By

Dr.Turky Al-MouhissenR4 Urology Resident

KKNGH

Invasive & metastatic bladder cancer

Clinical presentation and evaluationAxial imagingRadical cystectomy for invasive bladder Ca.Adjuncts to standard surgical therapyAlternative to standard therapyManagement of metastatic bladder Ca.Local salvage & palliative therapy

Outline:

Presentation:

hematurea (Gross / microscopic) 80%

Irritative voiding symptoms

Constitutional symptoms

Metastatic symptoms

Clinical presentation, Diagnosis & evaluation

TUR:

Defines detrusor invasion

Once histological diagnosis of invasion made,

noninvasive imaging may provide extent of

tumor

Pt with suspected invasive lesion before TUR,

axial imaging should be performed prior to

resection

Bimanual examination:

Sensitive & inexpensive for evidence of extravesical extension

Usually under anesthesia Bimanual palpation of bladder before & after

resection has been correlated with stage of lesion

Wijkstrom & colleages (1998) suggested that presence of palpable mass after TUR correlates significantly with stage T3 and prognosis after treatment

Restaging TUR:

Reduction of stage to p(O) by a 2nd TUR associated with favorable long term survival in selected pts (Herr, 1999)

Other Authors disagreed (Thrasher et al, 1994)

Recommended when definitive muscle invasion has been identified + the pt is candidate for alternative s to standard surgical intervention

CT:

Most commonly employed for stagingTends to understage advanced diseaseLike other imaging technique, can`t identify

microscopic extravesical extensionCorrelation of CT findings with pathologic

findings of cystectomy is 65-80% (kellett et al, 1980)

CT detects metstatic disease in regional LN in 50-85%

Axial imaging

MRI

Ideal for pts with renal insufficiency or contrast allergy

Failure to detect microscopic nodal disease with MRI is similar to that with CT

(tavaras and Haricak, 1990; Jagar et al, 1996)

Understaging & overstaging remain persistent problems with both CT & MRI, occurs in about 30%

(buy et al, 1988; kim et al, 1994)

Bone scan:

Several studies 1980-1990 support the impression that preop. Bone scan is not necessary for pts with clinically organ confined muscle invasive bladder Ca.

Pts who have signs & symptoms of bone mets, bone scan is suggested

Braendengen & colleages (1996) retrospectively evaluated 337 pts with T2 or higher treated in Norway 1980-1990.

Half of them had precystectomy bone scan, and 41% developed bone mets after surgical treatment

These investigators noted that ALP levels didn`t provide additional information regard to bone mets

They recommended that abnormal Bone scan to be correlated with MRI to increase diagnostic accuracy (Davey at al, 1985)

Positron Emission Tomography:

PET scan is based on the uptake of flurodeoxyglucose by tumor cells

Success in identifying malignant lymphadenopathy has been greater than that in staging bladder lesions

Reason is that the [flurodeoxyglucose tracer] in urine obscures details adjacent to bladder lumen ( can be partially overcomed by continuous irrigation

duriing the study)

Laparoscopic Staging:

Caution has been advised by those who have noted a significant incidence of port site recurrence in pts with bladder Ca. undergoing lap. Pelvic node dissection compared with comparable group of pts with prostate Ca. (Elbahnasy et al 1998)

Larger studies required especially with the advance of techniques facilitating

completely intracorporeal lap. / Robotic assisted cystectomy

The standard surgical approaches to muscle invasive nonmetastatic bladder TCC is

Radical cystoprostatectomy in male & anterior exenteration in female + en bloc pelvic lymphadenectomy

Metastatic bladder Ca. or pts with significant comorbidities alternative approaches

pts with local symptoms might be candidate for palliative cystectomy

Radical Cystectomy

Selected Series No. of Patients P2 P3 P4a N+Mathur 58 72 40 29 NAMontie 99 62 57 75 NAGiuliani 202 75 19 0 NASkinner 197 64 44 36 44

Malkowicz 160 76 NA NA NAWishnow 71 ∼80 NA NA NAWaehre 227 79 36 29 22

Schoenberg 101 84 56 NA 48Ghoneim 1026 66 31 19 23

Bassi 369 63 33 28 15

Efficacy of cystectomy% Disease-Specific Survival by Pathologic Stage after Radical Cystectomy with & without Pelvic Lymph Node Metastasis: Selected Series (1980-1999)

B/L pelvic lymphadenectomyIn male:

prostate & bladder en bloc +/- nerve sparing, +/- urethrectomy

In female: anterior exenteration requires removal of

uterus, fallopian tubes, ovarries, bladder, and a segment of anterior vaginal wall

