1. BLADDER CANCER
Ahmed Zeeneldin
Associate Professor of Medical Oncology

2. INCIDENCE IN USA
¢ 4.5% of cancers
¢ M: F: 2.5:1
¢ Age: 6th-7th decade

3. INCIDENCE IN EGYPT
¢ NCI males:
¢ 1st , 16%

4. INCIDENCE
¢ NCI combined:
¢ 4th, 4.4%
¢ M: F: 4:1
¢ Median age:
¢ M: 60
¢ F: 58

5. RISK FACTORS
¢ Occupational exposure:
— Aniline dyes
— Leather, rubber and paint industries
¢ Schistosoma haematobium:
— Associated with squamous histology
— In Africa and middle east
¢ Smoking
¢ Pelvic irradiation
¢ Drugs: cyclophosphamide

6. HISTOLOGY
¢ Urothelial (transitional cell) carcinoma TCC: commonest
¢ In situ
— Papillary
— Flat
— With squamous metaplasia
— With glandular metaplasia
— With squamous and glandular metaplasia
¢ Squamous cell carcinoma (SCC)
¢ Adenocarcinoma
¢ Undifferentiated carcinoma

7. HISTOLOGY IN EGYPT

8. HISTOLOGY
US EGY
¢ TCC: 90% ¢ TCC: 63%
¢ SCC: 6-8% ¢ SCC: 27%
¢ Adeno: 2% ¢ Adeno: 3%
¢ Small cell: 1% ¢ Undifferentiated: 2%
systemic chemotherapy regimens used to treat TCC
are ineffective in pure SCC or Adeno
If mixed tumor only TCC responds

9. STAGES

10. TNM STAGING 2010
URINARY BLADDER
¢ T0: non-invasive
— Ta: Noninvasive papillary carcinoma
— Tis: Carcinoma in situ “flat tumor”
¢ T1: mucosa or submucosa
¢ T2: muscle
— T2a: inner half
— T2b: outer half
¢ T3: outside muscle (adventitia)
— T3a: microscopic (histology, no
masses
— T3b: macroscopic (mass)
¢ T4: surroiundings
— T4a: prostate, uterus, vagina
— T4b: pelvic or abdominal
T T T T4 T4 M1
¢ N1: regional LN+
1 2 3 a b — N1: Pelvic LNs (1)
— N2 : pelvic LNS (>1)
N0 I II III III IV IV — N3: common iliac LN
N1- IV IV IV IV IV IV
M1: Distant mets
SIMPLIFICATION
3
¢
-I: T1 -II: T2
-III: T3/T4 a -IV: T4b OR LN+
OR M1

11. STAGING
T0: non-invasive
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ “flat tumor”
T1: sub-epithelial connective tissue
T2: Tumor invades muscle
T2a: inner half
T2b: outer half
T3: Tumor invades perivesical tissue
T3a: Microscopically
T3b: Macroscopically (extravesical mass)
T4: surroundings
T4a: prostate, uterus, vagina
T4b: pelvic wall, abdominal wall
N1: 1 pelvic LN
N2: > 1 pelvic LN
Tis/0 T1 T2 T3 T4 M1=IV
N3: common iliac LN
N0 0 I II III T4a: T4b: IV
M1: distant mets III IV
N1-3 IV

12. MANAGEMENT OF BLADDER CA
¢ Cystoscopy and biopsy:
— See lesions
— Biopsy and muscle should be included
— We will reach to a conclusion:
— MUSCLE IS INVADED OR NOT
¢ Not invaded àTURB
¢ Upper UT imaging
¢ CT if sessile or high grade T is suspected
¢ Invaded à CT:
¢ LN small (negative): T2,T3, T4a: cyatectomy
¢ LN large: biopsy: negative
— Positive:

13. NON MUSCLE INVASIVE
Grade Cyctectomy TURB IVsT+ Cystectomy
Tis High No Yes BCG Resistent
/relapsed
Ta Low No Yes May (chemo, mito) //
Once
? After 6ms
Ta high No Yes BCG > Chemo //
T1 Low No Yes BCG* If residual
Mito** //
T1 high May Yes BCG* if residual
Mito** //
+ not if extensive TURB or perforation
* Whether residual or no residual
** chemotherapy only if no residaul

14. INTRAVESICAL CHMOTHERAPY
¢ Drugs
— Chemotherapy
¢ Alkylating agents: thiotepa, mitomycin C (40mg in 20 cc st
Water),
¢ Anthracyclines: doxorubicin (50 mg in 25 cc St water),
epirubicin, valrubicin
¢ Value:
— Acts by diffusion
— Prevent seeding and Reduce recurrence by 6%
— No reduction in disease progression or mortality
— Within 6 Hrs post TUR, Not if extensive TURB or
perforation
— Overnight fast, empty bladder before
— Keep for .5 hr (post TUR) or 2Hrs, supine and prone (air
bubble)
— Alkalanize urine with mitomycin

