bladder cancer 12 2012

BLADDER CANCERAhmed ZeeneldinAssociate Professor of Medical Oncology

INCIDENCE IN USA

¢ 4.5% of cancers¢ M: F: 2.5:1¢ Age: 6th-7th decade

INCIDENCE IN EGYPT

¢ NCI males:¢ 1st , 16%

INCIDENCE

¢ NCI combined:¢ 4th, 4.4%¢ M: F: 4:1¢ Median age:¢ M: 60¢ F: 58

RISK FACTORS

¢ Occupational exposure:ó Aniline dyesó Leather, rubber and paint industries

¢ Schistosoma haematobium:ó Associated with squamous histologyó In Africa and middle east

¢ Smoking¢ Pelvic irradiation¢ Drugs: cyclophosphamide

HISTOLOGY

¢ Urothelial (transitional cell) carcinoma TCC: commonest¢ In situó Papillaryó Flató With squamous metaplasiaó With glandular metaplasiaó With squamous and glandular metaplasia

¢ Squamous cell carcinoma (SCC)¢ Adenocarcinoma¢ Undifferentiated carcinoma

HISTOLOGY IN EGYPT

HISTOLOGY

¢ TCC: 90%¢ SCC: 6-8%¢ Adeno: 2%¢ Small cell: 1%

¢ TCC: 63%¢ SCC: 27%¢ Adeno: 3%¢ Undifferentiated: 2%

US EGY

systemic chemotherapy regimens used to treat TCC are ineffective in pure SCC or AdenoIf mixed tumor only TCC responds

STAGES

TNM STAGING 2010URINARY BLADDER

¢ T0: non-invasiveó Ta: Noninvasive papillary carcinomaó Tis: Carcinoma in situ “flat tumor”

¢ T1: mucosa or submucosa¢ T2: muscle

ó T2a: inner halfó T2b: outer half

¢ T3: outside muscle (adventitia)ó T3a: microscopic (histology, no

massesó T3b: macroscopic (mass)

¢ T4: surroiundingsó T4a: prostate, uterus, vaginaó T4b: pelvic or abdominal

¢ N1: regional LN+ó N1: Pelvic LNs (1)ó N2 : pelvic LNS (>1)ó N3: common iliac LN

¢ M1: Distant mets

T1

T2

T3

T4a

T4b

M1

N0 I II III III IV IVN1-3

IV IV IV IV IV IV

OR M1

SIMPLIFICATION-I: T1 -II: T2-III: T3/T4 a -IV: T4b OR LN+ OR M1

STAGING

T0: non-invasiveTa: Noninvasive papillary carcinomaTis: Carcinoma in situ “flat tumor”

T1: sub-epithelial connective tissueT2: Tumor invades muscle

T2a: inner halfT2b: outer half

T3: Tumor invades perivesical tissueT3a: MicroscopicallyT3b: Macroscopically (extravesical mass)

T4: surroundingsT4a: prostate, uterus, vaginaT4b: pelvic wall, abdominal wall

N1: 1 pelvic LNN2: > 1 pelvic LN N3: common iliac LNM1: distant mets

Tis/0 T1 T2 T3 T4 M1=IV

N0 0 I II III T4a:III

T4b:IV

IV

N1-3 IV

MANAGEMENT OF BLADDER CA

¢ Cystoscopy and biopsy:ó See lesionsó Biopsy and muscle should be includedó We will reach to a conclusion:ó MUSCLE IS INVADED OR NOT

¢ Not invaded àTURB¢ Upper UT imaging¢ CT if sessile or high grade T is suspected

¢ Invaded à CT: ¢ LN small (negative): T2,T3, T4a: cyatectomy¢ LN large: biopsy: negativeó Positive:

NON MUSCLE INVASIVE

Grade Cyctectomy TURB IVsT+ Cystectomy Tis High No Yes BCG Resistent

/relapsedTa Low No Yes May (chemo, mito)

Once? After 6ms

//

Ta high No Yes BCG > Chemo //T1 Low No Yes BCG*

Mito**If residual//

T1 high May Yes BCG*Mito**

if residual//

+ not if extensive TURB or perforation* Whether residual or no residual** chemotherapy only if no residaul

