Presentation on theme: "Bladder Cancer Diagnosis and Treatment"— Presentation transcript:
1 Bladder Cancer Diagnosis and Treatment Albert McBride, MD, FICS
2 Epidemiology Incidence 74,690 new cases in 2014: Men 56,390Women 18,300Mortality 15,580 deaths in 2014Men 11,170Women 4,410201471,830 new cases of colo-rectal cancer2020Bladder cancer will be the 3rd most common malignancy in men
3 Epidemiology continued 90% of bladder cancers in the U.S. are urothelial cell tumors.Squamous cell carcinoma (7%)Adenocarcinoma (2%)Most common route of spread is local extension to surrounding tissues.
4 Risk Factors Risk Factors: Age Cigarette smoking: strongest RF M: median – 72F: median – 74Cigarette smoking: strongest RFAttributable risk: 46%RR of death from Bladder CAMales:Current smokers = 3.3; past smokers = 2.1Females:Current smokers = 2.2; past smokers = 1.9Smoking cessation: can reduce risk up to 40% (ROLE OF PHYSICIANS!)
5 Risk Factors (continued) RF’s continued…Chemicals:Aniline dyes (color fabrics)CyclophosphamideOccupational: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 engineers30-50 years after exposureArsenicNorthestern Taiwan (high water arsenic levels)Exposure to herb Aristolochia fangchi in Chinese herbal weight-reduction supplementThere are over 60 known carcinogens and reactive oxygen species present, including 4-aminobiphenyl (4-ABP), polycyclic aromatic hydrocarbons, N-nitroso compounds and unsaturated aldehydes
10 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 dysuriaFlank pain (hydronephrosis?, ureterovesical jxn tumor)
11 Cystoscopy Conventional or white light, “gold standard” Disadvantage: flat lesions (CIS) -> incomplete resection -> recurrenceFlexible: office procedure, w/w/o fulguration of small tumorsWell-toleratedFluorescent cystoscopy: [5-aminolevulinic acid (ALA)]:Visualization of tissue w/high metabolic rateImproves effectiveness of initial resection in superficial and early invasive CAComparison vs conventional cystoscopySingle-center studies(Denzinger, et al 2007; Filbeck et al, 2002 ) :Increased recurrence-free survivalLower residual tumor rateOverall improved dxMulticenter study (Schumacher et al, 2010):No difference in terms of recurrence-free and progression-free survivalCurrently not included in the NCCN nor the updated AUA guidelines on management of non-invasive bladder cancer
12 Imaging Staging, pretreatment planning CT: essentially replaced IVP in many centersMRI: patients with renal failureRisk of nephrogenic systemic fibrosis (NSF) from gadoliniumMore accurate staging85% accuracy (non-invasive vs invasive)82% accuracy (organ-confined vs nonorgan-confined)Disadv: overstagingEspecially after recent biopsy or resection (edema and hyperemia)
13 CT scansShould 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.Replacing IVP as the procedure of choice. Previously included delayed images to identify defects in the collecting system, but with the use of CT urograms this is no longer an issue.
16 Fluorescence cystoscopy Fluorescence cystoscopy uses an intravesical photoactive substance (such as 5-aminolevulinic acid, that is preferentially taken up by neoplastic tissue, allowing enhanced visualization between normal and neoplastic tissue using violet light( nm).Randomized trials have confirmed that fluorescence cystoscopy detects more tumors than white light cystoscopy. The drawbacks are that there is a slightly higher false positive rate and a higher cost. It remains investigational in the United States.
19 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
20 Combined PET/CT imaging (combined PET/CT device): Functional findings on PET with anatomic structures shown on CTDiagnosis of metastatic diseaseDrieskens 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
21 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.
24 Bladder Cancer: Stage Distribution Ta, Tis, TI 75% % of deathsT2-T4 15%N+, M+ 10%Progression15-20% of patients with NMIBC will progress18-45% of patients with MIBC will have metastatic disease85% of deaths
25 Bladder Cancer: Stage and Prognosis TNM5-yr SurvivalOccult N+Ta/TisN0M095%5%ITI65-75%IITa-b57%18-27%IIIT3a-4a31%45%IVT4b24%T anyN+M014%N any M+Median OS <9 months
26 Treatment (General Principles) TURBT (Transurethral resection of bladder tumor)Initial - Diagnostic, prognostic and often therapeutic80 percent of patients with high-risk tumors recur within 12 monthsRepeat: to optimize staging, 2 to 6 weeks after initial30 percent of T1 tumors will be under staged at initial TURBTBulky high-grade Ta tumorIncompletely resected tumorAny T1 tumor especially if no muscle in resected specimen34-76% with residual diseaseDivrik et al, 2006: initial only (+ MMC) vs repeat TURBT (+MMC)3-yr recurrence free survivalLater group had 30% higher survival rate
27 Treatment Non-muscle invasive Goal: prevent recurrence and progression decrease mortalityAdjuvant intravesical therapypermits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation2010 NCCN guidelines indicate use for:low grade Ta recurrencesHigh grade Ta and T1 lesionsCIS: Treatment of choice- Bacillus Calmette-Guerin (BCG)BCG is an attenutatedNational Comprehensive Cancer NetworkBCG is administered weekly for 6 weeks.