15. INTRAVESICLA IMMUNOTHERAPY
— Immunotherapy
¢ BCG (81 mg for TheraCys and 50 mg for TICE, both in 50 cc
physiologic saline)
— Value:
¢ Acts by enhancing immune response, drawing lymphocytes
and macrophages to the bladder and stimulating a cellular
(TH1) immune response
¢ Not immediate (at least 1-2 wks post TUR)
¢ Weekly x 6 w
¢ Maintenance
¢ (3 app x q 3ms)
¢ 3 weekly at 2, 6, 12, 18, 24, 30, 36 ms XXXX?
¢ NOT WITH CIPRO

16. MUSCLE INVASIVE
N Cystectomy Chemotherapy Radiotherapy
N- T2* Radical Neoadj or adjuvant No
Partial Neoadj or adjuvant May be used instead of CT
No CRT CRT
N- T3* Radical Neoadj or adjuvant No
No CRT CRT
N- T4a If possible CRT or chemo CRT or chemo
1st or after (Neoadj or adj) (Neoadj or adj)
Neoadj
N- T4b If possible CRT or chemo CRT or chemo
after Neoadj (Neoadj or adj) (Neoadj or adj)
N+ If possible CRT or chemo CRT or chemo
after Neoadj (Neoadj or adj) (Neoadj or adj)
M1 No Yes may

17. PROGNOSTIC FACTORS
¢ Stage :
— depth of invasion
¢ Grade:
— Low grade: 1-2
— High grade: 3-4

18. TREATMENT
Non-Muscle-invasive Muscle-invasive
— Ta ¢ T2
— Tis
¢ T3
— T1
¢ T4
¢ Treatment:
— Resection: Repeat TUR
¢ Treat.
— +/- intravesical therapy — Resection: cystectomy
¢ Grade ¢ Partial or complete
¢ depth — Chemo: adjuvant/neoadj
— RT:

19. TREATMENT MODALITIES
¢ Resection:
— TURBT: ONLY FOR non-muscle invasive
— Cystectomy:
¢ Partial cystectomy : selected cases of muscle invasion
¢ Radical cystectomy: standard treatment of muscle invasive
tumors and as salvage therapy
¢ Drug therapy:
— Local (intravesical): ONLY FOR non-muscle invasive
¢ Immunotherapy: BCG or INF
¢ Chemotherapy: MMC, Doxorubicin or Valrubicin, thiotepa
— Systemic (IV) chemotherapy: ONLY for muscle
invasive
¢ Radiotherapy: ONLY for muscle invasive

20. TREATMENT: NON-MUSCLE INVASIVE
¢ Includes: Ta, Tis, T1
¢ Tx:
— Repeated TURB
— Post TURB intravesical therapy:
¢ depends on grade and depth of invasion that determines:
¢ Bladder recurrence risk
¢ Progression to muscle invasion risk
¢ Modes:
¢ Adjuvant: to prevent bladder recurrence: MAINLY
¢ Complementary: to eradicate residual disease: RARELY
— Cystectomy: rare

21. TREATMENT: NON-MUSCLE INVASIVE
¢ Tis (CIS), always high grade
¢ Tx:
— TURB
— Post TURB intravesical BCG
therapy Weekly x 6
— Follow up: cystectoscopy +
cytology + imaging of upper
Urinary tract q3 m x 24m,
then increase intervals
— Recurrence:
¢ TURB +
¢ Adjuvant intravesical therapy
according to grade and
depth of invasion
¢ Follow up: cystectoscopy q3
m

22. TREATMENT: NON-MUSCLE INVASIVE
¢ Ta (papilloma), low grade ¢ Ta (papilloma), high grade
¢ Tx: ¢ Tx:
— TURB — TURB
— Post TURB intravesical therapy: — Post TURB intravesical therapy:
¢ None ¢ None
¢ Adjuvant intravesical ¢ Adjuvant intravesical BCG:
chemotherapy (Mitomycin C): ¢ Adjuvant intravesical
¢ Single chemotherapy (Mitomycin C):
¢ Within 24 Hours form TURB ¢ Single
— Follow up: cystectoscopy + ¢ Within 24 Hours form TURB
cytology q3 m x 12 m, then — Follow up: cystectoscopy +
increase intervals cytology + imaging of upper
Urinary tract q3 m x 24m, then
— Recurrence: increase intervals
¢ TURB + — Recurrence:
¢ Adjuvant intravesical therapy ¢ TURB +
according to grade and depth of ¢ Adjuvant intravesical therapy
invasion according to grade and depth of
¢ Follow up: cystectoscopy q3 m invasion
¢ Follow up: cystectoscopy q3 m