INTRAVESICAL CHMOTHERAPY

¢ Drugsó Chemotherapy

¢ Alkylating agents: thiotepa, mitomycin C (40mg in 20 cc stWater),

¢ Anthracyclines: doxorubicin (50 mg in 25 cc St water), epirubicin, valrubicin

¢ Value:ó Acts by diffusionó Prevent seeding and Reduce recurrence by 6%ó No reduction in disease progression or mortalityó Within 6 Hrs post TUR, Not if extensive TURB or

perforationó Overnight fast, empty bladder beforeó Keep for .5 hr (post TUR) or 2Hrs, supine and prone (air

bubble) ó Alkalanize urine with mitomycin

INTRAVESICLA IMMUNOTHERAPY

ó Immunotherapy¢ BCG (81 mg for TheraCys and 50 mg for TICE, both in 50 cc

physiologic saline)ó Value:

¢ Acts by enhancing immune response, drawing lymphocytes and macrophages to the bladder and stimulating a cellular (TH1) immune response

¢ Not immediate (at least 1-2 wks post TUR)¢ Weekly x 6 w¢ Maintenance ¢ (3 app x q 3ms)¢ 3 weekly at 2, 6, 12, 18, 24, 30, 36 ms XXXX?¢ NOT WITH CIPRO

MUSCLE INVASIVEN Cystectomy Chemotherapy Radiotherapy N- T2* Radical

PartialNo

Neoadj or adjuvantNeoadj or adjuvantCRT

NoMay be used instead of CT CRT

N- T3* Radical

No

Neoadj or adjuvant

CRT

No

CRTN- T4a If possible

1st or after Neoadj

CRT or chemo (Neoadj or adj)


N- T4b If possible after Neoadj



N+ If possible after Neoadj



M1 No Yes may

PROGNOSTIC FACTORS

¢ Stage :ó depth of invasion

¢ Grade:ó Low grade: 1-2ó High grade: 3-4

TREATMENT

ó Taó Tisó T1

¢ Treatment:ó Resection: Repeat TURó +/- intravesical therapy

¢ Grade¢ depth

¢ T2¢ T3¢ T4¢ Treat.ó Resection: cystectomy

¢ Partial or complete

ó Chemo: adjuvant/neoadjó RT:

Non-Muscle-invasive Muscle-invasive

TREATMENT MODALITIES

¢ Resection:ó TURBT: ONLY FOR non-muscle invasiveó Cystectomy:

¢ Partial cystectomy : selected cases of muscle invasion¢ Radical cystectomy: standard treatment of muscle invasive

tumors and as salvage therapy¢ Drug therapy:ó Local (intravesical): ONLY FOR non-muscle invasive

¢ Immunotherapy: BCG or INF¢ Chemotherapy: MMC, Doxorubicin or Valrubicin, thiotepa

ó Systemic (IV) chemotherapy: ONLY for muscle invasive

¢ Radiotherapy: ONLY for muscle invasive

TREATMENT: NON-MUSCLE INVASIVE

¢ Includes: Ta, Tis, T1¢ Tx:ó Repeated TURBó Post TURB intravesical therapy:

¢ depends on grade and depth of invasion that determines:¢ Bladder recurrence risk¢ Progression to muscle invasion risk

¢ Modes:¢ Adjuvant: to prevent bladder recurrence: MAINLY¢ Complementary: to eradicate residual disease: RARELY

ó Cystectomy: rare


¢ Tis (CIS), always high grade¢ Tx:ó TURBó Post TURB intravesical BCG

therapy Weekly x 6 ó Follow up: cystectoscopy +

cytology + imaging of upper Urinary tract q3 m x 24m, then increase intervals

ó Recurrence: ¢ TURB + ¢ Adjuvant intravesical therapy

according to grade and depth of invasion

¢ Follow up: cystectoscopy q3 m


¢ Ta (papilloma), low grade¢ Tx:

ó TURBó Post TURB intravesical therapy:

¢ None¢ Adjuvant intravesical

chemotherapy (Mitomycin C):¢ Single¢ Within 24 Hours form TURB

ó Follow up: cystectoscopy + cytology q3 m x 12 m, then increase intervals




¢ Ta (papilloma), high grade¢ Tx:

ó TURBó Post TURB intravesical therapy:

