Urinary Bladder Cancer

Transcription

1 Fellow GU Lecture Series, 2018 Urinary Bladder Cancer Asit Paul, MD, PhD 01/31/2018

2 Overview Non-muscle invasive bladder cancer Muscle invasive bladder cancer Bladder sparing chemo-radiation therapy T4b bladder cancer Systemic chemo-therapy PD1/PDL1-targeted therapy Non-urothelial bladder cancers

3 Bladder cancer 4 th most frequently diagnosed cancer in American males in times more prevalent in men than women Median age at diagnosis, around 77.3 y 4.7% of all new cancer cases in % of all cancer deaths in % of new cases are non-muscle invasive Even localized disease may not be curative. 5 y Survival rate for metastatic disease 5%

4 Survival by stage: SEER data SEER,

5 Challenges in bladder cancer Elderly patient population with comorbidity & poor tolerance to aggressive treatment Under-staging by TURBT & imaging (retrospective studies showed upstage up to 41%) High recurrence after loco-regional therapy Many patients are not cisplatin-eligible Lack of efficacy from salvage chemotherapy (RR of around 10-15%) Incide nce NMIBC 70-75% 70% MIBC 20% 15% MBC 5% 5% 5 Y survival

6 Morphologic Phenotypes 70% patients present with non-invasive & 30% with muscle invasive bladder cancer. Noninvasive papillary variants are single most common variants (60%).

7 AJCC staging, 2010 (7 th Ed) Level of invasion TNM Stage Ta Noninvasive papillary carcinoma T1N0M0 0a Tis Carcinoma in situ, flat TisN0M0 0is T1 Sub-epithelial connective tissue T1N0M0 I T2 Muscularis propria T2N0M0 II T3 Peri-vesical tissue (T3a: microscopic, T3b: macroscopic) T3N0M0 T4 T4a: prostate, uterus,vagina T4aN0M0 III T4b: pelvic or abdominal wall T4bN0M0 IV III N N1: single. N2: Multiple, N3: to Common iliac Tany Nany M0 IV M1 Distant metastasis Tany Nany M1 IV

8 Urinary Bladder Carcinogenesis Knowles & Hurst, Nat Rev Cancer, 2015

9 Non-muscle invasive bladder cancer

10 T stage 5 y recurrence rate Ta, Low Grade 50% Ta, High Grade 60% T1, Low-grade 50% T1, High grade 50%-70% Tis 50-90% NCCN V2.2015

11 Management of NMIBC TURBT is the mainstay of therapy Post-op intra-vesical therapy (BCG, mitomycin, doxorubicin) is needed for majority of NMIBCs Size, multifocal dz & prior recurrence are predictive of recurrence Close surveillance is critical with cystoscopy & urine cytology Recurrent NMIBCs & T1 high-grade cancers should be considered for cystectomy

12 Patient A A 75 yo M presented with 3 months of painless hematuria. PMHx included CAD with stents, HTN & DM. Cystoscopy shows a 2 cm papillary tumor. CT urogram showed no extra-vesical extension or hydronephrosis. Patient underwent TURBT. Pathology showed pt1 urothelial carcinoma with muscle in the specimen, but not involved What is the next step 1. Intravesical BCG 2. Cystectomy 3. Early repeat TURBT 4. Observation

13 Restaging TURBT: 27-78% patients can be under-staged in initial TURBT. Up to 30% can be upstaged to muscle invasive disease Early repeat TURBT (within 6 weeks) is indicated if Incomplete initial resection No muscle in specimen for high-grade dz Large (3 cm or more) or multifocal lesion Any T1 lesion All HG/G3 lesions, except primary CIS IBG 2011, EAU 2013

14 Patient A, continued Patient A underwent a repeat TURBT in 4 weeks. Pathology showed highgrade T1 tumor with adequate muscle in specimen. There is no evidence of muscle invasion What is the next step: 1. BCG 2. Early cystectomy 3. Intra-vesical chemotherapy 4. Observation

15 Indication for cystectomy in NMIBC Multiple, recurrent, HG tumors HG T1 tumors HG tumors with CIS Micro-papillary variant Muscle invasive on re-resection

16 SWOG-1605 Phase 2 trial of Atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer (Ta/T1/ CIS) Open in VCU Massey Cancer Center 01/2018

