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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