Download Bladder Cancer

Bladder Cancer
Bladder cancer:
• 90-95%
•
•
•
•
Histology
transitional-cell carcinoma
3%
squamos-cell carcinoma
2%
adenocarcinoma
<1%
small-cell carcinoma
Primary Tumor – Superficial or Muscle Invasive
– Superficial
• Carcinoma‐in‐situ (CIS) is a flat, intraepithelial carcinoma. It has a
high rate of spread to lymph nodes.
• Papillary tumors are superficial, non‐invasive cancers. They are
usually low‐grade tumors.
• Muscle‐invasive tumors are usually high‐grade tumors.
RISK FACTORS
• A. Higher in industrialized countries than in developing
countries,
• B. Smoking ‐ up to 60% of bladder cancers
• C. Chemicals ‐ α‐ & β‐naphthylamine, 4‐Aminobiphenyl,
Benzidine, Chlornaphazine, 4‐Chloro‐otoluidine, o‐Toluidine,
4,4’methylene bis (2‐chloraniline), methylene dianiline,
benzidine‐derived azo dyes, phenacetin‐containing compounds.
Workers, usually in the rubber paint and dye industries,
exposed to the above chemicals are at increased risk of bladder
cancer.
• D. Chronic bladder irritation or infections ‐ usually develop
squamous cell tumors
SIGNS & SYMPTOMS
• A. 80% of patients present with painless
microscopic or gross hematuria.
• B. 20% of patients complain of irritation
while voiding (frequency, urgency or
dysuria).
• C. Patients with advanced disease may
present with symptoms of uremia due to
obstruction of one or both kidneys.
Bladder cancer:
Epidemiology
Bladder cancer: Epidemiology
Case
• A 66 y/o male presents to his
primary care physician with the
chief complaintsn of urinary
frequency. During the work-up,
a urinalysis reveals
microscopic hematuria. Urine
cytology demonstrate
suspicious cells.
• A cytoscopy found a suspicious
lesion that was biopsied. The
biopsy showed transitional cell
carcinoma that invaded the
subepithelial connective tissue
(T1 lesion), node(-), M(-)
• What therapy should he
receive at the point?
•
75-85%
superficial bladder cancer
pTa, pTis, pT1 ( carcinoma in-situ, Papillary)
•
10-15%
muscle-invasive bladder cancer
pT2, pT3, pT4 (high grade)
•
5%
metastatic bladder cancer
N+, M+
Ta, Tis, T1 :
• Non-muscle invasive bladder cancers are divided
into 3 groups: Ta, Tis, and T1
– Ta are noninvasive papillary lesions confined to the
urothelium and have not penetrated the basement
membrane
– Tis : severe cellular dysplasias usually in the absence
of tumor formation
– T1 : tumors that have penetrated into underlying
lamina propria but without any involvement of the
muscularis propria.
Bladder cancer:
Stage and Prognosis
Stage TNM
5-y. Survival
0
Ta/Tis NoMo
>85%
I
II
T1
NoMo
T2a-b NoMo
65-75%
57%
III
T3a-4a NoMo
31%
IV
T4b NoMo
each T N+Mo
each T M+
24%
14%
med. 6-9 Mo
Superficial Bladder Cancer
• Histological grading is important
G1
G2
G3
Relapse rate
42% 50% 80%
Progression rate
2%
11% 45%
Natural History of bladder cancer
•
•
•
•
70-80% presents with superficial tumors
Grade 3 tumor are most likely to recur
If untreated, 60-70% of CIS will progress
Most common sites of metastatic disease
are lymph nodes, liver, lung, and bone.
TREATMENT BY STAGE
Radical cystectomy/TURBT
Orthotopic bladder replacement
(neobladder construction).
Figure 3c. Orthotopic bladder replacement (neobladder construction).
