Bladder Cancer

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Bladder Cancer BY DR / M. ASHOUR

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Bladder cancer is believed to develop primarily as a result of environmental factors Chronic damage to the cells lining the bladder ultimately leads to DNA changes (Somatic Mutation ) in the United States, it is one of the most expensive cancers to treat, costing the government an estimated $3.7 billion per year, mainly because of the rigorous follow-up needed to detect recurrent disease.[2]

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Outline General Review Epidemiology Risk Factors Pathology Staging Presentation Diagnosi s Management NMIBC MIBC

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General Review Epidemiology Incidence :- Accts for > 90% of UG tumors Estimated 386,300 new cases &150,000 deaths reported globally for the year 2008 European Union is 19.5/100 000/year Egypt 17.8 in 100.000 male population Age : > 65 worldwide , 48 Egypt 1979 Sex : 4 th men, 9 th in women (3:1) Geographic distribution : Europe, North America, and Northern Africa Race : 2x > African Americans > Hispanics & Asians

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Risk factors :- Cigarette smoking ( 2-4x higher relative risk) Chemical exposures : A romatic hydrocarbons (in burning, petroleum ,paint ,textiles, dyes pesticide& leather) Cyclophosphamide , Ifosfamide Arsenic ( well water as water near farms and mines) Radiation exposures Chronic inflammation and Irritation (UTI, calculi, neurogenic bladder) Genetic factors ( non inherited , but P53 mutation and 9p21 in 32%) Schistosoma haematobium ( ince . Both SCC, TCC)

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Pathology and staging :- Histopatholgy 3 distinct layers Urothelium , Lamina Propria , Detrusor ( Muscularis Propria )

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Histopathology : TCC (95%) occure at any area in urinary tract 50:3:! (bladder, renal pelvis , ureter ) UB 4 % UTC UTC 40% UB b . Squamous cell. (1-3%) Generally invasive. MET c. Adenocarcinoma (1-2%) – Generally invasive. MET orurachal R d. Small cell carcinoma (< 1%) e. Mixed-histology Gross pathology Exophytic , (P,N,S) endophytic ,(U,D) or mixied

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Tumor Biology & Pathogenesis First hit - it all starts with altered cellular metabolism after exposure to detoxified or partially detoxified carcinogens Oxidative cellular DNA damage is the result Second hit - genetic or acquired cellular failure that promotes tumor, fails to inhibit tumor, or fails to repair oxidized/damaged DNA… Activate oncogenes (RAS gene family) Mutated tumor suppressor genes ( Rb and P53) Damaged APEX-1

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Tumor Biology & Pathogenesis Invasive vs Non-invasive Urothelium - devoid of vessels or lymphatics Lamina propria - rich in both providing a suitable for metastasis and tumor dissemination Behavior (Progression) is primarily grade dependent HG has high recurrence and progression regardless of Ta or T1 status

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Tumor Biology & Pathogenesis Oxidative DNA damage causes chromosomal alterations Low Grade Pathway (Ta papillary tumors) 60% More common Much fewer chromosomal mutations & abnormalities Usually indolent unless convert to high grade pathway Loss of part or all of Chromosome 9 (q) High Grade Pathway (CIS, T1, and muscle invasive) 40% Numerous and variable chromosomal gains and losses Rb & P53 mutations , CH 7, 9, 17 (where p53 is located) Aggressivity : high p53, Ki-67, loss of E- Cadherin Low: No loss of E- Cadherin

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Tumor Biology Two pathway of progression NORMAL UROTHELIUM Ta Ta 9qDel RAS T1 T2-4 N+/M+ 9pDel (INK4A) (Veltman et al Ca Res, 2003 ) Tis T1 T2-4 N+/M+ TP53 RB 5qDel, 3pDel 10qDel, 11pDel, 18qDel 14qDel

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Staging :- TNM and UICC ( clinical & pathological )

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NMIBC :- WHO 2004 & ISUP Risk Category

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75% of all urothelial bladder tumors are NMI Ta (70%) T1 (20% CIS (10%) Pathological prognostic factor for cystoscopic biopsy ) Grade CIS Multicentricity Lymphovascular Invasion Detrouser muscle +_ invasion

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Carcinoma in Situ Ta Ca. Low Grade Ta Urothelial Ca High Grade

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WHO, International Society of Urological Pathology Consensus Classification of Urothelial Neoplasms NMIBC and Grade

