Surgical Management of Urothelial Carcinoma A 21 st Century Approach Douglas S. Scherr, M.D. Clinical Director, Urologic Oncology Weill Medical College.

Surgical Management of Urothelial Carcinoma

A 21st Century ApproachDouglas S. Scherr, M.D.

Clinical Director, Urologic OncologyWeill Medical College of Cornell

University

38 300

14 900

Estimated new cancer cases.10 leading sites by gender, US, 2000

8 100

4 100

Estimated cancer deaths.10 leading sites by gender, US, 2000

Epidemiology

• 5th most common cancer in men

• 12,000 cancer related deaths/year

• 70% present as superficial TCC

• “Superficial” = Ta, Tis, T1

• Men>Women

Epidemiology

• 2.8% lifetime risk in caucasian men0.9% lifetime risk in African American men

• 1% risk in caucasian women0.6% African American women

• Carcinogens implicated in bladder cancer – could have 40 year latency period

Risk Factors for Transitional Cell Carcinoma

• Cigarette smoking: 2-4 fold increase risk4-AminobiphenylO-toluidine

• Arylamine exposure2-NaphthylamineBenzidine4-Aminobiphenyl

• Chemotherapy – cyclophosphamide

• Pelvic radiation therapy

Overview

• Role of TUR

• Neoadjuvant Chemotherapy

• Surgical Principles of Importance

• Minimally Invasive Techniques-Robotics-Prostate Sparing Techniques

• Future Horizons

TUR vs. TUR + BCGT1, GIII

• 153 patients (92 TUR+BCG, 61 TUR alone) 23% in BCG arm had co-existing CIS compared with 10% in TUR alone arm (p=0.04)

• 5.3 year median follow up

• Recurrence rate:a.) BCG: 70%b.) TUR alone: 75%

• Time to recurrence:a.) BCG: 38 months

b.) TUR alone: 22 months

• Progression Rate:

a.) BCG: 33%b.) TUR alone: 36%

• Cystectomy Requirement:a.) BCG: 29%b.) TUR alone: 31%

• Overall Survival: No significant difference

Shahin et al. J Urol 169: 96-100, 2003

Overall Survival Time to cystectomy

Recurrence Free SurvivalProgression Free Survival

Shahin et al. J Urol 169: 96-100, 2003

Neoadjuvant Chemotherapy Meta-Analysis

• Analysis of data from 2688 individual patients from 10 randomized trials

• Clinical stage T2-T4a disease• Platinum based chemotherapy with a

significant benefit to overall survival– 13% reduction in risk of death– 5% absolute benefit at 5 years

• Overall survival increased from 45% to 50%

• No evidence for single agent CDDPLancet 2003; 361: 1927-34

Neoadjuvant Chemotherapy Meta-analysis

Lancet 2003; 361: 1927-34

Neoadjuvant Chemotherapy Meta-analysis

Lancet 2003; 361: 1927-34

Lancet 2003; 361: 1927-34

Neoadjuvant Chemotherapy Meta-analysis

N Engl J Med 349;9 859-66 August 28, 2003

Patient Characteristics

N Engl J Med 349;9 859-66 August 28, 2003

MVAC Toxicities Grade 3 (n = 150)

N Engl J Med 349;9 859-66 August 28, 2003

N Engl J Med 349;9 859-66 August 28, 2003

Grossman, H. B. et. al. N Engl J Med 2003;349:859-866

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

Grossman, H. B. et. al. N Engl J Med 2003;349:859-866

Survival According to Treatment Group and Whether Patients Were Pathologically Free of Cancer (pT0) or Had Residual Disease (RD) at the

Time of Cystectomy

Grossman, H. B. et. al. N Engl J Med 2003;349:859-866

Survival According to Treatment Group and Whether Patients Had Superficial Muscle Involvement (Stage T2 Disease) or More Advanced

Disease (Stage T3 or T4a)

