MIBC & Metastatic Urinary Bladder carcinoma

MIBC & Metastatic Urinary Bladder carcinoma

1. MIBC and
Metastatic
Bladder Cancer
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

2. MODERATORS:
Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D. Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.2

3. MUSCLEINVASIVE
BLADDER CANCER
3DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

4. Percentage of patients
presenting with muscle
invasive bladder cancer at
initial presentation.
20%
TO
30%
4DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

5. Will die if left
untreated
85%
IN
2 YRS
5DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

6. HOW WE COME ACROSS THE PATIENT?
1. Patient undergoes TURBT for bladder growth, report shows muscle invasion.
2. Patient undergoes ReTURBTwith no evidence on muscle invasion in the first biopsy,
repeat biopsy shows evidence of muscle invasion.
3. Patient comes with a large bladder mass, with obvious radiographic evidence of
muscle invasion in the form of perivesicalfat stranding, extravesicalmass, infiltration
into nearby structures.
4. Patient is a known case of TCC bladder, underwent TURBT and is on regular
cystoscopicfollowup. During a followupcystoscopy, a growth was found, and the
biopsy shows evidence of muscle invasion.
6DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

7. T STAGING
7DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

8. DIVERTICULUM
THERE IS NO T2
8DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

9. PROSTATE INVOLVEMENT
9DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

10. BLADDER –REGIONAL LYMPH NODES
PRIMARY DRAINAGE -
TRUE PELVIS
SECONDARY DRAINAGE-
ABOVE TRUE PELVIS UPTO
AORTIC BIFURCATION
10DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

11. REGIONAL LYMPHNODES
11DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

12. N1 STAGE
SINGLE LYMPHNODEIN TRUE
PELVIS
12DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

13. N2 STAGE
MULTIPLE LYMPHNODESIN
TRUE PELVIS
13DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

14. N3 STAGE
LYMPHNODE(S) IN COMMON
ILIAC REGION (SECONDARY
DRAINAGE AREA)
14DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

15. T STAGING
AJCC8
TH
EDITION
15DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

16. NSTAGING
16DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

17. DISTANT METASTASIS
17DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

18. STAGE GROUPING
18DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

19. PROGNOSTIC FACTORS
19DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

20. CLINICAL STAGING
1. Transurethral resection specimen
2. Bimanual examination of the patient under anaesthesia
3. Liver function tests
4. Chest radiography
5. Contrast enhanced cross sectional imaging
20DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

21. BIMANUAL EXAMINATION UNDER ANAESTHESIA
Place dominant hand on the suprapubic region and one or two fingers of the non
dominant hand in the rectum (in males) and vagina (in females).
Done before and after resection.
Finding (Marshall)
T2a –Non palpable
T2b-Induration but no three dimensional mass
T3a-Three dimensional mobile mass
T4a-Invading adjacent structures
T4b-Fixed to pelvic sidewall and not mobile
21DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

22. Do CECT abdomen and
pelvis in all cases
before TURBT???NO
22DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

23. Biopsy shows muscle
invasion now…
What next?
OK, NOT
DONE
BUT…
23DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

24. Do contrast study 7 days after TURBT.
To avoid overstagingas T3.
24DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

25. T2-4A, N0 M0
Radical Cystectomy
With
Bilateral pelvic lymph node
dissection
25DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

26. Optimal time from
diagnosis of muscle
invasion to cystectomy
12 WEEKS
26DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

27. RADICAL CYSTECTOMY
In men,
Removal of:
Bladder with surrounding perivesical soft
tissue
Prostate
Seminal vesicles
In Women,
Removal of:
Bladder with surrounding perivesicalsoft
tissue
Uterus with cervix
Ovaries
Anterior vagina
27DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

28. Patients with pathologic
lymph node metastasis
at the time of
cystectomy.
25 %
28DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

29. DRAINAGE SITES
Primary
Internal iliac
External iliac
Obturator
Presacral
Secondary
Common iliac
Para aortic
Interaortocaval
Paracaval
29DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

30. 25 NODES
TO
STAGE
30DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

31. LYMPH NODE DENSITY
Percentage of positive nodes relative to the total number of nodes removed.
<20 % is good prognosis. (Herr et al 2003)
31DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

32. LYMPH NODE
DENSITY
20%
32DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

33. PELVIC LYMPHADENECTOMY
1. Standard template pelvic lymphadenectomy
2. Extended pelvic lymphadenectomy
3. Dissection uptoinferior mesenteric artery origin
33DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

34. STANDARD TEMPLATE PELVIC LYMPHADENECTOMY
Laterally –Genitofemoral nerve
Medially –Internal iliac artery
Superiorly-Point at which the ureter
crosses the common iliac artery
Inferiorly-Cooper’s ligament
34DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

35. EXTENDED PELVIC LYMPHADENECTOMY
Extension to include Common iliac nodes
and presacralpacket.
Further extension to include preaortic
packet to the level of inferior mesenteric
artery have also been studied.
No benefit beyond resecting common
iliac nodes was observed.
35DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