17 MIBC & advanced bladder cancer T2-T4a T4b N+ : NA Chemotherapy -> radical cystectomy : Chemotherapy +- radiation : Chemotherapy +- radiation Metastatic : Systemic therapy NCCN V1.2018

18 Cystectomy in muscle-invasive bladder cancer Radical cystectomy is the primary treatment option for ct2, ct3, ct4a disease Should be preceded by neoadjuvant chemotherapy in cisplatin-eligible patients Bilateral pelvic lymphadenectomy is performed along with cystetcomy Partial cystetcomy is an option in carefully selected patient ct2 dz and a solitary lesion no CIS

19 5-year survival after cystectomy

20 Stein, JCO, 2001 While radical cystectomy had an acceptable outcome in bladder-confined disease in this series, there was a high recurrence rate & low-survival in patients with extra-vesical & node-positive disease. Adjuvant chemotherapy did not have an impact.

21 Patient with T2-T4a, MIBC Randomized to MVAC -> RC or RC Improved survival in MVAC->RC vs. RC alone Improved survival in patient with no residual disease after RC (38% vs. 15%, P<0.001) SWOG 8710, Grossman, NEJM, 2003

22 Selected neo-adjuvant randomized trials

23 11 trials, 3005 patients NA platinum-based combination, HR 0.86, P=0.003 Absolute benefit over 5 years, OS 5%, PFS 9% Eur Urology, 2005

24 Neoadjuvant Gem-Cis vs ddmvac/ MVAC: retrospective data Patients with ct2-ct4anomo, 28 centers Median age 63 years ddmvac/ MVAC, 3 cycles Patients Gem-Cis, 3 cycles pcr 29% 31% HR 0. 78, CI ,P=NS Galsky, Cancer, 2015

25 39 patients received 4 cycles of cis/gem prior to cystectomy At cystectomy, pt0 was 26%, <pt2 was 36%, comparable to MVAC (28% & 35%) All GC patients achieving <pt2 remained disease free at 30 months after cystectomy Dash, Cancer, 2008

26 Neoadjuvant Chemotherapy NAC is now standard for MIBC (T2-T4a), but is underutilized, used in about 20% of patients NAC should be offered to all cisplatin-eligible patients Cisplatin should not be substituted by carboplatin NAC has the benefit of down-staging disease, leading to better surgery & survival. Studies showed benefit from several cisplatin-based regimens, such as dd-mvac. MVAC & CMV. Cisplatin & gemcitabine (3 months) is used in USA because of toxicity of MVAC regimen. Phase II data showed feasibility of fractionated cisplatin with gemcitabine in patient with GFR ( Hussain,Cancer Letter, 2012) No data support use of adjuvant chemotherapy in patients with residual disease after NAC

27 Patient B, continued Mr B, A 68 yo patient with DM, HTN, CKD stage II & pt3 bladder cancer underwent radical cystectomy, b/l pelvic lymphadenectomy & ileal conduit. Pathology confirmed pt3, high-grade urothelial Ca with 1 of 3 pelvic LNs (external iliac) positive. Margins were negative. Patient s egfr improved to 60 ml/min at 4 weeks of surgery. Staging work-up was negative for distant metastasis What is the best next step? 1. Adjuvant chemotherapy with carboplatin 2. Adjuvant chemotherapy with cisplatin 3. Adjuvant radiation therapy 4. Observation

28 Who needs additional therapy after cystectomy?

29 Recurrence Survival Based on >9000 patients who received cystectomy and pelvic lymph node dissection in 12 centers J Clin Oncol 2005

30 nav=1&audience=1

31 PENN risk for local failure

32 Leow, Eur Eurology, patients in 9 RCTs pt2-t4a and or N+ HR for OS, 0.77 (CI: ) P=0.049 HR for DFS, 0.66, CI , P=0.014 DFS was more among patient with positive nodal status (P=0.010)

33 5653 patients, National cancer data base, pt3-t4 and or N+ All patient received multi-agent chemotherapy Improvement of OS (HR 0.70, CI ) Improved survival was consistent in all subgroups Galsky, JCO, 2016

34 Randomized adjuvant chemotherapy trials Prospective adjuvant studies in bladder cancer are inconclusive. Meta-analysis of RCTs, retrospective studies & recent data showed benefit of AC in patients (pt3-t4, N+) who did not receive NAC. Most of the benefit were from Cisplatin-based combination chemotherapy (MVEC, GC). Sonpavde, JCO, 2016

