1. Adjuvant treatment of Locally Advanced Bladder Cancer
Acad F.Todua , Natia Jokhadze. MD, Z. Kvirikashvili MD
Research Institute of Clinical Medicine

2. Epidemiology
Bladder cancer is the ninth most common cancer in the world, with 430,000 new cases diagnosed annually
Belgium has the highest rate of bladder cancer, followed by Lebanon and Malta.
About 59 per cent of bladder cancer cases occur in more developed countries.
The highest incidence of bladder cancer is in Northern America and Europe; and the lowest incidence is in Asia, Latin America and the Caribbean.
Incidence in Georgia : 515 new cases in 2016
77% males
23% females
9th most common cancer in both sexes
At diagnosis >70%: > 65 y of age
75% superficial TCC
25% muscle invasive or extravesical
Data source: GLOBOCAN 2012
All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement.
Graph production: Cancer Today
© International Agency for Research on Cancer 2016 (
World Health Organization

3. Estimated crude rate (incidence and mortality), both sexes, (top 10 cancer sites) in 2012
20.4
7.7
6.4
3.1
Data source: GLOBOCAN 2012
Graph production: Cancer Today (
© International Agency for Research on Cancer 2016

4. 5% Metastatic bladder cancer
Entities, Stage and Prognosis
Bladder Cancer
75-85% Superficial bladder cancer
pTa, pTis, pT1
10-15% Muscle-invasive bladder cancer
pT2, pT3, pT4
5% Metastatic bladder cancer
N+, M+
Stage
TNM
5y Survival
0 Ta/Tis
NoMo
>85% I
T1 NoMo
65-75% II
T2a-b NoMo
57%
III
T3a-4a
31% IV
T4b NoMo
24%
any T
N+Mo
14%
any T M+ med surv
6-9 Mo
In the group of patients with muscle-invasive cancer managed with primary cystectomy and lymph node dissection, disease stage at presentation has a significant impact on individual patient outcomes and long-term survival. In a retrospective series of 1054 patients, the 5- and 10-year recurrence-free and overall survival (OS) in organ-confined, lymph-node-negative disease was 85 and 82%, and 78 and 56%, respectively. Patients with lymph-node-positive disease had significantly worse survival outcomes with 5- and 10-year recurrence-free and OS of 35 and 35%, and 31 and 23%, respectively [2]. Due to the poor prognosis of lymph-node-positive or distant metastatic disease, with an estimated median OS between 14–15 months and 5-year OS of 15% [3], efforts have focused upon the early eradication of micrometastatic spread with perioperative chemotherapy. The use of neoadjuvant chemotherap
Prognostic Factors
Stage
Stage Ta, Tis, T1
Grade
Multicentricity and frequency of recurrence
Molecular markers

5. Histology 90-95% Transitional-cell carcinoma
3% Squamous-cell carcinoma
2% Adenocarcinoma
<1% Small-cell carcinoma

6. Treatment of Superficial Disease
Ta , T1 , TIS N0M0 ”Non Muscle-invasive"

7. Treatment options for NMIBC:
Endoscopic surgical management
Immunotherapy
Intravesical chemotherapy
Radical cystectomy
Radiotherapy

8. Superficial Bladder Cancer
pTa, pT1, Tis
Standard of care Transurethral resection
Despite complete TURBT, up to 80% of patients with high risk tumors will recur within 12 month. So, adjuvant therapy is widely used
Intra-vesical Therapy
Reduces relapse rate by 30-80%
Relapse rate: 70-80% adjuvant therapy

9. Intravesical therapy
Permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation
Indications :
Multiple, or large (>3cm) at presentation
Recurrence within 1 year
High grade Ta
Any T1
Cis
Positive cytology after resection of a visible tumor
Metaanalysis of seven randomized trial has demonstrated that one immediate installation of chemotherapy after TUR decrease the relative risk of recurrence by 40 %!