36. INTRA OPERATIVE
DECISION
MAKING
36DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

37. DON’T PERFORM CYSTECTOMY, WHEN..
1. Unresectablebulky lymphnodemetastasis
2. Extensive periureteraldisease
3. Bladder fixed to pelvic side wall
4. Tumouris invading rectosigmoidcolon.
37DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

38. NEGATIVE URETERIC MARGIN?
Intra operative frozen analysis remains controversial.
12.7 % -Positive margin rate.
Ureter margin status-independent predictor of upper tract recurrence after
cystectomy.
Hence, attempt to clear the distal ureter of tumourwhen feasible at the time of
radical cystectomy.
38DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

39. URETHRECTOMY IN MEN, IF..
Do transurethral prostatic biopsy before cystectomy,
Consider urethrectomy, if..
Diffuse CIS of the prostatic urethra or ducts is present.
Prostatic stromal invasion is present.
39DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

40. CHEMOTHERAPY
40DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

41. GHONEIMET AL 2008
50 % of patients treated with radical
cystectomy alone progress to metastatic
disease.
Surgery alone is not sufficient in large
number of patients with invasive bladder
cancer.
41DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

42. STEIN ET AL 2001
42DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

43. NEO ADJUVANT CHEMO -ADVANTAGES
1. Chemotherapy is delivered at the earliest time point, when the burden of
micrometastaticdisease is expected to be low;
2. in vivo chemo-sensitivity is tested; and
3. tolerability of chemotherapy is expected to be better before than after
cystectomy
43DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

44. NEO ADJUVANT CHEMO -DISADVANTAGES
1. Errors in staging may lead to overtreatment
2. delayed cystectomy, compromising outcome in patients not sensitive to
chemotherapy and
3. side effects of chemotherapy affecting the outcome of surgery and type of urinary
diversion
44DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

45. MOST STUDIES FAILED!!!
45DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

46. ABC META-ANALYSIS
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant
chemotherapy in invasive bladder cancer: update of a systematic review
and meta-analysis of individual patient data advanced bladder cancer
(ABC) meta-analysiscollaboration. EurUrol2005b;48(2):202–5.
46DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

47. CANCER CARE
ONTARIO
PROGRAM
47DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

48. STATISTICIANS
OR
MAGICIANS??
48DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

49. BASED ON THIS…
NCCN guidelines recommend clinicians:
-strongly consider neoadjuvantcisplatin basedchemotherapy for cT2N0M0 patients
-recommends neoadjuvantcisplatin-based chemotherapy for cT3-T4aN0M0 patients.
EAU guidelines recommend:
-neoadjuvantchemotherapy for T2-T4aN0M0 patients and also note that it should
always be a cisplatinum-based combination regimen
49DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

50. REMEMBER?? STEIN ET AL 2001
50DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

51. ADJUVANT CHEMOTHERAPY TRIALS
51DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

52. ABCMETA-ANALYSIS FOR ADJUVANT THERAPY
52DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

53. GUIDELINES FOR ADJUVANT THERAPY
NCCN -Consider adjuvant chemotherapy in pT3-4 or node positive disease setting.
EAU-Use within clinical trials, not as a routine therapeutic option.
53DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

54. ADJUVANT CHEMORADIATION
20% -40% of pT3 and pT4 patients have pelvic failures at 5 years.
Perioperative chemotherapy does not significantly improve the risk.
After pelvic failure, median survival is just 9 months.
Hence, radiation therapy was tried to reduce pelvic failure risk in pT3-4 lesions with
negative margins.
54DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

55. ZAGHLOULET AL 2017-SANDWICH CHEMORADIO
55DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

56. ZAGHLOULET AL 2017-SANDWICH CHEMORADIO
56DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

57. WHEN ADJUVANT RADIATION?
Substantially increase risk of postoperative small bowel obstruction.
Should be cautiously used.
Strongest case: Positive surgical margins noted after radical cystectomy.
Ongoing studies in:
pT3-4
Less than 10 nodes identified
N+ disease.
57DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

58. Percentage of pT0 in cystectomy specimens
of MIBC cancers.
In other words, all cancer tissue was
removed in the TURBT itself.
10%
58DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

59. BLADDER PRESERVATION IN MIBC
High incidence of perioperative complications
Classically older population with multiple medical comorbidities
Goal: Curative with functionally intact bladder.
Multimodality therapy:
1. Radical TUR
2. Chemotherapy
3. Systemic radiotherapy
59DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

60. ELIGIBLE CANDIDATES
1. Refusing for cystectomy
2. Medically unfit for cystectomy
3. Highly selected medically fit patients
60DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

61. AVOID BLADDER PRESERVATION IN…
1. Hydronephrosis
2. Obvious T3 disease on imaging
3. Presence of CIS
4. Multifocal tumoursand / or
5. Incomplete macroscopic tumor resection
61DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

