MIBC & Metastatic Urinary Bladder carcinoma

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

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

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

Percentage of patients
presenting with muscle
invasive bladder cancer at
initial presentation.
20%
TO
30%
4

Will die if left
untreated
85%
IN
2 YRS
5

HOW WE COME ACROSS THE PATIENT?
1. Patient undergoes TURBT for bladder growth, report shows muscle invasion.
2. Patient undergoes ReTURBT with 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 perivesical fat stranding, extravesical mass, infiltration
into nearby structures.
4. Patient is a known case of TCC bladder, underwent TURBT and is on regular
cystoscopic followup. During a followup cystoscopy, a growth was found, and the
biopsy shows evidence of muscle invasion.
6

T STAGING
7

DIVERTICULUM
THERE IS NO T2
8

PROSTATE INVOLVEMENT
9

BLADDER – REGIONAL LYMPH NODES
PRIMARY DRAINAGE -
TRUE PELVIS
SECONDARY DRAINAGE-
ABOVE TRUE PELVIS UPTO
AORTIC BIFURCATION
10

REGIONAL LYMPHNODES
11

N1 STAGE
SINGLE LYMPHNODE IN TRUE
PELVIS
12

N2 STAGE
MULTIPLE LYMPHNODES IN
TRUE PELVIS
13

N3 STAGE
LYMPHNODE(S) IN COMMON
ILIAC REGION (SECONDARY
DRAINAGE AREA)
14

T STAGING
AJCC 8TH EDITION
15

N STAGING
16

DISTANT METASTASIS
17

STAGE GROUPING
18

PROGNOSTIC FACTORS
19

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
20

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
21

Do CECT abdomen and
pelvis in all cases
before TURBT???
NO
22

Biopsy shows muscle
invasion now…
What next?
OK, NOT
DONE
BUT…
23

Do contrast study 7 days after TURBT.
To avoid overstaging as T3.
24

T2-4A, N0 M0
Radical Cystectomy
With
Bilateral pelvic lymph node
dissection
25

Optimal time from
diagnosis of muscle
invasion to cystectomy
12 WEEKS
26

RADICAL CYSTECTOMY
In men,
Removal of:
Bladder with surrounding perivesical soft
tissue
Prostate
Seminal vesicles
In Women,
Removal of:
Bladder with surrounding perivesical soft
tissue
Uterus with cervix
Ovaries
Anterior vagina
27

Patients with pathologic
lymph node metastasis
at the time of
cystectomy.
25 %
28

DRAINAGE SITES
Primary
Internal iliac
External iliac
Obturator
Presacral
Secondary
Common iliac
Para aortic
Interaortocaval
Paracaval
29

25 NODES
TO
STAGE
30

LYMPH NODE DENSITY
Percentage of positive nodes relative to the total number of nodes removed.
<20 % is good prognosis. (Herr et al 2003)
31

LYMPH NODE
DENSITY
20%
32

PELVIC LYMPHADENECTOMY
1. Standard template pelvic lymphadenectomy
2. Extended pelvic lymphadenectomy
3. Dissection upto inferior mesenteric artery origin
33

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
34

EXTENDED PELVIC LYMPHADENECTOMY
Extension to include Common iliac nodes
and presacral packet.
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.
35

INTRA OPERATIVE
DECISION
MAKING
36

DON’T PERFORM CYSTECTOMY, WHEN..
1. Unresectable bulky lymphnode metastasis
2. Extensive periureteral disease
3. Bladder fixed to pelvic side wall
4. Tumour is invading rectosigmoid colon.
37

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 tumour when feasible at the time of
radical cystectomy.
38

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.
39

CHEMOTHERAPY
40

GHONEIM ET 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.
41

STEIN ET AL 2001
42

NEO ADJUVANT CHEMO - ADVANTAGES
1. Chemotherapy is delivered at the earliest time point, when the burden of
micrometastatic disease 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
43

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
44

MOST STUDIES FAILED!!!
45

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-analysis collaboration. Eur Urol 2005b;48(2):202–5.
46

CANCER CARE
ONTARIO
PROGRAM
47

STATISTICIANS
OR
MAGICIANS??
48

BASED ON THIS…
NCCN guidelines recommend clinicians:
- strongly consider neoadjuvant cisplatin based chemotherapy for cT2N0M0 patients
- recommends neoadjuvant cisplatin-based chemotherapy for cT3-T4aN0M0 patients.
EAU guidelines recommend:
- neoadjuvant chemotherapy for T2-T4aN0M0 patients and also note that it should
always be a cisplatinum-based combination regimen
49

