1 management of difficult cases of non-muscle invasive bladder cancer

1

Management of Difficult Cases of Non-Muscle

Invasive Bladder Cancer

2

Bladder Cancer

• Recurrence is common

• Progression is uncommon

• Progression is more important than recurrence

• There are indicators of recurrence and progression

3

Clinical Prognostic Markers

Risk of recurrence of Ta/T1 TCC by tumor characteristics

Allard et al, Br J Urol 81:692, 1998

ATC = 0

ATC = 3

ATC = 2

ATC = 1

4

0%

5%

10%

15%

20%

25%

30%

Ta T1

Progression at 3 years after TUR

N = 207p < 0.001 Heney et al, J Urol 130:1083, 1983

4%

30%

5

26%

40%36%

58%

0%

10%

20%

30%

40%

50%

60%

T1a T1b

Grade 2

Grade 3

T1 Progression by Stage and Grade

Holmang J Urol 157:800, 1997

6

0%

5%

10%

15%

20%

25%

30%

Ta (N = 77)

T1 (N = 99)

Risk of Death from Bladder Cancerby Presenting Stage

20 year follow-up, Rx with cystoscopy ± thiotepa

Holmang et al, J Urol 153:1823, 1995

11%

30%

7

Adjuvant Therapy 2005

• Cystoscopic surveillance

• Repeat TUR

• Perioperative chemotherapy

• Intravesical therapy– BCG– BCG + Interferon– Chemotherapy

• Cystectomy

8

Multiple Recurrences

• Jan 2004 -63 y/o man with multifocal Ta G2 TCC– Perioperative treatment with mitomycin

• April 2004 – 5 small Ta G2 TCC– BCG x 6 weeks

• July 2004 – 4 small Ta G2 TCC– BCG + interferon x 3 weeks

• Oct 2004 – 8 small, Ta G2 TCC– Mitomycin 40 mg/20 ml x 6

• Jan 2005 – 6 small, Ta G2 TCC– Doxorubicin 50 mg/50 ml x 6

• April 2005 – 4 small, Ta G2 TCC Dr. Lamm?

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Refractory G2, Ta TCC

• We desperately need more drugs!

• Cystectomy may otherwise be required

• Look for and remove carcinogens

• Diet and life style changes

• Oncovite 2 tabs BID (Mission Pharm)

• New options: immediate gemcitabine 1000mg/25cc

• Improved BCG immunotherapy

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Prevention: Smoking cessation, carcinogen avoidance, nutrition

• 2-fold risk for bladder cancer associated with increased DNA adducts in smokers– Mutagenesis. 18:445, 2003

• Intake of fruit and vegetables in smokers decreased DNA adducts – Carcinogenesis. 23:861, 2002

• 286 Ta, T1 patients: Quitting recurrence-free (P<.003) and progression-free (P<.001) survival– J Urol 161:172, 1999

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Bladder Cancer Chemoprevention• Vitamins: A, B6, C, D, E, folic acid, C+K3

– A: Sporn’79, Moon’83; B6: Byar’77, C: Schlegel’75, D: Konety’01; E: Michaud’00; C+K3: Gilloteaux’98; A,B6,C, E: Lamm, ‘94

• Allium sativum (Garlic) – Lau’86, Riggs’97, Lamm’01

• NSAIDS, Cox 2 inhibitors – Goodwin’81, Waddell’83, Earnest’92, Moon’92

• DMFO – Messing’88, Boone’90, Kellog’92, Loprinzi’96

• Oltipraz – Wattenberg & Buening’86, Moon’94, Kensler’95

• Selenium – Helzlsouer’89

• Soy protein, Green Tea – Mokhtar’88, Kemberling ‘03

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Kaplan Meier Estimate of 5 Year Tumor Free Rate

Lamm DL, J Urol 151: 21-26, 1994100

90

80

70

60

50

40

30

20

10

0

Months After Registration0 5 10 15 20 25 30 35 40 45 50 55 60

Pe

rce

nt T

um

or

Fre

e 40,000u Vitamin A, 100mg B6, 2gm C, 400mg E: "Oncovite"

p=0.0014

RDA VitaminsMulti VitaminMega Vitamin

(N=30)(N=35)

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Improved BCG Administration

• Low grade tumors respond less favorably

• Minimize tumor burden with complete resection and immediate chemotherapy

• Immune status: check the PPD; add percutaneous BCG if negative

• Weekly BCG x3 every 6 months, reducing dose 1/3, 1/10, 1/30, 1/100th

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T1 TCC

• 56 y/o man with T1, G3 TCC and CIS

• BCG x 6 weeks

• Biopsy 6 weeks later demonstrates T1 G3 TCC

Dr. Theodorescu?

