bladder cancer management

Management of High Grade Bladder Cancer & Carcinoma In Situ

Management of High Grade Bladder Cancer & Carcinoma In Situ

Presented by –HARADIKAR VARADAPresented by –HARADIKAR VARADARAJRAJ

Instructor – Mr.D.MURPHYInstructor – Mr.D.MURPHY

Urology Registrars Teaching session – 10/11/2003

GRADES OF BLADDER CANCERGRADES OF BLADDER CANCERGRADES OF BLADDER CANCERGRADES OF BLADDER CANCER

G1G1 Well differentiated Well differentiated G2G2 moderately differentiated moderately differentiated G3G3 Poorly differentiated Poorly differentiated (Advisable for consistency not to use Grade 4)(Advisable for consistency not to use Grade 4)

G3pT1 most difficult to manageG3pT1 most difficult to manage because of conflicting because of conflicting good prognostic (superficial) and bad prognostic (high good prognostic (superficial) and bad prognostic (high grade) features.grade) features.

G3pT1 – inconsistency of diagnosisG3pT1 – inconsistency of diagnosis Without reference Pathology review as many as 30% of Without reference Pathology review as many as 30% of

cases may be incorrectly or inconsistently diagnosed.cases may be incorrectly or inconsistently diagnosed.

High-Risk Superficial BC (1)High-Risk Superficial BC (1)

• Established risk factors for progression of superficial bladder cancer are

• - presence of lamina propria invasion• - high grade ( grade 3)• - carcinoma in situ

• T1G3 disease – 10 times the chance of muscle invasion & death than with other Ta

• Overall 40% of T1G3 tumors will progress

Ta G3 tumors are also at high risk of life-long progression, not very different from that of patients with T1G3 tumors

125 such patients followed for 15 years and progression observed in 39% and cancer related death in 26%

Herr et al J Urol 2000; 163:60-2

High-Risk Superficial BC (2)High-Risk Superficial BC (2)

Prognostic Factors (1)Prognostic Factors (1)Prognostic Factors (1)Prognostic Factors (1)

Neither T category nor Grade significantly influence the recurrence rate: this rate depends mainly on

1) the number of tumors (single tumor, 51%

recurrence at 5 years; multiple tumors, 91%)

2) the previous recurrence rate or recurrence at

3 months

3) The size of the tumors; those >3 cm carry worse prog. Oosterlink W. The management of superficial bladder cancer,

BJU Int 2001;87:135-41

Treatment of aggressive SBCTreatment of aggressive SBCTreatment of aggressive SBCTreatment of aggressive SBC

Not Clearly defined and followedNot Clearly defined and followed

1999 BAUS Cancer Audit showed only a small 1999 BAUS Cancer Audit showed only a small minority of patients newly presenting with minority of patients newly presenting with CIS or T1 lesion had optimal treatmentCIS or T1 lesion had optimal treatment

* 15% of CIS – receiving BCG therapy* 15% of CIS – receiving BCG therapy

* 58% of T1 lesions being treated TUR alone* 58% of T1 lesions being treated TUR alone

Endoscopic AssessmentEndoscopic AssessmentEndoscopic AssessmentEndoscopic AssessmentAt initial diagnostic cystoscopy it is necessary to document the foll:

Tumor – Size, Number, Position Growth pattern ( Papillary or Solid)Mucosa – Normal, red areas or area of red, irregular mucosaLower tract – The Urethra, The Prostate

Bimanual - Is there mass before resection ? exam Is there mass after resection ? Size of mass and mobility

Ensuring Correct diagnosis (1)Ensuring Correct diagnosis (1)

Proper TURBT & resection should be complete; pT1G3 tumor recurring at same site suggests often resection is incomplete.

