1. Bladder Cancer

2. Bladder cancer: Histology 90-95%transitional-cell carcinoma 3%squamos-cell carcinoma 2%adenocarcinoma <1%small-cell carcinoma Primary Tumor – Superficial or Muscle Invasive –Superficial Carcinoma ‐ in ‐ situ (CIS) is a flat, intraepithelial carcinoma. It has a high rate of spread to lymph nodes. Papillary tumors are superficial, non ‐ invasive cancers. They are usually low ‐ grade tumors. Muscle ‐ invasive tumors are usually high ‐ grade tumors.

3. RISK FACTORS A. Higher in industrialized countries than in developing countries, B. Smoking ‐ up to 60% of bladder cancers C. Chemicals ‐ α‐ & β‐naphthylamine, 4‐Aminobiphenyl, Benzidine, Chlornaphazine, 4‐Chloro‐otoluidine, o‐Toluidine, 4,4’methylene bis (2‐chloraniline), methylene dianiline, benzidine‐derived azo dyes, phenacetin‐containing compounds. Workers, usually in the rubber paint and dye industries, exposed to the above chemicals are at increased risk of bladder cancer. D. Chronic bladder irritation or infections ‐ usually develop squamous cell tumors

4. SIGNS & SYMPTOMS A. 80% of patients present with painless microscopic or gross hematuria. B. 20% of patients complain of irritation while voiding (frequency, urgency or dysuria). C. Patients with advanced disease may present with symptoms of uremia due to obstruction of one or both kidneys.

5. Bladder cancer: Epidemiology

11. Case A 66 y/o male presents to his primary care physician with the chief complaintsn of urinary frequency. During the work-up, a urinalysis reveals microscopic hematuria. Urine cytology demonstrate suspicious cells. A cytoscopy found a suspicious lesion that was biopsied. The biopsy showed transitional cell carcinoma that invaded the subepithelial connective tissue (T1 lesion), node(-), M(-) What therapy should he receive at the point?

12. 75-85%superficial bladder cancer pTa, pTis, pT1 ( carcinoma in-situ, Papillary) 10-15%muscle-invasive bladder cancer pT2, pT3, pT4 (high grade) 5%metastatic bladder cancer N+, M+

13. Ta, Tis, T1 : Non-muscle invasive bladder cancers are divided into 3 groups: Ta, Tis, and T1 –Ta are noninvasive papillary lesions confined to the urothelium and have not penetrated the basement membrane –Tis : severe cellular dysplasias usually in the absence of tumor formation –T1 : tumors that have penetrated into underlying lamina propria but without any involvement of the muscularis propria.

14. Bladder cancer: Stage and Prognosis StageTNM5-y. Survival 0Ta/TisNoMo>85% IT1NoMo65-75% IIT2a-b NoMo57% IIIT3a-4aNoMo31% IVT4bNoMo24% each TN+Mo14% each TM+med. 6-9 Mo

15. Superficial Bladder Cancer Histological grading is important G1G2G3 Relapse rate42%50%80% Progression rate2%11%45%

16. Natural History of bladder cancer 70-80% presents with superficial tumors Grade 3 tumor are most likely to recur If untreated, 60-70% of CIS will progress Most common sites of metastatic disease are lymph nodes, liver, lung, and bone.

17. TREATMENT BY STAGE

18. Radical cystectomy/TURBT

19. Figure 3c. Orthotopic bladder replacement (neobladder construction). Catalá V et al. Radiographics 2009;29:461-476 ©2009 by Radiological Society of North America Orthotopic bladder replacement (neobladder construction).

20. Superficial Bladder Cancer pTa, pT1, Tis Standard treatment : complete transurethral resection of the bladder tumor (TURBT) Intravesical chemotherapy –as prophylactic or adjuvant therapy after complete endoscopic resection Relapse rate:70%  adjuvant therapy

21. Superficial Bladder Cancer Adjuvant Therapy High grade or T1 disease: – TURBT –intravesical bacillus Calmette-Guerin (BCG) Intravesical immunotherapy for non-muscle invasive bladder cancer –BCG 81 mg (TheraCys) or 50 mg (TICE) in 50 ml sterile saline injected into the bladder through a catheter and held for 2h; weekly for 6wk –Maintenance therapy : at 3, 6, 12, 18, 24, and 36mo after initiation, weekly for 3wk

22. Patients with non‐muscle‐invasive TCC of the bladder (Stage Tis, Ta, T1) treated with TURBT Observation or intravesicular Bacillus Calmette‐Guerin (BCG) –10‐year Progression‐free Rate –BCG (n=43) 61.9% : Control (n=43) 37% (p=0.0063) Non‐muscle‐invasive TCC of the bladder after TURBT were assigned to intravesicular BCG (40 mg weekly x 6 then at 3, 6, 12, 18, 24 months) or intravesicular doxorubicin J Clin Oncol 1995;13:1404 ‐ 8. NEJM 1991;325:1205 ‐ 9.

