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
4. Percentage of patients
presenting with muscle
invasive bladder cancer at
initial presentation.
20%
TO
30%
4
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
5. Will die if left
untreated
85%
IN
2 YRS
5
DEPT 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 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
DEPT 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
20
DEPT 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
21
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
22. Do CECT abdomen and
pelvis in all cases
before TURBT???
NO
22
DEPT 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)
31
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
33. PELVIC LYMPHADENECTOMY
1. Standard template pelvic lymphadenectomy
2. Extended pelvic lymphadenectomy
3. Dissection upto inferior mesenteric artery origin
33
DEPT 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
34
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
35. 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
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
37. 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
DEPT 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 tumour when feasible at the time of
radical cystectomy.
38
DEPT 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.
39
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
41. 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
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
42. STEIN ET AL 2001
42
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
43. 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
DEPT 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
44
DEPT 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-analysis collaboration. Eur Urol 2005b;48(2):202–5.
46
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
49. 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
DEPT 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.
53
DEPT 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.
54
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
55. ZAGHLOUL ET AL 2017- SANDWICH CHEMORADIO
55
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
56. ZAGHLOUL ET AL 2017-SANDWICH CHEMORADIO
56
DEPT 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.
57
DEPT 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%
58
DEPT 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
59
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
60. ELIGIBLE CANDIDATES
1. Refusing for cystectomy
2. Medically unfit for cystectomy
3. Highly selected medically fit patients
60
DEPT 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 tumours and / or
5. Incomplete macroscopic tumor resection
61
DEPT 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 resectable by TUR
4. Adequate bladder function
5. No CIS
6. Highly motivated patient
62
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
65. STENBERG ET AL 1985 – M-VAC REGIMEN
78 %
65
DEPT 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.
66
DEPT 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. Newyork heart association Class III or higher heart failure
67
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
70. SALVAGE TRIALS WITH SINGLE AGENT CHEMO
70
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
71. Second line therapy for
Metastatic bladder cancer
was suboptimal.
Search for newer drugs
lead to Novel Drugs
71
DEPT 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
72
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
78. TRIALS AND DRUGS
IMVigor – Atezolizumab
KEYNOTE- Pembrolizumab
CheckMate- Nivolumab
JAVELIN - Avelumab
78
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
79. 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
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
81. 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
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
82. FIRST LINE AGENTS IN CISPLATIN INELIGIBLE
PATIENTS
IMVigor210 – Atezolizumab
KEYNOTE 052 - Pembrolizumab
82
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
83. 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
DEPT 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 – Tumour infiltrating Immune Cells
84
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
89. 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
DEPT 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
91
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
