Dr.

Subrata Chatterjee
Surgical methods—
 TURB
 Cystectomy
 Salvage Cystectomy

Nonsurgical methods—
 Radiotherapy
 Chemotherapy
 Immunotherapy
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Ta Noninvasive papillary carcinoma
Tis Carcinoma in situ (flat tumor)
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades muscle
T2a Tumor invades superficial muscle (inner half)
T2b Tumor invades deep muscle (outer half)
T3 Tumor invades perivesical tissue
T3a Microscopic invasion only
T3b Macroscopic invasion (extravesical mass)
T4 Tumor invades prostate, uterus, vagina, pelvic wall, or abdominal wall
T4a Tumor invades prostate, uterus, vagina
T4b Tumor invades pelvic wall, or abdominal wall
 Nx Regional lymph nodes cannot be assessed
 N0 No regional lymph node metastasis
 N1 Metastasis in a single lymph node <2 cm in great dimension
 N2 Metastasis in a single lymph node >2 cm but not >5 cm in
greatest dimension; or multiple lymph nodes, none >5 cm in
greatest dimension
 N3 Metastasis in a lymph node >5 cm in greatest dimension
M-stage  
 Mx Distant metastasis cannot be assessed
 M0 No distant metastasis
 M1 Distant metastasis
 organ-confined, lymph node negative tumors
(pT0, pTa, pTis, pT1, pT2a, pT2b),
 nonorgan confined (extravesical) lymph node
negative tumors (pT3, pT4),
 and lymph node positive disease (N+);
representing 56%, 20%, and 24% of patients
respectively
 Superficial
 Muscle invasive
 Metastatic
 Treatment of Superficial Tumors
Most common presentation of bladder cancer .

TURB is the treatment of choice .

Tumor recurrence following TURB is found in 70% of patients, with 15% progressing to
muscle-invasive disease .

TURB only or TURB+Intravesical chemo or immunotherapy

Recurrence rate is reduced but, patient mortality rates is not affected by intravesical
therapy(EORTC)

Intravesical Bacillus Calmette-Guerin (BCG) in patients with Ta plus T1 disease

demonstrated a clear benefit
During the past 25 years there has been a steady
decrease in the importance of definitive irradiation
as a single modality therapy in the management of
patients with carcinoma of the bladder. There has
been a corresponding increase in the application of
radical cystectomy and in the use of radiotherapy as
a part of an organ-preservation multimodality
therapeutic approach
 A report on 701 patients treated between 1977 and 1994 in western Sweden,
showed results clearly inferior with RT to those of surgery, with the 5-year
survival for T2 and T3 tumors of only 15%. The 74 (10%) patients selected
for definitive external beam radiation therapy (EBRT) (more than 60 Gy)
were older and unfit for surgery.
 In another study,the combined-therapy(RT followed by cystectomy) patients
had better prognostic factors, including better T stage, than those treated with
EBRT alone .
5-year survival rate for the 263 combined-therapy patients was 48%,
whereas it was 22% for the 271 EBRT patients.
 Stanford University (1975)concluded that 30% to 40% of T3 patients are
expected to be controlled with EBRT . Failure in the bladder with or without
other organ involvement was noted in 217 (56%) patients. Severe bowel
toxicity was recorded in 8% of patients
 Patients treated with EBRT have a high incidence of
persistent tumor as well as high incidence of local
failure (about 50%) .
 The incidence of failure depends on tumor stage and
grade at diagnosis and & is higher than that reported
in patients treated with radical cystectomy .
 However, the incidence of urethral recurrence at 3%
in EBRT-treated patients is the same or lower than
surgical series (0.7% to 18%) .
 It implies the en bloc removal of the pelvic & iliac lymph nodes
along with the pelvic organs anterior to the rectum: the bladder,
urachus, prostate, seminal vesicles, and visceral peritoneum in men;
the bladder, urachus, ovaries, fallopian tubes, uterus, cervix, vaginal
cuff, and the anterior pelvic peritoneum in women. An appropriate
lymphadenectomy is an important component of radical
cystectomy .The boundaries of extended lymph node dissection :
superior limits --inferior mesenteric artery ,
lateral limits----- over the inferior vena cava/aorta upto the
genitofemoral nerve ,
distally to the lymph node of Cloquet medially (on Cooper's
ligament) and the circumflex iliac vein laterally. This dissection
includes bilaterally all obturator, hypogastric, presciatic, and
presacral lymph nodes.
The number of lymph nodes involved with tumor
and the extent of the lymph node dissection are
both important variables for patients undergoing
cystectomy for Ca bladder

Lymph node density is significant and

independent prognostic variable
 USC study (2001) --68% 5-year DFS & 66% OS in
pt.s treated with radical cystectomy . These results
were superior to those reported from an earlier
surgical series of 300 cystectomy patients from
MSKCC, where the 5-year overall survival rate was
36% in patients with T2 to T4 disease .