23. Superficial Bladder Cancer Adjuvant Therapy Reduces relpase rate by 30-80% –Doxorubicinweekly 6-8 w. / monthly 6-12 –Mitomycin C weekly 6-8 w. / monthly 6-12 –BCG weekly 6-8 w. /Mo 3 and 6 BCG Failures –BCG plus interferon :At a median follow‐up of 24 months, 45% of patients in the BCG‐failure groups were disease‐free with the combination

24. J Clin Oncol 1995;13:1404‐8

25. Case our patient undergoes a TURBT and then receives intravesicular BCG

26. Invasive bladder cancer Standard of care = Radical cystectomy with pelvic lymphadenectomy Only about 50% of patients with high- grade invasive disease are cured

27. Results of radical cystectomy StageRecurrence-FreeOverall Survival 5 y.10y.5 y.10y. T2N-89877757 N+50505252 T3aN-78766444 N+41374026 T3bN-62614929 N+29292412 T4aN-50454423 N+33332620 Stein et al JCO 2001;19:666

28. Results of radical cystectomy Stage Recurrence-Free /Overall Survival5 years Organ-confined (<pT2pNo) 73%62% non-organ-confined (>pT2pNo)56%49% Positiv lymph nodes (pT1-4, pN+)33%24% Madersbacher et al JCO 2003;21:690

29. Chemotherapy for bladder cancer Bladder cancer is a chemosensitive disease Active single agents. RR –Cisplatin30% –Carboplatin20% –Gemcitabine 20-30% –Ifosfamide20%

30. Chemotherapy for bladder cancer Combination chemotherapy. RRCR –MVAC40-75%<20% –Gemzar / Cisplatin40-70%5-15% –Gemzar / Carboplatin65%5% –Taxol / Carboplatin20-40%

31. Treatment Options for Muscle Invasion (T2‐T4, Stage II or above) TURBT All muscle invasive tumors : as high-grade urothelial carcinomas For organ‐confined disease, radical cystectomy is the gold standard. – If surgery is not an option, radiation therapy is recommended. –30%– 50%,5‐yr survival rate ( death due to local relapsed. ) Neoadjuvant chemotherapy

32. BA06 trial ( Jco. 2011;29:2171‐2177) – 3 cycles of neoadjuvant (cisplatin, vinblastine, methotrexate) vs observation – 3‐year survival : 55.5% vs 50%, p=0.075, –10‐year survival : 36% vs 30% (p=0.037) Intergroup Study N Engl J Med 2003;349:859‐66 –3 cycles of neoadjuvant M‐VAC followed by cystectomy or cystectomy alone (control). –Median Survival : Neoadjuvant 77 months vs Control 46 months (p=0.06)

33. Neoadjuvant chemotherapy A meta‐analysis of 11 randomized trials –platinum‐based combination chemotherapy Reduce 14% relative risk of death Improvement in 5‐year survival, 45% -> 50% (P =.003) No survival benefit with single‐agent cisplatin. To preserve bladder function and avoid a radical cystectomy ( are combining bladder preserving surgery (TURBT), irradiation and chemotherapy. – None has been compared to radical cystectomy. ( NEJM 1993;329:1377‐82.) Metaanalysis collaboration. Eur Urol. 2005;48:202 ‐ 205.

34. Neoadjuvant chemotherapy Meta-analysis of ten randomised trials (2688 patients) 13% reduction in risk of death 5% absolute benefit at 5 years OS increased from 45% to 50% ABC Meta-analysis Collaboration. Lancet 2003;361:1927

35. Adjuvant chemotherapy Randomized trials have not shown a survival advantage. T3 tumors may receive 3 cycles of adjuvant (chemotherapy or radiation) therapy to delay recurrence Ann Oncol 2006;17 Suppl 5:v118 ‐ 22

36. Case Two years later, he returns to the clinic complaining of abdominal & pelvic pain. A CT scan of the chest and abdomen demonstrate multiple pulmonary nodules & an abdominal mass. Based upon this information, what therapy should he now receive?

37. Treatment options for Advanced Disease (Stage IV) – rarely curable Cisplatin/chemotherapy better than single agent therapy. Cisplatin alone (70 mg/m2) vs M‐VAC (methotrexate 30 mg/m2 IV on days 1, 15, 22; vinblastine 3 mg/m2 IV on days 2, 15, 22; doxorubicin 30 mg/m2 IV on day 2; cisplatin 70 mg/m2 IV on day 2) q 28 days. 19 Response rate Overall Survival (Cisplatin 12% 8.2 months vs M‐VAC 39% (p<0.001) 12.5 months (p=0.002) – M‐VAC therapy : greater incidence of neutropenia, febrile neutropenia, mucositis, and nausea/vomiting. – Long‐term survival benefit for M‐VAC. J Clin Oncol 1997;15:2564 ‐ 69

38. First-line chemotherapy for muscle invasive bladder cancer Gemcitabine and cisplatin : Gemcitabine 1000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 IV on day 1; repeat cycle every 28d for a total of 4 cycles or MTX, vinblastine, doxorubicin, and cisplatin (MVAC): Methotrexate 30 mg/m2 IV on days 1, 15, and 22 plus vinblastine 3 mg/m2 IV on days 2, 15, and 22 plus doxorubicin 30 mg/m2 IV on day 2 plus cisplatin 70 mg/m2 IV on day 2; repeat cycle every 28d for a total of 3 cycles.

