Conferencia auspiciada por MSD para urología, Hotel InterContinental, Medellín, 16/08/2018.

1. Adjuvant, Neoadjuvant and Systemic Rescue in
Muscle-Invasive Bladder Cancer
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín
August 16, 2018, Hotel InterContinental, Medellín@Onconerd

2. @ONCONERD

3. Mauricio Lema: Conflicts of interest for
this lecture
Lecture honoraria
BMS, MSD
“Esta presentación, puede
contener medicamentos no
disponibles o no aprobados
en Colombia. Se
recomienda revisar la IP de
los productos y sus
indicaciones aprobadas por
la regulación local
(INVIMA)”

4. TNM /
Stage

5. TNM /
Stage
MIBC

6. TNM /
Stage
MIBC
Adjuvant
CT

7. TNM /
Stage
MIBC
Adjuvant
CT
Neo-
Adjuvant
CT

8. TNM /
Stage
MIBC
Adjuvant
CT
Neo-
Adjuvant
CT
Systemic
rescue

9. TNM /
Stage

10. Bladder Cancer - AJCC TNM 8th ed., 2017

11. N0 N1 N2 N3 M1a M1b
Ta Ta - - - - -
Tis Tis - - - - -
T1 I IIIA IIIB IIIB IVA IVB
T2a II IIIA IIIB IIIB IVA IVB
T2b II IIIA IIIB IIIB IVA IVB
T3a IIIA IIIA IIIB IIIB IVA IVB
T3b IIIA IIIA IIIB IIIB IVA IVB
T4a IIIA IIIA IIIB IIIB IVA IVB
T4b IVA IVA IVA IVA IVA IVB
AJCC – Prognostic Groups for Bladder Cancer
AJCC, TNM 8th ed., 2017

12. N0 N1 N2 N3 M1a M1b
Ta Ta - - - - -
Tis Tis - - - - -
T1 I IIIA IIIB IIIB IVA IVB
T2a II IIIA IIIB IIIB IVA IVB
T2b II IIIA IIIB IIIB IVA IVB
T3a IIIA IIIA IIIB IIIB IVA IVB
T3b IIIA IIIA IIIB IIIB IVA IVB
T4a IIIA IIIA IIIB IIIB IVA IVB
T4b IVA IVA IVA IVA IVA IVB
AJCC – Prognostic Groups for Bladder Cancer
AJCC, TNM 8th ed., 2017

13. N0 N1 N2 N3 M1a M1b
Ta Ta - - - - -
Tis Tis - - - - -
T1 I IIIA IIIB IIIB IVA IVB
T2a II IIIA IIIB IIIB IVA IVB
T2b II IIIA IIIB IIIB IVA IVB
T3a IIIA IIIA IIIB IIIB IVA IVB
T3b IIIA IIIA IIIB IIIB IVA IVB
T4a IIIA IIIA IIIB IIIB IVA IVB
T4b IVA IVA IVA IVA IVA IVB
AJCC – Prognostic Groups for Bladder Cancer
AJCC, TNM 8th ed., 2017
Non-Muscle Invasive (NMIBC)
Muscle Invasive (MIBC)
Advanced

14. Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Funt, SA. Nat Rev Clin Oncol, 2017
50%
Proportion of
newly
detected
cases
95%
5-Year OS

15. Tis
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Tis Tis Tis Tis Tis Tis Tis Tis Tis Tis
Tis Tis Tis Tis Tis
Funt, SA. Nat Rev Clin Oncol, 2017
15%
Proportion of
newly
detected
cases
90%
5-Year OS

16. T1
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Tis Tis Tis Tis Tis Tis Tis Tis Tis Tis
Tis Tis Tis Tis Tis T1 T1 T1 T1 T1
Funt, SA. Nat Rev Clin Oncol, 2017
5%
Proportion of
newly
detected
cases
90%
5-Year OS

17. II-III
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Tis Tis Tis Tis Tis Tis Tis Tis Tis Tis
Tis Tis Tis Tis Tis T1 T1 T1 T1 T1
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
Funt, SA. Nat Rev Clin Oncol, 2017
20%
Proportion of
newly
detected
cases
60%
5-Year OS