 This series, however, also included patients with

early disease, including 20% of those with
noninvasive tumors.
Local (pelvic),
Distant,
Urethral.
Overall, 30% of all patients in the USC series
experienced a local or distant tumor recurrence
86% of all patients developed their recurrences
within the first 3 years of cystectomy.
median time to distant recurrence 12 m
median time to local recurrence 18 months.
overall local pelvic recurrence rate -- 7% Patients
with organ confined, node-negative tumors ---
6% local recurrence rate,
Nonorgan confined node-negative tumors —
13%local rec.
Patients at highest risk of a local recurrence are
(lymph node positive disease) --13% or more
 Recurrences following radical cystectomy are most
commonly found at distant sites.
 Distant rec. depends on pathologic subgroups.
 Organ-confined, node-negative tumors -13%
 Extravesical lymph node negative -32%
 node-positive tumors -52% .
 Patients at high risk for tumor recurrence should
clearly be considered for adjuvant chemotherapy
protocols.
 Most urethral tumors probably represent simply
another occurrence of the transitional cell
carcinoma in the remaining urothelium.
 As radical cystectomy has emerged as the most
effective therapy for invasive bladder cancer,
and as orthotopic diversion has increasingly
been performed, the fate of the retained urethra
has become an increasingly important oncologic
issue.
 RT or CT or both?
 Neoadjuvant or adjuvant?
 No increase in the perioperative morbidity or morality
with [Link] or RT

 Neoadj. treatment strategies have not been routinely employed prior to

radical cystectomy.

 Preoperative radiation therapy is considered only in those patients with a

history of a previous partial cystectomy or those who have extravesical
tumor spill at the time of endoscopic management of the primary bladder
tumor.

 There has been a recent interest in neoadjuvant chemotherapy in patients

with muscle invasive bladder cancer , but routine administration is
debatable .
 Aims:

 Tumor size reduction in locally advanced, muscle-invasive and therefore

make surgery easier,

 Decrease in the incidence of local rec. following radical cystectomy,

 Decrease in the incidence of distant metastasis,

 Improvement of survival,

 No increase in the incidence of surgical complications.

Routine use of preoperative irradiation remains controversial.

[Link] of 40 Gy in 4 weeks followed by cystectomy vs.
definitive irradiation of 60 Gy in 6 weeks.
The 5-year survival in patients receiving the combined therapy
was 38% vs. 29% for those treated with RT alone .
This study demonstrated significant survival benefit of
[Link] in pt.s younger than 60 years of age and males, with
no benefit noted in older (>60 years of age) and female
patients. It is of importance to note that tumor-stage reduction
was obtained in 49% and no tumor was found in the resected
specimen in 31% of patients receiving preoperative irradiation.
 Patients are with T3b bladder cancer.

 The 5-year incidence of local control in the preoperative group(RT

dose 50 Gy in 5 wks.)
(n = 92) was 91%, as compared to 72% for those treated with radical
cystectomy alone (n = 43; p = .003).
There was also a benefit of preoperative irradiation in terms of OS
and DFS and in freedom from distant metastasis . In multivariate
analysis, preoperative irradiation was an independent predictor of
local control.

 Routine use of preoperative irradiation as an adjuvant therapy to

surgery and chemotherapy in patients with T3b disease is beneficial
& recommended.
 No statistical difference observed in important
treatment outcomes between the two groups of
pts.

