Bladder Cancer Review

AKA: why we all take private jobs

Daniel Lee, MD, MS

Perelman School of Medicine
University of Pennsylvania
Conflicts of Interest

 None
Outline

 NMIBC
 TURBT
 Intravesical therapy
 BCG
 MIBC
 NAC
 AC
 TMT
Name these guys
Quick Clinical Tidbits

 Median Age  73 years

 Of new diagnoses  75% NMIBC
 Smoking  6x increased risk
 History  Previous chemotherapy (Cytoxan)
 Family history (2x risk) / HNPCC
 UTI or CIC
 Gross hematuria  ~10% risk bladder CA
 Microhematuria  2.6% risk bladder CA
NMIBC

 CSS  70-85% at 10 yr
 LGTa  50% recurrence, 5% progression
 HGT1  70% recurrence, 30-40% progression

 Problems with TURBT

 30-50% will be upstaged
 Often incomplete, ~40% will have recurrence at
first cystoscopy
ABLE 4: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer
Low Risk Intermediate Risk High Risk
a
LG solitary Ta ≤ 3cm Recurrence within 1 year, HG T1
LG Ta
b
PUNLMP Solitary LG Ta > 3cm Any recurrent, HG Ta
LG Ta, multifocal HG Ta, >3cm (or
multifocal)
c d
HG Ta, ≤ 3cm Any CIS
LG T1 Any BCG failure in HG
patient
Any variant histology
e
Any LVI
Any HG prostatic
urethral involvement
Guidelines

 Initial TURBT Recs Reason

HGTa Re-TURBT 50% residual, 15% upstage
No Muscle Re-TURBT 40-50% upstage
HGT1 (+m) Re-TURBT If residual, 80% progression
15% upstage
 HGT1 randomized to re-TUR
 MMC

 ReTUR: 26% recurrence

 No ReTUR: 63% recurrence
Should we be giving MMC post-
TURBT

39% reduction
in recurrence
Should we be giving MMC post-
TURBT
 13% absolute reduction
 Number needed to treat: 7
 20% High Grade in trial
 No difference in HG
 $56 vs. $1026
 1hr dwell time
Should we be giving intravesical
chemotherapy post-TURBT
 YES
 MMC effective, but toxic / expensive
 Gemcitabine good option
 SWOG trial
 660 patients in 1980s
 Median RFS: 77 vs. 36 mo
 5yr RFS 60% vs. 40%
 16% completed
BCG overall

 4 RCT  Level 1 Evidence

 Prevents Recurrence 44% relative decrease
 Prevents Progression 61% relative decrease

 70% of people have SE; 8% have to stop

 HGTa: EORTC trial  1 year BCG = 3 year BCG
 HGT1: 3 year BCG
If +cytology, negative cysto after
BCG
 Think CIS, Check prostatic urethra and Upper Tracts
 20% urethral recurrence if +cytology and no visible tumors
 25% upper tract tumors in NMIBC

 Blue light cystoscopy valuable

 Increase CIS detection 40%
 50% lower recurrence rate
If NMIBC recurs after BCG induction

 HGTa / CIS  repeat BCG induction 50% respond to 2nd dose

 HGT1  Offer cystectomy CSS 69% (early RC) vs.
52% (re-BCG)
MIBC
5 year survival rates

Stage 5 year
survival*
0 98%

I 88%

II 63%

III 46%

IV 15%
*1988-2001 American Cancer Society Wong-You–Cheong J J et al. Radiographics
2006;26:553-580
Bladder Cancer Histology and Genetics Normal urothelium

FGFR3 TP53
PTEN
RAS RB
RB1

20%
70% Progression 30%
PTEN
TP53
Cystectomy
RB1 +/- perioperative
Re

RB
cu

chemotherapy
rre

LG papillary HG muscle-invasive
nc
e

TURBT 70% Basal-like Luminal

Case #1
 61-year-old diabetic male, 30 pack year history of
smoking (stopped 10 years ago) presents with gross
hematuria.

 He underwent transurethral resection of the bladder

tumor (TURBT) with pathology showing high-grade
papillary carcinoma with plasmacytoid features,
invading into the muscularis propria.

 He is an active gentlemen with a history of

hyperlipidemia and diabetes on metformin,
glimepiride and sitagliptin. He denies neuropathy.
Baseline labs include a normal complete blood Plasmacytoid variant;
count (CBC), normal liver function studies, magnification ×200.
creatinine of 1.0 mg/dL (calculated creatinine
clearance 122.5 mL/min)
CT Images at Baseline and History
 Abdominal/pelvic CT reveals a
plaque-like mass in the wall of
the urinary bladder that
measures up to 1.7 cm in
thickness. The lesion involves
the right posterior lateral
aspect, including the
ureterovesicular junction.