18. IV
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Tis Tis Tis Tis Tis Tis Tis Tis Tis Tis
Tis Tis Tis Tis Tis T1 T1 T1 T1 T1
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
IV IV IV IV IV IV IV IV IV IV
Funt, SA. Nat Rev Clin Oncol, 2017
10%
Proportion of
newly
detected
cases
5-30%
5-Year OS

19. Stage distribution 10 x 10
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
Tis Tis Tis Tis Tis Tis Tis Tis Tis Tis
Tis Tis Tis Tis Tis T1 T1 T1 T1 T1
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
II-III II-III II-III II-III II-III II-III II-III II-III II-III II-III
IV IV IV IV IV IV IV IV IV IV
Funt, SA. Nat Rev Clin Oncol, 2017

20. Genetic and epigenetic defects that characterize the divergent
pathways of urothelial tumorigenesis
Wu XR, Nature Reviews Cancer, 2005
RTK (PI3k)
TSG

21. N0 N1 N2 N3 M1a M1b
Ta Ta - - - - -
Tis Tis - - - - -
T1 I IIIA IIIB IIIB IVA IVB
T2a II IIIA IIIB IIIB IVA IVB
T2b II IIIA IIIB IIIB IVA IVB
T3a IIIA IIIA IIIB IIIB IVA IVB
T3b IIIA IIIA IIIB IIIB IVA IVB
T4a IIIA IIIA IIIB IIIB IVA IVB
T4b IVA IVA IVA IVA IVA IVB
AJCC – Prognostic Groups for Bladder Cancer
Muscle Invasive (MIBC)
20%
Proportion of
newly
detected
cases
60%
5-Year OS
Funt, SA. Nat Rev Clin Oncol, 2017

22. TNM /
Stage
MIBC

23. NCCN Guidelines Version 5.2018: Bladder Cancer
cT2/N0
NeoAdj CT
Radical
Cystectomy
Clinical Stage II
NeoAdj CT
Partial
Cystectomy
Solitary lesion, no Tis
Concurrent
Chemo-RT
Reassess 2-3 mo
Observation
Chemo-RT
TURBT
RT
Non-cystectomy candidates
Adjuvant RT
Adjuvant RT
pT3-4 or N+
pT3-4 or N+
Intra vesical
BCG
Tis, Ta, T1
Sugery
M0
Cisplatin-based
Cisplatin-based

24. NCCN Guidelines Version 5.2018: Bladder Cancer
cT3-T4a/N0;
cT1-T4a/N1
NeoAdj CT
Radical
Cystectomy
Clinical Stage IIIA
Concurrent
Chemo-RT
Reassess 2-3 mo
Observation
Chemo-RT
RT
Non-cystectomy candidates
Adjuvant RT
pT3-4 or N+
Intra vesical BCG
Tis, Ta, T1
Sugery
Cisplatin-based
Reassess 2-3 mo
Observation
Chemotherapy or palliative TURBT
or treat as metastatic disease
M0

25. NCCN Guidelines Version 5.2018: Bladder Cancer
cT1-T4a/N2,3
Downstaging
systemic therapy
Clinical Stage IIIB
Concurrent Chemo-
RT
M0
Complete response
Partial response
Progression
Cystectomy or ChemoRT or
Observation
Cystectomy or ChemoRT or treat as
metastatic
Treat as metastatic disease
Complete response
Partial response
Progression
Follow-up
BCG if Tis/Ta/T1, Cystectomy or
treat as metastatic
Treat as metastatic disease

26. TNM /
Stage
MIBC
Adjuvant
CT

27. Surgery followed by
adjuvant
chemotherapy is
NOT a standard
option in the NCCN
guidelines for MIBC

28. Adjuvant therapy in MIBC
Radical
Cystectomy
Adjuvant
Chemotherapy
30% of patients experience a
grade 2–5 complication within 90
days of surgery that could delay
the delivery of effective adjuvant
chemotherapy Donat SM, Eur Urol, 2009