REMEMBER?? STEIN ET AL 2001
50

ADJUVANT CHEMOTHERAPY TRIALS
51

ABC META-ANALYSIS FOR ADJUVANT THERAPY
52

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.
53

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.
54

ZAGHLOUL ET AL 2017- SANDWICH CHEMORADIO
55

ZAGHLOUL ET AL 2017-SANDWICH CHEMORADIO
56

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.
57

Percentage of pT0 in cystectomy specimens
of MIBC cancers.
In other words, all cancer tissue was
removed in the TURBT itself.
10%
58

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
59

ELIGIBLE CANDIDATES
1. Refusing for cystectomy
2. Medically unfit for cystectomy
3. Highly selected medically fit patients
60

AVOID BLADDER PRESERVATION IN…
1. Hydronephrosis
2. Obvious T3 disease on imaging
3. Presence of CIS
4. Multifocal tumours and / or
5. Incomplete macroscopic tumor resection
61

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 resectable by TUR
4. Adequate bladder function
5. No CIS
6. Highly motivated patient
62

TRIMODAL BLADDER PRESERVATION
63

METASTATIC
BLADDER CANCER
64

STENBERG ET AL 1985 – M-VAC REGIMEN
78 %
65

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.
66

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. Newyork heart association Class III or higher heart failure
67

FRONTLINE THERAPY TRIALS
68

SECONDLINE THERAPY TRIALS
69

SALVAGE TRIALS WITH SINGLE AGENT CHEMO
70

Second line therapy for
Metastatic bladder cancer
was suboptimal.
Search for newer drugs
lead to Novel Drugs
71

IMMUNE CHECKPOINT INHIBITORS
Anti CTLA 4 antibodies
Ipilumumab
Tremelimumab
PD L1 Inhibitors
Atezolizumab
Durvalumab
Avelumab
PD 1 Inhibitors
Pembrolizumab
Nivolumab
72

TUMOUR IMMUNE MECHANISMS
73

T CELL ‘STEROIDS’ - IPILUMUMAB
74

ANTIDOTES TO THE POISON
75

PEMBROLIZUMAB VACCINATION FOR T CELLS
76

IMMUNE CHECKPOINTS
77

TRIALS AND DRUGS
IMVigor – Atezolizumab
KEYNOTE- Pembrolizumab
CheckMate- Nivolumab
JAVELIN - Avelumab
78

Aim:
- Comparison of Pembrolizumab with 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
79

KEYNOTE 45
80

PEMBROLIZUMAB
Based on this trial, FDA has given approval for the use of Pembrolizumab for:
Metastatic urothelial carcinoma previously treated with platinum-based
chemotherapy
81

FIRST LINE AGENTS IN CISPLATIN INELIGIBLE
PATIENTS
IMVigor210 – Atezolizumab
KEYNOTE 052 - Pembrolizumab
82

IMVIGOR 210- ATEZOLIZUMAB
Previously cisplatin untreated ineligible patients.
Patients received 1200 mg intravenous atezolizumab every 21 days until
unacceptable toxicity or investigator-assessed radiographic progression.
Progression of lesions were monitored using RECIST criteria for solid tumours.
83

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 – Tumour infiltrating Immune Cells
84

IC2/3 PATIENTS
85

IC 1 PATIENTS
86

IC O PATIENTS
87

OVERALL SURVIVAL
88

KEYNOTE 052
First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and
unresectable or metastatic urothelial cancer.
Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks.
Response was evaluated using RECIST criteria for solid tumours.
89

KEYNOTE 052
90

CURRENT STATUS
Metastatic urothelial cancer in second line setting.
Atezolizumab,
Durvalumab,
Avelumab.
Metastatic urothelial cancer first line setting in Cisplatin ineligible candidates:
Atezolizumab
Pembrolizumab
91

GUIDELINES 2020
92

NEOADJUVANT CHEMOTHERAPY
93

PREOPERATIVE RADIOTHERAPY
94

T2-4A, NO, MO
95

T2-4A, NO, MO
96

UNRESECTABLE TUMOURS…PALLIATIVE
CYSTECTOMY??
NO !!!
97

CLINICAL OR N+ DISEASE
98

ADJUVANT CHEMOTHERAPY
99

METASTATIC
BLADDER
CANCER
100

METASTATIC
BLADDER
CANCER
101

102

MIBC & Metastatic Urinary Bladder carcinoma

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