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Pathological prognostic factor after cystectomy . Stage , Grade Histopathological type CIS Multicentricity Lymphovascular Invasion NO. of LN resected (10 or less) & NO of + ve node

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Examination:- General Local : DRE under anesthesia

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Dx of Bladder CA Urinary Cytology :- ( 40 – 60 %) sensitivity Sensitivity ø grade. 2. Cystoscopy Indication :- Hematuria + normal imaging unexplained symptoms + ve cytology follow up of bladder cancer Describe tumor :- ( shape , site, size , number, distance from bladder neck , gross type and associated mucosal lesions, condition of the urethra and ureteric orifices Biopsies When carcinoma in situ is suspected (positive cytology in absence of gross tumors) random biopsies (at least 4) are taken from bladder mucosa.

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CTU :- ( to evaluate UTD) OR IVU Non contrast phase ( stone ) Early post contrast ( M after IV, renal lesion, LN) Pyleographic phase ( durig excretion of dye, defect in collecting system) 4. bone scan 5. CXR 6. Bladder tumor antigen 7. Genetic study ( FISH) 8. CBC, LFT, RFT 9. Urine analysis

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Prognosis vs stging Stage TNM 5-y. Survival 0 Ta/Tis NoMo >85% I T1 NoMo 65-75% II T2a-b NoMo 57% III T3a-4a NoMo 31% IV T4b NoMo 24% each T N+Mo 14% each T M+ med. 6-9 Mo

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Management NMIBC MIBC Metastatic bladder CX

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NMIBC Low risk patients ( G1,2 / < 3cm) TUR followed by single instillation of cth. within 24h Intermediated risk (GI,II recurrent ,multiple,> 3cm) TUR followed by multiple instillation of cth about 6 w. High risk ( high grad and CIS ) 20- 40 % have understaged either residual disease no muscle. It is preferred in such patients to repeat cystoscpic resection followed by BCG instillation.

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Intravesical Therapy Urologists should discuss treatment options and associated risks, side-effects, and benefits. A wide variety of agents, combinations, durations, and outcomes are reported. There is a true lack of uniformity regarding optimal doses, number of doses, and timing of instillations for inductions and maintenance therapies The optimal interval nor duration of cystoscopic follow up has been defined.

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Indications of intravasical treatment : Adjuvant ttt (to reduce recurrence by 40% Destroys residual microscopic tumor at the TURBT site Prevent tumor implantation( given post oper .) Delay the need for more aggressive surgical intervention

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induction 6 week alone is insufficient to achieve optimal response. Maintenance decrease progression by 20 -30% ( Lamm and SWOG) after 6 week induction) at 3 months- 3 weekly instillations OR at 6 months- 3 weekly instillations then every 6 months for 3 years (18 more instillations) Side effect : Bladder irritability / spasm, hematuria , dysuria , & rarely systemic TB. Contraindication : infection, hematuria , immunosuppression .

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Mitomycin C Antitumor antibiotic inhibits DNA synthesis Reduces recurrence and progression, although inferior to BCG induction & maintenance Attractive due to much less toxic than BCG 20-40mg/20-40mL of sterile water 6 th weekly injection Intravesical Chemotherapy

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TUR vs. TUR + BCG T1, GIII 153 patients (92 TUR+BCG, 61 TUR alone) 5.3 year median follow up Recurrence rate: a.) BCG: 70% b.) TUR alone: 75% Time to recurrence: .) BCG: 38 months .) TUR alone: 22 months Progression Rate: a.) BCG: 33% b.) TUR alone: 36% No significant Overall Sur:vival difference Shahin et al. J Urol 169: 96-100, 2003

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Overall Survival Recurrence Free Survival Progression Free Survival Shahin et al. J Urol 169: 96-100, 2003

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Maintenance BCG Author # Patients Follow-up Maintenance protocol Randomized Toxicity Recurrence Progression Bedalament et al. 93 22 mos. Monthly x 2 years yes increased No change No change Hudson et al. 80 14 vs. 17 Quarterly BCG x 2 years yes increased No change No change Witjes et al. 49 43 mos. 6 biw + 8 monthly yes Yes 16 pts. Did not complet maintence No change No change Lamm et al. SWOG Tiw BCG @3,6,12,18,24,30,36 mos. yes Decreased No change Lamm et al. SWOG 384 91 vs. 87 mos Weekly at 3,6,12,18,24,30,36 mos. yes yes yes yes