 Moderate hydronephroureter
on the right, due to obstruction
at the ureterovesicular
junction.

 There are no abnormally

enlarged or abnormally
enhancing retroperitoneal or
mesenteric lymph nodes.
Chest is negative for
metastases.
Next steps?

A. Radical cystectomy with extended node dissection, consider

adjuvant chemotherapy with either M-VAC or
gemcitabine/cisplatin.
B. Neoadjuvant chemotherapy with gemcitabine/carboplatin,
followed by radical cystectomy with extended node dissection.
C. Neoadjuvant chemotherapy with dd-MVAC or GC, followed by
radical cystectomy with extended node dissection.
D. Radical cystectomy with extended node dissection, consider
adjuvant chemotherapy with either gemcitabine/carboplatin or
paclitaxel/carboplatin.
Next steps?

A. Radical cystectomy with extended node dissection, consider

adjuvant chemotherapy with either M-VAC or
gemcitabine/cisplatin.
B. Neoadjuvant chemotherapy with gemcitabine/carboplatin,
followed by radical cystectomy with extended node dissection.
C. Neoadjuvant chemotherapy with dd-MVAC or GC, followed by
radical cystectomy with extended node dissection.
D. Radical cystectomy with extended node dissection, consider
adjuvant chemotherapy with either gemcitabine/carboplatin or
paclitaxel/carboplatin.
 Muscle-Invasive Bladder Cancer
(MIBC): Surgery
Radical Cystectomy
Gold Standard in the U.S.
Male: cystoprostatectomy
Female: anterior exenteration
bladder, anterior vagina, uterus, ovaries,
fallopian tubes
Open vs Laparoscopic
Robotic assisted
Fully or partially intracorporeal
 Outcomes After Cystectomy

Stein JP et al: J Clin Oncol. 2001;19(3):666-675.

Integrated Therapy:
Rationale
Recurrence following radical cystectomy remains fairly
common
20-30% pT2 or less
50-60% pT3 or greater

Risk of clinical understaging significant

especially unrecognized lymph node involvement

Majority of recurrences are distant disease

Stage IVA

Stage IIIB

Stage IIIA/B

Mustafa Ozan Horsanali and Kutan Ozer (2017). Lymphadenectomy in

Muscle Invasive Bladder Cancer, Bladder Cancer - Management of NMI
and Muscle-Invasive Cancer, Prof. M Hammad Ather (Ed.), InTech, DOI:
10.5772/67443.
5-year survival rates

Stage 5 year survival*

0 98%

I 88%

II 63%

III 46%

IV 15%

*1988-2001 American Cancer Society Wong-You–Cheong J J et al. Radiographics

2006;26:553-580
 MIBC:
Role of Chemotherapy
 Urothelial carcinoma is a chemosensitive disease

 Response rates in metastatic setting are 50-70% for

cisplatin-based regimens However, the long-term (5+
yr) survival for patients with metastatic urothelial carcinoma is only
10-15%.
 MIBC:
Role of Chemotherapy
Can be given neoadjuvant or adjuvant setting
Evidence favors neoadjuvant chemotherapy (NAC)
Cisplatin based multi-drug regimens
Most common options
Gemcitabine & cisplatin (GC)
Dose-dense methotrexate, vinblastine,
doxorubicin & cisplatin (ddMVAC)
 Neoadjuvant Chemotherapy
Advantages
Treatment of micrometastatic disease without delay in treatment

The ability to assess tumor response in vivo Allows one to change

chemotherapy regimens

Patient’s performance status is optimal

Treatment is better tolerated before surgery

Drug delivery not compromised by postsurgical changes

Sternberg CN et al. Urology. 2007; 69 (1 suppl): 62-79.

 Neoadjuvant Chemotherapy

Disadvantages
Over-treat some patients

Up to 30% clinically overstaged

May delay definitive local therapy
Delay of >12 weeks has been associated with worse outcome
in some series
Mortality and morbidity from chemotherapy itself

Sternberg CN et al. Urology. 2007; 69 (1 suppl): 62-79.

Under-utilization of NAC

 One retrospective review of 7,161 patients with stage III bladder cancer
diagnosed from 1998 – 2003 demonstrated 1.2 % received NAC (11.6 %
adjuvant).1
 A more recent study of 4,541 patients from 14 academic centers in US
from 2003 – 2008 showed that 12% of patients received NAC.2
 Reasons include patient preference, physician bias as well as difficulty in
giving cisplatin-based therapy to an older population.