Two kinds of error

- foci of T1 cancer are left

- first resection fails to diagnose muscle

invasive cancer ( =/ > T2)

48% T1 tumors under-staged if no muscle present in TUR specimen

14% T1 tumor under-staged if muscle present in specimen was not involved with tumor

(Herr HW. Urol Oncol 1996; 2:92-5)

Data from patients undergoing cystectomy for “T1” disease show that

- 30% actually have muscle invasive disease - 50% initial tumor not completely resected (Amling CL et al. J Urol 1994; 151: 31-36)


THE SECOND RESECTION

second TURBT in all pts with pT1 tumors 10 days and no later than 2-3 weeks

(to facilitate the choice of cystectomy or conservative tx)

SECOND RESECTION to seek

- foci of T1 tumor not completely resected

- any infiltration of muscularis propria not

recognised previously


Random Biopsies often useless & do not contribute to Random Biopsies often useless & do not contribute to choice of therapy after TURBTchoice of therapy after TURBT

(EORTC study Eur Urol 1999;35:267-71)(EORTC study Eur Urol 1999;35:267-71)

Random Biopsies indicated if there is severe dysplasia Random Biopsies indicated if there is severe dysplasia or CIS in adjoining or distant epithelium as these or CIS in adjoining or distant epithelium as these increase risk of progressionincrease risk of progression

- progression in 8% of T1 tumors with no dysplasia - progression in 8% of T1 tumors with no dysplasia and in 38% with concomitant mild or severe dysplasia and in 38% with concomitant mild or severe dysplasia

( Heney et al, Herr et al)( Heney et al, Herr et al)

Biospy of Prostatic UrethraBiospy of Prostatic Urethra


Management (1)Management (1)

Subject of debate always between those Urologists who Subject of debate always between those Urologists who advocate advocate Conservative approachConservative approach and risk “missing the and risk “missing the boat” AND those with aggresive boat” AND those with aggresive immediate cystectomy immediate cystectomy approachapproach who could be removing far too many who could be removing far too many bladdersbladders

Immediate cystectomy Immediate cystectomy - treats occult muscle invasive disease- treats occult muscle invasive disease - avoids need for very reg. Bladder surveillance- avoids need for very reg. Bladder surveillance - may result in 5 year survival in 80% patients- may result in 5 year survival in 80% patients - 2-3% risk of treatment related death- 2-3% risk of treatment related death

- loss of QOL associated with urinary diversion & impotence- loss of QOL associated with urinary diversion & impotence

EORTC study (2435 patients from six clinical trials, EORTC study (2435 patients from six clinical trials, median FU 7.8 years) median FU 7.8 years)

- intravesical chemotherapy - intravesical chemotherapy ↓↓ long-term long-term

recurrence rate but not disease progression recurrence rate but not disease progression

or mortalityor mortality (Kurth KH et al . J Urol 1996:156; 1934-41)(Kurth KH et al . J Urol 1996:156; 1934-41)

Therefore unlikely that TURBT with Therefore unlikely that TURBT with

intravesical chemotherapy could decrease the intravesical chemotherapy could decrease the

risk of progression of T1G3 SBC risk of progression of T1G3 SBC


Intravesical BCG immunotherapy reducing Intravesical BCG immunotherapy reducing progression & mortality is based on few trialsprogression & mortality is based on few trials

*10-year progression-free rate was 62% for*10-year progression-free rate was 62% for TURBT with BCG & 37% for TURBT aloneTURBT with BCG & 37% for TURBT alone * Disease specific survival – 75% & 55% resp.* Disease specific survival – 75% & 55% resp. (Herr et all in 1988 & 1995, Silverio et al 1997, Herr & Lamm)(Herr et all in 1988 & 1995, Silverio et al 1997, Herr & Lamm)

Large retrospective study has shown BCG does not Large retrospective study has shown BCG does not influence recurrence, progression or survival in T1G3 influence recurrence, progression or survival in T1G3 diseasedisease

(Struder et al. J Urol 2000; 163 (suppl.1):151,A672) (Struder et al. J Urol 2000; 163 (suppl.1):151,A672)


AUA Guidelines panel reported …..“ there is no evidence AUA Guidelines panel reported …..“ there is no evidence that any intravesical therapy affects the rate of progression that any intravesical therapy affects the rate of progression to muscle invasive disease”to muscle invasive disease”

SWOG study 391 patients – 4 year survival was 86% for SWOG study 391 patients – 4 year survival was 86% for those treated with inductive BCG regimen and 92% for those treated with inductive BCG regimen and 92% for those on maintenance schedule (m.s) those on maintenance schedule (m.s)

{m.s- 3W @ 3 & 6 months & every 6 months for 3 years}{m.s- 3W @ 3 & 6 months & every 6 months for 3 years} (Lamm et al. J Urol 2000; 165:1124-1129)(Lamm et al. J Urol 2000; 165:1124-1129)

Despite the evidence maintenance schedule of intravesical Despite the evidence maintenance schedule of intravesical BCG is currently the best option that can be advocated for BCG is currently the best option that can be advocated for patients with T1G3 SBCpatients with T1G3 SBC


When to stop conservative treatment of When to stop conservative treatment of T1G3 tumors ?T1G3 tumors ?