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Maintenance BCG Lamm et al. J Urol, 163: 1124-29, 2000 Recurrence free survival Worsening free Survival Survival P<0.0001 P=0.04 P=0.08 SWOG 8507 BCG given weekly for 3 Weeks at 3,6,12,18,24,30,36 months

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BCG vs. Mitomycin Meta analysis – 11 trials (1421 patients-BCG and 1328 – Mitomycin ) 26 mos median follow-up BCG: 38.6% recurrence Mitomycin : 46.4% recurrence BCG superior to Mitomycin in preventing recurrence Superiority of BCG over Mitomycin in preventing recurrence mostly seen in maintenance BCG trials Bock et al. J Urol 169: 90-95, 2003

T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Survival:

T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Survival Cookson J Urol 158:62, 1997 People not treated by cystectomy continue to die of bladder cancer!

T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Outcomes:

T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Outcomes It has been estimated that between 30% and 45% of bladder cancer deaths could be avoided by earlier implementation of cystectomy in surgically fit patients with NMIBC.

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Clinical Follow-Up Patient History and GU Physical U/A & Cystoscopy 1 st 3 – 6 mo post-TURBT for 2 year then annually Imaging of urinary tract every 1-2 year Urine Cytology (Sensitivity and specificity are high for HG and CIS) Urinary Markers? Many commercially available NMP-22 , BTA TRAK , ImmunoCyt , Urovysion FISH Nuclear matrix protein 22

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Diagnosis of treatment failure Persistent disease at 3 months following induction BCG therapy in high-risk NMIBC. Failure to achieve disease-free status at 6 months following initial BCG therapy with either maintenance or retreatment at 3 months.

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Why Do Patients Recur? Nature of the tumor…(CIS, G3,T1……) Missed tumors at TURBT Incomplete TURBT resection Implantation of shed tumor cells at TURBT A de novo tumor due to a tumor-sensitized, “at-risk” urothelium

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Management of recurrent or peresistant NMIBC Radical cystectomy Indication Micropapillary histology Do not tolerate intravesical therapy Failed attempts at disease control with TURBT +IVT Lesions not amenable to endoscopic resection ( pro.u ) Failure of TURBT and intravesical therapy Recurrence at higher grade and multifocality Progression on intravesical therapy (Grade Progression) Invasion into detrusor (T progression) Especially in HGTa or CIS

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2. Radiation Therapy Has not been studied extensively in NMI Urothelial Ca Initial very good response, short term Not effective long term for Ta or CIS 90% recur in 5 years

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MIBC Surgery = radical cystectomy Neoadjuvant &Adjuvant chemotherpy Neoadjuvant & Adjuvant radiotherapy Baldder conservative managmnet

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Surgery The treatment of choice for muscle-invasive bladder cancer continued for decades to be radical cystectomy .

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Indications for radical cystectomy MIBC without evidence of metastasis or with low-volume, resectable locoregional metastases (stage T2-T3b) NMIBC(Ta,T1,CIS) characterized by any of the following: Refractory to cystoscopic resection and intravesical chemotherapy or immunotherapy Extensive disease not amenable to cystoscopic resection Invasive prostatic urethral involvement Palliation for pain, bleeding, or urinary frequency Primary adenocarcinoma, SCC, or sarcoma

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Modern Radical Cystectomy Radical Cystectomy Removal of bladder with surrounding fat Prostate/seminal vesicles (males) Uterus/fallopian tubes/ovaries/cervix (females) + Urethrectomy Pelvic Lymphadenectomy 1 st Obturator > external iliac > and the internal iliac nodes > presacral . 2 nd commen iliac node. Urinary Diversion Ileal conduit Continent cutaneous reservoir , Orthotopic neobladder

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Urinary Diversion Use of intestinal segment to bypass/ reconstruct/ replace the normal urinary tract Goals: Storage of urine without absorption Maintain low pressure even at high volumes to allow unobstructed flow of urine from kidneys Prevent reflux of urine back to the kidneys Socially-acceptable continence Empties completely “Ideal” diversion has yet to be discovered

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Types of Urinary Diversion ILEAL CONDUIT (incontinent diversion to skin) CONTINENT CUTANEOUS RESERVOIR (continent to skin ORTHOTOPIC NEOBLADDER (continent diversion to urethra ) Figures from www.clevelandclinic.org/health/health-info/docs