35 Role of adjuvant PD1/PDL1 therapy? To open in VCU soon

36 Option for deferred adjuvant treatment: EORTC trial Patient with T3,T4 or N+, following radical cystectomy Immediate adjuvant MVAC (max 4 cycles) or chemo at relapse (max 6 cycles). Median follow-up 7 years Immediate treatment prolonged DFS (HR 0.54, P<0.0001) with 48% disease free at 5 years, compared to 31.8% in deferred group No overall survival benefit in immediate vs. deferred group (5 y OS: 53.6% vs 47.7%) Sternberg, Lancet Oncol, 2015

37 Role of radiation in bladder cancer Settings Post-cystectomy adjuvant Bladder sparing chemo-radiation Definitive chemoradiation Palliative Candidate ct3, N+, positive margin ct2, ct3a T4b uncontrolled hematuria, large bladder mass with pain, oligometastatic lesion, solitary recurrence after cystectomy

38 Post-operative Radiotherapy Retrospective Study from Egypt 61% urothelial, 31% squamous DFS & locoregional control No survival benefit Bayoumi, Ca Manag Res, 2014 Data on adjuvant radiation is limited. Adjuvant radiation is reasonable in selective patients with pt3-t4 patients and patients with +ve surgical margin, because of risk of high local recurrence (32% & 68% respectively)

39 Bladder-preserving chemoradiation therapy Alternative to cystectomy in patients o Who are not a candidate for cystectomy o Who wants to preserve bladder

40 Bladder preserving chemo-radiation o Smaller, solitary tumor o T2 or T3a o Negative LNs o No CIS o No hydronephrosis Chemotherapy used with radiation: Cisplatin, paclitaxel, 5FU+mitomycin, Cisplatin+ Gemcitabine Reported outcome in MIBC: CR 60-80%, 5 y DFS 60-70%, Bladder-intact survival 40-45%, 5 y OS 57%, 10 Y OS 36%

41 Mak, J Clin Oncol, 2014

42 Phase III study Chemo-radiation therapy vs. Radiation alone 360 patients with MIBC Chemo-radiation arm includes: 5FU (500 mg/m2) with F1-5, F Mitomycin (12 mg/m2) D1 Radiation Radiation arm 55 Gy 20F, 64 Gy in 32 F 2 Y locoregional survival, 67% vs. 54%, HR 0.68, P= Y OS: 48% vs. 35%, HR 0.82 GIII-IV toxicity: 36% vs 27.5% BC2001, James, NEJM 2012

43 Meta-analysis of 8 studies including 9,554 patients 5 y or 10 y overall survival and PFS were not different between cystectomy & CMT: Not different Vahistha, Int J Rad Bio Phy, 2017

44 Vahistha, Int J Rad Bio Phy, 2017

45 Bladder Preserving Approach in VCU T2 MIBC Maximal TURBT Concurrent Chemo-radiation RTOG 8903* Pelvic RT daily to 39.6 Gy + cisplatin 100 mg/m2, Q 3 weeks X 2 Re-biopsy CR on Rebiopsy: Consolidation RT to 25.2 Gy + Cisplatin 100 mg/m2x 1 Residual disease on rebiopsy: Cystectomy Close cystoscopic monitoring, q 3 months *Shilpley, J Clin Oncol 1998

46 T4b Bladder cancer NCCN V1.2008

47 Metastatic Bladder Cancer

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49 MBC: 1 st line Gemictabine/Cisplatin is the standard front line in US Split-dose cisplatin is better tolerated Carboplatin can substitute cisplatin in patients with GFR ml/min. RR 30-60%, Median PFS <1 year

50 Chemotherapy in mbc

51 ddmvac vs. MVAC: EORTC Metastatic bladder Ca, 263 patients ddmvac vs. MVAC CR 21% vs. 9%, ORR 62% vs. 50% *7 years updated survival analysis: PFS 9.5 m vs 8. 1 m, HR 0.76 Median OS 15.1 m vs months Progression-free survival Sternberg, J Clin Oncol, 2001 Sternberg. Eur J Cancer, 2006

