Bladder CA Flashcards
What is the most common presenting symptom in bladder cancer?
Painless haematuria
Seen in >80% of patients
What is the most common histology of bladder carcinomas?
Transitional cell carcinomas
Besides transitional cell carcinomas, what are the other histologies?
Lymphoepithelioma-like Sarcomatoid carcinomas Micro papillary or nested variants Primary squamous cell carcinomas Adeno carcinomas
What is the standard treatment of muscle-invasive bladder cancer?
Radical cystectomy with extended lymphadenectomy
What supports the use of CDDP-based neoadjuvant chemotherapy for bladder cancer?
Advanced Bladder Cancer Meta-analysis collaboration published in Eur Urology in 2005
A meta-analysis of 11 RCTs with 3000 patients
5% absolute increase in 5-year OS
9% absolute increase in 5-year DFS
This is compared with Radical cystectomy alone
What is the evidence for adjuvant chemotherapy for bladder cancer?
Leow et al. 2013 updated meta-analysis in Eur Urol 2014
Updated meta-analysis of 9 RCTs including 950 patients for usage of CDDP-based adjuvant chemotherapy
OS benefit with HR 0.8 and DFS benefit with HR 0.65
- DFS benefit more apparent in those with Positive lymph node involvement.
What are the clinical indicators that determine if a patient is suitable for bladder preservation?
Early tumor stage
- including high-risk T1 disease, T2
What are the 5 bladder tumor marker tests?
BTA-Stat BTA-TRAK NMP-22 uCyt+ UroVysion
Non shown to be superior to Urine cytology and cystoscopy
What are the risk factors for Bladder CA?
1) Age
2) Toxins
- Smoking
- Aniline-containing dyes, arsenic
- Phenacetin
- Arsenic
3) Chronic inflammation
- Chronic cystitis/UTI
- Schistosomiasis (S.Haematobium –> SCC)
4) Cytotoxic agents
- Pelvic RT
- Cyclophosphamde
Tell me about the bladder cancer staging for T.
Ta = Non-invasive papillary carcinoma
T1 = Tumor invades sub epithelial connective tissue
T2 = invades muscle
- T2a=invades superficial muscle (inner half)
- T2b=invades deep muscle (outer half)
T3 = invades perivesical tissue
- T3a=microscopically
- T3b=Macroscopically with extravehicular mass
T4=Tumor invades any of the following: prostate, vagina, pelvic wall/abdominal wall
- T4a=invades prostate, uterus, vaginalis
- T4b=invades pelvic wall/abdominal wall
Tell me about the N staging for bladder cancer
Regional LN are those within true pelvis.
All others are distant lymph nodes
N1 = mets in a single LN, 2cm or less
N2 = Single lymph node, >2cm, but 5cm or smaller; OR
- multiple LN, but none >5cm
N3 = Mets in a LN >5cm
How does completeness of TURBT relate to OS?
Completeness of TURBT is a strong prognostic factor for OS for both superficial and muscle-invasive disease
R0 = 10y OS 50% R1 = 10y OS 30% R2 = 10y OS 20%
What are the characteristics that are a/w higher chance of recurrence?
High Grade
Diffuse Tis alone or in a/w papillary tumors
>3 bladder lesions (any >3-5cm)
Vascular invasion
T1b - invasion of the deep portion of the lamina propria
Multiple recurrences within a short period of time (eg >2 in a year)
Incomplete resection due to diffuse bladder involvement or unfavorable location
Presence of tumor within 3-6 months after initial TUR
What is considered intermediate and high risk disease?
Multifocal Tis
G3 Ta or T1 with Tis
Rapidly recurring after TURBT
When do you treat with prophylactic intravesical chemotherapy ?
Immediately after TURBT (within 24 hours) for ALL superficial bladder cancer
What is the usual treatment for prophylactic intravesical chemo?
Usually Mitomycin-C
40mg in 40 Mls
Evidence comes from meta-analysis of 1500 patients of 7 RCTs over 3.5 years
- Sylvester 2004 in J Urol
What is the additional therapy for intermediate and high risk disease?
BCG most commonly used
Alternatives: Mitomycin C, or Epirubicin
Induction course of BCG once every week for 6 weeks–>
Intermittent maintenance cycles of e-week courses repeated Q3-6monthly –>
Q6-monthly up to 3 years
- This provides a 20% absolute reduction in recurrence rate
- Saint et al 2001 Urology
What are the agents used in intravesical treatment?
1) Intravesical BCG
2) Intravesical Chemotherapy
- Thiotepa
- Mitomycin-C
- Epirubicin/Doxorubicin
How would you monitor a patient after TURBT?
1) Cystoscopy
2) Urinary Cytology
3) Image upper urinary tract every 12-24 months as there is a 5% lifetime risk for development of upper tract tumor after Dx of bladder cancer
Cystoscopy/cytology:
- every 3 months for 2 years
- 6-monthly for 2 years
- yearly indefinitely
What are the side-effects of BCG?