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Ileal Conduit ADVANTAGES Simplest to perform Least potential for complications No need for intermittent catheterization Less absorption of urine DISADVANTAGES Need to wear an external collection bag Stoma complications Parastomal hernia Stomal stenosis Long-term sequelae Pyelonephritis Renal deterioration

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Continent Cutaneous Reservoir ADVANTAGES No external bag Stoma can be covered with bandaid DISADVANTAGES Most complex Need for regular intermittent catheterization Potential complications: Stoma stenosis Stones Urine infections

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Orthotopic Neobladder ADVANTAGES No external bag Urinate through urethra May not need catheterization DISADVANTAGES Incontinence (10-30%) Retention (5-20%) Risk of stones, UTI’s Need to “train” neobladder

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Type of Pelvic Lymphadenectomy

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Standard LND Extended LND Pelvic Lymphadenectomy

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Radical Cystectomy OUTCOMES 35-40% will develop a recurrence after surgery Most recur within first 3 yrs after surgery Usually at a distant site Almost all will eventually die from their disease Stein JP, et al. J Clin Oncol 19:666, 2001

radical cystectomy Outcome :

radical cystectomy Outcome Stage Recurrence-Free Overall Survival 5 y 10y. 5 y. 10y. T2 N- 89 87 77 57 N+ 50 50 52 52 T3a N- 78 76 64 44 N+ 41 37 40 26 T3 N- 62 61 49 29 N+ 29 29 24 12 T4a N- 50 45 44 23 N+ 33 33 26 20 Stein et al JCO 2001;19:666

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Factor Affecting Outcome After RC Pathological stage as the most important prognostic factor after RC (Viewing J,1999) Pelvic LN involovment (5-year survival rates ranging between 8 and 35%) Total number of LN resected corelate with the survival rates, even in negative node patients , LN density ( LN density is superior to TNM pathologic nodal staging and to the absolute number of positive lymph nodes DFS, Kassouf 2008.

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Pathological stage Stein JP, et al. J Clin Oncol 19:666, 2001

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Bladder Cancer-specific Survival Probability Years after Radical Cystectomy 100 90 80 70 60 50 40 18 30 20 16 14 8 3 yr. ± SE 7 yr. ± SE 10 yr. ± SE No. LN removed ≥12 78.1 ±1.9% 71.8 ±2.4% 63.6 ± 3.6 NO. LN removed <12 59.2 ±5.1% 44.9 ±6.3% 44.9 ± 6.3 10 0 4 6 10 12 No. lymph node removed ≥12 n=613 No. lymph node removed <12 n=113 Log rank test P<0.0001 Lymph node

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Number of Nodes Sampled Affects Survival in Both Node Negative and Node Positive Patients Node negative Node Positive Herr Urology 61:105, 2003

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Herr et  al. indicated that the probability of detecting lymph node metastases would be clearly correlated with the total number of removed nodes [12]. On the other hand, Abdel-Latif et  al., [11] and Leissner et al. [13] were not able to confirm such a correlation. Many studies reported favorable results (>60% achieved 5-year survival) for patients with pathologically organ-conf ined disease However, the results were significantly worse when reporting upon locally advanced tumors (pT3N0, pT4aN0 or with pelvic nodal involve-

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Tumor size few studies showed that tumor size had a significant effect in determining the distant metastasis-free survival , cancer-specific and all-cause survival, Cheng et al 2000 The histological grade was shown to be a significant prognostic Zaghloul MS 1996 Lymphovascular Invasion as an independent prognostic factor in different studies. Leisser J, A 2003 P53 , P21 , angiogenesis and Rb gene were shown to be strong predictors of disease outcome in postoperative multivariate models that adjusted for the effects of other cell cycle regulators and standard pathologic features . Shariat SF 2004 What are the important of sex , age and histopathological type on out come?

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Analysis SEER data showed The only difference of statistical importance was that adenocarcinoma patients underwent RC at more advanced disease stages than their UC counterparts. Lughezzani G2010. Analysis the same SEER date showed that SCC was also more aggressive than UTC after adjusting for common prognostic factors, such as stage and grade. Scosyrev2009. Ploeg et  al . studied all invasive bladder cancer cases treated in The Netherlands during the period of 1995 and 2006 exclusive (28,807 patients) . The relative survival of adenocarcinoma patients equals that of UTC patients. For stage II and III disease, these patients have better outcomes. SCC patients show worse survival regardless of stage.