1) When there is systemic or local toxicity 1) When there is systemic or local toxicity from intravesical therapyfrom intravesical therapy 2) When patient is not compliant2) When patient is not compliant 3) persistence of tumor despite therapy 3) persistence of tumor despite therapy 4) tumor progression4) tumor progression


When interval between initial tumor & recurrence is When interval between initial tumor & recurrence is >21 months the risk of progression is very low>21 months the risk of progression is very low

Risk of progression is highest (100% in 3 years) for Risk of progression is highest (100% in 3 years) for patients with T1G3 on follow-up cystoscopy at patients with T1G3 on follow-up cystoscopy at 6 months 6 months

Such refractory T1 tumors have a 50% chance of Such refractory T1 tumors have a 50% chance of developing into muscle invasive disease within developing into muscle invasive disease within 5 years 5 years

(Herr et al)(Herr et al)


Radiotherapy has been reported to give good long Radiotherapy has been reported to give good long term disease control for pT1G3 tumors with term disease control for pT1G3 tumors with preservation of the bladder preservation of the bladder BUT NOTBUT NOT in randomised in randomised controlled trialscontrolled trials

(Duncan et al. Br J Urol 1986, 58:147)(Duncan et al. Br J Urol 1986, 58:147)

MRC has a trial running comparing RT to either MRC has a trial running comparing RT to either TUR alone or to intravesical therapy with BCG or TUR alone or to intravesical therapy with BCG or chemotherapy – until this trial is completed we will chemotherapy – until this trial is completed we will not know if RT has a place in treating pT1G3 disease.not know if RT has a place in treating pT1G3 disease.


Carcinoma In Situ (1)Carcinoma In Situ (1)Carcinoma In Situ (1)Carcinoma In Situ (1)

CIS of bladder is a serious condition characterised by CIS of bladder is a serious condition characterised by malignant change in urothelium without invasion malignant change in urothelium without invasion through basement membrane or papillary growth.through basement membrane or papillary growth.

CIS will progress to deeply invasive bladder cancer CIS will progress to deeply invasive bladder cancer unless aggressively and adequately treatedunless aggressively and adequately treated

CIS first described by Melicow in 1952 as full CIS first described by Melicow in 1952 as full thickness replacement of the urothelium by thickness replacement of the urothelium by cytologically malignant cellscytologically malignant cells

Prognosis for patients treated by endoscopic Prognosis for patients treated by endoscopic surgery alone is very poor, with 40-85% surgery alone is very poor, with 40-85% progressing to invasive cancer.progressing to invasive cancer.

Intravesical BCG therapy has become Intravesical BCG therapy has become mainstay.mainstay.

Review of 18 studies (718 patients) suggested a Review of 18 studies (718 patients) suggested a 72% response rate to the first course of BCG72% response rate to the first course of BCG

(Lamm DL, CIS Urol Clin North Am; 1992 Aug: 19(3) : 499-508 )(Lamm DL, CIS Urol Clin North Am; 1992 Aug: 19(3) : 499-508 )


Aims of intravesical treatmentAims of intravesical treatment- to treat residual disease- to treat residual disease- to prevent recurrence- to prevent recurrence

- to prevent progression- to prevent progression- to conserve the bladder- to conserve the bladder

- to prolong survival- to prolong survival

Little agreement about the followingLittle agreement about the following - who should be treated- who should be treated

- when should treatment start- when should treatment start - how should complications be treated- how should complications be treated - how many instillations per course- how many instillations per course - how many courses and how often- how many courses and how often - does maintainance therapy improve survival- does maintainance therapy improve survival


Traditional 6-week induction course of weekly BCG Traditional 6-week induction course of weekly BCG therapy has no scientific or immunological basis and is therapy has no scientific or immunological basis and is traditional.traditional.

