Management of High

Grade Bladder Cancer

& Carcinoma In Situ
Presented by –HARADIKAR VARADARAJ

Instructor – Mr.D.MURPHY

Urology Registrars Teaching session – 10/11/2003

 GRADES OF BLADDER CANCER
 G1 Well differentiated
 G2 moderately differentiated
 G3 Poorly differentiated
(Advisable for consistency not to use Grade 4)
 G3pT1 most difficult to manage because of conflicting
good prognostic (superficial) and bad prognostic (high
grade) features.
 G3pT1 – inconsistency of diagnosis
Without reference Pathology review as many as 30% of
cases may be incorrectly or inconsistently diagnosed.
 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
 High-Risk Superficial BC (2)

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
 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 SBC
 Not Clearly defined and followed
1999 BAUS Cancer Audit showed only a small
minority of patients newly presenting with
CIS or T1 lesion had optimal treatment
* 15% of CIS – receiving BCG therapy
* 58% of T1 lesions being treated TUR alone
 Endoscopic Assessment
At 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 mucosa
Lower 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)

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)
 Ensuring Correct diagnosis (2)
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)
 Ensuring Correct diagnosis (3)
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
 Ensuring Correct diagnosis (4)
 Random Biopsies often useless & do not contribute to
choice of therapy after TURBT
(EORTC study Eur Urol 1999;35:267-71)

 Random Biopsies indicated if there is severe dysplasia

or CIS in adjoining or distant epithelium as these
increase risk of progression
- progression in 8% of T1 tumors with no dysplasia
and in 38% with concomitant mild or severe dysplasia
( Heney et al, Herr et al)

 Biospy of Prostatic Urethra

 Management (1)
 Subject of debate always between those Urologists who
advocate Conservative approach and risk “missing the
boat” AND those with aggresive immediate cystectomy
approach who could be removing far too many bladders
 Immediate cystectomy
- treats occult muscle invasive disease
- avoids need for very reg. Bladder surveillance
- may result in 5 year survival in 80% patients
- 2-3% risk of treatment related death
- loss of QOL associated with urinary diversion & impotence
 Management (2)
 EORTC study (2435 patients from six clinical trials,
median FU 7.8 years)
- intravesical chemotherapy ↓ long-term
recurrence rate but not disease progression
or mortality
(Kurth KH et al . J Urol 1996:156; 1934-41)

 Therefore unlikely that TURBT with

intravesical chemotherapy could decrease the
risk of progression of T1G3 SBC
 Management (3)
 Intravesical BCG immunotherapy reducing
progression & mortality is based on few trials
*10-year progression-free rate was 62% for
TURBT with BCG & 37% for TURBT alone
* Disease specific survival – 75% & 55% resp.
(Herr et all in 1988 & 1995, Silverio et al 1997, Herr & Lamm)

 Large retrospective study has shown BCG does not

influence recurrence, progression or survival in T1G3
disease
(Struder et al. J Urol 2000; 163 (suppl.1):151,A672)
 Management (4)
 AUA Guidelines panel reported …..“ there is no evidence that
any intravesical therapy affects the rate of progression to
muscle invasive disease”

 SWOG study 391 patients – 4 year survival was 86% for those
treated with inductive BCG regimen and 92% for those on
maintenance schedule (m.s)
{m.s- 3W @ 3 & 6 months & every 6 months for 3 years}
(Lamm et al. J Urol 2000; 165:1124-1129)

 Despite the evidence maintenance schedule of intravesical

BCG is currently the best option that can be advocated for
patients with T1G3 SBC
 Management (5)
 When to stop conservative treatment of
T1G3 tumors ?
1) When there is systemic or local toxicity
from intravesical therapy
2) When patient is not compliant
3) persistence of tumor despite therapy
4) tumor progression
 Management (6)
 When interval between initial tumor & recurrence is
>21 months the risk of progression is very low
 Risk of progression is highest (100% in 3 years) for
patients with T1G3 on follow-up cystoscopy at
6 months
 Such refractory T1 tumors have a 50% chance of
developing into muscle invasive disease within
5 years
(Herr et al)
 Management (7)
 Radiotherapy has been reported to give good long
term disease control for pT1G3 tumors with
preservation of the bladder BUT NOT in randomised
controlled trials
(Duncan et al. Br J Urol 1986, 58:147)