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The outcomes of both schistosoma-associated and non associated bladder cancer patients, when compared stage by stage were equal. Ghoneim MA 2008 Rogers et al. reported a 5-year progression-free survival of 60 (± 2%) after RC for TCC and 55 (± 11%) for SCC. This difference was statistically insignificant Therefore, one can cautiously conclude that RC treatment end results were not affected by patients’ sex, age, tumor histology (TCC, SCC or adenocarcinoma) or etiology, but were affected by other prognostic factors. These data emphasized the extreme need to compare the results head to head, and to test all possible variables before reaching a conclusion. Therefore, the need for prospective comparative study is still warranted.

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There are many prognostic models had been emerged by different group and institute to predict out come after RC as useful estimates for recurrence risk and survival outcomes, significant variation within each prognostic group has been observed. The c index is defined by the proportion of all usable patients in which the predictions an outcomes are concordant". 0.5 is the point of differentiation below which is bad concordance above which is good concordance the higher the level the more concordance

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The International Bladder Cancer Nomogram Consortium (2006)

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AJCC staging Pathologic groupings Zaghlol model ( pelvic LN, pathological stage and grade). Ghoneim et  al. and Khaled et  al . model. The International Bladder Cancer Nomogram Consortium (2006)

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Variation In Outcomes Heterogeneity of tumor biology and patient characteristics within each subgroup Models capable of simultaneous evaluation of multiple relevant variable To help patient/clinician decision making with regard to the need of adjuvant therapy

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A total of 12 centers of excellence provided data collected from their institutional databases for analysis of data were on more than 9064 postoperative patients The International Bladder Cancer Nomogram Consortium (2006) Nomograms are statistical models specifically designed to maximize predictive accuracy. Nomograms provide prognostic information based on a combination of variables that allow for a more individualized prediction of outcome. While other predictive models that assign prognosis based on risk groups.

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The predictive accuracy of the constructed international nomogram ( concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P 0.001) or standard pathologic subgroupings ( concordance index, 0.62; P   0.001). Tailoring of treatment

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CI 0.62. CI 0.62. DFS

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(concordance index, 0.75

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Preoperative radiotherapy The rationale for the use of preoperative radiotherapy is to prevent intra operative seeding of tumor cells in the operative field and to sterilize microscopic extensions in the perivesical tissues.

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Meta-analysis of these six randomized trials demonstrated a corrected odds ratio of 0.94 (95% CI: 0.57–1.55), indicating no benefit to preoperative irradiation collectively. Huncharek M, M1998)

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Postoperative radiotherapy Aim : The advantage of dealing with microscopic cells that are easier to sterilize These results emphasized the high rate of disease-free survival and local control rates obtained by adding postoperative radiotherapy to cystectomized patients. The value of post-operative radiotherapy was illustrated in all tumor types and all tested stages Zaghlol etal 2002. Studied 89 patients with bladder cancer presented 1998 to 2001 were treated by radical cystectomy or anterior pelvic exenteration plus postoperative radiotherapy(50Gy /25F)

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Patient selection for PORT Bladder cancer patients who underwent RC within 3–6 months. pathological stages ≥ pT2b–pT4a LN positive or G3 with any muscle invasion pT2a positive safety margin or gross residual disease Good performance status, liver and kidney functions

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Role of neoadjuvant chemotherapy Advantages Better tolerated Less Toxicity Greater dose intensity and more cycles Allows in vivo testing Downstage tumors Disadvantage Delay in cystectomy. Delaly >12 wk had a poorer outcome May increase of the incidence of perioperative morbidity.

