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UROTHELIAL UROTHELIAL CANCERCANCER

E. Elamin, MDE. Elamin, MD

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Bladder :Bladder : Ureters:Ureters: Renal PelvisRenal Pelvis

50 :50 : 3 :3 : 11

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EpidemiologyEpidemiology

2005: 63,000 new cases (13,000 2005: 63,000 new cases (13,000 death)death)

Male:Female: 3:1Male:Female: 3:1 Incidence: increasing (aging)Incidence: increasing (aging) Age: >65 yrsAge: >65 yrs

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Risk FactorsRisk Factors Smoking: 80% of casesSmoking: 80% of cases Occupational:Occupational:

Aniline Dye, Rubber workers, Painters Aniline Dye, Rubber workers, Painters

Drugs: Drugs: Phenacetin, oral cytoxan Phenacetin, oral cytoxan

Upper U tract TCC: 30-50% risk of Upper U tract TCC: 30-50% risk of bladder cabladder ca

Bladder TCC: 2-3% risk of Upper U Tract caBladder TCC: 2-3% risk of Upper U Tract ca

Chronic irritation/infection:Chronic irritation/infection: Schistosomiasis, UTIsSchistosomiasis, UTIs

Balkan nephropathyBalkan nephropathy

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ScreeningScreening??

Dipstick for microhemturiaDipstick for microhemturiaMessing et al. Urology 45;1995Messing et al. Urology 45;1995

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Clinical presentationClinical presentation

Hematuria (painless)Hematuria (painless) Irritable bladder symptoms: TisIrritable bladder symptoms: Tis Urinary voiding symptoms Urinary voiding symptoms Symptoms of advanced dzSymptoms of advanced dz

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DiagnosisDiagnosis Cystoscopy

Papillary exophyticErythema/edema of mucosa: High

grade, invasive

IVP, Retrograde pyelogram Bimanual exam (EUA) US, CT, Bone scan, MRI

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BiopsyBiopsy

Biopsy of the primary tumor must include Biopsy of the primary tumor must include muscle if possiblemuscle if possible

Biopsy of selected mucosal sites to detect Biopsy of selected mucosal sites to detect possible concomitant Tispossible concomitant Tis

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PATHOLOGYPATHOLOGY

TCC: 90 - 95%TCC: 90 - 95% Sq CC: 3 - 7% Sq CC: 3 - 7%

• Renal pelvis and uretersRenal pelvis and ureters Adeno: < 3%Adeno: < 3%

• Trigone Trigone

• Dome: UrachalDome: Urachal

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Carcinoma in SituCarcinoma in Situ

Usually accompany higher Disease stageUsually accompany higher Disease stage MultifocalMultifocal Considered Aggressive if:Considered Aggressive if:

• Associated with superficial tumorsAssociated with superficial tumors• DiffuseDiffuse

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PROGNOSTIC PROGNOSTIC FEATURESFEATURES

GradeGrade TNM stageTNM stage

• T2 (Muscle invasion): 20-50% 5YST2 (Muscle invasion): 20-50% 5YS

• N +ve: 0-20% 5YSN +ve: 0-20% 5YS

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TNM stagingTNM staging Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Ta Noninvasive papillary tumor Tis Carcinoma in situ: “flat tumor” T1 Tumor invades subepithelial connective

tissue T2 Tumor invades muscle

• pT2a Tumor invades superficial muscle (inner half)

• pT2b Tumor invades deep muscle (outer half)

T3 Tumor invades perivesical tissue• pT3a Microscopically• pT3b Macroscopically (extravesical

mass) T4 Tumor invades any of the following:

prostate, uterus, vagina, pelvic wall, abdominal wall

• T4a Tumor invades prostate, uterus, vagina

• T4b Tumor invades pelvic wall, abdominal wall

Nx Regional lymph nodes cannot be assessed N0 No regional node involvement

N1 Metastasis in a single node, ≤ 2 cm in greatest dimension

N2 Metastasis in a single node, > 2 cm but ≤ 5 cm in greatest dimension; or multiple lymph nodes, none > 5 cm in greatest dimension