10. BCG : weekly 6-8 w. /Mo 3 and 6 next maintenance for 1 year.
Live attenuated form of Mycobacterium Bovid
The exact mechanism of action is UNKNOWN
Mononuclear cell infiltratration (CD4 T, Macrophages)
Interferon gamma and cytokines level are increased in the urine following treatment
BCG is superior to chemotherapy for preventing recurrence in patients with intermediate risk and high risk tumors
At least 1 year maintenance therapy is recommended for complete treatment , but the optimal schedule and does have not yet been defined
Mitomycin C : weekly 6-8 w. / monthly 6-12
Alkylating agent that is minimally absorbed from the bladder circulation into the systemic circulation mg. Weekly for 6-8 weeks
Side effects include chemical cystitis and skin reactions
Anthracyclines : weekly 6-8 w. / monthly 6-12
Epirubicin, Doxorubicin, and Valrubicin
Approved for use in patients who have failed BCG, and in whom immediate cystectomy is either refused or contraindicated

11. Summary Recommendations for Intravesical Treatment
POST-OP SINGLE INSTALATION
All Low risk tumors
DELAYED INDUCTION CHEMOTHERAPY
Intermediate Risk
6 weeks appear OK
BCG
Intermediate and high risk bladder tumors
Needs Maintenance to reduce recurrence and progression of Disease

12. Treatment of Locally Advanced Disease
T2a-T4aN0M0 "Muscle-invasive"

13. Salvage Cystectomy for residual/ recurent/invasive disease
Standard treatment of
muscle-invasive BC – Radical Cystectomy
5 year survival about 50%
Metastases !
Only about 50% of patients with high-grade invasive disease are cured
Neoadjuvant Chemotherapy
NAC
Surgery: Cystectomy + pelvic l/n dissection
TURBT
Salvage Cystectomy for residual/ recurent/invasive disease
RT + Chemo
Regular Cystoscopy
TURBT +Local Therapy

14. Peri-operative chemotherapy of Invasive Bladder Cancer
Deaths from TCC are generally not local events
Patients die as a result of metastatic disease
Local interventions will not deal with micro-metastatic disease
Systemic therapy must be given to eradicate micrometastatic disease
For many malignancies, there is clear cut evidence for the order of therapies
colon cancer: surgery first then chemotherapy later
Inflammatory breast cancer: chemo first then local therapy
For a long time, there was little evidence to guide us in TCC as to optimal sequencing

15. Clinical Case How to treat
Medically fit 75 y.o patient with Resectable Muscle Invasive Urothelial Carcinoma T3N0M0
Radical Cystectomy alone
Neoadjuvant Chemotherapy followed by Radical Cystectomy
Radical Cystectomy followed by Adjuvant Chemotherapy
Bladder preserving approach
How to treat

16. Neoadjuvant Adjuvant Pros: • Give systemic Pros: therapy when the
pelvic blood supply
is intact
Deal with micrometastatic disease immediately
• In vivo testing of
chemosensitivity
• Patient is fitter. Tolerance and
compliance↑
Pros:
• If the bladder is the
problem, deal with it
immediately
Chemotherapy decisions can be based on true pathology
No delay of surgery
Cons:
• Delayed chemotherapy
• No control of sensitivity
• Compliance ↓
30-50% of patients who
were candidates before
operation do NOT recceive
chemotherapy after
operation
• No convincing data for
effectiveness
Cons:
• No pathological staging
• Delay of potentially
curative cystectomy
[Operation after
chemotherapy with more
complications: NO]

17. Complications after NAC in Bladder Cancer
Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer
H. Barton Grossman, M.D., Ronald B. Natale, M.D., Catherine M. Tangen, Dr.P.H., V.O. Speights, D.O., Nicholas J. Vogelzang, M.D., Donald L. Trump, M.D., Ralph W. deVere White, M.D., Michael F. Sarosdy, M.D., David P. Wood, Jr., M.D., Derek Raghavan, M.D., Ph.D., and E. David Crawford, M.D.
Complications after NAC in Bladder Cancer
Grade III
Grade IV
Grade V
Cystectomy
(n=124) 22 10 2
NAC + Cystectomy
(n= 126) 21 12 1
Survival among Patients Randomly Assigned to Receive Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) Followed by Cystectomy or Cystectomy Alone, According to an Intention-to-Treat Analysis.