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Trial for neoadjuvant chemotherapy

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MRC / EORTC NO . 976 from 106 institutions, Study design: Rndomized to receive CMV neo CT or no CT followed by either RC or RT. Aim : OS Fu : 7,4 yr Result : At 1 st publication after 5.5yr FU showed no survival benefit . However Update of this trial at ASCO 2002 after 7.4 FU showed OS : 5.5% (Survival at 5 yr was 50% versus 44% ( p 0.048) & OS at 8 yr was 43% versus 37%, pCR : 32.5% Chemotherapy arm . NO: increase in postoperative toxcicty

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N Engl J Med 349;9 859-66 August 28, 2003

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Patient Characteristics N Engl J Med 349;9 859-66 August 28, 2003

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MVAC Toxicities Grade  3 (n = 150) N Engl J Med 349;9 859-66 August 28, 2003

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N Engl J Med 349;9 859-66 August 28, 2003

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Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival among Patients Randomly Assigned to Receive (M-VAC) Followed by Cystectomy or Cystectomy Alone, According to an Intention-to-Treat Analysis

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Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival According to Treatment Group and Whether Patients Were Pathologically Free of Cancer (pT0) or Had Residual Disease (RD) at the Time of Cystectomy pCR (38% vs 15%; p < 0.001).

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Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival According to Treatment Group and Whether Patients Had Superficial Muscle Involvement ( Stage T2 Disease) or More Advanced Disease ( Stage T3 or T4a ) (65 mo vs 24 mo).

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Neoadjuvant chemotherapy Meta-analysis of 11 randomised trials (3005 patients) recieved platinum based treatment In patients received single-agent cisplatin chemotherapy, neoadjuvant CT was actually no benefit ; however , In a subset analysis of patients received cisplatin -based combination CT prior to cystectomy , 5% OS benefit from 45% to 50% at 5 yr (HR: 0.86; 95% CI: 0.77–0.95; p = 0.003). 13% reduction in risk of ABC Meta-analysis Collaboration. Lancet 2003;361:1927

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In the EORTC, SWOG, and Nordic studies, the majority of patients were young (median age: 63–65 yr), with excellent performance status and good renal function. The a potential 5% advantage in OS is not great enough to justify giving toxic chemotherapy to all patients before surgery. The results refer only to older chemotherapeutic regimens, as none of the trials employed new drugs such as gemcitabine or the taxanes. The efficacy of the GC combination in the neoadjuvant setting, however, has not yet been proven. What are the problems facing the use of neoadjuvant chemotherapy ?

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Adjuvant chemotherapy Advantages Selection of high risk patients based on pathology of RC. Avoids overtreating with organconfind tumor. NO delay of surgery. Disadvantages Bladder is not preserved . Delay in starting systemic therapy for occult metastases . Response cannot be easily evaluated.

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Adjuvant chemotherapy

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Adjuvant chemotherapy Six randomised trials have compared CT with observation after cystectomy 4x no survival benefit 2x benefit from adjuvant CT  no standard of care node positive disease, lymphovascular invasion, positive margins

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Ongoing trial EORTC with several international groups have begun a large adjuvant trial that will enlist 1,344 patients worldwide. The study will evaluate four cycles of immediate chemotherapy versus therapy at the time of relapse in high-risk patients with pT3-pT4 or node-positive disease. Three different chemotherapy regimens are permitted: MVAC , high-dose MVAC (HD-MVAC), and gemcitabine plus cisplatin ( GC) Finally , We can say from the available data about the adjuvant chemotherapy the result are controversial because of the small sample size and confusing analyses and methodology

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Bladder conservative management Aim of treatment: Preservation of bladder & quality of life. Radical treatment for cancer Indication: Alternative for patients seeking for alternative. palliative option for medically unfit for surgery. Clinical criteria for ideal patients: ESMO guidline Early tumour stage (high-risk T1 disease,T2 <5 cm). Visibly complete TURBT. Absence of associated CIS. NO hydronephrosis . Adequate bladder capacity and function. Cooperative patients for follow up.

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Bladder conservative management The idea of bladder sparing management started Since the late 1980. The strategy based on trimodality approach using maximal TURBT followed by CCRT in two phases with cystoscopic assessment after the 1 st phase if no residual to complete radical CCRT if residual to go for cystectomy. Three centers (University of Erlangen, Germany; MGH, USA; and the University of Paris V, France) together with RTOG . .