N3 Metastasis in a lymph node, > 5 cm in greatest dimension

Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Stage grouping Stage 0a Ta N0 M0 Stage 0is Tis N0 M0 Stage I T1 N0 M0 Stage II T2a N0 M0 T2b N0 M0 Stage III T3a N0 M0 T3b N0 M0 T4a N0 M0 Stage IV T4b N0 M0 Any T N1-N3 M0 Any T Any N M1

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NON-INVASIVENON-INVASIVEWork-upWork-up

Imaging of upper tract collecting system Cytology x 1 Consider pelvic CT before TURBT if sessile

or high grade

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NON-INVASIVENON-INVASIVE

Examination Under Anesthesia (bimanual) TURBT If sessile, high grade or suspicious for CIS:

Random biopsy Consider TUR biopsy of prostate

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Muscle-invasiveMuscle-invasivework-upwork-up

CBC, CMP Chest x-ray Imaging of upper tract collecting system Abdominal/pelvic CT or MRI Examination under anesthesia/cystoscopy TURBT Bone scan if alkaline phosphatase elevated or

symptoms

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METASTATICMETASTATICwork-upwork-up

CBC, CMP Chest CT Abdominal/pelvic CT or MRI Bone scan ECG Creatinine clearance

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TREATMENTTREATMENT

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Superficial Disease Papillary noninvasive (Ta) and T1:

• Few lesions: TUR

• 5 yr Survival rate: 70%

• Multiple, >5 cm, Recurrent, +CIS: TUR +

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Papillary or solid

cTa, G1-2:• Observe or • Single dose intravesical chemo within 24 hours

(not immunotherapy) • Cystoscopy at 3 m

• increasing interval as appropriate

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Papillary or solid cTa, G3 and cT1, G1-2:

• Observe or intravesical chemo• BCG (preferred) or Mitomycin

cT1, G3:• Uncertain complete resection based on:

Size/location No muscle in specimen Inadequate staging Lymphovascular invasion

• Reresect or Cystectomy: If –ve: BCG or Mitomycin If +ve BCG or Cystectomy

• Completely resected: BCG or Mitomycin or Consider cystectomy

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Any CIS/Tis(abnormal mucosa)

BCGBCG Cystoscopy and urine cytology q 3 m for 2 y

Then q 6 m for 2 y then annually

Imaging of upper tract collecting system q 1–2 y Urinary urothelial tumor markers (optional)

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Intravesical TreatmentIntravesical Treatment Indications:Indications:

• Multiple T1Multiple T1• Multifocal Ta, (G2-3)Multifocal Ta, (G2-3)• Diffuse TisDiffuse Tis• Rapidly recurring dzRapidly recurring dz

Cytotoxic agents: Mitomycin, Adriamycin, Cytotoxic agents: Mitomycin, Adriamycin, ThiotepaThiotepa• Reduce recurrence rateReduce recurrence rate

Immune modulator: BCG (Tis)Immune modulator: BCG (Tis)• Decrease progression rateDecrease progression rate

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? Cystectomy for Superficial Dz? Cystectomy for Superficial Dz

Large tumorsLarge tumors Some high G Some high G Impractical TUR Impractical TUR

multiple tumorsmultiple tumors Multiple recurrencesMultiple recurrences

Diffuse Tis unresponsive to intravesical Diffuse Tis unresponsive to intravesical therapytherapy

Prostatic stromal involvementProstatic stromal involvement

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POST-TREATMENT Ta, T1, CISPERSISTANT OR RECURRENT DISEASE

Cystoscopy +ve: TURBT Adj therapy based on tumor and G

Cytology positive, Imaging negative, Cystoscopy –ve:• Random bx:

-ve: Follow-up q 3 m or Maintenance BCG +ve: BCG (maintenance BCG, if complete response)

• If incomplete response: Cystectomy or Other intravesical chemo or immunotherapy

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Recurrence post-intravesical treatment with BCG or MMC; no more than 2 consecutive cycles

CR CR Maintenance BCG (optional) Tis or Ta:

• Change intravesical agent or• Cystectomy

T1G3:• Cystectomy

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Papillary or solidF/UF/U

Cystoscopy and urine cytology q 3 m for 2 y Then q 6 m for 2 y then annually

Imaging of upper tract collecting system q 1–2 y

Urinary urothelial tumor markers (optional)

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PROBABILITY OF RECURRENCE AND PROGRESSION

Pathology Probability of Recurrence Probability of Progression to Muscle-Invasive

Ta, G1 50% Minimal

Ta, G2 50% Low

Ta, G3 60% Moderate

T1, G2 50% Moderate

T1, G3 70% High

CIS 50%–90% High

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Invasive CancerInvasive Cancer CystectomyCystectomy

Partial cystectomy:Partial cystectomy:• Single tumor without CISSingle tumor without CIS

Radical cystectomyRadical cystectomy• Overall 5-ys S:Overall 5-ys S: 50%50%

• Recurrence rate:Recurrence rate: 10-20%10-20%

Bladder preservation:Bladder preservation: TURBT TURBT →→ RT/Chemo RT/Chemo

• Salvage CystectomySalvage Cystectomy

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cT2TREATMENT

Radical cystectomy • consider neoadj chemo in selected pts• Consider adj chemo if no neoadj treatment given

(+ve LN, pT3)

Segmental cystectomy (solitary lesion in a suitable location; no CIS)• Consider adj RT or chemo (+ve LN, +ve margin,

high G, pT3)

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cT2cT2TREATMENTTREATMENT

Selective bladder sparing following maximal TUR (only if no hydronephrosis); Chemotherapy/RT• Evaluate with cystoscopy and TURBT

+ve: Radical cystectomy -ve: Observation and/or Chemo/RT and/or Adj chemo

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cT2cT2TREATMENTTREATMENT

Highly selected pts with extensive comorbid diseases or poor PS:• TURBT alone or RT alone or Chemo alone:

Evaluate with cystoscopy and TURBT

• +ve: Radical cystectomy

• -ve: Observation and/or Chemo+ RT and/or Adj chemo

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If TURBT aloneIf TURBT alone

Aggressive re-resection of the site within 4 weeks of the primary procedure to ensure that there is no residual disease.

If the repeat TURBT is -ve, repeat cysto every 3 months until a relapse is documented.

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RT or Chemotherapy alone RT or Chemotherapy alone is not considered adequate and standard without additional treatment to the bladder and remains investigational

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cT3, N0cT3, N0

Radical cystectomy, consider neoadj chemo:• Consider adj chemo (pT3, +ve LN) if no neoadj

treatment given Selective bladder sparing following maximal

TURBT; chemo/RT:• cystoscopy, cytology and TURBT

-ve: Observe and/or Consolidation chemo/RT and/or Adj chemo

+ve: Cystectomy or salvage therapy

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Bladder-sparingBladder-sparing

Reasonable alternative to cystectomy for pts: who are medically unfit for surgery who seek an alternative

No hydronephrosis. Mets must be excluded. Complete TURBT as safely as possible Exam Under Anesthesia

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Muscle-invasiveConcurrent ChemoRT

Complete TURBT Induction ohase:

• 40 Gy of external beam RT + Two doses of cisplatin on weeks 1 and 4. Repeat cysto:

• If residual disease, a cystectomy is advised. • If is no visible disease and the cytology and biopsy are negative (T0):

Add 25 Gy of external-beam RT + one dose of cisplatin.