+/- urethra sparing, +/- vaginal preserving

Surgical points in cystectomy

Usually feasible to preserve the neurovascular bundles during cystectomy As TCC doesn`t frequently extend beyond

prostate

Unless the primary bladder Ca. is extensive

If any question regarding tumor involvement, wide excision of the neurovascular bundle on the ipsilateral side of tumor is done

Nerve-Sparing Approach in male:

In the past, both ovaries & much of vagina were often excised with no potential of sexual function

In younger pts, it `s possible to leave one ovary and to reconstruct the vagina

Sexual function can be maintained

Majority of surgical candidates, urethral, vaginal, and cervical involvement is unusual exceptPts with extremely large tumorsTumors involving bladder neckDiffuse CISLocally / regionally advanced tumors (Schoenberg et al,

1999)

Vagina-Preserving Approach:

The incidence of urethral recurrence has been documented 4%- 18% (Darson et al, 2000)

( 7.9% reported by Skinner & Colleages)

Prostatic urethral involvement by Ca. is the most significant factor in anterior urethra recurrence

Estimated 5 year probability of urethral recurrence 5 % without any prostatic involvement 12 % with superficial prostate involvement18 % with deep prostate involvement (stein et al, 2005)

Male urethra:

CIS of bladder neck & trigone was also significantly associated with prostatic urethra involvement in this study

(wood et al, 1989)

Some reported the significance of prostatic stromal invasion in ant. Urethral recurrence64 % those with stromal invasion25 % with prostatic ducts0 % with prostatic urethral urethelium (hardeman and Solowa, 1990;

levinson et al, 1990)

Other reported less incidence (Skinner & Colleages 1998)21% with prostatic stromal invasion15% with prostatic urethra or ductal involvement

Male pts undergoing cutaneous diversion should go simultaneous / delayed urethrectomy if CIS prostatic urethraGross tumor prostatic urethra

In orthotopic diversion with residual urethra, should be done after frozen section documenting tumor free distal urethral margin

(Lebret et al, 1998)

Mapping studies showed 2-12 % of female pts undergoing cystectomy for cure have urethral involvement

(De Paepe et al, 1990)

Stein & colleages (1998) performed prospective path. Evaluation of 17 female cystec. Specimens removed for 1ry TCCTumors of bladder neck and urethra found in 19% & 7%

respec.Bladder neck involvement was found to be the most

significant risk for tumor involvement of the urethra

Female urethra:

Intraoperative frozen-section of the proximal urethra is the best way to determine whether a female pt is a suitable candidate for orthotopic reconstruction

(Darson et al, 2000)

Pts with :Overt Ca. at bladder neck & urethraDiffuse CIS+ve margin

Are poor candidates for orthotopic diversion, and should go immediate en bloc urethrectomy as part of cystectomy

Ureteral Frozen-Section Analysis at time of cystectomy before anastomsis is standard practice

Urologists historically resected +ve margins to effect clearance of all documented ca. assuming better long term local disease control

Retrospective studies failed to demonstrate long term benefit (Linker & Whitmore et al, 1975; Johnson & Bracken 1977; Schoenberg et al, 1996)

These studies were small, single institution retrospective experiences

Ureteral Frozen-Section Analysis:

Provides insight into the local extent of disease

Pts with limited tumor burden, have improved long term survival in absence of additional intervention

(Skinner, 1982; Skinner & Lieskovsky, 1984; Lerner et al, 1993; Viewed et al, 1994, 1999; Schoenberg et al, 1996)

Risk of pelvic L.N. mets. Increases with tumor stage pT2disease have 10-30% risk of +ve L.N. at time

of surgerypT3 & higher have 30-65% risk

Obturator & external iliac L.N. are the most common nodes involved by mets

Role of lymphadenectomy:

L.N. dissection done before/after cystectomy

The standard dissection:Lateral limit is genitofemoral nerveMedial limit is bladderCephalad limit is bifurcation of the common iliac art. Caudal limit is endopelvic fascia

Obturaor fossa nodes included during dissection medially Care to avoid accessory obturator vein, frequently

presentThe node of Cloquet is mobilized at the junction of the

femoral canal and should be included

Extended lymphadenectomy

shown to improve survival in pts with both L.N. –v & limited L.N. metastatic disease

(Herr et al, 2002)

Includes tissues along the common iliac up to the bifurcation of aorta (distal paraaortic & paracaval) + includes presacral nodes