Conclusions

• Median survival of cystectomy alone was 46 mo c/w 77 mo for combination therapy (p=0.06 by two-sided stratified log rank test)

• In both groups, improved survival associated with the absence of residual cancer in the cystectomy specimen

• Significantly more patients in the combination group had no residual disease than patients in the cystectomy group (38% vs. 15%, p=<0.001)

N Engl J Med 349;9 859-66 August 28, 2003

Diagnosis and StagingThe “Re-Staging TURB”

• 78% of T1 tumors have residual tumor at the time of re-staging TURB

• 25-40% are upstaged to T2

• If no muscle in first biopsy, approximately 50% of pts are upstaged to T2

• If T1 is restaged and remains T1, only 13% are upstaged at time of cystectomy

Herr et al. J Urol, 162: 74-76, 1999Brauer et al. J Urol, 165: 808-10, 2001Dalbagni et al, Urology, 10: 19-24, 2003Dutta et al. J Urol, 166: 490-3. 2001

Radical Cystectomy for T1 TCC

• USC Experience: 208 pts with T1 disease Recurrence Free Survival Overall Survival

5 Year 10 Year 5 Year 10 Year

80% 75% 74% 51%

Stein et al., J Clin Oncol, 19(3): 666-75, 2001

Early Vs. Late Cystectomy

• 90 pts who had TUR + BCG ultimately underwent cystectomy

• 41/90 had T1 disease

• Median Follow up of 96 mosEarly cystectomy (<2 years): 92% survivalLate cystectomy (>2 years): 56% survival

Herr and Sogani, J Urol, 166: 1296-9, 2001

Natural HistoryT1, GIII TCC

• Natural history of T1, G3: -69-80% recurrence rate-33-48% progression rate

• “Rule of 30%” a.) 30% never recurb.) 30% die of metastatic TCC

c.) 30% require deferred cystectomy

Was the Effect all Chemotherapy?Are surgical variables important?

• Post cystectomy survival predicted by:a.) ageb.) stagec.) node statusd.) negative surgical marginse.) >10 nodes removed

• Hazard ratio for death:a.) 2.7 for + surgical marginb.) 2.0 for <10 nodes removed

Herr et al. JCO, 22(14): 2781, 2004

Extent of Lymphadenectomy

• Is there more to the node dissection than staging?

• 1936 Colston and Leadbetter performed studies on 98 cadavers “limited metastatic disease was restricted to the pelvic nodes”

• 1946 – Dr. Jewett “cardinal site of metastasis”

Colston and Leadbetter, J Urol, 36: 669, 1936Jewett et al. J Urol, 55: 366, 1946

Extent of Lymphadenectomy

• Node positive patients can enjoy long term survival

• 24% of grossly node positive disease survived 10 years without adjuvant therapy

• More nodes removed correlates with improved survival

Sanderson et al. Urol Oncol., 22: 205, 2004

Extent of Lymphadenectomy

• Likely no staging advantage to extending the node dissection above the aortic bifurcation

• 33% of unsuspected nodes found at common iliacs

• Practice patterns vary widely:a.) 40% of cystectomies have no LNDb.) 12.7% of LND had <4 nodes removed

Lymph node density (# pos nodes/total # nodes)

Konety et al. J Urol, 170: 1765, 2003

IMA

Genitofemoralnerve

Genitofemoralnerve Aortic

Nodes

Common Iliac Nodes

Hypogastric and Obturator Nodes

Extent of Pelvic Lymph Node Dissection

Survival By Number Of Lymph Nodes Removed

Herr et al. JCO, 22(14): 2781, 2004

Herr, H. W. et al. J Clin Oncol; 22:2781-2789 2004

Postcystectomy survival by node status and number of nodes removed

Post Cystectomy Survival

Variable HR* 95% CI P Value

Treatment RC v MVAC + RC 1 0.7 to 1.4 0.97

Age ≥65 v < 65 years 1.5 1.0 to 3.6 0.03

pT stage 3-4 v 0–2 2.3 1.5 to 3.6 0.0002

Node status positive v negative 1.6 1.0 to 2.5 0.04

Margins Positive v negative 2.7 1.5 to 4.9 0.0007

Nodes removed < 10 v ≥10 2 1.4 to 2.8 0.0001

Herr, H. W. et al. J Clin Oncol; 22:2781-2789 2004

T1 Bladder Cancer“Superficial?”

