Management of muscle-invasive bladder cancer

Todd M. Morgan

Vanderbilt University

Case #1Case #163-year-old male referred with T2

bladder ca. Re-TUR shows small amt of muscle-invasive cancer

Staging work-up negativeManagement:

1) Cystectomy?

2) Neoadjuvant chemotherapy + cystectomy?

3) Chemotherapy?

4) Radiation?

5) Cystoscopy in 3 months?

GoalGoal

Practical information to help guide clinical management of patients with muscle-invasive

bladder cancer

Outline

Surgical management

Metastatic disease

Neoadjuvant/adjuvant chemotherapy

Bladder preservation

Bladder cancer68,810 new cases/yr in US

14,100 deaths annually

Peak age: 70 yrs

80% initially non-invasive15-25% will progress

20% initially invasive

~50% have occult distant metastases

Staging

T2a: superficial m. propria

T2b: deep m. propria

T3a: micro extension into fat

T3b: macro extension into fat

T4a: invades pelvic viscera

T4b: extends to abd/pelvic walls

StagingStaging

TUR – local staging

CT abd/pelvis – regional/distant staging

Relatively inaccurate for local invasionFails to detect nodal mets in 20-60%MRI no better

CXR (or CT chest)

CBC, complete metabolic panel

Bone scan if elevated alk phos or sx’s

Outline

Surgical management

Metastatic disease

Neoadjuvant/adjuvant chemotherapy

Bladder preservation

Overall survival after cystectomy

Path stage

N 5-year (%) 10-year (%)

T0, Ta, Tis N0

208 85 67

T1N0 194 76 52

T2N0 94 77 57

T3N0 98 64 44

T4N0 79 44 23

N+ 246 31 23

Stein 2001 JCO

24% with LN involvement

Lymph node involvement varies with tumor stage

Stage Lymph node positive

T0, Ta, Tis, T1 5%

T2a 18%

T2b 27%

T3 45%

T4 45%

Stein 2001 JCO

Perioperative complications

MSKCC:

64% complication rate within 90 days

13% grade 3-5 complications

1.5% 30-day mortality

GI > infectious > wound

Donat 2009 Eur Urol

Vanderbilt:45% complication rate within 30 d (7.4% major)1.7% 30 day mortality

Cookson 2008 J Urol

Perioperative complications

Surgical factors affecting cancer

outcomes Surgical marginsMSKCC: 67/1589 (4.2%) positive margins21% with local recurrence at 5 yrs (vs. 6%)

Median time to recurrence: 16 moHR 1.98 (1.2-2.43) for disease-specific

death

Lymph node dissectionNumerous studies showing correlation

between node count and survival post-RCeg. Stein et al (J Urol 2003), Herr et al (J

Urol 2002), Leissner et al (BJUI 2000), May (Eur Urol 2011)

Rationale for between node count-survival

associationMore LNs removed/examined =

more accurate staging“Will Rogers” phenomenonApplicable to node-negative patients

Improved disease controlRemoval of LNs with micrometatases

Surrogate marker for quality of care

Observed association may actually be due to confounding by indication

Proposed surgical standards

At least 10 yearly cystectomies to maintain proficiency

Positive margin rate <10%

At least 10-14 LNs should be retrieved

BCOG 2001 J Urol

Case #269M with large, muscle-invasive

bladder tumor and bulky lymphadenopathy.

Treatment:

1)MVAC?

2)Gemcitabine/cisplatin?

3)High-dose intensity MVAC?

4)Cystectomy?

Chemotherapy questions

Best regimen?

Neoadjuvant vs. adjuvant?

MVACMethotrexate/vinblastine/doxorubicin/

cisplatinEfficacy in phase III trials in advanced

bladder ca3-4% toxic death rate

Cisplatin (n=120)

%

MVAC (n=126)

(%) p

Thrombocytopenia 2 6 0.1

Neutropenia 1 24 <0.0001

Granulocytopenic fever

- 10 0.0002

Sepsis 1 6 0.04

Renal 3 7 0.22

Mucositis 0 17 <0.0001

Hepatic 3 1 0.2

Loehrer 1992 JCO

Grade 3/4 toxicities

MVAC vs. GC

Gemcitabine/cisplatin: better safety profile

Phase III trial: 405 patients with locally advanced or metastatic TCC

GC: Median survival 7.7 mo

MVAC: Median survival 8.3 mo

Log rank p =0.41

von der Maase 2005 JCO

In-service break: 2 key In-service break: 2 key prognostic factors in advanced prognostic factors in advanced