Catalá V et al. Radiographics 2009;29:461-476
©2009 by Radiological Society of North America
Superficial Bladder Cancer
pTa, pT1, Tis
• Standard treatment : complete transurethral
resection of the bladder tumor (TURBT)
• Intravesical chemotherapy
– as prophylactic or adjuvant therapy after complete
endoscopic resection
• Relapse rate: 70%
 adjuvant therapy
Superficial Bladder Cancer
Adjuvant Therapy
• High grade or T1 disease:
– TURBT
– intravesical bacillus Calmette-Guerin (BCG)
• Intravesical immunotherapy for non-muscle
invasive bladder cancer
– BCG 81 mg (TheraCys) or 50 mg (TICE) in 50 ml sterile
saline injected into the bladder through a catheter
and held for 2h; weekly for 6wk
– Maintenance therapy : at 3, 6, 12, 18, 24, and 36mo
after initiation, weekly for 3wk
Patients with non‐muscle‐invasive TCC of the
bladder (Stage Tis, Ta, T1) treated with TURBT
• Observation or intravesicular Bacillus Calmette‐Guerin
(BCG)
– 10‐year Progression‐free Rate
– BCG (n=43) 61.9% : Control (n=43) 37% (p=0.0063)
• Non‐muscle‐invasive TCC of the bladder after TURBT
were assigned to intravesicular BCG (40 mg weekly x 6
then at 3, 6, 12, 18, 24 months) or intravesicular
doxorubicin
NEJM
1991;325:1205‐9.
J Clin Oncol 1995;13:1404‐8.
Superficial Bladder Cancer
Adjuvant Therapy
• Reduces relpase rate by 30-80%
– Doxorubicin
weekly 6-8 w. / monthly 6-12
– Mitomycin C
weekly 6-8 w. / monthly 6-12
– BCG
weekly 6-8 w. /Mo 3 and 6
• BCG Failures
– BCG plus interferon :At a median follow‐up of 24
months, 45% of patients in the BCG‐failure groups
were disease‐free with the combination
J Clin Oncol 1995;13:1404‐8
Case
• our patient undergoes a TURBT and then
receives intravesicular BCG
Invasive bladder cancer
• Standard of care =
Radical cystectomy with pelvic
lymphadenectomy
Only about 50% of patients with highgrade invasive disease are cured
Results of radical cystectomy
Stage
T2
T3a
T3b
T4a
NN+
NN+
NN+
NN+
Recurrence-Free
5 y.
10y.
Overall Survival
5 y.
10y.
89
50
78
41
62
29
50
33
77
52
64
40
49
24
44
26
87
50
76
37
61
29
45
33
57
52
44
26
29
12
23
20
Stein et al JCO 2001;19:666
Results of radical cystectomy
Stage
Recurrence-Free /Overall Survival5 years
Organ-confined (<pT2pNo)
73%
62%
non-organ-confined (>pT2pNo)
56%
49%
Positiv lymph nodes (pT1-4, pN+)
33%
24%
Madersbacher et al JCO 2003;21:690
Chemotherapy for bladder cancer
• Bladder cancer is a chemosensitive disease
• Active single agents.
RR
– Cisplatin
30%
– Carboplatin
20%
– Gemcitabine
20-30%
– Ifosfamide
20%
Chemotherapy for bladder cancer
Combination chemotherapy.
–
–
–
–
MVAC
Gemzar / Cisplatin
Gemzar / Carboplatin
Taxol / Carboplatin
RR
CR
40-75%
40-70%
65%
20-40%
<20%
5-15%
5%
Treatment Options for Muscle Invasion
(T2‐T4, Stage II or above)
• TURBT
• All muscle invasive tumors : as high-grade urothelial
carcinomas
• For organ‐confined disease, radical cystectomy is the
gold standard.
– If surgery is not an option, radiation therapy is
recommended.
– 30%– 50% ,5‐yr survival rate ( death due to local
relapsed. )
• Neoadjuvant chemotherapy
Neoadjuvant chemotherapy
• BA06 trial ( Jco . 2011;29:2171‐2177)
– 3 cycles of neoadjuvant (cisplatin, vinblastine,
methotrexate) vs observation
– 3‐year survival : 55.5% vs 50%, p=0.075,
– 10‐year survival : 36% vs 30% (p=0.037)
• Intergroup Study N Engl J Med 2003;349:859‐66
– 3 cycles of neoadjuvant M‐VAC followed by
cystectomy or cystectomy alone (control).