39. Gemcitabine/Cisplatin vs. M ‐ VAC phase III study. J Clin Oncol 2000;17:3068‐3077

40. Intravenous Carboplatin/Paclitaxel 23‐26 3 phase II and 1 phase III trial with advanced bladder cancer Limited data for carboplatin substitution Consider in patients “unfit” for cisplatin (PS > 2; CrCl < 60ml/min) 23. J Clin Oncol 1998;16:1844 ‐ 48., 24. Br J Cancer 1997;78:370 ‐ 4. 25. J Clin Oncol 1998;16:1844 ‐ 8. 26. EORTC study 30986. J Clin Oncol. 2012;30:191 ‐ 199.

41. Non‐Platinum Regimens: Paclitaxel & Gemcitabine Phase Ⅱ a. 54 pts with advanced unresectable bladder cancer ; the 65% of patients had no prior therapy. b. Paclitaxel 200mg/m2 on day 1 & gemcitabine 1000 mg/m2 IV on days 1, 8, & 15. repeated q 21 days. J Clin Oncol 2001;19:3018 ‐ 24.

42. Combined Radio- and Chemotherapy CR 5y.OS Radiotherapy57%47% RT and cisplatin85%69% RT and carboplatin70%57% Birkenhake et al. Strahlenther Onkol 1998;174:121

43. Bladder-sparing therapy for invasive bladder cancer High probability of subsequent distant metastasis after cystectomy or radiotherapy alone (50% within 2 years) Radiotherapy im comparison with cystectomy has inferior results (local control 40%) Muscle-invasive bladder cancer is often a systemic disease  combined modality therapy

44. Bladder-sparing protocol Transurthral resection Induction Therapy: Radiation + chemotherapy (cisplatin, paclitacel) Cystoscopy after 1 month no tumor tumor Consolidation: RT + CTcystectomy

45. Bladder-sparing protocol Shiply et al. Urology 2002;60:62 T2: 5y / 10y OS: 74% / 66% T3-T4a: 5y / 10y OS: 53% / 52%

46. Results of bladder-sparing therapy and cystectomy Bladder-sparing n Pat.5y. OS 5y. Survival therapy % with Bladder % Houssett 199712063 NA Sauer 19981625544 Shipley 19981234938 Shipley 20021905445 Rodel 20024155042 Cystectomy Dalbagni 200118136NA Stein 200163348NA

47. Combined-modality treatment and organ preservation in invasive bladder cancer Rödel et al. JCO 2002;20:3061 415 patients with T1 high-risk, T1-4, No-1 Treatment:1. Transurethral resection 2. RT (n=126), RCT (n=289) RT median 54 Gy, CT cisplatin week 1, 5 3. Restaging-TUR

48. Combined-modality treatment and organ preservation in invasive bladder cancer Rödel et al. JCO 2002;20:3061 Complete remission72% Local control after CR64% (10 y.) distant metastasis35% (10 y.) Disease-specific survival42% (10 y.) Preservation of bladder>80%

49. Local control Distant metastasis Rödel et al. JCO 2002;20:3061

50. Disease-specific survival for patients after salvage cystectomy 50% 45% 21% 18% Rödel et al. JCO 2002;20:3061

51. TUR and adjuvant Radio-Chemotherapy 5 year Survival50-65% Preservation of Bladder38-43%

52. Conclusion Superficial tumors have a 5‐year survival rate of > 50%. With muscle invasive carcinoma have a 5‐year survival rate of 20‐50% Regional lymph nodes are involved the 5‐year survival drops to 0‐20% The treatment of advanced metastatic bladder cancer is palliative. – M‐VAC or gemcitabine + cisplatin survival is just over one year.

53. A 65 year‐old male presents with painful urination. Upon work‐up microscopic hematuria is detected and a cystoscopy is performed. He is found to have a stage III bladder cancer with muscle invasion. The best treatment option for this patient after cystectomy would be: A. Observation. B. Intravesicular bcg vaccine. C. Three cycles of neoadjuvant single ‐ agent cisplatin. D. Three cycles of neoadjuvant m ‐ vac followed by radical cystectomy.

54. 2. JM is a 62‐year‐old female diagnosed with stage IV bladder cancer. Her laboratory values are largely unremarkable except for long‐standing chronic renal disease that has resulted in a baseline serum creatinine of 1.9mg/dL. Which of the following is the best treatment option for JM? A. M‐VAC chemotherapy repeated every 28 days with a reduced dose of cisplatin. B. Dose‐dense M‐VAC repeated every 14 days C. Cisplatin on day 2 + Gemcitabine on days 1, 8, and 15 repeated every 28 days D. Paclitaxel on day 1 + Gemcitabine on days 1, 8, and 15 repeated every 21 days