% of pts with node +ve disease who are identified are similar between standard V.s. Extended lymphadenectomy

(bochner et al, 2004)

L.N. yield is > 3 fold when dissecting and submitting separate L.N. pockets compared with en bloc

(bochner et al, 2001)

Among pt with L.N. +ve, total no. of nodes removed at time of surgery affects prognosisPts with < or = 15 nodes removed had 25% 10-year

recurrence-free survival & when > 15 removed, 36 RFS

10 year RFS was significantly higher when pts had 8 or fewer L.N. +ve compared to more than 8 L.N. +ve (40% V.s 10%)

(stien et al, 2003)

Mortality rate 1-2%Complication rate 25%

Morbidity 2ry to Preexisting or comorbid conditionsRelated to removal of bladder and adjacent

structuresRelated to use of bowel segment

Immediate / Early/ Late

Complications of radical cystectomy:

Long term surveillance for Tumor recurrenceComplications related to use of intestinal segment

Frequency of F/U controversial

Slaton & colleages (1999) did a retrospective reviewAnnual screening with physical exam, chemistry, CXR

for pT1Semiannual for pT2Quarterly for pT3 + semiannual CT

Upper tract imaging after cystectomy is useful to exclude ureteral stenosis or upper tract tumor

F/U after Radical Cystectomy:

Preoperative Radiation Therapy:

Available randomized data suggests that for pts with pT3, preoperative Radiation Therapy May improve local controlNo survival advantage (Blackard, 1972; Ghoniem et al, 1985; smith et al, 1997)

Other nonrandomized trials supported that it doesn`t improve survival

(Cole et al, 1995; Pollack et al, 1997)

Adjuncts to standard surgical therapy

Neoadjuvant chemotherapy:

Allows potential downstaging in inoperable

tumors

Treatment of micromets. When pt is not

debilitated by a surgical procedure

Potential disadvantage is delay in delivery of

definitive local therapy

Select Randomized Neoadjuvant Chemotherapy Trials for Bladder Ca

Trial No. of Pts Chemotherapy Local Therapy OutcomeCUETO, Spain 122 Cisplatin Cystectomy No difference

WMURG, United Kingdom 159 Cisplatin XRT No difference

ABSCG, Australia 96 Cisplatin XRT No differenceGUONE, Italy 206 MVAC Cystectomy No difference

Nordic I 325 Cisplatin, doxorubicin

XRT +cystectomy

Improved survival (T3/T4a)

Nordic II 316 Cisplatin, methotrexate Cystectomy No difference

MRC/EORTC 976Cisplatin,

methotrexate, vinblastine

XRT or cystectomy

Improved survival

Intergroup-0080, United States 317 MVAC Cystectomy Improved

survival

Egypt 196Carboplatin,

methotrexate, vinblastine

Cystectomy Improved survival

   

Modified from Winquist E, Kirchner TS, Segal R, et al: Neoadjuvant chemotherapy for TCC

A systematic review and meta-analysis. J Urol 2004;171:561-569.

The Nordic 1 Trial Group used neoadjuvant chemo + low dose radio + cystectomy5 year OS was 59% in chemo group V.s. 51% in

control (p= .1)No difference observed for T1 & T215% improved survival for pts with T3-T4a who

received neoadjuvant chemo. (p=.03)

2 comprehensive meta-analysis of RCT also concludedNeoadjuvant cisplatin based combination chemo.

May offer improvement in OS. Of 5-6% among pts with locally advanced disease

(Advanced Bladder Cancer Meta-analysis Collaboration, 2003; Winquist et al , 2004)

Perioperative Chemotherapy:

M.D. Anderson Hospital evaluated 100 pts randomized either to 2 cycles of MVAC before & 3 cycles after cystectomy

At 32 months, no difference in survival was identified between 2 groups

A trend toward downstaging of larger lesion was noted in perioperative chemo. Group (Logothetis et al, 1998)

Adjuvant Chemotherpy:

Pts with pathologicaly staged tumors with evidence of mets. may benefit from systemic therapy that could reduce local recurrence ordistant metastatic relapse

DisadvantagesDifficult to assess tumor response to chemo in

absence of radiological residual diseaseInterference of post. Op. complicationsDelay of administration of systemic therapy in

proven mets

Results of Select Adjuvant Chemo. Trials after Cystectomy

Trial No. of PatientsChemothera

pySurvival Benefit P Value

Skinner et al 87 CISCA

Median 4.3 vs 2.4 yr 0.006

Overall 5-yr 44% vs 39%

Not significant

Studer et al 77 Cisplatin

Overall 5-yr 54% vs 57%

Not significant

Freiha and Torti 50 CMV

Overall 5-yr 54% vs 34%

Not significant

Stockle et al

49 randomized, 117

nonrandomized

MVAC/MVEC

5-yr disease free 50% vs

22%0.002

   