Two courses is better than one with improved response Two courses is better than one with improved response rates from 35% to 70%rates from 35% to 70%

{SWOG8507, Kavoussi et al, J Urol;139 (5) 1988: 935-40 }{SWOG8507, Kavoussi et al, J Urol;139 (5) 1988: 935-40 }

(6+3)(6+3) 6 weeks then 3 weeks @ 3 & 6 months & every 3 6 weeks then 3 weeks @ 3 & 6 months & every 3 monthly for 3 years (27 instillations) - monthly for 3 years (27 instillations) - ? Gold standard? Gold standard

- 82% long term tumor free response- 82% long term tumor free response - toxicity more severe, non completion of course - toxicity more severe, non completion of course

CIS Treatment (1)CIS Treatment (1)CIS Treatment (1)CIS Treatment (1)

What is Reasonable clinical practise in CIS ?What is Reasonable clinical practise in CIS ? 1) Patchy, minimal primary CIS & CIS associated with non 1) Patchy, minimal primary CIS & CIS associated with non invasive papillary TCC should receive 6 weekly instillation ofinvasive papillary TCC should receive 6 weekly instillation of BCG & review cystoscopy & biopsies one month laterBCG & review cystoscopy & biopsies one month later

(CIS lesions can be made to fluoresce by prior treatment with 5-amino levulinic acid. This technique is used for photodynamic detection of CIS)

2) Evidence of progression at above cystoscopy means 2) Evidence of progression at above cystoscopy means changechange of of treatment strategy neededtreatment strategy needed Proper to have LOW THRESHOLD for cystectomy. Proper to have LOW THRESHOLD for cystectomy.


3) Failure of the CIS to clear or absence of CIS on biopsy – indication 3) Failure of the CIS to clear or absence of CIS on biopsy – indication for SWOG regimen intravesical BCGfor SWOG regimen intravesical BCG

70% will have complete response and 64% of responders70% will have complete response and 64% of responders

will remain disease free at 5 yearswill remain disease free at 5 years

Most recurrences occur during the first 5 years of followupMost recurrences occur during the first 5 years of followup

BCG therapy failure have a 48% risk of developing muscle BCG therapy failure have a 48% risk of developing muscle invasive cancerinvasive cancer

CIS gives rise to poorly diff. invasive cancer – CIS gives rise to poorly diff. invasive cancer –

50% disease related mortality in this group = G3 TCC50% disease related mortality in this group = G3 TCC


Finally regarding pT1G3 & CISFinally regarding pT1G3 & CIS High risk bladder cancers and need to closely monitoredHigh risk bladder cancers and need to closely monitored

? Followup schedule? Followup schedule

urine cytology (urine tests bladder ca- low sensitivity)urine cytology (urine tests bladder ca- low sensitivity)

Word “superficial” may encourage false reassurance & Word “superficial” may encourage false reassurance & even complacency with check cystoscopy done by junior even complacency with check cystoscopy done by junior staff ….time word “superficial” was dropped from staff ….time word “superficial” was dropped from classification !classification !

Treatment failures Treatment failures must bemust be recognised and conservative recognised and conservative treatment abandoned in good time.treatment abandoned in good time.

TNM Classification of Bladder tumorsTNM Classification of Bladder tumorsTNM Classification of Bladder tumorsTNM Classification of Bladder tumors

TisTis Carcinoma in situCarcinoma in situ Tis puTis pu Carcinoma in situ in prostatic urethraCarcinoma in situ in prostatic urethra Ta Ta Non invasive papillary carcinomaNon invasive papillary carcinoma T1T1 Tumor invades subepithelial conn tissueTumor invades subepithelial conn tissue T2 T2 Tumor invades muscleTumor invades muscle

T2aT2a – invades sup muscle (inner half) – invades sup muscle (inner half)

T2bT2b – invades deep muscle (outer half) – invades deep muscle (outer half) T3T3 Tumor invades Perivesical tissueTumor invades Perivesical tissue

T3aT3a – Microscopically – Microscopically

T3bT3b – Macroscopically (extravesical mass) – Macroscopically (extravesical mass) T4T4 Tumor invades any- prostate, uterus, vagina, Tumor invades any- prostate, uterus, vagina,

pelvic wall, abdominal wallpelvic wall, abdominal wall

bladder cancer management

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