 MRC has a trial running comparing RT to either

TUR alone or to intravesical therapy with BCG or
chemotherapy – until this trial is completed we will
not know if RT has a place in treating pT1G3 disease.
 Carcinoma In Situ (1)
 CIS of bladder is a serious condition characterised by
malignant change in urothelium without invasion
through basement membrane or papillary growth.
 CIS will progress to deeply invasive bladder cancer
unless aggressively and adequately treated
 CIS first described by Melicow in 1952 as full
thickness replacement of the urothelium by
cytologically malignant cells
 Carcinoma In Situ (2)
 Prognosis for patients treated by endoscopic
surgery alone is very poor, with 40-85%
progressing to invasive cancer.
 Intravesical BCG therapy has become
mainstay.
 Review of 18 studies (718 patients) suggested a
72% response rate to the first course of BCG
(Lamm DL, CIS Urol Clin North Am; 1992 Aug: 19(3) : 499-508 )
 Carcinoma In Situ (3)
 Aims of intravesical treatment
- to treat residual disease
- to prevent recurrence
- to prevent progression
- to conserve the bladder
- to prolong survival

 Little agreement about the following

- who should be treated
- when should treatment start
- how should complications be treated
- how many instillations per course
- how many courses and how often
- does maintainance therapy improve survival
 CIS Treatment (1)
 Traditional 6-week induction course of weekly BCG
therapy has no scientific or immunological basis and is
traditional.
 Two courses is better than one with improved response
rates from 35% to 70%
{SWOG8507, Kavoussi et al, J Urol;139 (5) 1988: 935-40 }

 (6+3) 6 weeks then 3 weeks @ 3 & 6 months & every 3

monthly for 3 years (27 instillations) - ? Gold standard
- 82% long term tumor free response
- toxicity more severe, non completion of course
 CIS Treatment (2)
 What is Reasonable clinical practise in CIS ?
1) Patchy, minimal primary CIS & CIS associated with non
invasive papillary TCC should receive 6 weekly instillation of
BCG & 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 change of

treatment strategy needed
Proper to have LOW THRESHOLD for cystectomy.
 CIS Treatment (3)
3) Failure of the CIS to clear or absence of CIS on biopsy – indication
for SWOG regimen intravesical BCG
 70% will have complete response and 64% of responders

will remain disease free at 5 years

 Most recurrences occur during the first 5 years of followup

 BCG therapy failure have a 48% risk of developing muscle

invasive cancer

 CIS gives rise to poorly diff. invasive cancer –

50% disease related mortality in this group = G3 TCC
 Finally regarding pT1G3 & CIS
 High risk bladder cancers and need to closely monitored
 ? Followup schedule
urine cytology (urine tests bladder ca- low sensitivity)
 Word “superficial” may encourage false reassurance &
even complacency with check cystoscopy done by
junior staff ….time word “superficial” was dropped
from classification !
 Treatment failures must be recognised and conservative
treatment abandoned in good time.
TNM Classification of Bladder tumors
 Tis Carcinoma in situ
 Tis pu Carcinoma in situ in prostatic urethra
 Ta Non invasive papillary carcinoma
 T1 Tumor invades subepithelial conn tissue
 T2 Tumor invades muscle
T2a – invades sup muscle (inner half)
T2b – invades deep muscle (outer half)
 T3 Tumor invades Perivesical tissue
T3a – Microscopically
T3b – Macroscopically (extravesical mass)
 T4 Tumor invades any- prostate, uterus, vagina,
pelvic wall, abdominal wall