TCCTCC

von der Maase 2005 JCO

Visceral metastases

Performance score

High-dose intensity MVAC

EORTC 30924: phase III trialStandard MVAC vs. HD MVAC + GCSF

Sternberg Eur Urol 2006

Q28 days

Q15 days

HD MVAC toxicity

Toxicity Grade

MVAC (n=129)

(%)

HD MVAC(n=134)

(%) p

Neutropenia3 46 12

<0.001

4 16 8

Neutropenic fever

26 10<0.00

11 toxic death in each armLess WBC toxicity in HD MVAC

likely secondary to GCSFToxicities otherwise similar

Sternberg Eur Urol 2006Sternberg Eur Urol 2006

MVAC vs. HD MVAC

Sternberg Eur Urol 2006

HD MVAC median survival: 9.5 mo

MVAC median survival: 8.0 mo

Log rank p=0.017

HR = 0.73 (9%CI 0.56-0.95) for HD MVAC vs. MVAC

Chemotherapy in advanced/metastatic

TCC

MVAC ~ GC

HD MVAC > MVAC

Case #3

65F with T2 bladder cancer s/p TURBT, (5cm, complete resection) negative staging work-up.

Recommendation:

1)Neoadjuvant chemo + cystectomy?

2)Cystectomy, consider adjuvant chemo?

3)Chemo + RT?

4)Re-TUR?

Why neoadjuvant or adjuvant

chemotherapy?

Path stage

N 5-year (%) 10-year (%)

T0, Ta, Tis N0

208 85 67

T1N0 194 76 52

T2N0 94 77 57

T3N0 98 64 44

T4N0 79 44 23

N+ 246 31 23

Stein 2001 JCO

Neoadjuvant rationale

Early treatment of microscopic mets

Downstaging of primary tumor

Drug delivery not compromised by previous surgery/radiation

Precise end-point of treatment

Better patient tolerance

Phase 3 trials of neoadjuvant

chemotherapyStudy group Neoadjuvant arm Standard arm

Patients (n) Survival

Australia/United Kingdom

DDP/RT RT 255 No difference

Canada/NCICDDP/RT or preop RT

+ CystRT/preop RT +

Cyst99 No difference

Spain (CUETO) DDP/Cyst Cyst 121 No difference

EORTC/MRC CMV/RT or Cyst RT or Cyst 9765.5% difference in

favor of CMV

SWOG M-VAC/Cyst Cyst 307Trend in survival

benefit with M-VAC (p=0.06)

Italy (GUONE) M-VAC/Cyst Cyst 206 No differenceItaly (GISTV) M-VEC/Cyst Cyst 171 No differenceGenoa DDP/5FU/RT/Cyst Cyst 104 No difference

Nordic 1 ADM/DDP/RT/Cyst RT/Cyst 311No difference, 15% benefit with ADM +

DDP in T3-T4aNordic 2 MTX/DDP/Cyst Cyst 317 No differenceAbol-Enein CarboMV/Cyst Cyst 194 Benefit with CarboMV

From Calabro Eur Urol 2009

EORTC neoadjuvant trial

Largest trial of neoadjuvant chemoRx

987 pts undergoing RT or cystectomy

Randomized to MVC or no treatment

106 institutions

Powered to detect 10% difference in overall survival

5.5% difference in 3-year survival (p=0.075)

EORTC Lancet 1999

SWOG 8710

307 pts with locally advanced bladder cancer

Randomized to neoadjuvant MVAC + cystectomy vs. cystectomy aloneGrossman 2003 NEJM

SWOG 8710SWOG 8710

Increased risk of death in cystectomy alone group: HR 1.33 (CI 1.00-1.76)

Disease specific HR 1.66 (CI 1.22-2.45)Survival benefit linked to downstaging

MVAC + cystecto

myCystecto

my p

Median survival

77 mo 46 mo 0.06

pT0 38% 15% <0.001

Grossman 2003 NEJM

Neoadjuvant meta-Neoadjuvant meta-analysisanalysis

ABC Eur Urol 2005

5% survival benefit in favor of neoadjuvant chemotherapy

CritiquesCritiques

Driven by SWOG and EORTC trials

Majority in these trials were young (63-65 yrs), had excellent performance status, and good renal function

Quality of surgery—confounding factor?

