Ruolo dell' oncologo nei tumori vescicali infiltranti o localmente avanzati

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1 Ruolo dell' oncologo nei tumori vescicali infiltranti o localmente avanzati Clinica di Oncologia Medica Ospedali Riuniti Ancona Luciano Burattini

2 CARCINOMA VESCICALE IN ITALIA Nuovi casi maschi : (10,7% di tutti i casi incidenti) Nuovi casi femmine : (2,9% di tutti i casi incidenti) Decessi maschi (2011): (6,5% di tutti i tumori) Decessi femmine (2011): (1,6% di tutti i tumori) Incidenza: primi 5 tumori più frequenti (pool AIRTUM ) Nord-Ovest: M: 66,3; F: 12,0 Nord-Est: M: 67,3; F: 13,1 M: 64,2 F: 11,4 AIRTUM : tassi st. ITA x Centro: M: 50,1; F: 8,9 Sud-Isole: M: 64,2; F: 10,1

3 Chirurgia AIOM 2016

4 Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients. Stein, J. P. et al. J Clin Oncol 2001

5 Recurrence after radical cystectomy

6 Incidence of linphnode metastases in bladder cancer by stage

7 Bladder cancer: 5 yr survival after cystectomy

8 Bladder Cancer: survival after cystectomy

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10 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati

11 Razionale per una strategia terapeutica integrata Terapia neoadiuvante Cistectomia Terapia adiuvante

12 Chemioterapia Il tumore vescicale è una neoplasia chemiosensibile Attività agenti singoli. RR Cisplatino 30% Carboplatino 20% Gemcitabina 20-30% Ifosfamide 20% Paclitaxel 42%

13 Chemioterapia Schemi di combinazione RR CR MVAC 40-75% <20% Gemcitabina/Cisplatino 40-70% 5-15% Gemcitabina/Carboplatino 65% 5% Taxolo/Carboplatino 20-40%

14 Chemioterapia adiuvante - razionale Vantaggi Lo staging patologico consente di predire accuratamente il rischio di recidiva Trattamento della malattia minima residua Chirurgia immediata Svantaggi Ritardo del trattamento delle micrometastasi occulte La risposta non può essere valutata e l unico parametro di riferimento rimane il tempo alla progresisone Difficoltà in molti pazienti ad un trattamento ottimale dopo chirurgia

15 Terapia adiuvante Sei studi randomizzati hanno comparato chemioterapia vs osservazione dopo cistectomia radicale o radioterapia 4 studi non beneficio di sopravvivenza 2 studi beneficio della chemioterapia adiuvante Studi di piccole dimensioni Eterogeneicità di schemi di chemioterapia Solo cisplatino in uno studio Non sempre contemplato ruolo della ct di salvataggio Analisi ad interim con chiusura anticipata studio in alcuni casi METANALISI

16 Terapia adiuvante

17 Terapia adiuvante

18 Terapia adiuvante 491 patients: 3y : + 9% OS (HR = 0.75) P = Can Urol Assoc J (supp4)S:223-7

19 23% reduction in the risk of death for Adjuvant CT Jeow JJ, Eur Urol 2013

20 Final results of EORTC intergroup randomized phase III trial comparing immediate versus deferred chemotherapy after radical cystectomy in patients with pt3t4 and/or N+ M0 transitional cell carcinoma (TCC) of the bladder. Background: Patients (pts) with muscle invasive TCC of the bladder have poor overall survival (OS) due to systemic disease at diagnosis. This randomized intergroup phase III trial compared immediate vs deferred chemotherapy after radical cystectomy in pts with pt3t4 and/or N+ M0 TCC of the bladder. Methods: Within 90 days after cystectomy, pts were randomized to 4 cycles of GC, HD-MVAC or MVAC adjuvant chemotherapy or 6 cycles of deferred chemotherapy at relapse. Main endpoint was OS with PFS a secondary endpoint. Analysis was by intent-to-treat using Cox models stratified by group and adjusted for T stage (pt1t2 vs pt3t4) and nodal status (N- vs N+). Results: 284 of 660 pts were enrolled in 63 sites from 13 countries from 4/2002 to 8/2008 when the trial closed for poor accrual. Follow up (f/u) continued for 5 yrs to 8/2013. Pt characteristics were well balanced in the treatment groups; median age was 61 yrs with similar pt and nodal status (70% N+). Most received GC. Median and maximum f/u is 7.0 and 10.4 yrs in the immediate and 7.2 and 10.6 yrs in the deferred arm. An IDMC reviewed the trial twice and recommended continuation. 176 pts (62.0%) progressed or died, 73 (51.8%) on the immediate and 103 (72.0%) on the deferred arm. Median and 5 yr PFS are 2.9 yrs and 46.8% on the immediate and 0.9 yrs and 29.5% on the deferred arm (p< ). 148 pts (52.1%) died, 66 (46.8%) on the immediate and 82 (57.3%) on the deferred arm. Median and 5 yr OS are 6.8 yrs and 53.6% on the immediate and 4.6 yrs and 47.7% on the deferred arm, HR=0.78 (95.09% CI: 0.56, 1.10, p=0.13). Grade 3/4 AEs in the immediate arm included myelosuppression (26%), neutropenia (38%) and thrombocytopenia (28%). One pt died due to toxicity in the immediate arm. Conclusions: This is the largest reported randomized trial of adjuvant chemotherapy in pts with muscle invasive bladder cancer. Immediate adjuvant cisplatin based combination chemotherapy led to a statistically significant improvement in the secondary endpoint PFS and a non-significant decrease of 22% in the risk of death after radical cystectomy, the primary endpoint. The 2005 IPD meta-analysis should be updated.

