Bladder Cancer Diagnosis and Treatment Albert McBride, MD, FICS Epidemiology Incidence 74,690 new cases in 2014: • Men 56,390 • Women 18,300 Mortality 15,580 deaths in 2014 • Men 11,170 • Women 4,410 2014 • 71,830 new cases of colo-rectal cancer 2020 • Bladder cancer will be the 3rd most common malignancy in men Epidemiology continued • 90% of bladder cancers in the U.S. are urothelial cell tumors. – Squamous cell carcinoma (7%) – Adenocarcinoma (2%) Risk Factors • Risk Factors: – Age • M: median – 72 • F: median – 74 – Cigarette smoking: strongest RF • Attributable risk: 46% • RR of death from Bladder CA – Males: » Current smokers = 3.3; past smokers = 2.1 – Females: » Current smokers = 2.2; past smokers = 1.9 • Smoking cessation: can reduce risk up to 40% (ROLE OF PHYSICIANS!) Risk Factors (continued) • RF’s continued… – Chemicals: • Aniline dyes (color fabrics) • Cyclophosphamide – Occupational: • Aromatic amines (betanaphthylamine, 4-aminobiphenyl, and benzidine) • Painting, leather industries, autoworkers, truck drivers, metalworkers, paper and rubber manufacturers, foundry workers, dry cleaners, dental technicians, hairdressers, and marine engineers • 30-50 years after exposure – Arsenic • Northestern Taiwan (high water arsenic levels) – Exposure to herb Aristolochia fangchi in Chinese herbal weight-reduction supplement Risk Factors (continued) • • • • • Urinary tract infection - SCC Chronic irritation (catheters, bladder stones) -SCC Non-functional bladder – SCC Schistosoma haematobium (SCC, Egypt) Radiation • Lower risk: – increased fluid intake (still controversial) • Rationale: – Increased urine output – Decreased contact time of carcinogens – Dilution of carcinogen concentration – Fruits and vegetables (still controversial) • Cost Analysis: – Predicted life-time cost per patient: $99,270$120,684(best case-worst case scenario) (Avritscher,et al, 2006) – 5-yr net cost: $1B (7th highest all cancers) Tumor Genetics Diagnosis • Signs and symptoms – Asymptomatic – Hematuria: MC (85%) • AUA’s Best Practice Policy Panel on Asymptomatic Microscopic Hematuria : at least 3 RBC’s/hpf from 2 of 3 properly collected specimens. – Irritative voiding symptoms: frequency or dysuria – Flank pain (hydronephrosis?, ureterovesical jxn tumor) • Cystoscopy – Conventional or white light, “gold standard” • Disadvantage: flat lesions (CIS) -> incomplete resection -> recurrence – Flexible: office procedure, w/w/o fulguration of small tumors • Well-tolerated – Fluorescent cystoscopy: [5-aminolevulinic acid (ALA)]: • Visualization of tissue w/high metabolic rate • Improves effectiveness of initial resection in superficial and early invasive CA • Comparison vs conventional cystoscopy – Single-center studies(Denzinger, et al 2007; Filbeck et al, 2002 ) : » Increased recurrence-free survival » Lower residual tumor rate » Overall improved dx – Multicenter study (Schumacher et al, 2010): » No difference in terms of recurrence-free and progression-free survival • Currently not included in the NCCN nor the updated AUA guidelines on management of non-invasive bladder cancer • Imaging – Staging, pretreatment planning – CT: essentially replaced IVP in many centers – MRI: patients with renal failure • Risk of nephrogenic systemic fibrosis (NSF) from gadolinium • More accurate staging • 85% accuracy (non-invasive vs invasive) • 82% accuracy (organ-confined vs nonorgan-confined) • Disadv: overstaging – Especially after recent biopsy or resection (edema and hyperemia) CT scans • Should include abdomen and pelvis, and be done with and without contrast. • May demonstrate extravesical extension, nodal involvement, or metastases. • Cannot differentiate depth of bladder wall invasion and may miss tumors <1cm in size. CT scan Fluorescence cystoscopy Fluorescence cystoscopy Jacobs et al, 2010 • PET (18-FDG): – Detection of early mets or lymph node spread (adv over CT or MRI) – Increased glycolytic activity in neoplastic cells with a high metab rate -> increased 18-FDG uptake – Combined PET/CT imaging (combined PET/CT device): • Functional findings on PET with anatomic structures shown on CT • Diagnosis of metastatic disease – Drieskens et al, 2005: » Sensitivity: 60% » Specificity: 88% » PPV: 75% » NPV: 79% – Kibel et al, 2009: » Prospective study on 43 muscle-invasive bladder cancer patients