– Median Survival : Neoadjuvant 77 months vs Control
46 months (p=0.06)
Neoadjuvant chemotherapy
• A meta‐analysis of 11 randomized trials
– platinum‐based combination chemotherapy
• Reduce 14% relative risk of death
• Improvement in 5‐year survival, 45% -> 50% (P = .003)
• No survival benefit with single‐agent cisplatin.
• To preserve bladder function and avoid a radical
cystectomy ( are combining bladder preserving surgery
(TURBT), irradiation and chemotherapy.
– None has been compared to radical cystectomy. (NEJM
1993;329:1377‐82.)
Metaanalysis collaboration. Eur Urol. 2005;48:202‐205.
Neoadjuvant chemotherapy
• Meta-analysis of ten randomised trials
(2688 patients)
13% reduction in risk of death
5% absolute benefit at 5 years
OS increased from 45% to 50%
ABC Meta-analysis Collaboration. Lancet 2003;361:1927
Adjuvant chemotherapy
• Randomized trials have not shown a survival
advantage.
• T3 tumors may receive 3 cycles of adjuvant
(chemotherapy or radiation) therapy to delay
recurrence
Ann Oncol 2006;17 Suppl 5:v118‐22
Case
• Two years later, he returns to the clinic
complaining of abdominal & pelvic pain. A CT
scan of the chest and abdomen demonstrate
multiple pulmonary nodules & an abdominal
mass. Based upon this information,
• what therapy should he now receive?
Treatment options for Advanced Disease
(Stage IV) – rarely curable
• Cisplatin/chemotherapy better than single agent therapy.
• Cisplatin alone (70 mg/m2) vs M‐VAC (methotrexate 30 mg/m2
IV on days 1, 15, 22; vinblastine 3 mg/m2 IV on days 2, 15, 22;
doxorubicin 30 mg/m2 IV on day 2; cisplatin 70 mg/m2 IV on day
2) q 28 days. 19
• Response rate Overall Survival (Cisplatin 12% 8.2 months vs
M‐VAC 39% (p<0.001) 12.5 months (p=0.002)
– M‐VAC therapy : greater incidence of neutropenia, febrile
neutropenia, mucositis, and nausea/vomiting.
– Long‐term survival benefit for M‐VAC. J Clin Oncol 1997;15:2564‐69
First-line chemotherapy for muscle
invasive bladder cancer
• Gemcitabine and cisplatin : Gemcitabine 1000
mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 IV
on day 1; repeat cycle every 28d for a total of 4
cycles or
• MTX, vinblastine, doxorubicin, and cisplatin (MVAC):
Methotrexate 30 mg/m2 IV on days 1, 15, and
22 plus vinblastine 3 mg/m2 IV on days 2, 15, and
22 plus doxorubicin 30 mg/m2 IV on day
2 plus cisplatin 70 mg/m2 IV on day 2; repeat cycle
every 28d for a total of 3 cycles.
Gemcitabine/Cisplatin vs. M‐VAC
phase III study. J Clin Oncol 2000;17:3068‐3077
Intravenous Carboplatin/Paclitaxel 23‐26
3 phase II and 1 phase III trial with advanced bladder cancer
Limited data for carboplatin substitution
Consider in patients “unfit” for cisplatin (PS > 2; CrCl < 60ml/min)
23. J Clin Oncol 1998;16:1844‐48., 24. Br J Cancer 1997;78:370‐4.
25. J Clin Oncol 1998;16:1844‐8. 26. EORTC study 30986. J Clin Oncol. 2012;30:191‐199.
Non‐Platinum Regimens: Paclitaxel & Gemcitabine
Phase Ⅱ
a. 54 pts with advanced unresectable bladder cancer ; the 65% of
patients had no prior therapy.
b. Paclitaxel 200mg/m2 on day 1 & gemcitabine 1000 mg/m2 IV on
days 1, 8, & 15. repeated q 21 days.