30. pT3-pT4 or N+
Cisplatin based
CT
Observation
Arms OS (yr) DFS (yr)
Cisplatin based CT 6.74 3.1
Observation 4.60 0.99
HR, p 0.78, 0.13 0.54, 0.0001
7-year follow-up
Planned accrual: 1344
Actual accrual: 284
EORTC 30994: Adjuvant chemotherapy in MIBC
Stermberg C, Lancet Oncol, 2015
Gemcitabine + Cisplatin
MVAC
ddMVAC

31. Observational
study
T3/T4 and/or N+
Cystectomy +
Cisplatin based
CT
Cystectomy +
Observation
NCCD
5,653 patients
23% received adjuvant chemotherapy
Effectiveness of Adjuvant Chemotherapy for
Locally Advanced Bladder Cancer
Galsky M, JCO, 2016
HR 95% CI
Favors CT 0.70 0.64-0.76

32. TNM /
Stage
MIBC
Adjuvant
CT
Neo-
Adjuvant
CT

33. Neoadjuvant (ie,
pre-operative)
cisplatin-based
chemotherapy is
the OPTIMAL
standard-of-care
for cN0 MIBC

34. NCCN Guidelines Version 5.2018: Bladder Cancer
cT2/N0
NeoAdj CT
Radical
Cystectomy
Clinical Stage II
NeoAdj CT
Partial
Cystectomy
Solitary lesion, no Tis
Concurrent
Chemo-RT
Reassess 2-3 mo
Observation
Chemo-RT
TURBT
RT
Non-cystectomy candidates
Adjuvant RT
Adjuvant RT
pT3-4 or N+
pT3-4 or N+
Intra vesical
BCG
Tis, Ta, T1
Sugery
M0
Cisplatin-based
Cisplatin-based

35. NCCN Guidelines Version 5.2018: Bladder Cancer
cT3-T4a/N0;
cT1-T4a/N1
NeoAdj CT
Radical
Cystectomy
Clinical Stage IIIA
Concurrent
Chemo-RT
Reassess 2-3 mo
Observation
Chemo-RT
RT
Non-cystectomy candidates
Adjuvant RT
pT3-4 or N+
Intra vesical BCG
Tis, Ta, T1
Sugery
Cisplatin-based
Reassess 2-3 mo
Observation
Chemotherapy or palliative TURBT
or treat as metastatic disease
M0

36. SWOG 8710: Neoadjuvant Chemotherapy plus Cystectomy Compared
with Cystectomy Alone for Locally Advanced Bladder Cancer
Patients with clinical tumor–node–metastases (TNM) stage
T2N0M0 to T4aN0M0 bladder cancer who were candidates for
radical cystectomy were eligible.
Prior pelvic irradiation was not allowed. Patients were required
to have adequate renal, hepatic, and hematologic function and
a SWOG performance status of 0 or 1.
Barton Grossman, NEJM (2003) 10.1056/NEJMoa022148
T2-T4aN0M0
Bladder Cancer
M-VAC + Cystectomy
Cystectomy
R
T hree 28-day cycles of M-VAC, as follows: methotrexate (30 mg per square meter of body-surface area) on days
1, 15, and 22; vinblastine (3 mg per square meter) on days 2, 15, and 22; and doxorubicin (30 mg per square
meter) and cisplatin (70 mg per square meter) on day 2.
To compare the survival among patients treated with
cystectomy alone with survival among those treated with M-
VAC followed by cystectomy in a randomized phase 3 trial

37. Neoadjuvant Chemotherapy plus Cystectomy Compared with
Cystectomy Alone for Locally Advanced Bladder Cancer
Barton Grossman, NEJM (2003) 10.1056/NEJMoa022148

38. Neoadjuvant Chemotherapy plus Cystectomy Compared with
Cystectomy Alone for Locally Advanced Bladder Cancer
Barton Grossman, NEJM (2003) 10.1056/NEJMoa022148

39. Neoadjuvant Chemotherapy plus Cystectomy Compared with
Cystectomy Alone for Locally Advanced Bladder Cancer
Barton Grossman, NEJM (2003) 10.1056/NEJMoa022148

