Bladder CancerDiagnosis and Treatment

Albert McBride, MD, FICS

EpidemiologyIncidence 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 75% 15% of deaths‒ T2-T4 15%‒ N+, M+ 10%

• Progression‒ 15-20% of patients with NMIBC will progress‒ 18-45% of patients with MIBC will have metastatic disease

85% of deaths

Bladder Cancer: Stage and PrognosisStage 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

TreatmentNon-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 invasiveGoal: 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 therapyBCG 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