70% of pts were rendered tumor-free in the bladder at the initial 70% of pts were rendered tumor-free in the bladder at the initial post-treatment cystoscopy exam.post-treatment cystoscopy exam.• About 1/4 developed a new superficial or invasive lesion requiring About 1/4 developed a new superficial or invasive lesion requiring

additional therapyadditional therapy

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cT4a - T4b, N0cT4a - T4b, N0

Chemo or Chemo/RT:• Good response: Consider consolidation chemo +/-

RT or Surgery

Surgery ± chemo (select cT4a pts only)

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NeoAdj ChemotherapyNeoAdj Chemotherapy

MVACx2->surg ->MVACx3 orMVACx2->surg ->MVACx3 or Surgery -->MVACx5Surgery -->MVACx5

• 58% DFS58% DFS SWOG 8710: Neoadj MVACx3 vs SWOG 8710: Neoadj MVACx3 vs

cystectomy:cystectomy:• 5YS: 57% vs 42%5YS: 57% vs 42%• MS: 6.2 vs 3.8YMS: 6.2 vs 3.8Y

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Always biopsy enlarged LN Always biopsy enlarged LN if technically possible and if technically possible and no distant mets.no distant mets.

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Muscle invasiveMuscle invasiveF/UF/U

LFTs, Cr, electrolytes, C-x-ray q 6-12 m Collecting system imaging at baseline and q 2 y CT at baseline and q 3-6 m for 2 y, then as indicated If bladder sparing:

• cystoscopy + cytology ± biopsy q 3 m x 4, then increasing intervals If cystectomy:

• urine cytology q 6-12 m If cystectomy + cutaneous diversion:

• urethral wash cytology q 6-12 m If cystectomy + continent orthotopic diversion:

• Vit B12 annually

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Muscle invasiveMuscle invasiveRECURRENCERECURRENCE

Local recurrence, Preserved bladder:• Invasive:

Cystectomy or salvage chemo or RT or Palliative TURBT

• Tis, Ta, or T1: Intravesical BCG or cystectomy

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Muscle invasiveMuscle invasiveRECURRENCERECURRENCE

+ve cytology, Preserved bladder (Cystoscopy, EUA, random biopsy -ve):

Retrograde selective washings of upper tract, prostatic urethra biopsy

Metastatic or local recurrence postcystectomy: Chemo and/or RT

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Relapses in the Bladder After Relapses in the Bladder After Bladder-Sparing ApproachesBladder-Sparing Approaches

Invasive disease:• 2nd attempt of bladder preservation is not advisable.• Radical cystectomy:

Salvage cystectomy may not be possible for pts who has received a full course RT (> 65 Gy) and has bulky residual disease.

• salvage non-cross-resistant chemo is advised

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Mets: pN +veMets: pN +ve

Chemo or Chemo/RT:

• Cystoscopy:Cystoscopy: -ve: -ve: Observe or Boost with RT or Surgery +ve: Salvage therapy+ve: Salvage therapy

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High Risk/Locally AdvancedHigh Risk/Locally Advanced(T3-4, vascular invasion, N+ve)(T3-4, vascular invasion, N+ve)

Cystectomy; 20-30% cure rateCystectomy; 20-30% cure rate MVACx2 MVACx2 →→Surg Surg →→ MVACx3 MVACx3 Surg Surg →→ MVAC MVAC

58% DFS58% DFS

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Mets: DisseminatedMets: Disseminated

ChemotherapyChemotherapy

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ChemotherapyChemotherapyMetastatic DiseaseMetastatic Disease

CisCA:CisCA: MVAC: MVAC: RR=39%RR=39%

• MVAC vs CisCA: MVAC vs CisCA: RR = 65% vs 46%RR = 65% vs 46%

CMVCMV CisplatinCisplatin Taxol:Taxol: RR=42%RR=42% CarboTaxol: CarboTaxol: RR=52%RR=52% Gemzar:Gemzar: RR=27%RR=27% Gemzar/Cis:Gemzar/Cis: RR=66%RR=66% TaxolCisIfex:TaxolCisIfex:

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NON-TRANSITIONAL CELL CARCINOMA (TCC)NON-TRANSITIONAL CELL CARCINOMA (TCC)

Same as TCC management with the following issues:• Mixed Histology:

Complete response less likely with bladder sparing• Pure Squamous:

Cystectomy or RT• Adenocarcinoma:

MVAC ineffective Cystectomy or partial cystectomy Consider 5-FU-based therapy Urachal tumors require complete urachal resection

• Small-cell: Neoadjuvant or adjuvant small-cell chemo regimens Local treatment (surgery, RT)

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PRINCIPLES OF CHEMOTHERAPYPRINCIPLES OF CHEMOTHERAPY

MVAC:• Toxicities limit its use• Historical standard of care based on improved survival and

response rates when compared to older regimens. Gemcitabine/cisplatin

• Not inferior to MVAC in terms of survival.• Favorable toxicity profile. • standard 1st choice for most pts.

Alternative Regimens• Cisplatin/paclitaxel• Gemcitabine/paclitaxel• Carboplatin/paclitaxel

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PRINCIPLES OF CHEMOTHERAPYPRINCIPLES OF CHEMOTHERAPY

Adj: At least 4 cycles of a cisplatin-based chemo (eg. M-VAC).

Adj for High Risk pts:• T2 tumors with nodal involvement

• high-G

• transmural invasion, or vascular invasion

• P53 positive

No data support the use of adj chemo for non-TCC, regardless of stage.

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PRINCIPLES OF R.T. OF PRINCIPLES OF R.T. OF INVASIVE DISEASEINVASIVE DISEASE

RT is rarely appropriate for pts with recurrent superficial tumors or diffuse CIS.

Precede RT by maximal TURBT. Concurrent chemoRT is encouraged. Simulate and treat pts with the bladder empty. Use multiple fields from high-energy linear accelerator

beams. Treat the whole bladder with or without pelvic LN with

40-55 Gy and then boost the bladder tumor to a total dose of 64-66 Gy.

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Upper GU Tract Upper GU Tract TumorsTumors

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Renal pelvisRenal pelvis

Operable Low grade:• Nephroureterectomy with cuff of bladder• Nephron-sparing procedure• Endoscopic resection ± postsurgical intrapelvic chemo

or BCG Operable High G, large, or parenchymal invasion:

• Nephroureterectomy with cuff of bladder + regional lymphadenectomy

Metastatic:• Chemotherapy

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TCC ureterTCC ureter Upper:

• Nephroureterectomy with cuff of bladder and regional lymphadenectomy if high G or

• Endoscopic resection Mid Low G:

• Excision and ureteroureterostomy or• Endoscopic resection or• Nephroureterectomy with cuff of bladder

Mid High G:• Nephroureterectomy with cuff of bladder and Regional

lymphadenectomy Distal:

• Distal ureterectomy and reimplantation of ureter or• Endoscopic resection or• Nephroureterectomy with cuff of bladder and Regional

lymphadenectomy if high grade

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Upper GU Tract TumorsUpper GU Tract TumorsAdj TherapyAdj Therapy

pT0, pT1: None

pT2, pT3, pT4, pN+: Consider adjuvant chemo

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Upper GU Tract TumorsUpper GU Tract TumorsF/UF/U

Cystoscopy every 3 m for 1 y, then at increasing intervals

Upper tract imaging 1-2 y Ureteroscopy 3-12 m intervals if endoscopic

resection ± CT scan or MRI ± Chest x-ray

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Urothelial Carcinoma of the ProstateUrothelial Carcinoma of the Prostate

Stromal invasion:• Cystoprostatectomy ± urethrectomy

• Consider adj chemo Ductal + acini:

• Cystoprostatectomy ± urethrectomy or

• TURP and BCG Prostatic urethra:

• TURP + BCG or

• Cystoprostatectomy± urethrectomy for recurrence