18. Neoadjuvant Chemotherapy
11 trials, 3005 patients
5% absolute improvement in OS at 5 years
HR = 0.86, 95% CI 0.77–0.95, p = 0.003
9% absolute improvement In DFS at 5 years
HR =  % CI 0.71–0.86, p < 0.0001
14% reduction in risk of
death (med. FU 6.4 yrs)

19. Chemotherapy for bladder cancer
Bladder cancer is a chemo sensitive disease
Responses to Chemotherapy Agents
Active single agents. RR
Cisplatin
30%
Carboplatin
20%
Gemcitabine
28-38%
Ifosfamide
20-40%
Metotraxate
29%
Doxorubicine
!7%
Vinblastin
16%
Mitomicin C
13%
Taxol
42-56%
Combination RR CR
MVAC
40-75%
<20%
Gemzar/ Cis
40-70%
5-15%
Gemzar / Carboplatin
65% 5%
Taxol / Carboplatin
20%
40%
• MVAC developed in 1980s; before the advent of antiemetics and growth factors (Sternberg et al, Cancer, 1989)
• Dose intensity or dose dense or accelerated MVAC (Sternberg et al, Eur J Cancer, 2006; Choueiri et al, JCO, 2014; Plimack et al, JCO 2014)
• GC with similar efficacy but improved toxicity in metastatic setting (von der Maase et al, JCO, 2000)
Adapted from M. De Santis

20. Adjuvant Chemotherapy
Multiple trials
Small number of patients ranging from
NO survival benefit
Two trials suggest survival benefit
Skinner et al. J Urol 1991
An updated meta-analysis of nine randomized trials (after 2005) including 945 patients found
OS benefit [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.59–0.99, P = 0.049]
DFS benefit (HR 0.66, 95% CI 0.45–0.91, P = 0.014) among those who received cisplatin-based adjuvant chemotherapy.
The DFS benefit was more apparent among those with positive lymph node involvement
No standard of care
Node positive disease, lymphovascular invasion, positive margins, Pts without NAC
70% of the patients assigned to chemotherapy are free of disease at 3 years compared to 46% in the observation group.

21. International Guidelines
Witjes JA et al. EAU guidelines on muscle invasive bladder cancer

22. Bladder-sparing therapy for invasive bladder cancer
Transurethral Resection
Induction Therapy : Radiation+ Chemotherapy ( Cisplatin+Paclitaxel)
Cystoscopy after 1 month
No Tumor
Tumor
Consolidation: RT+CT
Cystectomy
High probability of subsequent distant metastasis after cystectomy or radiotherapy alone (50% within 2 years)
Radiotherapy in comparison with cystectomy has inferior results (local control 40%)
muscle-invasive bladder cancer is often a systemic disease
 combined modality therapy

23. Kaplan–Meier Analysis of Survival.
N = 360 (median age: 72 years)
T2-4, N0. PS ≤ 2, GFR ≤ 25 ml/min, liver function < 1.5 upper limit
Rx : RX + 5FU 500 mg/sqm/day [D1-5 / 16-20] + MMC: 12 mg/sqm D1
Population based series comparing outcomes of cystectomy and radiotherapy
SEER Kozaket al 2012
Yorkshire UK Munro et al 2010
James N et al, New Engl J Med 2012

24. Bladder sparing procedures for muscle-invasive
bladder cancer
Benefits:
Preserves bladder function
Preserves sexual function
Maintains QOL
Avoids Major surgery: elderly and Pt with comorbidities
In most countries reserved for patients:
• unfit / unsuitable for cystectomy
• unwilling to undergo radical cystectomy
Best results if
T2, complete TUR-B, single lesion
NO hydronephrosis. NO CIS
NO tumour invasion into stroma of the prostate
Well functioning bladder
• Equivalent survival to cystectomy
• Lower peri-treatment mortality
• Improving local control with radiosensitisers
• Modest toxicity

25. Conclusions for MIBC:
Muscle invasive bladder cancer carries a significant risk of mortality
Most deaths are due to systemic disease
Strength of evidence for perioperative chemotherapy lies with neoadjuvant therapy
Treatment should be a cisplatin-based combination therapy
Magnitude of benefit is similar to many other oncology situations – node negative breast cancer, high risk stage II colon cancer
Despite evidence, referrals are still low
Multidisciplinary approach is critical for good outcomes
Hopefully in the future we will be able to better select patients for therapy

26. Thank you
For
Attention!