¢ None¢ Adjuvant intravesical BCG: ¢ Adjuvant intravesical

chemotherapy (Mitomycin C):¢ Single¢ Within 24 Hours form TURB

ó Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then increase intervals




TREATMENT: NON-MUSCLE INVASIVE¢ Persistent or recurrent Ta and Tis

ó TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à still recurrence or persistence at W 24

¢ Tx:ó Cystectomy is the first optionó TURB and Post TURB intravesical therapy may be considered to avoid cyctectomy

¢ Use different agents¢ Chemo: MMC, Valrubicin¢ BCG + INF a¢ Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then q 6m x 24

m¢ Recurrence/persistence: cystectomy

¢ Another scenario:ó TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à CR:ó Maintenance BCG ó Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x

24m, then q 6m x 24 m¢ Recurrence/persistence: TRUB + different IVT or cystectomy


¢ T1 , low riskó No high risk features

¢ Tx:ó TURBó Post TURB intravesical therapy:

¢ Adjuvant intravesical BCG:¢ Adjuvant intravesical chemotherapy

(Mitomycin C):¢ Single¢ Within 24 Hours form TURB

ó Follow up: cystectoscopy + cytology q3 m x 12 m, then increase intervals




¢ T1, high riskó multifocal lesions, ó vascular invasion, ó recurrence after BCG ó High grade.

¢ Tx:ó TURBó Post TURB intravesical therapy:

¢ Adjuvant intravesical BCG: ¢ Adjuvant intravesical chemotherapy

(Mitomycin C):¢ Single¢ Within 24 Hours form TURB

ó Cystectomyó Follow up: cystectoscopy + cytology

+ imaging of upper Urinary tract q3 m x 24m, then increase intervals

ó Persistence after conservative management : ¢ Cystectomy

FOLLOW UP

¢ Low risk lesion: high risk lesions+ Cystoscopy and cytology Cystoscopy and cytology

¢ imaging upper tract¢ q3 m x 12 q3 m x24 ¢ Then increasing q 6m x 24

TREATMENT: MUSCLE INVASIVE DISEASE

¢ Workup:ó Lab: CBC, chemistry, Alk phosó Cystoscopy, EAU/TRUBTó Imaging:

¢ Chest Xray¢ CT/MRI of abdomen and pelvis¢ +/- Bone scan

¢ Aim:ó Organ confined T2, N0, M0ó Non-organ confined T3, T4, N1, M0

ó Metastatic disease M1

Tis/0 T1 T2 T3 T4 M1=IV

N0 0 I II III T4a:III

T4b:IV

IV

N1-3 IV

ORGAN CONFINED (T2) DISEASE

¢ Surgery (cyctectomy):ó Primary Txó radical : standard particularly in recurrenceó Partial (segmental)

¢ More in dome and solitary¢ Less in neck, trigone and multiple or associated Tis

¢ Chemotherapy:ó Cisplatin-based

¢ Neoadjuvant: in T3 or T2 or ¢ Adjuvant : pT3 and pT4 and LN+

¢ RT: ¢ Adjuvant: pT3 and pT4, LN+, SM+ or high grade

¢ Concurrent chemoradiotherapy (CCRT):ó Preoperative: in advanced diseaseó Definitive: in severe comorbidities and poor PSó If CCRT is not tolerable: chemo or radio can be given alone

ORGAN CONFINED (T2 N0)

NON-ORGAN CONFINED (T3, N0)

NON-ORGAN CONFINED (T4 OR N1-3 OR M1)

CYSTECTOMY

¢ Radical cystectomy: standardó Male:

¢ removes bladder, prostate, seminal vesiclesó Females:

¢ Removes bladder and maybe uterus, ovaries and tubesó Pelvic LND:

¢ decreases recurrence and ¢ increase OS

ó Urinary diversion or neobladder¢ Partial systectomy: selective

ó More in dome and solitaryó Less in neck, trigone and multiple or associated Tisó Recurrence after partial cystectomy:

¢ Consider as new cancer¢ Non-M invasive: TURB and IVT¢ M invasive: as usual but do not consider conservation

again

NEOADJUVANT CHEMO

¢ Cisplatin-basedó MVACó CMVó Cis-Gemó Cis-adiaó Cis-Mtx

¢ 3 cycles¢ In T3 (category 1) or T2 (category 2A)

NEOADJUVANT M-VAC CHEMO

¢ Grossman et al, N Engl J Med. 2003;349(9):859-66.

