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Bladder Cancer Bladder cancer: • 90-95% • • • • Histology 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. 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 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. Bladder cancer: Epidemiology Bladder cancer: Epidemiology 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? • 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+ 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. Bladder cancer: Stage and Prognosis Stage TNM 5-y. Survival 0 Ta/Tis NoMo >85% I II T1 NoMo T2a-b NoMo 65-75% 57% III T3a-4a NoMo 31% IV T4b NoMo each T N+Mo each T M+ 24% 14% med. 6-9 Mo Superficial Bladder Cancer • Histological grading is important G1 G2 G3 Relapse rate 42% 50% 80% Progression rate 2% 11% 45% 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. TREATMENT BY STAGE Radical cystectomy/TURBT Orthotopic bladder replacement (neobladder construction). Figure 3c. Orthotopic bladder replacement (neobladder construction). Catalá V et al. Radiographics 2009;29:461-476 ©2009 by Radiological Society of North America 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 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 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 NEJM 1991;325:1205‐9. J Clin Oncol 1995;13:1404‐8. Superficial Bladder Cancer Adjuvant Therapy • Reduces relpase rate by 30-80% – Doxorubicin weekly 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 J Clin Oncol 1995;13:1404‐8 Case • our patient undergoes a TURBT and then receives intravesicular BCG Invasive bladder cancer • Standard of care = Radical cystectomy with pelvic lymphadenectomy Only about 50% of patients with highgrade invasive disease are cured Results of radical cystectomy Stage T2 T3a T3b T4a NN+ NN+ NN+ NN+ Recurrence-Free 5 y. 10y. Overall Survival 5 y. 10y. 89 50 78 41 62 29 50 33 77 52 64 40 49 24 44 26 87 50 76 37 61 29 45 33 57 52 44 26 29 12 23 20 Stein et al JCO 2001;19:666 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 Chemotherapy for bladder cancer • Bladder cancer is a chemosensitive disease • Active single agents. RR – Cisplatin 30% – Carboplatin 20% – Gemcitabine 20-30% – Ifosfamide 20% Chemotherapy for bladder cancer Combination chemotherapy. – – – – MVAC Gemzar / Cisplatin Gemzar / Carboplatin Taxol / Carboplatin RR CR 40-75% 40-70% 65% 20-40% <20% 5-15% 5% 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 Neoadjuvant chemotherapy • 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) 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. 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 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 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? 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 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. Gemcitabine/Cisplatin vs. M‐VAC phase III study. J Clin Oncol 2000;17:3068‐3077 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. 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. Combined Radio- and Chemotherapy CR 5y.OS • Radiotherapy 57% 47% • RT and cisplatin 85% 69% • RT and carboplatin 70% 57% Birkenhake et al. Strahlenther Onkol 1998;174:121 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 Bladder-sparing protocol Transurthral resection Induction Therapy: Radiation + chemotherapy (cisplatin, paclitacel) Cystoscopy after 1 month no tumor Consolidation: RT + CT tumor cystectomy Bladder-sparing protocol T2: 5y / 10y OS: 74% / 66% T3-T4a: 5y / 10y OS: 53% / 52% Shiply et al. Urology 2002;60:62 Results of bladder-sparing therapy and cystectomy Bladder-sparing n Pat. therapy 5y. OS % 5y. Survival with Bladder % Houssett 1997 120 63 NA Sauer 1998 Shipley 1998 Shipley 2002 Rodel 2002 162 123 190 415 55 49 54 50 44 38 45 42 Dalbagni 2001 181 36 NA Stein 2001 633 48 NA Cystectomy 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 Combined-modality treatment and organ preservation in invasive bladder cancer • Rödel et al. JCO 2002;20:3061 • • • • • Complete remission Local control after CR distant metastasis Disease-specific survival Preservation of bladder 72% 64% (10 y.) 35% (10 y.) 42% (10 y.) >80% Local control Distant metastasis Rödel et al. JCO 2002;20:3061 Disease-specific survival for patients after salvage cystectomy 50% 21% 45% 18% Rödel et al. JCO 2002;20:3061 TUR and adjuvant Radio-Chemotherapy • 5 year Survival 50-65% • Preservation of Bladder 38-43% 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. 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. 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