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What are this man’s chances of progressing?...or for harboring invasive disease already?

• After BCG failure each additional course of BCG carries a 7% actuarial risk of progression– Catalona, 1987

• In patients with T1G3 cancers, multiple tumors and/or presence of CIS are major determinants of upstaging at radical cystectomy– Masood, 2004– N=17 (single tumor, no CIS): upstaging in 1 (6%)– N=13 (mult. Tumor +/- CIS): upstaging in 7 (55%)

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There is a Survival Advantage in patients with sTCC treated with “early” cystectomy

N=307 high risk sTCCtreated with TURBT+BCG90 underwent cystectomy for recurrent tumor: 35 superficial and 55 invasive recurrence

Of 35 with sTCC, 92% and 56% survived who underwent cystectomy <2 yrs after initial BCG therapy vs. >2 yrs

Multivariate analysis: survival in patients who underwent earlier cystectomy for sTCC relapse

Herr, 2001

Months Follow Up

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Defining BCG refractory sTCC

• 93 patients received a 6-week induction course of BCG

• Evaluated for response after 3 and 6 months

• 57% were negative for tumor at 3 months

• 80% of the patients were tumor-free at 6 mo

• Tumor-free interval during 24 mo followup best predicted by response to BCG at 6 mo

Herr, 2003

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Excellent Prognosis of sTCC with cystectomy for sTCC

• 5 and 10 year cancer-specific survival rates as a function of pathological tumor stage:

• Amling 1994– pT0 (43) 80% and 66% – pTa (11) 88% and 75% – pTis (19) 100% and 92% – pT1 (91) 76% and 62%

• Stein 2001– pT0, pTa, pTis (N0): (208) 89% and 85%– pT1 (N0): (194) 83% and 78 %

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Practical approach to T1G3 after 1st BCG failure

Multiple tumors or CIS (original or rec)

Cystectomy Second Line Intravesical Tx

Cystectomy

T1G3

BCG

Initial Treatment

1st Evaluation

2nd Evaluation(>6 mo)

Yes No

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Positive Cytology

• 71 y/o man with T1 G3 TCC with CIS• BCG x 6 weeks• After last dose had severe irritative

sx and fever to 102 x 24 hours• 6 weeks later – cysto negative and

cytology positive

Dr. Ratliff?

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Issues Highlighted by Case

• What defines BCG intolerance & contra-indication for further BCG therapy

• Approach to patients with positive cytology post-BCG

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Issue 1: Fever & Irritative Symptoms after BCG

• Irritative symptoms occur in 35-90% of patients (median, 75%)

– AUA Bladder Cancer Guidelines

• Transient fever > 102 in 1-2% at each instillation

– Lamm, DL and Torti, FM, Cancer Journal for Clinicians, 1996

• Fever longer than 24 hrs considered infection and treated accordingly

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• Reduction of transient symptoms (30-50%) by either:– BCG dose reduction (1/2 to 1/3)

• Martinez-Pineiro, BJU International 2002

– Slow dosing BCG on an every other week schedule

• Bassi, Eur. Urol. 2002

• Current patient not considered BCG intolerant

Issue 1: Fever & Irritative Symptoms after BCG

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Issue 2: Positive Cytology Post-BCG

• Positive cytology strong indicator of presence of TCC (>95%)

• BCG induced antitumor activity can be delayed – CIS without maintenance: 57% to 68% CR

• Lamm J Urol 2002

• Additional treatment increases response– maintenance 55% to 84% CR

• Lamm, J Urol 2002Tim, you could consider quoting the Herr paper from

my section to tie these 2 sections together

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• Determine source of positive cytology– >80% in bladder while ≈ 20% outside

bladder (ureter, kidney, prostatic ducts)

• At U. Iowa routinely restage patients with post-treatment positive cytology– Bladder barbotage, random bladder bx,

prostatic urethra bx, upper tract washings, bilateral retrograde pyelograms

Issue 2: Positive Cytology Post-BCG

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Treatment

• If disease localized to bladder, 3 reduced doses BCG (1/3, 1/10, 1/10) with IFNα (50 MU followed 1 mo later with another 3 treatment cycle

• Evaluate at 6 mo.

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Positive Cytology

• 53 y/o non-smoker

• History of Ta, G2 TCC 2 years ago

• Positive cytology

• IVP negative

• Bladder and prostatic urethral biopsies negative

• 3 months later – positive cytology

Dr. Lamm?