J Clin Oncol 2001;19:3018‐24.
Combined Radio- and Chemotherapy
CR
5y.OS
• Radiotherapy
57%
47%
• RT and cisplatin
85%
69%
• RT and carboplatin
70%
57%
Birkenhake et al. Strahlenther Onkol 1998;174:121
Bladder-sparing therapy for invasive
bladder cancer
• High probability of subsequent distant
metastasis after cystectomy or radiotherapy
alone (50% within 2 years)
• Radiotherapy im comparison with cystectomy
has inferior results (local control 40%)
• Muscle-invasive bladder cancer is often a
systemic disease
 combined modality therapy
Bladder-sparing protocol
Transurthral resection
Induction Therapy: Radiation + chemotherapy
(cisplatin, paclitacel)
Cystoscopy after 1 month
no tumor
Consolidation: RT + CT
tumor
cystectomy
Bladder-sparing protocol
T2: 5y / 10y OS: 74% / 66%
T3-T4a: 5y / 10y OS: 53% / 52%
Shiply et al. Urology 2002;60:62
Results of bladder-sparing therapy
and cystectomy
Bladder-sparing
n Pat.
therapy
5y. OS
%
5y. Survival
with Bladder %
Houssett 1997
120
63
NA
Sauer 1998
Shipley 1998
Shipley 2002
Rodel 2002
162
123
190
415
55
49
54
50
44
38
45
42
Dalbagni 2001
181
36
NA
Stein 2001
633
48
NA
Cystectomy
Combined-modality treatment and organ
preservation in invasive bladder cancer
Rödel et al. JCO 2002;20:3061
415 patients with T1 high-risk, T1-4, No-1
Treatment: 1. Transurethral resection
2. RT (n=126), RCT (n=289)
RT median 54 Gy, CT cisplatin week 1, 5
3. Restaging-TUR
Combined-modality treatment and organ
preservation in invasive bladder cancer
• Rödel et al. JCO 2002;20:3061
•
•
•
•
•
Complete remission
Local control after CR
distant metastasis
Disease-specific survival
Preservation of bladder
72%
64% (10 y.)
35% (10 y.)
42% (10 y.)
>80%
Local control
Distant metastasis
Rödel et al. JCO 2002;20:3061
Disease-specific survival for patients after salvage
cystectomy
50%
21%
45%
18%
Rödel et al. JCO 2002;20:3061
TUR and adjuvant
Radio-Chemotherapy
• 5 year Survival
50-65%
• Preservation of Bladder
38-43%
Conclusion
• Superficial tumors have a 5‐year survival rate of > 50%.
• With muscle invasive carcinoma have a 5‐year survival
rate of 20‐50%
• Regional lymph nodes are involved the 5‐year survival
drops to 0‐20%
• The treatment of advanced metastatic bladder cancer is
palliative.
– M‐VAC or gemcitabine + cisplatin survival is just over
one year.
A 65 year‐old male presents with painful urination. Upon
work‐up microscopic hematuria is detected and a cystoscopy is
performed. He is found to have a stage III bladder cancer with
muscle invasion. The best treatment option for this patient
after cystectomy would be:
•
•
•
•
A. Observation.
B. Intravesicular bcg vaccine.
C. Three cycles of neoadjuvant single‐agent cisplatin.
D. Three cycles of neoadjuvant m‐vac followed by radical
cystectomy.
2. JM is a 62‐year‐old female diagnosed with stage IV bladder
cancer. Her laboratory values are largely unremarkable except for
long‐standing chronic renal disease that has resulted in a baseline
serum creatinine of 1.9mg/dL. Which of the following is the best
treatment option for JM?
• A. M‐VAC chemotherapy repeated every 28 days
with a reduced dose of cisplatin.
• B. Dose‐dense M‐VAC repeated every 14 days
• C. Cisplatin on day 2 + Gemcitabine on days 1, 8,
and 15 repeated every 28 days
• D. Paclitaxel on day 1 + Gemcitabine on days 1, 8,
and 15 repeated every 21 days