23. TREATMENT: NON-MUSCLE INVASIVE
¢ Persistent or recurrent Ta and Tis
— TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à still recurrence or
persistence at W 24
¢ Tx:
— Cystectomy is the first option
— TURB and Post TURB intravesical therapy may be considered to avoid cyctectomy
¢ Use different agents
¢ Chemo: MMC, Valrubicin
¢ BCG + INF a
¢ Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x 24m, then q 6m x 24
m
¢ Recurrence/persistence: cystectomy
¢ Another scenario:
— TURB+/- IVTà recurrence/persistence at W12à TURB+IVT à CR:
— Maintenance BCG
— Follow up: cystectoscopy + cytology + imaging of upper Urinary tract q3 m x
24m, then q 6m x 24 m
¢ Recurrence/persistence: TRUB + different IVT or cystectomy

24. TREATMENT: NON-MUSCLE INVASIVE
¢ T1 , low risk ¢ T1, high risk
— No high risk features — multifocal lesions,
— vascular invasion,
— recurrence after BCG
¢ Tx:
— High grade.
— TURB
— Post TURB intravesical therapy: ¢ Tx:
¢ Adjuvant intravesical BCG: — TURB
¢ Adjuvant intravesical chemotherapy — Post TURB intravesical therapy:
(Mitomycin C): ¢ Adjuvant intravesical BCG:
¢ Single ¢ Adjuvant intravesical chemotherapy
¢ Within 24 Hours form TURB (Mitomycin C):
— Follow up: cystectoscopy + cytology ¢ Single
q3 m x 12 m, then increase intervals ¢ Within 24 Hours form TURB
— Cystectomy
— Recurrence: — Follow up: cystectoscopy + cytology
¢ TURB + + imaging of upper Urinary tract q3
¢ Adjuvant intravesical therapy m x 24m, then increase intervals
according to grade and depth of — Persistence after conservative
invasion management :
¢ Follow up: cystectoscopy q3 m ¢ Cystectomy

25. FOLLOW UP
¢ Low risk lesion: high risk lesions+
Cystoscopy and cytology Cystoscopy and cytology
¢ imaging upper tract
¢ q3 m x 12 q3 m x24
¢ Then increasing q 6m x 24

26. TREATMENT: MUSCLE INVASIVE DISEASE
¢ Workup:
— Lab: CBC, chemistry, Alk phos
— Cystoscopy, EAU/TRUBT
— Imaging:
¢ Chest Xray
¢ CT/MRI of abdomen and pelvis
¢ +/- Bone scan
¢ Aim:
Tis/0 T1 T2 T3 T4 M1=IV
— Organ confined T2, N0, M0 N0 0 I II III T4a: T4b: IV
III IV
— Non-organ confined T3, T4, N1, M0
N1-3 IV
— Metastatic disease M1

27. ORGAN CONFINED (T2) DISEASE
¢ Surgery (cyctectomy):
— Primary Tx
— radical : standard particularly in recurrence
— Partial (segmental)
¢ More in dome and solitary
¢ Less in neck, trigone and multiple or associated Tis
¢ Chemotherapy:
— Cisplatin-based
¢ Neoadjuvant: in T3 or T2 or
¢ Adjuvant : pT3 and pT4 and LN+
¢ RT:
¢ Adjuvant: pT3 and pT4, LN+, SM+ or high grade
¢ Concurrent chemoradiotherapy (CCRT):
— Preoperative: in advanced disease
— Definitive: in severe comorbidities and poor PS
— If CCRT is not tolerable: chemo or radio can be given alone

29. ORGAN CONFINED (T2 N0)

30. NON-ORGAN CONFINED (T3, N0)

31. NON-ORGAN CONFINED (T4 OR N1-3 OR M1)

32. CYSTECTOMY
¢ Radical cystectomy: standard
— Male:
¢ removes bladder, prostate, seminal vesicles
— Females:
¢ Removes bladder and maybe uterus, ovaries and tubes
— Pelvic LND:
¢ decreases recurrence and
¢ increase OS
— Urinary diversion or neobladder
¢ Partial systectomy: selective
— More in dome and solitary
— Less in neck, trigone and multiple or associated Tis
— Recurrence after partial cystectomy:
¢ Consider as new cancer
¢ Non-M invasive: TURB and IVT
¢ M invasive: as usual but do not consider conservation
again