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Positive Cytology, Negative Bx

• 0.2% Methylene blue vital staining will increase yield of biopsy

• UroVysion should be positive, but can be checked if there are doubts

• Differential wash: bladder and each ureter for cytology

• Ureteroscopy with biopsy of any suspicious urothelium

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Unusual Histology

• 58 y/o man with T1 micropapillary bladder cancer

Dr. Theodorescu?

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Clinical demographics of “Micropapillary” bladder cancer

N Country % of All BC

Mean Age M:F Author Year

18 USA n/a 67 5:1 Amin 1994

20 Sweden 0.7% 69 2:1 Johansson 1999

20 Australia n/a 69 4:1 Samaratunga 2004

38 Mexico 6% 68 37:1 Alvarado 2005

7 Several n/a 60-70 n/a Case reports 1995-2001

Literature review 1966 to 3/2005

Search Terms: “micropapillary bladder cancer (carcinoma)”

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What is micropapillary (MPC)bladder cancer?

Clinical Features• Variant of carcinoma in various anatomic sites

(breast, urinary bladder, lung, and salivary glands)• High propensity for lymphovascular invasion and

lymph node metastases• Often high-stage disease at presentation• Tumors with <10% MPC have a high chance of

detection at an early stage• Poor clinical outcome compared with that of

patients with urothelial carcinoma (N=38, 40% DFS at 3yrs)

• Radiation and chemotherapy do not seem to be effective

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What is micropapillary (MPC)bladder cancer?

Pathology• immunohistochemical staining pattern supports that

MPC is a variant of adenocarcinoma• small tight clusters of neoplastic cells floating in clear

spaces resembling lymphatic channels• pattern is mixed with a variable component of

conventional urothelial carcinoma or other variants

Low Power High Power

Figures from: webpathology.com

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58 y/o man with T1 MPC

• Very lucky to have detected it at an early stage

• Staging workup (CT chest, CT-IVP and BS)

• Given aggressive clinical behavior and lack of evidence intravesical therapy, radiation therapy or systemic chemotherapy of benefit patient CYSTECTOMY ASAP!

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Carcinoma in Situ

• 68 y/o woman former smoker with CIS

• BCG x 6 weeks

• Biopsy 6 weeks later demonstrates CIS

Dr. Ratliff?

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Issues Highlighted by Case

• Conservative vs radical therapy

• Conservative treatment options

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Issue 1 Conservative vs Radical Therapy

• Natural history CIS progression 7% annually and 3.3% at 6 mo – Cheng, Cancer, 1999– Millan-Rodriquez, J Urol, 2000

• Cystectomy mortality 2%

• Thus another 3 mo for additional conservative therapy is acceptable risk

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Issue 2: Treatment Options

• BCG induced antitumor activity can be delayed CIS without maintenance: 57% to 68% CR

Lamm J Urol 2002

• Additional treatment increases response maintenance 55% to 84% CR

Lamm, J Urol 2002

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Issue 2: Treatment Options

• Chemotherapy for BCG failures provides poor response rates 19% for MMC post BCG

Malmstrom, J Urol, 2001

• Low Dose BCG after one cycle BCG failure provides 60% durable CR (same as BCG naive)

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Maymi et al, AUA Abstract 918

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Treatment

• Low dose BCG + IFN (50 MU)

• Evaluate at 3 and 6 mo.

• If fail at 6 mo., cystectomy

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Recurrent High Grade TCC

• 65 y/o woman with a history of Ta G2-3 TCC

• Intravesical BCG for 6 weeks

• Regular surveillance cystoscopy

• 2 years after her initial tumor has a 2 cm, Ta G3 TCC

Dr. Lamm?

42

High Grade Recurrenceafter BCG Induction

• Meta analysis shows BCG reduces progression, but only with maintenance

• Repeated 6 week treatments is historically suboptimal, suppresses cytokines, risks immunosuppression, and is ineffective in a controlled trial

• 3 weekly BCG (extending if there are no symptoms), repeating at 3 months, then q. 6 months would be my choice for her

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3 Week Maintenance BCG 550 pts. 6 wk vs. 3 wk maintenance at

3, 6, 12, 18, 24, 30, & 36 months

Recurrence -freeSurvival Survival

Worsening -freeSurvival

Lamm DL et al, J Urol 163, 1124, 2000

p < 0.0001 p = 0.08p = 0.04

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BCG Maintenance: Not Created Equal

YearsCompletion of Therapy*Apparent Increase in Rate of Recurrence One Year After Completion of Maintenance

**

Per

cent

Tum

or R

ecur

renc

e

100

90

80

70

60

50

40

30

20

10

0

M, TaT1, 3wk maintenance BCG M, CIS, 3wk maintenance BCG I, CIS, 6wk induction BCG I, TaT1, 6wk induction BCG

M. Ta, T1

M. CIS

I. CIS

I. Ta, T1

0 1 2 3 4 5 6 7 8 9* **

N=385, 3q 3-6mo.