CISCA, cisplatin, cyclophosphamide, and Adriamycin (doxorubicin); CMV, cisplatin, methotrexate, and vinblastine; MVAC/MVEC, methotrexate, vinblastine,

doxorubicin/epirubicin, and cisplatin.Modified from Rosenberg JE, Carroll PR, Small EJ: Update on chemotherapy for

advanced bladder cancer. J Urol 2005;174:14-20.

The reports suggests that for pts with locoregional disease & pelvic L.N. involvement, Cisplatin based adjuvant therapy may provide survival advantage worth discussing with selected pts

there is no evidence to suggest administration of adjuvant chemo. To pts with T1-T2

Radiation Therapy:

No randomized trials performed comparing radiation alone with cystectomy

Conventional Ext. Beam Rx control locally invasive tumors in 30-50%

(Walace & bloom, 1976; Hyter et al 1999)

To improve rate of success, hyperfractionation schedules used

Randomized trials of hyperfractionation suggests that it may be useful in the future (larger controlled trials needed)

Alternatives to standard therapy

TUR & partial cystectomy:

Some groups reported good local & distant control in small, low stage T2 treated with Radical TUR or partial cystectomy

(Henry et al, 1988; Solsona et al, 1998;Roosen et al , 1997)

Solsona & colleages (1998) reported 5 year disease specific survival (similar to radical cystectomy !! ) with pts with –ve tumor bed and normal peripheral biopsy post Radical TUR

Non randomized

Combined TUR / partial cystectomy + chemo:

Complete TUR alone for moderate to large T2 is unlikely (Kolozsy ,

1991)

To augment conservative intervention, chemo. was added by some

(Herr & scher, 1998; Sternberg et al 1999)

Hall & colleages (1984) described 61 pt treated with TUR + chemo. for T2 48 were free of muscle invasion on 1st surveillance cystosopy

after initial complete TUR5 year disease specific survival was 75% compared with 25%

those with residual or recurrent disease

Chemo. Shown to improve survival in pts downstaged to P0 at time of surgery (Herr, 1994)

Prospective randomized trials still needed

Ideal pt for partial cystectomy:Normally functioning bladder with good capacity1st time tumor recurrence with solitary tumorLocated in area allows 1-2 cm margin of resection

Only 5.8-18% of pts with muscle invasive bladder Ca. are suitable for partial cystectomy (Sweeny et al, 1992)

Survival rates ranges 25-55% in retrospective studies

Can reach up to 58% in well selected pts (Brananet al, 1978)

Rate of local recurrence 40-78% (Lindahal et al, 1984)

Partial cystectomy:

Pelvic L.N. dissection + complete pathological staging of tumor should be done in partial cystectomy

Other indications of partial cystectomy:

Urachal adeno.Primary pheochromocytoma of bladderOsteosarcoma of bladderTumor within diverticulum

Absolute contraindications of partial cystectomy :CIS in bladderMultifocal tumor

Relative contraindications:High grade tumorsLocated in trigone or bladder neckTumor that would require ureteral reimplnat.

As local recurrence is high ( 40-79% )Pt . post partial cystectomy needs cystoscopy +

cytology Q 3/12 for the 1st 2 years, + regular CT abd. & pelvis

Bladder preservation protocolsTrial No. of

Pts Stage Treatment Survival with Intact Bladder

Housset et al 40 T2-T4 TURBT +chemo +XRT 81% 3-yr overall survival

Vikram et al 21 T2-T3 TURBT +chemo +XRT 37% 5-yr overall survival

Kachnic et al 76 T2-T4a TURBT +chemo +XRT 43% 5-yr overall survival

Fellin et al 56 T2-T4 TURBT +chemo +XRT 59% 5-yr disease-specific survival

Chauvet et al 109 T2-T4 TURBT +chemo +XRT 42% 4-yr overall survival

Shipley et al 190 T2-T4a TURBT +chemo +XRT 45% 10-yr disease-specific survival

Rodel et al 415 T1-T4 TURBT +chemo +XRT 42% 5-yr overall survival

Housset et al 54 T2-T4 TURBT +chemo +XRT 62% 3-yr disease-specific survival

Sternberg et al 104 T2-T4 Neoadjuvant MVAC

+TURBT44% 5-yr overall

survival

Herr 99 T2 TURBT alone 57% 10-yr disease-specific survival

   

Modified from Torrres-Roca JF: Bladder preservation protocols in the treatment of muscle-invasive bladder cancer.