¢ MVAC x 3 q 28dó Mtx: 30 mg sm d1, 15, 22ó Vinblastine: 3 mg sm d2, 15, 22ó Adrai: 30 mg sm d2ó Cisplatin: 70 mg sm d2

¢ T2-T4a¢ Pathological CR: 38%

ADVERSE EVENTS OF MVAC

COMPLICATIONS AFTER SURGERY

Figure 1. Survival among Patients Randomly Assigned to Receive Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) Followed by Cystectomy or Cystectomy Alone, According to an Intention-to-Treat Analysis.

OS in pT0 vs RD

NEOADJ CIS-ADRIA OR CIS-MTX

¢ Sherif et al, Eur Urol 2004;45:297–303.¢ Combined analysis of 2 trials¢ Regimens:ó Cis 70 mg/sm & A 30 mg/sm q 3w x2 + RTó Cis 100mg/m & Mtx 250mg/sm q3w x 3 NO RT

¢ OS HR 0.80 (95% CI 0.64–0.99) in favor of neoadjuvanttreatment.

¢ 5 Y OS was 56% for neoadjuvant and 48% in the control group,

¢ 8% reduction in risk of death.

NEOADJ CMV¢ 967 pts¢ 16% reduction in mortality with NACT

NEOADJUVANT CHEMOTHERAPY FOR TRANSITIONAL CELLCARCINOMA OF THE BLADDER:

A SYSTEMATIC REVIEW AND META-ANALYSIS.

¢ Winquist et al, J Urol. 2004 Feb;171(2 Pt 1):561-9.¢ 11 trials (2,605 patients)¢ Conducted between 1984 and 2002¢ TCC stages II and III (T2-T4, Nx-N3, M0)¢ Pooled HR of death was 0.90 (95% CI 0.82 to 0.99, p =

0.02).¢ Absolute OS benefit of 6.5% (95% CI 2 to 11%) from

50% to 56.5%¢ PFS benefit consistent with OS benefit¢ CR rates: 14-38%, Major Pathological response: 43%¢ Major pathological response was associated with

improved OS in 4 trials

REGIMENS

NEOADJUVANT CHEMO

CONCURRENT CHEMORADIOTHERAPY

¢ Improved local control of invasive bladder cancer by concurrent cisplatin and

preoperative or definitive radiation. The National Cancer Institute of Canada Clinical

Trials Group.

¢ Coppin et al, J Clin Oncol. 1996 Nov;14(11):2901-7.¢ RCT in 99 patients¢ T2 to T4b TCC¢ Randomized to CCRT or RTó (cisplatin 100 mg/m2 at 2-week intervals x 3 cycles

concurrent with pelvic radiation), or RT (radiation without chemotherapy)

DESIGN

CCRT VS RT IN TCC OF BLADDER

¢ Pelvis relapse significantly lower in CCRT¢ Distant relapse were similar¢ PFS better with CCRT (P 0.08)¢ 3 y OS rates 47% in CCRT and 33% in RT (P0.34)

OS & PFS

ADJUVANT CHEMOTHERAPY

¢ Non-urothelial CAó No data in any stage

¢ Urothelial CAó Conflicting dataó Many trials showing benefit are not randomizedó Metaanalysis of 6 trails

¢ 25% mortality reduction¢ But many limitations ¢ Regimens¢ GC¢ MVAC, MVEC¢ CAP

¢ No. of cycles: at least 3

ADJUVANT CHEMOTERAPY FOR TCC OFBLADDER

CHEMOTHERAPY IN METASTATIC TCC

ADJ RT¢ Dat are scarce¢ Possible role in T3a, T3b, T4aó Due to High recurrence (30% that increase to 60% if

SM+)¢ May be given with concurrent cisplatin¢ Adj chemotherapy is also indicated in these cases¢ Adj RT and Adj CT are not give together

BLADDER PRESERVATION

¢ Partial cystectomy alone¢ Chemotherapy then partial cystectomy¢ TUR alone¢ TUR followed byó Chemotherapy and radiotherapy (BEST)

¢ Cisplatin w1, 4 +/-8ó Chemo onlyó Radio only

¢ Indicationsó Urothelial caó Unfit ptsó Refusing pts

bladder cancer 12 2012

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