62. MEDICALLY FIT PATIENT SELECTION CRITERIA
1. Limited burden of disease (< 4 cm in maximal dimension, unifocal, not cT3b)
2. No hydronephrosis
3. Can be grossly resectableby TUR
4. Adequate bladder function
5. No CIS
6. Highly motivated patient
62DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

63. TRIMODALBLADDER PRESERVATION
63DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

64. METASTATIC
BLADDER CANCER
64DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

65. STENBERG ET AL 1985 –M-VACREGIMEN
78 %
65DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

66. METASTATIC BLADDER CANCER
Systemic cisplatin-based combination chemotherapy is the standard of care.
First line regimens: MVAC, HD-MVAC and gemcitabine/cisplatin.
Median survival after chemotherapy 14 months.
66DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

67. NON-CISPLATIN CANDIDATES CRITERIA
1. ECOG performance status >2
2. Creatinine clearance <60 ml/min
3. Grade 2 or above of audiometric hearing loss
4. Grade 2 or above of peripheral neuropathy
5. Newyorkheart association Class III or higher heart failure
67DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

68. FRONTLINE THERAPY TRIALS
68DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

69. SECONDLINETHERAPY TRIALS
69DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

70. SALVAGE TRIALS WITH SINGLE AGENT CHEMO
70DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

71. Second line therapy for
Metastatic bladder cancer
was suboptimal.
Search for newer drugs
lead to Novel Drugs
71DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

72. IMMUNE CHECKPOINT INHIBITORS
Anti CTLA 4 antibodies
Ipilumumab
Tremelimumab
PD L1 Inhibitors
Atezolizumab
Durvalumab
Avelumab
PD 1 Inhibitors
Pembrolizumab
Nivolumab
72DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

73. TUMOURIMMUNE MECHANISMS
73DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

74. T CELL ‘STEROIDS’ -IPILUMUMAB
74DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

75. ANTIDOTES TO THE POISON
75DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

76. PEMBROLIZUMABVACCINATION FOR T CELLS
76DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

77. IMMUNE CHECKPOINTS
77DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

78. TRIALS AND DRUGS
IMVigor–Atezolizumab
KEYNOTE-Pembrolizumab
CheckMate-Nivolumab
JAVELIN -Avelumab
78DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

79. Aim:
-Comparison of Pembrolizumabwith investigator’s choice
of chemotherapy with paclitaxel, docetaxel, or vinflunine
-as second-line therapy in patients with advanced
urothelial carcinoma that progressed during or after the
receipt of platinum-based chemotherapy.
KEYNOTE 45
79DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

80. KEYNOTE 45
80DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

81. PEMBROLIZUMAB
Based on this trial, FDA has given approval for the use of Pembrolizumabfor:
Metastatic urothelial carcinoma previously treated with platinum-based
chemotherapy
81DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

82. FIRST LINE AGENTS IN CISPLATIN INELIGIBLE
PATIENTS
IMVigor210 –Atezolizumab
KEYNOTE 052 -Pembrolizumab
82DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

83. IMVIGOR210-ATEZOLIZUMAB
Previously cisplatin untreated ineligible patients.
Patients received 1200 mg intravenous atezolizumabevery 21 days until
unacceptable toxicity or investigator-assessed radiographic progression.
Progression of lesions were monitored using RECIST criteria for solid tumours.
83DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

84. PD L1 SCORING CRITERIA
IC0 (PD-L1 expression on <1% of IC),
IC1 (PD-L1 expression on ≥1% and <5% of IC), or
IC2/3 (PD-L1 expression on ≥5% of IC)
IC –Tumourinfiltrating Immune Cells
84DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

85. IC2/3 PATIENTS
85DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

86. IC 1 PATIENTS
86DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

87. IC O PATIENTS
87DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

88. OVERALL SURVIVAL
88DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

89. KEYNOTE 052
First-line pembrolizumabin cisplatin-ineligible patients with locally advanced and
unresectableor metastatic urothelial cancer.
Enrolled patients received intravenous pembrolizumab200 mg every 3 weeks.
Response was evaluated using RECIST criteria for solid tumours.
89DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

90. KEYNOTE 052
90DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

91. CURRENT STATUS
Metastatic urothelial cancer in second line setting.
Atezolizumab,
Durvalumab,
Avelumab.
Metastatic urothelial cancer first line setting in Cisplatin ineligible candidates:
Atezolizumab
Pembrolizumab
91DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

92. GUIDELINES 2020
92DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

93. NEOADJUVANTCHEMOTHERAPY
93DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

94. PREOPERATIVE RADIOTHERAPY
94DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

95. T2-4A, NO, MO
95DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

96. T2-4A, NO, MO
96DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

97. UNRESECTABLETUMOURS…PALLIATIVE
CYSTECTOMY??
NO !!!
97DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

98. CLINICAL OR N+ DISEASE
98DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

99. ADJUVANT CHEMOTHERAPY
99DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

100. METASTATIC
BLADDER
CANCER
100DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

101. METASTATIC
BLADDER
CANCER
101DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

102. 102DEPT OF UROLOGY, GRH AND KMC, CHENNAI.