1 David KA et al, The Journal of Urology, Volume 178, Issue 2, August 2007, Pages 451-454
2 Feifer A, et al, J Clin Oncol 2011; 29 (Suppl 7)
Bladder Cancer
EVIDENCE SUPPORTING NEOADJUVANT CHEMOTHERAPY
SWOG 8710: Neoadjuvant M-VAC versus Immediate Cystectomy?

Arm A
Immediate
317 patients
Radical cystectomy Overall Survival
Phase III, multi-center with bilateral pelvic
lymphadenectomy

Randomized
Southwest Oncology Group
Tumor down-staging
Key Eligibility Criteria
• cT2N0M0 to cT4aN0M0 UC
• No prior pelvic irradiation
• SWOG PS of 0 or 1 Arm B

M-VAC q 28 days
3 cycles of
M - Methotrexate 30 mg/m2 on day 1, 15, 22
Preoperative
V - Vinblastine 3 mg/m2 on day 1, 15, 22
A - Doxorubicin 30 mg/m2 on day 2 1:1 M-VAC plus surgery
C - Cisplatin 70 mg/m2 on day 2
RESULTS:
Arm A: median survival: 46 months
Arm B: median survival: 77 months
Stratified Cox proportional hazards model:
HR 1.33 (1.00, 1.76)

Downstaging to pT0 38% in Arm B

50% of cT2
30% of cT3
Grossman, H. et al. N Engl J Med 2003;349:859-866
15% in immediate RC arm
 Neoadjuvant Chemotherapy:
SWOG 8710

Grossman et al., NEJM, 2003.

Grossman, H. et al. N Engl J Med 2003;349:859-866
EORTC/MRC: Neoadjuvant CMV versus Immediate Cystectomy/EBRT?

Arm A

976 patients Immediate

Radical cystectomy Overall Survival
Phase III, multi-center, international with bilateral pelvic
EORTC/MRC

Randomized
lymphadenectomy
Key Eligibility Criteria
Metastasis-free survival
• cT2 (G), cT3, cT4a UC
• Excluded tumors > 7 cm Locoregional disease-free
• Mixed histology eligible survival
• Stratified by local RX and tumor stage Arm B
Disease-free survival
CMV q 21 days 3 cycles of
C - Cisplatin 100 mg/m2 on day 2 1:1 Preoperative
M - Methotrexate 30 mg/m2 on days 1, 8 CMV plus surgery
V - Vinblastine 4 mg/m2 on days 1, 8
RESULTS:

5-Year Overall survival

Arm A: 43%
Arm B: 49%
HR 0.84 (95% CI 0.72 – 0.99)

5-yr Metastasis-free survival

Arm A: 38%
International Collaboration of Trialists, Lancet, 1999.. Arm B: 47%
International Collaboration of Trialists, JCO, 2011.
 Neoadjuvant Chemotherapy:
EORTC/MRC

International Collaboration of Trialists, Lancet, 1999.

International Collaboration of Trialists, JCO, 2011.
 Neoadjuvant Chemotherapy:
EORTC/MRC

EBRT RC
HR 0.8 95%CI 0.63 to 1.02 HR 0.74 95%CI 0.57 to 0.96
P=0.070 P=0.022

International Collaboration of Trialists, Lancet, 1999.

International Collaboration of Trialists, JCO, 2011.
 Meta-analysis:
Neoadjuvant Chemotherapy
Pooled results of 11 RCTs comprising 3005
patients
98% of patients from all known eligible RCTs (T2-T4a, N0, M0)
Urothelial Carcinoma

Overall Survival: absolute benefit at 5 yrs

Single-agent cisplatin: -5%
Cisplatin-based combo: 5%

ABC Collaboration, Eur Urol, 2005

 Meta-analysis:
Neoadjuvant Chemotherapy

ABC Collaboration, Eur Urol, 2005

 Is Neoadjuvant ddM-VAC better?
44 patients
Pathologic complete
response (pT0)
Phase II,

Open- Label
multicenter, open-label
Toxicity
Key Eligibility Criteria
• cT2-cT4, N0-1 (node < 2 cm) MIUC 3 cycles of
• Adequate organ function Preoperative
ddM-VAC plus Response
• CCl > 50 cc/min
• Split-dose cisplatin allowed surgery

Dose dense M-VAC q 14 days

M - Methotrexate 30 mg/m2 on day 1
V - Vinblastine 3 mg/m2 on day 1 RESULTS:
A - Doxorubicin 30 mg/m2 on day 1 • 15 of 40 (38%) achieved pT0
C - Cisplatin 70 mg/m2 on day 1 (95% CI, 23 to 53).
Pegfilgrastim 6 mg SC on day 2
• 53% were downstaged to
NMIBC. 93% completed all 3
cycles.