40. Neoadjuvant Chemotherapy in Invasive Bladder Cancer:
Update of a Systematic Review and Meta-Analysis of
Individual Patient Data
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. European Urology (2005)
Absolute 5% improved OS at 5-yr

41. Neoadjuvant Chemotherapy in Invasive Bladder Cancer:
Update of a Systematic Review and Meta-Analysis of
Individual Patient Data
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. European Urology (2005)

42. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin,
and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large,
Randomized, Multinational, Multicenter, Phase III Study
Von der Maase, J Clin Oncol (2000)
GC: Gemcitabine 1,000 mg/m2 over 30 to 60 minutes on
days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2.
GC provides a similar survival advantage to MVAC with a
better safety profile and tolerability.

43. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin,
and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large,
Randomized, Multinational, Multicenter, Phase III Study
Von der Maase, J Clin Oncol (2000)

44. Multicenter prospective phase II trial of
neoadjuvant (neo) dose dense gemcitabine and
cisplatin (DD-GC) in patients (pts) with muscle-
invasive bladder cancer (MIBC) cN0
Balar A et al. Multicenter prospective phase II trial of
neoadjuvant (neo) dose dense gemcitabine and cisplatin (DD-
GC) in patients (pts) with muscle-invasive bladder cancer
(MIBC) [abstract]. J. Clin. Oncol34 (Suppl. 2S), 436 (2016)
Gemcitabine 2500 mg/m2 d1 +
Cisplatin 35 mg/m2 d1, d2
Q14d x6
Radical cystectomy + LND
Within 8 weeks
Of 40 pts with RC pathology available to
date, 24 (60%) were ≤ pT1 and 7 (18%)
were pT0.

45. Cisplatin inelegibility
• ECOG PS ≥ 2
• Creatinine Clearance < 60 ml/min
• Grade >2 Hearing-loss
• Grace >2 Neuropathy
• NYHA class III heart failure
Galsky DA, Cancer, 2006
30-50% of patients are
Cisplatin-inelegible

46. Cisplatin
Carboplatin

47. Neoadjuvant cisplatin-
based CT improves OS
in muscle-invasive,
cN0, bladder cancer
(GC or M-VAC)

48. Can we observe CR
patients after
Neoadjuvant CT (NACT)?

49. Can we observe CR
patients after
Neoadjuvant CT?
Placing patients who have
achieved a clinical complete
response to NACT under
observation only is “akin to
playing Russian roulette”
Apolo AB, Urol Oncol, 2012

50. N0 N1 N2 N3 M1a M1b
Ta Ta - - - - -
Tis Tis - - - - -
T1 I IIIA IIIB IIIB IVA IVB
T2a II IIIA IIIB IIIB IVA IVB
T2b II IIIA IIIB IIIB IVA IVB
T3a IIIA IIIA IIIB IIIB IVA IVB
T3b IIIA IIIA IIIB IIIB IVA IVB
T4a IIIA IIIA IIIB IIIB IVA IVB
T4b IVA IVA IVA IVA IVA IVB
AJCC – Prognostic Groups for Bladder Cancer
Muscle Invasive (MIBC)
Funt, SA. Nat Rev Clin Oncol, 2017
Level I evidence for NACT No level I evidence for NACT (6, not 3-4 preoperative CT cycles)

51. TNM /
Stage
MIBC
Adjuvant
CT
Neo-
Adjuvant
CT
Systemic
rescue

52. NeoAdjuvant or
preoperative CT
Radical
Cystectomy +
Bilateral Pelvic
LND
Cure
Relapsed

71. Take-home messages
• Cisplatin-based neoadjuvant chemotherapy improves OS in cN0
MIBC
• Other treatment options are based on “reasonable” assumptions:
– Carboplatin-based for Cisplatin-inelegible patients
– Preoperative CT for cN+ disease
– Adjuvant cisplatin-based CT
• Observation after cCR after CT is NOT supported by any evidence,
and should be discouraged.
• Pembrolizumab improves OS, and is superior to CT, in relapsed
bladder cancer

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