w/o mets on conventional CT or MRI: » Sensitivity: 70% » Specificity: 94% » PPV: 78% » NPV: 91% » Conclusion: Lower recurrence-free, disease-specific, and overall survival in patients with positive 18-FDG PET/CT Scans Staging • Stage 0: noninvasive papillary carcinoma or CIS • Stage I: involves lamina propria. • Stage II: invasion of muscularis propria or microscopic invasion of perivesical tissue. • Stage III: macroscopic invasion of perivesical tissue or invasion of prostatic stroma/uterus/vagina. • Stage IV: Involvement of pelvic wall/abdominal wall, or any lymph node involvement or metastases. Staging Bladder Cancer: Stage Distribution • Stage Distribution ‒ Ta, Tis, TI ‒ T2-T4 ‒ N+, M+ 75% 15% 10% 15% of deaths 85% of deaths • Progression ‒ 15-20% of patients with NMIBC will progress ‒ 18-45% of patients with MIBC will have metastatic disease Bladder Cancer: Stage and Prognosis Stage TNM 5-yr Survival Occult N+ 0 Ta/Tis N0M0 95% 5% I TI N0M0 65-75% 5% II Ta-b N0M0 57% 18-27% III T3a-4a N0M0 31% 45% IV T4b N0M0 24% 45% T any N+M0 14% T any N any M+ Median OS <9 months Treatment (General Principles) • TURBT (Transurethral resection of bladder tumor) – Initial - Diagnostic, prognostic and often therapeutic • 80 percent of patients with high-risk tumors recur within 12 months – Repeat: to optimize staging, 2 to 6 weeks after initial • • • • • • 30 percent of T1 tumors will be under staged at initial TURBT Bulky high-grade Ta tumor Incompletely resected tumor Any T1 tumor especially if no muscle in resected specimen 34-76% with residual disease Divrik et al, 2006: initial only (+ MMC) vs repeat TURBT (+MMC) – 3-yr recurrence free survival » Later group had 30% higher survival rate Treatment Non-muscle invasive Goal: prevent recurrence and progression decrease mortality • Adjuvant intravesical therapy – permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation 2010 NCCN guidelines indicate use for: • low grade Ta recurrences • High grade Ta and T1 lesions • CIS: Treatment of choice- Bacillus Calmette-Guerin (BCG) Tx: Non-muscle invasive Goal: prevent recurrence and progression decrease mortality – Periop intravesical tx during TURBT • 2007 Update AUA guidelines • meta-analysis of 7 randomized trials comprising 1476 patients (Sylvester, 2004) – – – – 1 immediate instillation intravesical chemo vs TUR alone Outcome: recurrence median follow-up of 3.4 years Either epirubicin, MMC, thiotepa, pirarubicin: » Immediately postop or within 24 hours » No significant difference between chemo agents – 37% vs 48% (p< 0.0001) – Contraindications: » Bladder perforation » Extensive TURBT Adjuvant intravesical therapy BCG immunotherapy BCG shown to delay tumor progression to more advanced stage, decrease subsequent cystectomy and increase overall survival compare to TURBT alone • 6 randomized trials that included 585 eligible patients with Ta or T1 disease – TURBT plus BCG had significantly fewer recurrences at 12 months compared to those managed with TURBT alone (odds ratio 0.30; 95% CI 0.21-0.43) • BCG + IFN-alpha combination ‒ Still controversial results ‒ Not yet recommended in NCCN guidelines Shelley, M.D., Court, J.B., Kynaston, H., Wilt, T.J., Fish, R.G., and Mason, M. (2000). Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev CD001986. • Failure rate (BCG): – 20-40% recurrence rate • 35% success rate after 2nd BCG cycle • ~15% success rate after conventional chemo (Valrubicin) Surveillance • Nonmuscle-invasive – Cystoscopy + Urine cytology: • 1st 1-2 yrs: q 3mos • 3-4 yrs: up to q 6months • >4 years: annually – Upper tract imaging: for high-grade tumors • q1-2 years Surveillance • Muscle-Invasive Disease – 1st 2 yrs: • Urine cytology, electrolyte and creatinine levels, chest xray, A/P imaging q 3-12 months • Urethral washing q 6-12 mos • Vitamin B12 level annually (continent diversion) • Cystoscopy, urine cytology and/or bladder biopsies q3-6 mos x 2 years (bladder-sparing protocols) • Bone scans: only indicated for patients with suspicious bone pains and advance disease (at least pT3 and pN+) – After 2 years: as needed • Tx of Recurrence(Non-muscle invasive): – 2007 Update AUA Guidelines • Cystectomy : tx of choice • Further intravesical therapy (patients who are poor surgical candidates) Tx: Muscle-Invasive • Radical Cystectomy • Robotic Cystectomy • Urinary Diversion • Periop Chemo Ileal Conduit Procedure Figures from Campbell-Walsh Urology, Ninth Edition Indiana Pouch Appendix removed Right colon is opened lengthwise and folded down to create a sphere Figures from Campbell-Walsh Urology, Ninth Edition Modified Hautmann with Studer Chimney http://www.sciencedirect.com/science/article/pii/S0022534701642551 • Radical Cystectomy – – – – – Organ-confined muscle-invasive Ca 5 year survival: 45-66% Operative mortality rate: up to 3% Complication rate: 25-57% (first month post op) Surgery alone (failure rates): • pT2 : 20-30% • pT3: 40-60% • pT4: 70-90% – Delay greater than 12 weeks associated with advanced pathologic stage and decreased survival – concensus: should be done within 3 mos of dx of muscle-invasive disease – Low- vs high-volume hospitals – Low-vs high-volume surgeons – Surgical margin status – No of LN’s removed: higher -> better survival • Minimum: 9-20 nodes • Robotic cystectomy – Potential advantages: • • • • • Lower blood loss Less intraop fluid needs Smaller incisions Reduced bowel exposure Greater ergonomics – Disadvantages: • Less lymph nodes (controversial) • Cost • Urinary Diversion – Options: • Neobladder (47%) – Orthotopic neobladder (50-90% in some centers): » No need for cutaneous stoma and urostomy appliance -> decreased physician reluctance and increased patient acceptance for early cystectomy – Tissue-engineered neobladder: » Still under research » Uses autologous urothelial and smooth muscle cells cultured on biocompatible synthetic or naturally derived substrates • • • • Conduit (33%) Anal(10%) Continent cutaneous(8%) Incontinent cutaneous(2%) – Factors in choosing method: • • • • safety (patient, cancer control) Complications (short , long term) Quality of life Physician experience • Perioperative chemotherapy – Rationale: • 30-50% understaged clinically • pT3/4 or node positive: >50% failure rate after cystectomy – Goal: • • • • Downstage Eradicate micromets Reduce implantation of circulating tumor cells intraop Improve survival – Neoadjuvant Chemo • Grossman et al, 2003: – Intergroup 8710 trial – Cystectomy alone vs neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) – Neoadjuvant gp: » Higher likelihood of eliminating residual cancer in the cystectomy specimen(pT0) » Improved survival • Adjuvant chemo: • Insufficient studies for inclusion in latest recommendations • Theoretical advantages: • • • • Careful patient selection based on P staging Lack of delay to cystectomy Alleviation of patient anxiety Enhancement of chemotherapy against small-volume dse • Disadvantages: • Poor tolerance • Delay in receiving postop chemo due to postop complications ‒ Donat et al, 2009: 30% of patients may have postop complications that might preclude or delay adjuvant chemo • Main disadvantages of chemo regimens: Toxic – MVAC: • • • • Severe granulocytopenia n/v Stomatitis Diarrhea/constipation – Alternative regimens: • G-MVAC (G-CSF + MVAC): no difference in survival • GC (gemcitabine + cisplatin) – Similar efficacy/survival rates but less toxicity » Less neutropenia/mucositis/neutropenic fever • Cisplatin based chemo: – Contraindicated in patients with poor renal function – Alternative: carboplatin • Hussain et al, 2001: PCG (paclitaxel, carboplatin,gemcitabine) – Higher response rate with median survival of 14.7 months Summary/Conclusions • Bladder cancer is one of the most costly cancers from dx until death. • Improvements in diagnosis and treatment of bladder cancer (tumor markers, fluorescent cystoscopy, PET/CT imaging, neoadjuvant chemo, extended lymph node dissection, use of orthotopic neobladder) • A lot of room for improvement in management: – – – – Periop and adjuvant intravesical therapies remain underused (31%) Understaging at time of cystectomy (30-50%) High complication rates after cystectomy (25-57%) Improvement in imaging techniques and molecular markers to improve clinical staging – Neoadjuvant chemo and extended LN dissection underused References • Jacobs, et al. Bladder Cancer in 2010: How Far Have We Come?. CA Cancer J Clin 2010; 60: 244-272 • 2010 NCCN Guidelines for Bladder Cancer • 2007 Update of AUA Guidelines for Bladder Cancer • Glenn’s Urologic Surgery, 7th ed. 2010 • Campbell-Walsh Urology, ninth edition • UCLA State-of-the-Art Urology Symposium, March 2014