• Well tolerated, 82% Grade II

AE; median time from start of
chemo to cystectomy was 9.7
Elizabeth R. Plimack et al. JCO 2014;32:1895-1901
weeks.
 Neoadjuvant ddM-VAC

Elizabeth R. Plimack et al. JCO 2014;32:1895-1901

 Neoadjuvant ddM-VAC

Elizabeth R. Plimack et al. JCO 2014;32:1895-1901

 Neoadjuvant ddM-VAC
39 patients
Pathologic response
(PaR)
Phase II,

Open - Label
IIT, multicenter, open-label

4 cycles of Toxicity
Key Eligibility Criteria
• cT2-cT4, N0-1 MIUC Preoperative
• Adequate organ fucntion ddM-VAC plus
Disease-free survival
• CCL> 50 cc/min surgery

Dose dense M-VAC q 14 days Radiologic Response

M - Methotrexate 30 mg/m2 on day 1 (RaR)
V - Vinblastine 3 mg/m2 on day 2
Other: Correlatives,
A - Doxorubicin 30 mg/m2 on day 2
ERCC1
C - Cisplatin 70 mg/m2 on day 2
Pegfilgrastim 6 mg SC on day 3 RESULTS:
• 19 of 39 (49%) achieved PaR
(two-sided 80% CI, 38 to 61)

• 26% achieved a complete PaR (pT0);

95% completed 4 cycles; 62% RaR.

• Median time to surgery was 6 weeks

after the last dose of chemotherapy.

Toni K. Choueiri et al. JCO 2014;32:1889-1894

 Neoadjuvant Chemotherapy:
ddMVAC > MVAC
Conclusions

-Well tolerated, safe, and effective

Alternative to the standard MVAC
Regimen.

-PaR rates which included 43% with

cN1 disease compared equally to
MVAC. 14 of 17 patient had pN0 at
surgery.

-No patients had nodal positive disease

Toni K. Choueiri et al. JCO 2014;32:1889-1894

 Choice of Chemotherapy Agent
Tested regimens for neoadjuvant therapy
ddMVAC: methotrexate, vinblastine,
doxorubicin, & cisplatin
CMV: cisplatin, methotrexate, vinblastine
others
One used most often:
Gemcitabine & cisplatin (GC)
Phase III trial in metastatic disease vs MVAC
found to have similar survival but GC better
tolerated
 Take Home
Excellent level one evidence to support neoadjuvant
chemotherapy plus cystectomy for MIBC

- Combination therapy
- Cisplatin-based
- Number of cycles, 3-4 (not fully defined)
- Interim assessment for response
Yes: complete neoadjuvant chemotherapy
No: proceed to cystectomy
Case #2

 47-year-old gentlemen with a history of type 2 diabetes mellitus on

insulin, IgA nephropathy following cadaveric kidney transplant in
2006 and a recent history of MIBC who declined neoadjuvant
chemotherapy is here for evaluation.

 One month ago, he underwent a radical cystoprostatectomy with a

left pelvic LN dissection and bilateral nephroureterectomy. His
pathology demonstrated tumor invading the deep muscularis
propria (pT2b) with a single regional lymph node metastasis in the
true pelvis (N1).

 He denies neuropathy. Baseline labs include a normal complete

blood count (CBC), normal liver function studies, creatinine of 1.0
mg/dL (calculated creatinine clearance 74.8 mL/min)
Next steps?

A. Active surveillance with scans including CT of abdomen/pelvis

every 3 months.
B. Start carboplatin-based adjuvant chemotherapy due to pT2b
disease.
C. Start cisplatin-based adjuvant chemotherapy due to N1 disease.
D. Start ifosfamide-based adjuvant chemotherapy due to N1 disease.
Next steps?

A. Active surveillance with scans including CT of abdomen/pelvis

every 3 months.
B. Start carboplatin-based adjuvant chemotherapy due to pT2b
disease.
C. Start cisplatin-based adjuvant chemotherapy due to N1 disease.
D. Start ifosfamide-based adjuvant chemotherapy due to N1 disease.
Bladder Cancer
EVIDENCE SUPPORTING ADJUVANT CHEMOTHERAPY
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Bladder Cancer (Version 2.2016). Available at: NCCN.org. © National Comprehensive Cancer Network, Inc. All rights reserved.
The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
 Adjuvant Chemotherapy
Advantages
• Therapy based on pathologic staging more accurate
• Primary therapy (cystectomy) delivered immediately
• Treat micro-metastases when volume is lowest

Disadvantages
 Cannot assess response to therapy
 Poorly tolerated in post-operative period
 Any surgical complication leads to delayed
therapy
 Adjuvant Chemotherapy