Delay in surgery for non-responders (~40%)

Is 5% benefit sufficient given toxicities?

Minimal benefit for T2

What about gemcitabine/cisplatin?

Adjuvant rationaleAdjuvant rationale

Selection of patients at highest risk for failure

Avoids over-treating patients likely to have good outcome from surgery alone

Surgery performed without delay

Adjuvant Adjuvant chemotherapy trialschemotherapy trials

Investigator Year Regimen Chemo No chemo Results

Logothetis 1988 CISCA 62 71Benefit but not

randomized

Skinner 1991 CAP 47 44Benefit few patients

received therapy

Stockle 1992 M-VAC/M-VEC 23 26Benefit no treatment

at relapse

Studer 1994 DDP 40 37 No benefit

Bono 1995 CM 48 35 No benefit for N0

Freiha 1996 CMV 25 25Benefit in relapse-

free survival

Otto 2001 M-VEC 55 53 No benefit

Cognetti 2008 GC 97 86No benefit for N0 or

N+

From Calabro Eur Urol 2009

Is it reasonable to extrapolate neoadjuvant data to adjuvant

setting?

140 pts randomized to neoadjuvant (peri-operative) MVAC vs. adjuvant MVAC

Suggests similar survival rates between the two groups

Millikan 2001 JCO

Problems with this study

At least 2 cycles of chemo received by 97% in neoadj group vs. 77% in adj group

Significant delays in treatment in adjuvant group

Positive surgical margins: 2% in neoadj group vs. 11% in adj group

Millikan 2001 JCO

Case #1

63-year-old male referred with T2 bladder ca. Re-TUR shows small amt of muscle-invasive cancer

Staging work-up negativeManagement:

1) Cystectomy?

2) Neoadjuvant chemotherapy + cystectomy?

3) Chemotherapy?

4) Radiation (+/- chemo)?

5) Cystoscopy in 3 months?

Outline

Surgical management

Metastatic disease

Neoadjuvant/adjuvant chemotherapy

Bladder preservation

Chemotherapy + radiation

Goal = bladder preservation

“Radiosensitizers” – 5-fluorouracil, cisplatin, gemcitabine, paclitaxil

No randomized trials of chemoradiation vs. surgery

Efficacy of chemoradiation

415 pts treated with radiotherapy +/- chemotherapy

Re-TUR 6 wks after treatment

Cystectomy recommended if incomplete response

Median f/u 5 yrs

Rodel 2002 JCO

Complete response: 72%

Local control after CR (no muscle invasion) maintained in 64% at 10 yrs

10-year disease-specific survival = 42%

>80% of survivors preserved their bladder

Tumor stage and TUR most important predictors of outcome

Efficacy of chemoradiation

Rodel 2002 JCO

Chemoradiation toxicity

Toxicity %

Grade 4

Salvage cystectomy due to contracted bladder

2

Bowel obstruction requiring surgery 1.5

Grade 3

Bladder capacity < 200cc 3

Grade 2

Frequency/urgency 10

Dysuria 8

Diarrhea 5

Proctitis 2Rodel 2002 JCO

Candidates for chemoradiation

Solitary tumor <5 cm

Clinical stage T2-T3a

No CIS

No hydronephrosis

No evidence of LN or distant mets

Normally functioning bladder

Bladder preservation with chemo + TUR

only63 pts with m.-inv ca with CR to

neoadj chemo who then refused cystectomyAll underwent re-staging TUR64% survived54% with intact bladder8/14 pts who underwent salvage

cystectomy died of bladder cancerPrognostic factors: single invasive

tumor, size <5cm, complete resectionHerr 2008 Eur Urol

SummarySurgical management

MarginsLN dissection

Metastatic diseaseMVAC, HD MVAC, and GC

Neoadjuvant/adjuvant chemotherapyModest benefitBest regimen?

Bladder preservationChemoradiationChemotherapy + TUR

“Optimal” management

Quality of cystectomy, LN dissection, and peri-operative management critical

Best evidence supports neoadjuvant chemo + cystectomy for pts who will tolerate it

Chemotherapy regimen still under debate – need more trial data

Bladder-sparing approaches may be considered in selected individuals