• Balance between over treatment and under diagnosis

• Role of cystectomy

• Intravesical Therapy

Prostate Sparing Cystectomy

• Role for improved continence and potency

• Need to rule out prostate cancer or TCC of prostatic urethra

• Functional Results are good:a.) 97% complete continenceb.) No episodes of retentionc.) 82% maintained potency

Vallancien et al. J Urol, 168: 2413, 2002

Prostate Sparing Cystectomy

• Incidence of Pca is 30-50% with approx. 48% are clinically significant

• 60% of CaP involve the apex (79% significant and 42% insignificant)

• 48% of prostates had urothelial ca involvement of which 33% had apical involvement

• 61% had no prostatic apical involvement of CaP or Urothelial ca.

(6/71-12/97)

USC/Norris Bladder Cancer Experience in 1054 Patients

Probability of Not RecurringAccording to Pathologic Group

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of N

ot R

ecur

ring

P <0.001

Organ Confined (n=594)

Extravesical (n=214)

Lymph Node (+) (n=246)

(6/71-12/97)

USC/Norris Bladder Cancer Experience in 1054 Patients

Probability of SurvivalAccording to Pathologic Groups

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of S

urvi

val

P <0.001

Organ Confined (n=594)

Extravesical (n=214)

Lymph Node (+) (n=246)

(6/71-12/97)

USC/Norris Bladder Cancer Experience

Patients with Positive Lymph Nodes (N=246):Probability of Not Recurring

According to Pathologic Groups

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of N

ot R

ecur

ring

LN+: Organ Confined (n=75)

LN+: Extravesical (n=171)

P = 0.004

(6/71-12/97)

USC/Norris Bladder Cancer Experience

Patients with Positive Lymph Nodes (N=246):Probability of Survival

According to Pathologic Groups

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of S

urvi

val

LN+: Organ Confined (n=75)

LN+: Extravesical (n=171)P < 0.001

(6/71-12/97)

USC/Norris Bladder Cancer Experience

Probability of Not RecurringAccording to # of Lymph Nodes Involved

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of N

ot R

ecur

ring

P <0.001

Lymph Node - (n=808)

1-4 Lymph Nodes + (n=160)

> 5 Lymph Nodes + (n=86)

(6/71-12/97)

USC/Norris Bladder Cancer Experience

Probability of SurvivalAccording to # of Lymph Nodes Involved

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of S

urvi

val

P <0.001

Lymph Node - (n=808)

1-4 Lymph Nodes + (n=160)

> 5 Lymph Nodes + (n=86)

(6/71-12/97)

USC/Norris Bladder Cancer Experience

Incidence of Recurrence Following Surgery:Lymph Nodes Positive TCC (N=246)

0 5 10 15

Years from Cystectomy

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Inci

denc

e of

Rec

urre

nce

Distant Recurrence (f=113)

Local Recurrence (f=28)

Dodd et al, JCO, 1999

Outcome of Postchemotherapy Surgery After MVAC for Advanced Transitional Cell

Carcinoma

Role of Robotics In Bladder Cancer

• Decrease in hospital stay

• Lower morbidity

• Can it compete oncologically?

Conclusion

• Bladder cancer is a multidisciplinary disease

• Surgery plus chemotherapy are the cornerstone of therapy

• New advances in biomarkers and better characterization of T1 disease is necessary

Karakiewicz et al., Eur Urol, Vol 50:6, p. 1254-62, 2006