Far fewer high-quality studies evaluating the

potential survival benefit

Nonetheless, evidence suggests that

chemotherapy is more frequently administered
in the adjuvant setting as opposed to the
neoadjuvant setting
 Adjuvant Chemotherapy:
Meta-analysis
 Trial inclusion:
 Proper randomization
 Biopsy proven locally invasive (T2-T4a)
 Local therapy +/- adjuvant chemotherapy
 Urothelial carcinoma
 6 RCTs included
 493 patients representing 90% of all patients randomized to
adjuvant cisplatin-based chemotherapy

ABC Collaboration, Eur Urol, 2005

 Adjuvant Chemotherapy:
Meta-analysis
Overall Survival: HR 0.75 (95% CI 0.60–0.96,
p=0.019)
Corresponds to absolute improvement of 9% at 3yrs

Disease-specific Survival: HR 0.68 (95% CI

0.53–0.89, p=0.010)
Corresponds to absolute improvement of 12% in DFS at 3yrs

ABC Collaboration, Eur Urol, 2005

 Adjuvant Chemotherapy:
Meta-analysis
Limitations to meta-analysis:
SMALL numbers render authors “unable to provide a definitive comment on
the true effect of this therapy”
Challenges with differences in study design/ execution
Receipt of subsequent-line chemotherapy in control arms
Early closure secondary to benefit in 3 trials included in analysis

ABC Collaboration, Eur Urol, 2005

 Adjuvant Chemotherapy:
Updated Meta-analysis
 Trial inclusion:
 Proper randomization
 Biopsy proven locally invasive (T2-T4a)
 Local therapy +/- adjuvant chemotherapy
 Urothelial carcinoma
 9 RCTs included (5 previous, 1 updated, 3 new)
 945 patients representing 90% of all patients randomized to
adjuvant cisplatin-based chemotherapy

Leow, JJ et. Al, Eur Urol, 66 (2014), pp. 42-54

 Adjuvant Chemotherapy:
Updated Meta-analysis
Overall Survival: HR 0.77 (95% CI 0.59–0.99,
p=0.049)

Disease-free Survival: HR 0.66 (95% CI 0.45–

0.91, p=0.014)
The disease-free survival more apparent for positive nodal
involvement (p = 0.010)

Leow, JJ et. Al, Eur Urol, 66 (2014), pp. 42-54

EORTC-30994: Immediate vs. Delayed Adjuvant Chemotherapy?
Arm A
284 patients
Post-cystectomy
Delayed chemotherapy Overall Survival
Phase III, multi-centered, international (clinical relapse)
EORTC/MRC

Randomized
Key Eligibility Criteria Progression-free survival
Within 90 days of cystectomy (PFS)
pT3 – pT4 or N+M0 UC of the bladder

Arm B
Immediate arm consisted of
4 cycles of M-VAC, or GC or ddM-VAC;
Delayed arm, 6 cycles Immediate
Chemotherapy
Stratified by chemotherapy regimen, nodal 1:1
status, T category or participating co-op group. RESULTS:

• Overall survival
No significant improvement
(adjusted HR 0.78, 95%
CI 0.56 -1.08; p=0.13)

• 5-yr PFS
Arm A: 31.8%
Arm B: 47.6%
Sternberg, CN et al, the Lancet Oncology, Volume 16, Issue 1, January 2015, Pages 76-86.
EORTC-30994: Immediate vs. Delayed Adjuvant Chemotherapy

No significant improvement in OS was

noted with immediate treatment when
compared with deferred treatment
(adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13).

Immediate treatment significantly

prolonged progression-free survival
compared with deferred treatment
(HR 0.54, 95% CI 0.4 -0.73, p<0.0001).

Sternberg, CN et al, the Lancet Oncology, Volume 16, Issue 1, January 2015, Pages 76-86.
Take Home

 Evidence for adjuvant chemotherapy lower than for neoadjuvant

 Remains an option for those with poor risk (e.g., T3+ or N+) who
have NOT received neoadjuvant chemotherapy
 Multi-agent, cisplatin-based regimen
Summary Question?

A 60 year old F with cT2, N0,M0, Urothelial cancer with a creatinine of 0.9 is
contemplating a cystectomy with perioperative chemoRx.

Which of the following statements is a compelling reason to choose neoadjuvant

over adjuvant therapy?

A. Carboplatin containing regimens are more effective than cisplatin containing

regimens.
B. After cystectomy many patients have prolonged recoveries and/or impaired
renal function making them poor candidates for adjuvant chemotherapy
C. Level 1 evidence favors adjuvant over neoadjuvant chemotherapy
D. Disease progression during neoadjuvant chemotherapy is a common event,
rending most patients who receive it ineligible for undergoing cystectomy.
Summary Question?