 So, routine use of preop. RT in the treatment of

muscle-invasive bladder
 Patients with extravesical tumor extension or
with lymph node positive disease are at increased
risk for recurrence and should be considered for
adjuvant chemotherapy protocols. Additionally,
the application of molecular markers, may also
serve to identify pt.s at risk for tumor rec. who
may benefit from adjuvant therapy .
 The main advantage of postoperative RT is the availability of
pathologic staging. This allows the administration of adjuvant
irradiation only to those patients who have a high probability of
tumor recurrence following radical cystectomy.
 No large clinical trials on the use of postoperative radiotherapy
have been reported.
RTOG phase II trial using a single fraction preoperative
radiotherapy (5 Gy) followed by postoperative irradiation (45
Gy in 5 weeks) in pathologically determined high-risk patients .
Of the study's 65 patients, 29 received preoperative and
postoperative radiotherapy. The treatment program was very
well tolerated, and there was no pelvic recurrence. The 3-year
actuarial survival was 78%.
 The Nordic Cystectomy Trial II administered three preoperative
cycles of cisplatin and methotrexate prior to cystectomy and
compared the results to those of cystectomy alone . No
preoperative radiation therapy was used in this study.
Interestingly, despite a statistically significant pathological
down staging (26.4% CR), no survival benefit was observed (5-
year survival 53% vs. 46%; p = NS). A similar study from M.D.
Anderson Hospital compared three preoperative cycles of M-
VAC chemotherapy followed by cystectomy, to cystectomy
alone . The median survival was 77 months versus 44 months
(p = .06) and the 5-year survival was 57% versus 43% (p = .
06).
 A large international prospective randomized trial
of neoadjuvant chemotherapy prior to radical
cystectomy or prior to EBRT demonstrated
32.5% pathologically proven CR but failed to
demonstrate substantial benefit in survival, the
results showing only a possible 5.5% difference
in 3-year survival between the treatment groups.
 2006 the Advanced Bladder Cancer Meta-analysis
Collaboration published a meta-analysis of six trials
of adjuvant chemotherapy, after primary local
treatment of bladder cancer). The meta-analysis
included 491 patients with stages T2 to T4a
transitional cell carcinoma of the bladder. The
overall HR for survival was 0.75 (95% CI, 0.6 to
0.96; p = .019), suggesting a 25% relative reduction
in the risk of death for chemotherapy recipients
compared to that of patients in the control arm.
 Results of a phase I/II study conducted in the University of Erlangen
 n =67, patients with muscle-invasive carcinoma .
 Treatment protocol ---- optimal TURB followed by 50.4 Gy EBRT given
at 1.8 Gy daily with simultaneous cisplatin
(25 mg/m2 daily for 5 days during the first and last week of radiotherapy).
CR at 6 weeks of completion of therapy was obtained in 75% study
patients. At 18 months 18% CR pt.s had a local recurrence. The overall
3-year survival at 66% was not significantly different from that of
matched control. The combined-therapy program was well tolerated
without severe toxicity.
 Combined-modality therapy has become a standard approach in patients
seeking bladder-preservation therapy.
 Tumor stage & morphology,
 Presence of intravesical versus extravesical tumor,
 Presence of solitary vs. multiple bladder tumors,
 Presence of ureteric obstruction,
 Completeness of TURB or perfection
of cystectomy,
 Presence of CR after EBRT & radiation dose,
 Hb%.
 molecular biology related prognostic factors:
expression of p53, p21, and retinoblastoma tumor suppressor
genes, Ki67, and apoptotic index
 The anterior &posterior fields extend laterally about 1.5 cm to the bony
pelvis at its widest section with inferior corners excluded to protect the
femoral heads.
 The lateral fields extend anteriorly to about 1.5 to 2 cm from the most
anterior aspect of the bladder as seen on an imaging study (CT). The
posterior border lies about 2.5 cm posterior to the most posterior aspect of
the bladder and falls within the rectum. Inferiorly, the tissue above the
symphysis and the anal canal is blocked.
 The inferior border is placed below the middle of the obturator foramen.
The superior border is usually at the L5-S1 disc space.
 Accelerated fraction RT
 Particle beams
 Radiation sensitisers
 Brachytherapy
Ta low grade -TURBT
Ta high grade – TURBT +intravesical chemo
T1- TURBT +intravesical BCG
T2- Radical Cystectomy
T3- Radical Cystectomy + RT
[Link]+ Radical Cystectomy + RT
T4b-CT+RT
N+-- Radical Cystectomy +[Link]
Comorbid condition(muscle invasive)– RT+CT
M+---Palliative CT+Palliative RT