28 Tx: Non-muscle invasive Goal: prevent recurrence and progression decrease mortalityPeriop intravesical tx during TURBT2007 Update AUA guidelinesmeta-analysis of 7 randomized trials comprising 1476 patients (Sylvester, 2004)1 immediate instillation intravesical chemo vs TUR aloneOutcome: recurrencemedian follow-up of 3.4 yearsEither epirubicin, MMC, thiotepa, pirarubicin:Immediately postop or within 24 hoursNo significant difference between chemo agents37% vs 48% (p< )Contraindications:Bladder perforationExtensive TURBT
29 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 alone6 randomized trials that included 585 eligible patients with Ta or T1 diseaseTURBT plus BCG had significantly fewer recurrences at 12 months compared to those managed with TURBT alone (odds ratio 0.30; 95% CI )BCG + IFN-alpha combinationStill controversial resultsNot yet recommended in NCCN guidelinesShelley, 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 CD
30 Failure rate (BCG): 20-40% recurrence rate 35% success rate after 2nd BCG cycle~15% success rate after conventional chemo (Valrubicin)
31 Surveillance Nonmuscle-invasive Cystoscopy + Urine cytology: 1st 1-2 yrs: q 3mos3-4 yrs: up to q 6months>4 years: annuallyUpper tract imaging: for high-grade tumorsq1-2 years
32 Surveillance Muscle-Invasive Disease 1st 2 yrs: Urine cytology, electrolyte and creatinine levels, chest xray, A/P imaging q 3-12 monthsUrethral washing q 6-12 mosVitamin 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
33 Tx of Recurrence(Non-muscle invasive): 2007 Update AUA GuidelinesCystectomy : tx of choiceFurther intravesical therapy (patients who are poor surgical candidates)
37 Ileal Conduit Procedure 15-20 cm of small intestine (ileum) is separated from the intestinal tractIntestines are sewn back together (re-establish intestinal continuity) ~ cm of terminal ileum is preserved to prevent malabsorption of B12The ureters that drain the kidneys are then sewn into one end of the ileum – either through bricker technique as shown or wallaceAnd the other end is brought up to an opening on the abdomen as a stoma.The intestine naturally has a propulsive movement, almost like a snake, that normally would be moving food through the GI tract, but in this instance, is pushing the urine through the segment and out of the body.Figures from Campbell-Walsh Urology, Ninth Edition
38 Indiana Pouch Appendix removed Right colon is opened lengthwise and folded down to create a sphereThe Indiana Pouch is probably the most commonly used cutaneous reservoir.Here, the right colon and ileum are isolated. The appendix is removed.The right colon is opened lengthwise and folded down to create a sphere.Figures from Campbell-Walsh Urology, Ninth Edition
39 Modified Hautmann with Studer Chimney Neourethra formation and folding and anastamosis
41 Radical Cystectomy Organ-confined muscle-invasive Ca 5 year survival: %Operative mortality rate: up to 3%Complication rate: % (first month post op)Surgery alone (failure rates):pT2 : %pT3: %pT4: %Delay greater than 12 weeks associated with advanced pathologic stage and decreased survivalconcensus: should be done within 3 mos of dx of muscle-invasive diseaseLow- vs high-volume hospitalsLow-vs high-volume surgeonsSurgical margin statusNo of LN’s removed: higher -> better survivalMinimum: nodes
43 Urinary Diversion Options: Factors in choosing method: 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 cystectomyTissue-engineered neobladder:Still under researchUses autologous urothelial and smooth muscle cells cultured on biocompatible synthetic or naturally derived substratesConduit (33%)Anal(10%)Continent cutaneous(8%)Incontinent cutaneous(2%)Factors in choosing method:safety (patient, cancer control)Complications (short , long term)Quality of lifePhysician experience
44 Perioperative chemotherapy Rationale:30-50% understaged clinicallypT3/4 or node positive: >50% failure rate after cystectomyGoal:DownstageEradicate micrometsReduce implantation of circulating tumor cells intraopImprove survival
45 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
46 Adjuvant chemo:Insufficient studies for inclusion in latest recommendationsTheoretical advantages:Careful patient selection based on P stagingLack of delay to cystectomyAlleviation of patient anxietyEnhancement of chemotherapy against small-volume dseDisadvantages:Poor toleranceDelay in receiving postop chemo due to postop complicationsDonat et al, 2009: 30% of patients may have postop complications that might preclude or delay adjuvant chemo
47 Main disadvantages of chemo regimens: Toxic MVAC:Severe granulocytopenian/vStomatitisDiarrhea/constipationAlternative regimens:G-MVAC (G-CSF + MVAC): no difference in survivalGC (gemcitabine + cisplatin)Similar efficacy/survival rates but less toxicityLess neutropenia/mucositis/neutropenic fever
48 Cisplatin based chemo: Contraindicated in patients with poor renal functionAlternative: carboplatinHussain et al, 2001: PCG (paclitaxel, carboplatin,gemcitabine)Higher response rate with median survival of 14.7 months
50 Summary/ConclusionsBladder 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 stagingNeoadjuvant chemo and extended LN dissection underused
51 ReferencesJacobs, et al. Bladder Cancer in 2010: How Far Have We Come?. CA Cancer J Clin 2010; 60:2010 NCCN Guidelines for Bladder Cancer2007 Update of AUA Guidelines for Bladder CancerGlenn’s Urologic Surgery, 7th edCampbell-Walsh Urology, ninth editionUCLA State-of-the-Art Urology Symposium, March 2014