A 60 year old F with cT2, N0,M0, Urothelial cancer with a creatinine of 0.9 is
contemplating a cystectomy with perioperative chemoRx.

Which of the following statements is a compelling reason to choose neoadjuvant

over adjuvant therapy?

A. Carboplatin containing regimens are more effective than cisplatin containing

regimens.
B. After cystectomy many patients have prolonged recoveries and/or impaired
renal function making them poor candidates for adjuvant chemotherapy
C. Level 1 evidence favors adjuvant over neoadjuvant chemotherapy
D. Disease progression during neoadjuvant chemotherapy is a common event,
rending most patients who receive it ineligible for undergoing cystectomy.
Case #3
 61-year-old farmer with history bladder cancer presents with
worsening abdominal pain.

 His bladder cancer history includes a TURBT with high-grade

papillary MIBC in November 2015. He was started on gemcitabine
plus cisplatin in mid-January with completion of 3 cycles. A
restaging CT of the abdomen demonstrated new periaortic LN
and interval progressive disease in retrocrural, para-aortic,
bilateral iliac region LN. There were no visceral metastases.

 Despite the severe pain in his abdomen, he remains very active.

He does report mild weakness and fatigue. He denies hematuria.
He quit smoking five years ago. He denies neuropathy. Baseline
labs include a normal complete blood count (CBC), normal liver
function studies, creatinine of 0.87 mg/dL (calculated creatinine
clearance 93.2 mL/min). CD4 count is 344.
CT Images
Next steps?

A. Start salvage chemotherapy with single agent pemetrexed.

B. Start salvage chemotherapy with single agent docetaxel.
C. Referral for clinical trial consideration.
D. Start immunotherapy.
Next steps?

A. Start salvage chemotherapy with single agent pemetrexed.

B. Start salvage chemotherapy with single agent docetaxel.
C. Referral for clinical trial consideration.
D. Start immunotherapy.
Bladder Cancer
EVIDENCE SUPPORTING TREATMENT OF METASTATIC
Metastatic UC:
Independent Prognostic factors
 Bajorin et al retrospectively reviewed 203 patients who were
enrolled in 5 M-VAC trials. Of 18 factors, KPS < 80 or presence of
visceral metastases (liver, lung or bone) were independently
predictive of OS.
 Median survival affected by presence of risk factors (P=0.0001)
 No risk factor, 33 months
 1 risk factor, 13.4 months
 2 risk factors, 9.3 months

Bajorin DF et. Al, J Clin Oncol 17:3173-81, 1999

 - 5% of patients present with metastatic disease

- 20% present with MIBC requiring a radical cystectomy with nearly half
developing metastatic disease and succumbing within two years.

- Nearly three decades ago, systemic cisplatin-based combination

chemotherapy resulted in an improved OS and still remains the
standard of care.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Bladder Cancer (Version 2.2016). Available at: NCCN.org. © National Comprehensive Cancer
Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN ®.
Von der Maase: GC = M-VAC
 Enrollment of 405 patients international,
multicenter, randomized phase III
Advanced (T4b, N2 or N3) or metastatic (M1)

 Randomized to chemotherapy GC versus M-VAC

Primary endpoint: Overall survival

Hans von der Maase et al. JCO 2005;23:4602-4608

 Kaplan-Meier curves for overall survival.

Toxic death rate was 1% in

GC group vs 3% for M-VAC

More patients had grade 3

neutropenia, neutropenic
sepsis in M-VAC.

QOL measures favored GC

based on PS, fatigue, and
weight.

Hans von der Maase et al. JCO 2005;23:4602-4608

EORTC 30924: ddM-VAC > M-VAC

263 patients

Conclusion:
No difference in OS
ddM-VAC had treatment delays, less toxicity
Sternberg CN et al. J Clin Oncol 19:2638-46, 2001
 7-yr Update EORTC 30924: ddM-VAC > M-VAC

Overall Survival

Sternberg CN et al. Eur J Cancer. 2006. Jan; 42(1): 50-4.

 7-yr Update EORTC 30924: ddM-VAC > M-VAC

Progression-free Survival

Sternberg CN et al. Eur J Cancer. 2006. Jan; 42(1): 50-4.

Defining Cisplatin eligibility

Consensus definition: Patients must meet at least one of the following to be

considered “unfit” for cisplatin

 WHO or ECOG performance status of 2, or Karnofsky performance status

of 60 – 70%
 Creatinine clearance (calculated or measured) less than 1 mL/s
 CTCAE version 4, grade 2 or above audiometric hearing loss
 CTCAE version 4, grade 2 or above peripheral neuropathy
 NYHA class III heart failure

Galsky MD et. al The Lancet Oncology Volume 12, Issue 3, march 2011, pages 211-214
EORTC-30986: Gem/Carbo vs. M-
CAVI for cisplatin-ineligible?
 Enrollment of 238 patients
N+, M1, stage IV or unresectable primary (T3-4)
PS of 2 and/or impaired renal function (GFR < 60
mL/min)

 Randomized to Gem/Carbo vs.