Time in months

Glo

bal r

ecur

renc

e

Maintenance

0 12 24 36 48 60 72

1.0.9

.8

.7

.6

.5

.4

.3

.2

.10.0

Control

N=126, 6q 6mo.

Months

90100

7080

60

4050

3020

010

0 369 18 27

% D

isea

se F

ree

N=93 pts. 1q 1mo.

M BCGI BCG

Months

100

50

0

% T

umor

Fre

e

3 21

12

15

18

33

24

27

30

6 9

M BCGI BCG

N=42 pts. 1q 3mo.

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Meta Analysis: BCG vs Control

24 trials with 4863 patients were eligible:

Start of Patient Entry:Date of Publication:Duration of Follow Up:

Five BCG strains:

1978 to 19931982 to 2001Median: 2.5 yearsMaximum: 15 years

TICE, Connaught, Pasteur, RIVM, A. Frappier

Sylvester, R: J Urol, 2002

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Progression: Maintenance BCG

Patients No BCG BCG OR

No Maint 1049 10.3% 10.8% 1.28

Maintenance 3814 14.7% 9.5% 0.63

Test for heterogeneity: P = 0.008

BCG was only effective in trials with maintenance, where it reduced the risk of progression by 37%

p = 0.00004.

Study Publ YearAuthor and Group

Events / PatientsNo BCG BCG

Statistics (O-E) Var.

OR & CI:(BCG No BCG)

|1-OR|% ± SD

ProgressionAll Studies With Maintenance

1991 Pagano (Padova) 11 / 63 3 / 70 -4.4 3.1


1987 Badalament (MSKCC) 6 / 46 6 / 47 -0.1 2.6


2000 Lamm (SW8507) 102 / 192 87 / 192 -7.5 24.1


2001 Palou 2 / 61 3 / 65 0.4 1.2


1996 Rintala (Finnbl 2) 3 / 90 3 / 92 0 1.5


1995 Rintala (Finnbl 2) 4 / 40 2 / 28 -0.5 1.3


1995 Lamm (SW8795) 24 / 186 15 / 191 -4.8 8.8


1999 Malmstrom (Sw-N) 22 / 125 15 / 125 -3.5 7.9


2001 Nogueira (CUETO) 8 / 127 10 / 247 -1.9 3.9


1991 Rintala (Finnbl 1) 2 / 58 3 / 51 0.7 1.2


2001 de Reijke (EORTC) 18 / 84 10 / 84 -4 5.9


2001 vd Meijden (EORTC) 19 / 279 24 / 558 -4.7 9.1


1982 Brosman (UCLA) 0 / 22 0 / 27 0 0


1990 Martinez-Pineiro 4 / 109 1 / 67 -0.9 1.2


1999 Witjes (Eur Bropir) 2 / 25 1 / 28 -0.6 0.7


1997 Jimenez-Cruz 7 / 61 6 / 61 -0.5 2.9


1994 Kalbe 2 / 35 0 / 32 -1 0.5


1991 Kalbe 2 / 17 0 / 21 -1.1 0.5


1993 Melekos (Patras) 7 / 99 2 / 62 -1.5 2


1988 Ibrahiem (Egypt) 12 / 30 5 / 17 -1.1 2.6

Total 257 / 1749 196 / 2065 -36.8 80.9(14.7 %) (9.5 %)

37% ±9reduction

0.0 0.5 1.0 1.5 2.0BCG No BCGTest for heterogeneitybetter better2

=9.73, df=18: p=0.9Treatment effect: p=0.00004

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Survival

Death Patients No BCG BCG Total ORAll 2930 26.7% 23.2% 24.8% 0.89Bladder 2370 7.7% 5.6% 6.5% 0.81

The reductions in the odds of death, 11% overall and 19% bladder cancer, are not statistically significant, as might be expected with 2.5 year mean follow up

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• Use perioperative therapy for low-risk TCC• Use maintenance BCG for high-risk TCC• Lower the dose for BCG toxicity• Don’t abandon BCG therapy for CIS at 3

months• Recurrent T1 disease is dangerous• Be more aggressive with micropapillary &

small cell histology• Don’t follow your patient to the grave –

consider cystectomy when local Rx fails

1 management of difficult cases of non-muscle invasive bladder cancer

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