Cancer Control 2004;11:358-363.

Alternative to radical cystectomy

General criteria:Presence of muscle invasive diseaseAbsence of hydro.Normal renal functionNormal CBCSuitable candidate for cystectomyAbsence of metastatic disease on imaging

Salvage cystectomy is performed for incomplete nonresponders before they have received full dose of radiation

(shipley et al, 2005)

Bladder preservation protocols:

Toxicities associated with preservation regimen 40-70%Nausea, vomitting, fatigue, neutropenia, & diarrhea

Others toxicitiesTreatment related mortality in 1% (neutropenic sepsis)Radiation induced bladder dysfunction 1%Sexual dysfunction 25%

Contraindications of preservation therapy:Presence of hydronephrosisCISTumor that can't be resected completely transurethraly

Results of Selected Bladder Preservation Studies: Radiation Therapy Oncology Group

(RTOG)

TrialNo. of

PtsRadiation Therapy

Radiosensitizing

Chemotherapy

5-Year Survival

(%)

RTOG 88-02 91 Daily (64.8 Gy) Cisplatin 51

RTOG 89-03 123 Daily (64.8 Gy) Cisplatin 49

RTOG 95-06 34

Hyperfractionated

Cisplatin+ 5-fluorouracil N/A

RTOG 97-06 52

Hyperfractionated Cisplatin N/A

RTOG 99-06

84 Hyperfractionated

Cisplatin+paclitaxel

N/A   

Modified from Shipley WU, Zietman AL, Kaufman DS, et al: Selective bladder preservation by trimodality therapy for patients with muscularis propria-

invasive bladder cancer and who are cystectomy candidatesthe Massachusetts General Hospital and Radiation Therapy Oncology Group experiences.

Semin Radiat Oncol 2005;15:36-41.

Employed in few centers only

Preop. External-beam radiation + partial

cystectomy / TUR+ subsequent placement of

iridium 192 wires

Reported Overall survival for T1-T2 60-80%

(Grossman, 1993; Wijnmaalen

et al, 1997)

Complications mainly from interstitial therapy:

Delayed wound healing, fistula, hematurea,

chronic cystitis

Intersititial Radiatin Therapy:

Systemic chemotherapy:

Pts with metastatic bladder ca. routinely treated with systemic chemo. Especially when unresectable, diffusely metastatic, measurable disease

Multiagent regimen better than single agentUsed to be Most commonly used MVAC

Methotrexate, Vinblastine, Doxorubicin, Cisplatin MVAC produce complete response in 20% of

pts with rare long term disease free survival

Management of metastatic bladder Ca.

MVAC has significant toxicities:20% experience neutropenic feverDeath from sepsis reported 3-4%

GCGC= Gemcitabine (Gemzar), CisplatinGemcitabine as a single agent showed 25%

complete responseCombined GC 40% partial & complete responseCombination demonstrated similar survival

outcomes with less toxicity compared with MVAC (von der Maase et al,

2000)

405 pts with locally advanced or metastatic TCC randomized to receive GC or MVACOverall survival, time to disease progression, time to

treatment failure & response rate were similar

Most significant toxic effects with GCThrombocytopenia & neutropenia occurs up to 50%

The improved risk/benefit ratio changed the standard of care for pts with locally advanced & metastatic disease from MVAC to GC

(Aparicio et al, 2005)

Taxoids (microtubule disassembly inhibitors)New class of agentsPaclitaxel, DocetaxelUsed in clinical trials for bladder Ca. with response

25-83% in combination

Gallium nitrateNaturally occuring metal with antineoplastic activitySignificant txicity limiting its use

TrimetrexateAntifolate, ? Used in methotrexate resisitant

Other drugs used:

In pts choosing conservative or primarily nonsurgical form of therapy for invasive or locoregionally advanced bladder Ca.When conservative treatment produced partial

response & residual disease remains clinically confined to the bladder

Donat & assiciates (1996) reviewed pts with locoregional disease treated with systemic disease & susequent salvage surgery22% survival advantage among pts with complete

or near complete response to systemic therapy

Salvage cystectomy

Resection appears to help pts who had complete response to systemic therapy

Surgery for residual extravesical disease have NO long term survival advantage and should generally be discouraged

Thank You