Methotrexate/carbo/vinblastine (M-CAVI)
Primary endpoint: Overall survival
Secondary endpoint: Overall response rate
(ORR), PFS, toxicity and quality of life
Maria De Santis et al. JCO 2012;30:191-199
 Duration of survival by
treatment group

Maria De Santis et al. JCO 2012;30:191-199

 Salvage Treatment of Metastatic
Urothelial Carcinoma
PFS, OS,
Drug Study Phase N RR, %
Months Months

Paclitaxel plus
Phase II 37 24.3% 3 7.1
Carboplatin [1]

Gemcitabine plus
Phase III 96 37.5% 4 7.8
paclitaxel [2]

Pemetrexed [3] Phase II 13 8% NR NR

Docetaxel [4] Phase II 30 13% NR 9

2nd Line systemic therapy was an unmet need in metastatic UC

1. Vaughn DJ, et al. Cancer. 2002;95:1022-1027;

2. Albers P, et al. Ann Oncol. 2011;22:288-294;
3. Galsky MD, et al. Invest New Drugs. 2007; 25:265-270;
4. McCaffrey JA, et al. J Clin Oncol. 1997; 15:1853-1857.
Immunotherapy & Urothelial Carcinoma

 Programmed death ligand 1 (PD-L1) acts as an

immune checkpoint which negatively regulates T-cell
function by binding to its receptors PD-1 or B7-1 on
activated T lymphocytes.
 Like other malignancies, urothelial carcinoma has
broad expression of PD-L1.
 High activity with checkpoint inhibitors in
malignancies with high mutation rates. UC has the
third highest rate based on TCGA data.1
Cancer Genome Atlas Research Network. Nature. 2014;507:315-322
PD-L1 (PD-L2) bind to PD-1 to inhibit T-Cell activation

Brahmer et al. Future Oncology 11(9) 2015

Chism. J Natl Compr Cancer Netw 2017;15: 1277-1284
Summary Question

 Which of the following best describes an immunologic checkpoint

blockade?

A. A strategy of enhancing antitumor immunity by turning on a T cell

through blockade of co-stimulatory molecules such as CD28.
B. A strategy of enhancing antitumor immunity by turning on a T cell
through blockade of co-inhibitory molecules such as PD-1
C. A strategy of enhancing antitumor immunity by turning on a T cell
through stimulation of co-inhibitory molecules such as PD-1
D. A strategy of enhancing antitumor immunity by turning on a T cell
through stimulation of co-stimulatory molecules such as CD28.
Summary Question

 Which of the following best describes an immunologic checkpoint

blockade?

A. A strategy of enhancing antitumor immunity by turning on a T cell

through blockade of co-stimulatory molecules such as CD28.
B. A strategy of enhancing antitumor immunity by turning on a T cell
through blockade of co-inhibitory molecules such as PD-1
C. A strategy of enhancing antitumor immunity by turning on a T cell
through stimulation of co-inhibitory molecules such as PD-1
D. A strategy of enhancing antitumor immunity by turning on a T cell
through stimulation of co-stimulatory molecules such as CD28.
Bladder cancer
FIRST-LINE IMMUNOTHERAPY FOR CISPLATIN-INELIGIBLE
Bladder cancer
SECOND-LINE IMMUNOTHERAPY FOR
 Atezolizumab

Rosenberg JE et. Al, Lancet. 2016 May 7; 387 (10031): 1909-20.

Atezolizumab: 1st FDA approved 2nd line therapy for locally advanced or metastatic UC?

Phase II, multi-center (IMvigor210)

310 patients
Key Eligibility Criteria

Open label
• Advanced or metastatic UC, cohort 2
• Patients consisted of prior treatment of Objective response
platinum-containing regimen Atezolizumab rate (ORR)
1200 mg IV q 3
- During or following or within 12 months weeks
of treatment with a platinum-containing Duration of response
NAC or adjuvant chemotherapy (DoR)
RESULTS:

Median follow-up was 14.4 months. • All patients ORR was 14.8% (95% of 11.1, 19.3);
CR – 5.5%; PR – 9.4%.

• ORR for high PD-L1 (N=100), 26%;

low PD-L1 (N=210) was 9.5%.
Prior NAC/Adjuvant (N=59), ORR was 22%

• Median DoR for all patients was not reached.