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The University of Erlangen : carboplatin, or cisplatine and 5FUdose of 45–54Gy & boost to 55.8–59.4 Gy total dose or cystectomy The University of Paris V, Hopital Necker: TURBT CCRT 5-FU and cisplatin & bifractionated split course. MGH protocols TURBT CCRT cisplatin-based followed by radical RT or cystectomy Bladder conservative management

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After TURBT three preservation protocols are avaliable Full course 2-3 cycles middle of therapy middle of therapy

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Bladder conservative management

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Bladder conservative management

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

Combined-modality treatment and organ preservation in invasive bladder cancer:

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:

Combined-modality treatment and organ preservation in invasive bladder cancer Rödel et al. JCO 2002;20:3061 Complete remission 72% Local control after CR 64% (10 y.) distant metastasis 35% (10 y.) Disease-specific survival 42% (10 y.) Preservation of bladder >80%

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

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

Chemotherapy for bladder cancer:

Chemotherapy for bladder cancer Bladder cancer is a chemosensitive disease Active single agents. RR Cisplatin 30% Carboplatin 20% Gemcitabine 20-30% Ifosfamide 20% Taxol 42- 56% Taxotere 13%

Chemotherapy for bladder cancer:

Chemotherapy for bladder cancer Combination chemotherapy. RR CR MVAC 40-75% <20% Gemzar / Cisplatin 40-70% 5-15% Gemzar / Carboplatin 65% 5% Taxol / Carboplatin 20-40%

TUR and adjuvant Radio-Chemotherapy:

TUR and adjuvant Radio-Chemotherapy 5 year Survival 50-65% Preservation of Bladder 38-43%

Results of radical cystectomy:

Results of radical cystectomy Stage Recurrence-Free /Overall Survival 5 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

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Conclusions Surgery is the cornerstone of treatment for invasive bladder cancer Accurate staging (after surgery) is the most important determinant of prognosis A properly performed lymph node dissection makes a difference Choice of urinary diversion must be individualized for optimal outcomes

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Adjuvant radiotherapy showed some benefit in pT2-pT4a and LN positive and high grade tumor local control and DFS. The role of adjuvant chemotherapy is not well established Neoadjuvant chemotherapy with MVAC or CMV showing Promising result in OS (5%) and dose.not affect morbidty or mortality from cystectomy ispite of increaseing toxicity with CT newer agents may resolve this problem Conclusions

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Bladder-preservation results are comparable to those of RC with the obvious advantage of preservation of the bladder. However, Disadvantages : Salvage cystectomy is required in 25–50% of patients. Poorer survival when comparing early vs delayed cystectomy Salvage cystectomy is associated with higher morbidity, and difficulty in creation of a neobladder. Acute radiation cystitis, proctitis, hematologic toxicity. Conclusion

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Decision and Aim of radiotherapy Patient preparation Type of radiotherapy Technique:- Position & Immobilization 1ry simulation CT planning Target volume delineation Organ at risk delineation Dosimetric calculation Field arrangement Dose description & distribution Plan evaluation Re-simulation Treatment execution and verification Follow up during treatment and after Radiotherapy technique

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The treatment volume initially includes the whole bladder, proximal urethra, and, in male patients, the prostate with the prostatic urethra and the regional lymphatics. The regional lymphatics adjacent to the bladder include hypogastric, external iliac, and obturator lymph nodes. Subsequently, patients receive radiotherapy to a smaller boost volume, which usually includes the bladder with about a 2-cm margin. such as an anterior and two-wedged lateral or posterior oblique

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Position: supine with arms folded across the chest Immobilization: pelvic thermoplastic cast Ankle supports to stabilise the legs and pelvis, and a knee support for comfort. Preperation Urine analysis. Empty bladder and rectum during scanning and treatment Oral contrast is given 1 h before the planning CT scan to show the small bowel. CT simulation Slice thickness 3–5 mm slices from the umblicus to the inferior border of the ischial tuberosities .

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GTV Primary tumour and any extravesical spread) (which is difficult to define on CT alone but MRI/CT fusion CTV GTV and the whole bladder. In patients with tumours at the bladder base, the proximal urethra and in men the prostate and prostatic urethra are included on the CTV. The regional lymphatic hypogastric , external iliac, and obturator lymph nodes PTV CTV with a 1.5–2 cm target volume and some authors recommend a margin of 3 cm from CTV to PTV..

PowerPoint Presentation:

OAR Rectum Femoral heads Small bowel. Recommended dose constraints are: Rectum V50 60 per cent, Femoral heads V50 50 per cent; Small bowel V45 250 cm .

PowerPoint Presentation:

OAR rectum, femoral heads and small bowel. Recommended dose constraints are: rectum V50 60 per cent, V60 50 per cent; femoral heads V50 50 per cent; small bowel V45 250 cm 3 .

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