate42%58% Pogr. Rate9,3%22% DSM5,6%16,2%0.01 OM21,5%32,4%0.045 RPT: 212 high risk BCG –naïve NMIBC pts./fu 88 months 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 Sequential BCG+EMDA MMC

23 BCG failure Εν δυνάμει νέες θεραπείες

24 BCG failure Second-line intravesical therapy 2 nd 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

25 ευχαριστώ

26 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

27 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)

28 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.myeloma

29 recombinant adenovirus-interferon SCH A replication-deficient recombinant adenovirus encoding human interferon alpha-2b with potential antineoplastic activity. Upon intravesical administration, recombinant adenovirus-interferon SCH 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 Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer (BOND) 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.

30 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


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