52 Gem-Cis vs. MVAC: randomized phase III Stage IV, GC (n=203), MVAC (n=202) TTPD, TTF, OS were comparable GC was better tolerated than MVAC More GC patients completed 6 cycles Von Der Mosse, J Clin Oncol 2000

53 GC vs. MVAC: updated survival data Progression-free survival Overall survival Long-term FU confirmed comparable PFS & OS 5 Y OS rate: 13.0% vs. 15.3% (P=NS) Base-line PS & visceral metastasis had the highest impact on survival Von Der Mosse, J Clin Oncol 2005

54 Carboplatin-Gemcitabine in patient cisplatin-ineligible patients: EORTC Carboplatin D1 AUC 4.5 ; Gem D1, 8, Q21 D De Santis, J Clin Oncol, 2009

55 Salvage therapy in Bladder Cancer Sonpavde, Lancet Oncol, 2010

56 Ramucirumab & Docetaxel as 2 nd line: Phase II data Petrylak, J Clin Oncol, 2016

57 Retreatment with cisplatin-based regimen Recurrent Initial response & >6 months off treatment Resistant Refractory Initial response, but recurrence within 6 months of treatment No response, progression while on treatment Retreatment Yes No No Han BJC 2008, Edeline EJC 2012, Lee Cancer Res Treat 2014

58 PD-1/PD-L1 targeted therapy i

59 FDA approved PD1/PDL1 targeted immunotherapy in bladder cancer Drug Target Approval Pemborlizumomab PD1 May 2017 Avelomab PD-L1 May 2017 Dervalumab PD-L1 May 2017 Nivulomab PD-1 Feb 2017 Atezolizumab PD-L1 May 2016

60 PD-1/PD-L1 blockade in metastatic urothelial cancers: Major Trials

61 PD-1/PD-L1 blockade: response across the trials

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63 1 st line: Cisplatin ineligible patients Chism, JNCCN 2017

64 Imvigor: Phase II of Atezolizumab in cisplatin-ineligible patients Balar et al, Lancet Oncol 2017 (Dec 2016)

65 Keynote 052: First-line pembrolizumab in cisplatin-ineligible patients, Phase 2 Balar et al, Lancet Oncol 2017 (Sept 2017)

66 2 nd line in Cisplatin-treated patients Chism, JNCCN 2017

67 Keynote 045: Phase 3 pembrolizumab vs. chemotherapy in platinum-treated patients PD-L1 expression: 10% or more Bellmunt et al, NEJM 2017 (Feb 2017)

68 Grade 3 or more AES: 15% vs 49% Belmunt et al, NEJM, 2017

69 Imvigor 211: Phase III Atezolizumab vs chemotherapy Platinum treated patients Atezolizumab (n=467) vs. Chemotherapy (n=464) of choice (Vinflunine, paclitaxel or docetaxel) Patients with PDL1 5%, OS & PFS were not different ORR 23% vs. 22%, DOR 15.9 m vs. 8.3 m, AES 20% vs. 43% Powles et al, Lancet Oncol 2017 (Dec 2017)

70 Selected Immune-mediated toxicities NCCN Webinar, 2018

71 Bladder cancer: Summary Multidisciplinary discussion is critical NMIBC has high-recurrence rate despite of localized therapy NAC should be considered for all cisplatin-eligible & T2-T4a, N0M0 BC. Cisplatin should not be substituted by carboplatin in NAC setting Radical Cystectomy for T2-T4a, N0M0 AC may be offered for high-risk patients (T3-T4, N+), who did not receive NAC Bladder preservation approach for selective patients (T2), although prospective data vs. cystectomy is lacking Cisplatin-based regimen for metastatic dz. Carboplatin based regimen or immunotherapy are the choices for cisplatin- ineligible patients RR of 2 nd line chemotherapy is low. Five PD1/PD-L1 targeted drugs have been approved for platinum-treated patients. Pembrolizumab showed survival over chemotherapy in 2 nd line setting and is the current standard of care.

72 Non-urothelial bladder cancer Mixed with urothelial Any small cell component: Localized disease Any small cell component: Metastatic disease Pure Squamous Pure adenocarcinoma Treat as Urothelial CA NAC (Cis/etop) -> Cystetcomy or radiation Rx as small cell lung cancer ITP (Ifosfamide/ Paclitaxel/ Cisplatin) No role of NAC/AC, 5 FU, GemFLP