33. NEOADJUVANT CHEMO
¢ Cisplatin-based
— MVAC
— CMV
— Cis-Gem
— Cis-adia
— Cis-Mtx
¢ 3 cycles
¢ In T3 (category 1) or T2 (category 2A)

34. NEOADJUVANT M-VAC CHEMO
¢ Grossman et al, N Engl J Med. 2003;349(9):859-66.
¢ MVAC x 3 q 28d
— Mtx: 30 mg sm d1, 15, 22
— Vinblastine: 3 mg sm d2, 15, 22
— Adrai: 30 mg sm d2
— Cisplatin: 70 mg sm d2
¢ T2-T4a
¢ Pathological CR: 38%

35. ADVERSE EVENTS OF MVAC

36. COMPLICATIONS AFTER SURGERY

37. Figure 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.

39. OS in pT0 vs RD

40. NEOADJ CIS-ADRIA OR CIS-MTX
¢ Sherif et al, Eur Urol 2004;45:297–303.
¢ Combined analysis of 2 trials
¢ Regimens:
— Cis 70 mg/sm & A 30 mg/sm q 3w x2 + RT
— Cis 100mg/m & Mtx 250mg/sm q3w x 3 NO RT
¢ OS HR 0.80 (95% CI 0.64–0.99) in favor of neoadjuvant
treatment.
¢ 5 Y OS was 56% for neoadjuvant and 48% in the control
group,
¢ 8% reduction in risk of death.

41. OS

42. NEOADJ CMV
¢ 967 pts
¢ 16% reduction in mortality with NACT

43. NEOADJUVANT CHEMOTHERAPY FOR TRANSITIONAL CELL
CARCINOMA OF THE BLADDER:
A SYSTEMATIC REVIEW AND META-ANALYSIS.
¢ Winquist et al, J Urol. 2004 Feb;171(2 Pt 1):561-9.
¢ 11 trials (2,605 patients)
¢ Conducted between 1984 and 2002
¢ TCC stages II and III (T2-T4, Nx-N3, M0)
¢ Pooled HR of death was 0.90 (95% CI 0.82 to 0.99, p =
0.02).
¢ Absolute OS benefit of 6.5% (95% CI 2 to 11%) from
50% to 56.5%
¢ PFS benefit consistent with OS benefit
¢ CR rates: 14-38%, Major Pathological response: 43%
¢ Major pathological response was associated with
improved OS in 4 trials

44. REGIMENS

45. NEOADJUVANT CHEMO

46. CONCURRENT CHEMORADIOTHERAPY
¢ Improved local control of invasive bladder
cancer by concurrent cisplatin and
preoperative or definitive radiation. The
National Cancer Institute of Canada Clinical
Trials Group.
¢ Coppin et al, J Clin Oncol. 1996 Nov;14(11):2901-7.
¢ RCT in 99 patients
¢ T2 to T4b TCC
¢ Randomized to CCRT or RT
— (cisplatin 100 mg/m2 at 2-week intervals x 3 cycles
concurrent with pelvic radiation), or RT (radiation without
chemotherapy)

47. DESIGN

48. CCRT VS RT IN TCC OF BLADDER
¢ Pelvis relapse significantly lower in CCRT
¢ Distant relapse were similar
¢ PFS better with CCRT (P 0.08)
¢ 3 y OS rates 47% in CCRT and 33% in RT (P0.34)

49. OS & PFS

50. ADJUVANT CHEMOTHERAPY
¢ Non-urothelial CA
— No data in any stage
¢ Urothelial CA
— Conflicting data
— Many trials showing benefit are not randomized
— Metaanalysis of 6 trails
¢ 25% mortality reduction
¢ But many limitations
¢ Regimens
¢ GC
¢ MVAC, MVEC
¢ CAP
¢ No. of cycles: at least 3

51. ADJUVANT CHEMOTERAPY FOR TCC OF
BLADDER

52. CHEMOTHERAPY IN METASTATIC TCC

54. ADJ RT
¢ Dat are scarce
¢ Possible role in T3a, T3b, T4a
— Due to High recurrence (30% that increase to 60% if
SM+)
¢ May be given with concurrent cisplatin
¢ Adj chemotherapy is also indicated in these cases
¢ Adj RT and Adj CT are not give together

55. BLADDER PRESERVATION
¢ Partial cystectomy alone
¢ Chemotherapy then partial cystectomy
¢ TUR alone
¢ TUR followed by
— Chemotherapy and radiotherapy (BEST)
¢ Cisplatin w1, 4 +/-8
— Chemo only
— Radio only
¢ Indications
— Urothelial ca
— Unfit pts
— Refusing pts