21 Terapia adiuvante

22 Effects of adjuvant chemotherapy on hazard ratio for Overall Survival to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients. The 5-year OS was 37.0% (95% CI, 34.3% to 39.7%) vs 29.1% (95% CI, 27.7% to 30.5%) (P,.001). In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively. Galsky MD et al, JClinOncol 2016

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24 Carcinoma della vescica: chemioterapia neoadiuvante RAZIONALE: numerosi studi di fase II negli stadi precoci di malattia 70% di risposte obiettive 25-30% di risposte patologiche complete VANTAGGI determinare in vivo la chemiosensibilità downstaging e downsizing controllo precoce delle micrometastasi sistemiche migliore compliance del paziente alla chemioterapia migliore PS preoperatorio SVANTAGGI possibile overtreatment inevitabile ritardo del trattamento radicale rischio di progressione in caso di malattia non responsiva alla chemioterapia

25 SWOG 8710 (INT0080)

26 SWOG trial Neoadjuvant MVAC vs surgery only (n 307) Disease-specific Survival: 1.66 in favor of chemotherapy (p=.002) Overall Survival: 1.33 in favor of chemotherapy (p=.06) Grossman HB, NEJM 2003

27 85% OS a 5 anni per chi ottiene pt0; (50% T2; 30% T3-T4a)

28 Neoadjuvant chemotherapy: randomized trials

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31 International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA trial. International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. J Clin Oncol 2011

32 The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P =.037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. J Clin Oncol 2011

33 Galsky, Cancer 2015

34 BLADDER CANCER IMPROVING OUTCOMES Selection of patients Better therapies

35 Gene expression profiling (GEP) suggests 3 main subtypes of urothelial cancer Courtesy of E. Cortesi (modified)

36 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati

37 ERCC1 may predict survival in CDDP-treated patients 57 PTS GC (14) GCT (43) Retrospective study Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months)

38 Somatic ERCC2 mutations correlate with cisplatinum sensitivity in muscle invasive urothelial carcinoma Whole-exome sequencing from 50 pts 25 NAC responders 25 NAC non responders To identify somatic mutations in responders ERCC2, nucleotide excision repair gene was the only mutated in responders The lack of normal ERCC2 function may contribute to cisplatin sensitivity SOMATIC ERCC2 MUTATIONS CORRELATE WITH COMPLETE RESPONSE TO CISPLATIN-BASED CHEMOTHERAPY NUCLEOTIDE EXCISION REPAIR PATHWAY DEFECTS MAY DRIVE RESPONSE TO CONVENTIONAL CHEMOTHERAPY Van Allen, Cancer Discovery 2014

39 Mutations in the gene ERBB2 are exclusively present in patients responding to NAC none of 33 nonresponders had ERBB2 mutations Groenendijk, Eur Urol 2015

40 Linee Guida AIOM 2016

41 Linee Guida ASCO-EAU 2016 EAU ASCO

42 Linee Guida ASCO-EAU 2016 EAU ASCO

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44 TRYMODALITY THERAPY TURBT CHEMO RADIATION +/- CISTECTOMY Organ conserving option in invasive bladder cancer

45 Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder- Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233 Mak RH et al - J Clin Oncol 32 (2014) studi 468 pazienti risposta completa 69% follow-up mediano 4.3 a combined-modality therapy can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery

46 Ploussard et al BLADDER PRESERVATION: OUTCOME 60% of surviving patients maintain wellfunctioning bladder (40% of all patients) Salvage cystectomy: 20% 5-year survival rates 50-60% (as surgery) Cystectomy for treatment toxicity < 1%

47 ACUTE TOXICITY of TMT Ploussard et al Grade 3-4: 10%-36% Hematologic GI GU Neuropathy (if cisplatin) 80%-90% completed therapy Higher tox with neoadiuvant chemotherapy LATE TOXICITY of TMT GU GI Grade % 5% Events urgency, nicturia, dysuria diarrhoea, and proctitis