Rosenberg JE et. Al, Lancet. 2016 May 7; 387 (10031): 1909-20.

Rosenberg JE et. Al, Lancet. 2016 May 7; 387 (10031): 1909-20.
Pembrolizumab: Category 1 second-line therapy for locally advanced or metastatic UC

Investigator’s
Phase III, multi-center (KEYNOTE-045) Choice
542 patients
(Taxanes or
Key Eligibility Criteria vinflunine)

1:1 Randomized
• Advanced or metastatic UC, cohort 2
Overall survival or
• Patients consisted of prior treatment of
PFS
platinum-containing regimen
Pembrolizumab
- Stratified based on PD-L1 expression 200 mg IV q 3
weeks Objective Response

Median follow-up was 14.1 months.
RESULTS:
• Median OS was 10.3 months 995% CI 8 to 11.8) in
Pembrolizumab group compared to 7.4 months (95% CI, 6.1 to
8.3 in chemotherapy group. HR of 0.73; 95% CI, 0.59 to 0.91;
P=0.002).

• The median OS for PD-L1 group was 8 months (95 % CI, 5 to

12.3) for pembrolizumab compared to 5.2 months (95% CI, 4.0
to 7.4) in the chemotherapy group (HR, 0.57; 95% CI, 0.37 to
0.88; P=0.005).

• There was not a significant difference in the PFS for all

patients and the PD-L1 group. ORR was higher in
pembrolizumab (21.2% vs. 11.4%). Pembrolizumab had less
treatment-related AEs (60.9% vs. 90.2%).
Bellmunt, J et al., NEJM, 2017. 376(11): p. 1015-1026.
Bellmunt, J et al., NEJM, 2017. 376(11): p. 1015-1026.
Bellmunt, J et al., NEJM, 2017. 376(11): p. 1015-1026.
Immunotherapies Approved by
FDA in 2nd Line for mUC
Immunotherapy Phase Patients, ORR OS Adverse Reference
N Events
Atezolizumab II - IMvigor210 310 15 %  Fatigue (30%) Rosenberg J, et.
(1,200 mg q 3 weeks) Cohort 2 Nausea (14%) al
Decreased
III – IMvigor211 911 23% 11.1 mo^^ appetite (12%)
[8 CRs] (10.6 mo) Balar, A et. al
Durvalumab I/II 61 31 %  Fatigue (39%) Massard C et. al
PDL-1 (10 mg/kg q 2 weeks) MSK pain (24%)
Constipation
Avelumab I 44 18.2 % 13.7 mo Fatigue (31.8%) Apolo AB et. al
(10 mg/kg q 2 weeks) [5 CRs] Infusion-related
Nausea
Nivolumab * II – CheckMate 270 19.6% 8.7 mo Elevated lipase Sharma P, et. al
(3 mg/kg q 2 weeks) 275 Elevated amylase
Fatigue
PD-1 78 19% 9.7 mo Sharma P, et. al
I/II – CheckMate [5 CRs]
032
Pembrolizumab I - KEYNOTE-012 27 26%  Pruritus (19.5% Plimack ER, et. al
(200 mg q 3 weeks) Fatigue 913.9%)
Nausea (10.9%)
III - KEYNOTE-045 545 21.1 % 10.3 mo Bellmunt J et. al
(7.4 mo)
Take Home

 Poor performance and visceral metastases predict poor

outcome
 For cisplatin-eligible patients with metastatic disease, GC or
ddM-VAC are category 1.
 For cisplatin-ineligible, gemcitabine plus carboplatin,
atezolizumab or pembrolizumab may be options.
 Atezolizumab was the first FDA-approved second-line systemic
therapy; now a total of 5 are approved with pembrolizumab
(category 1).
Targetable Pathways in Bladder Cancer

Pathways RTK/Ras/PI3K pathway, 72% altered

FGFR3 EGFR ERBB2 ERBB3
p53/Rb pathway ATM
11% 3% 0% 11% 5% 7% 11% 2%
93% altered 12% 16%

CDKN2A p14 HRAS/NRAS PIK3CA

MDM2 TP53
5% 47% 5% 1% 15% 5%
0% 9% 49% 21%
p16
CCND1 NF1 PTEN INPP4B
CDKN1A Apoptosis 3% 13% 3% 7%
0% 10% 8% 3%
14% 6%
Akt
RB1
CCNE1 FBXW7 TSC1
10% 15% STK11
0% 12% 10% 9% 8% 16% mTOR
0% 11%
E2F3 TSC2
Cell Cycle 2% 9% Proliferation,
0% 18% Progression Survival

Pathways Gene percent of cases

legend inhibition activation switchable
mutation CNA inactivating activating component

TCGA, Nature, 2014

Thank you