48 Crit Rev Oncol Hematol 2015

49 TRIMODALITY TREATMENT OF MUSCLE-INVASIVE BLADDER CANCER

50 Arcangeli G et al. Crit Rev Oncol Hemat 2015

51 Cumulative results from all evaluated trials CR = Complete response; OS = overal survival; BIS = bladder intact survival (5 Y); SC = salvage cytectomy; LF = local failure Arcangeli G et al. Crit Rev Oncol Hemat 2015

52 Forest plot of Hazard Ratios of outcomes comparing continue vs. split treatment Arcangeli G et al. Crit Rev Oncol Hemat 2015

53 Forest plot of Hazard Ratios of CR and OS in T2 and >T2 Tumors Arcangeli G et al. Crit Rev Oncol Hemat 2015

54 Bladder sparing criteri di selezione Buona funzione e capacità vescicale, no ostruzione severa No idronefrosi, lesioni multiple o CIS No T4 o N+ TURV macroscopicamente completa Compliance

55 Compliance Il paziente deve essere preparato al follow up endoscopico e alle eventuali terapie di salvataggio Alto livello di coordinamento fra urologo, oncologo medico e radioterapista (criteri di selezione, trattamenti integrati, follow-up, terapie di salvataggio)

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57 CHEMIOTERAPIA NEOADIUVANTE CHEMIOTERAPIA ADIUVANTE TERAPIA TRIMODALE

58 GUIDELINES TMT in the WORLD UK 60% USA 10% ITALY 1% Munro, IJROBP 2010

59 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati Immunotherapy in bladder cancer Presented By Nicholas James at Genitourinary Cancers Symposium 2016

60 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati Agents under evaluation Presented By Nicholas James at Genitourinary Cancers Symposium 2016

61 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati IMMUNOTHERAPY FOR BLADDER CANCER 2) Checkpoint Inhibitors/Immune Modulators Atezolizumab (MPDL3280A): A PD-L1 Antibody Muscle Invasive Bladder Cancer -A phase III study of atezolizumab as adjuvant therapy in patients with PD-L1-positive, high-risk muscle invasive bladder cancer after surgery to remove all or part of the bladder (NCT ). -A phase II preoperative study of atezolizumab in patients with transitional cell cancer of the bladder (NCT ). Advanced ormetastatic Bladder Cancer -A phase I/II study of atezolizumab in patients with advanced cancer, including bladder cancer, in combination with varlilumab (CDX-1127), an anti-cd27 antibody (NCT ). -A phase I trial for patients previously treated for metastatic bladder cancer (NCT ). -A phase I study of CPI-444, which targets the adenosine-a2a receptor that suppresses the antitumor activity of immune cells, +/- atezolizumab for patients with advanced cancer, including bladder cancer (NCT ). Atezolizumab (MPDL3280A) was given Breakthrough Therapy designation from the FDA for bladder cancer in June 2014.

62 Ruolo dell' oncologo nei tumori infiltranti o localmente avanzati IMMUNOTHERAPY FOR BLADDER CANCER 2) Checkpoint Inhibitors/Immune Modulators Pembrolizumab (Keytruda, MK-3475): A PD-1 Antibody Non Muscle Invasive Bladder Cancer -A phase II trial for patients with high-risk non-muscle invasive bladder cancer (NCT ). -A phase I trial for patients with high-risk superficial bladder cancer, combined with BCG (NCT ). Advanced ormetastatic Bladder Cancer -A phase II trial after initial chemotherapy for patients with metastatic bladder cancer (NCT ). -A phase II trial for patients with advanced urothelial cancer (NCT ). -A phase I/II trial for patients with advanced cancer, including bladder cancer, combined with PLX3397, a tyrosine kinase inhibitor of KIT, CSF1R, and FLT3 (NCT ). -A phase I trial for patients with metastatic or advanced epithelial cancers, including bladder cancer, in combination with enadenotucirev, an oncolytic virus (NCT ). -A phase I trial plus chemotherapy for patients with recurrent or stage 3-4 bladder cancer (NCT ). -A phase I trial for patients with transitional cell cancer of the urothelium, in combination with ramucirumab (Cyramza ), a VEGFR2 inhibitor (NCT )

63 Conclusioni La ricerca scientifica sta modificando rapidamente la storia del carcinoma della vescica E necessario personalizzare i trattamenti per migliorare la sopravvivenza dei pazienti con malattia ad alto rischio di recidiva o già metastatica Necessità di nuovi trattamenti per i pazienti con malattia muscolo invasiva Importanza dei team multidisciplinari

64 Grazie per l attenzione