Frequency (70%) Cystitis (70%) Fever (25%) Haematuria (25%) BCG-osis = BCG-sepsis (very rare, but can be fatal)
What is the role of maintenance BCG?
Lamm et al.
Many experienced Significant G3 toxicity
Only 16% completed treatment
3-week courses every 3-6 months, then every 6 months for up to 3 years
Provides a 20% absolute reduction in recurrence rate
What is the side-effect of intravesical thiotepa ?
Significant systemic absorption and toxicities of myelosuppression
Irritating voiding symptoms
What are the general complications of intravesical treatment?
Dysuria
Frequency
Urgency
Bladder fibrosis and contracture
What are the treatment modalities for muscle-invasive disease?
1) Surgery
2) Neo-adjuvant chemotherapy
3) Adjuvant chemotherapy
4) Bladder-Sparing approaches
What does radical Cystectomy entail removal of?
1) Bladder
2) Prostate
3) Seminal vesicles
4) Proximal urethra
5) Fallopian tubes
6) Ovaries
7) Anterior vaginal wall
8) Bilateral pelvic LN dissection
- Recent data shows that removal of prostate may be spared when there is no direct extension of tumor to urethra, prostatic duct or stroma
- Improved potency ad urinary incontinence
What are the methods of urinary diversion that you know of?
1) Ileal conduit
2) Continent Cutaneous diversion
- Pouch made of aperistaltic bowel segment
- requires CIC
- no stoma
3) Orthotopic neo bladder
What is the minimum number of LN tt should be removed?
10
From retrospective data from INT 0080, those with >10 LN removed had significantly better outcome
When is chemo radiotherapy an option for bladder preservation?
More effective in:
Solitary T2 or early T3
Tumors
How is chemo radiotherapy done?
CDDP or Carboplatin
- CDDP 40 mg/m2 or Carboplatin AUC2. Weekly for 6/52
Alternative radiosensitizers:
- Capecitabine
- Paclitaxel
- Gemcitabine
Outcome of local control dependent on goal RT dose. ~60-70Gy
Requires repeat TURBT with multiple biopsies 6weeks after chemo radiotherapy.
When is neoadjuvant chemotherapy considered?
Operable T2-4a muscle-invasive disease
This came about because failure rate of 30-45% after surgery
What are the advantages and disadvantages of neoadjuvant chemotherapy?
Advantages:
- delivered early when burden of micromet expected to be low
- Allows evaluation of response (Chemosensitivity of tumor tested)
- Tolerability of chemo likely to be better before surgery
Disadvantages:
- delay cystectomy
- S/e of chemo may affect outcome of surgery
- error in staging may lead to over treatment
What is the evidence for neoadjuvant treatment?
1) MRC/EORTC Lancet 1999
N=1000 for curative surgery or radical RT
2 arms:
1) neoadjuvant chemo with CMV
2) No neoadjuvant.
Neoadjuvant chemo
- Cisplatin, methotrexate, Vinblastine
- q21days X 3 cycles
Results:
pT0 after CMV = 32% in cystectomy group (55% of all patients)
Initially no survival improvement seen, but data reached significance are 8y f/u showing 15% reduction in risk of death with neoadjuvant chemo.
But difficult to compare outcomes as groups are unbalanced. Those who got RT tended to have poorer PS, earlier T and N stage and were older. ======== 2) Grossman NEJM 2003 Planned for radical cystectomy. N=300 2 arms: 1) Radical cystectomy alone 2) 3# of MVAC --> Radical cystectomy
Chemo Cycle Q28days
RESULTS:
- med OS 45m vs 75m (neoadjuvant)
- 5y OS 55% vs 40%
- improvement in survival a/w absence of residual cancer in cystectomy specimen.
- pCR Rae 40% vs 15% (no chemo)
Under what circumstances may TURBT alone be curative?
Solitary lesion
Describe the Tri-modality approach of TURBT+ChemoRT
As part of bladder preservation, uses TURBT, Chemotherapy and RT
1) TURBT
- as complete as possible
2) ‘adjuvant’ CRT with either approach:
- Concurrent CRT
- Induction chemo –> Concurrent ChemoRT
3) Restaging TURBT
4) 2 scenarios:
- Consolidative Therapy in responding patients
- Cystectomy in non-responders if residual tumor still present
What is the outcome of Tri-modality treatment ?
Typical 5-yr survival is 50%
- 80% of whom has an intact bladde
Any role for CDDP-free RT sensitization?
Yes BC 2001
NEJM 2012
N=360
>80% T2 tumors
All N0
2 arms:
1) ChemoRT
2) RT alone
Chemo:
- 5FU 500/day X 5 days Week 1 and 4
- MMC 12 D1
Results:
No OS difference, likely due to salvage Sx in RT alone patients.
PEP met: 2y LR DFS 60% vs 50%
5y OS 50% vs 35% (trend)
What are the poor prognostic factors in metastatic bladder cancer in second line setting?
PS >0
Hb
What are the CDDP-containing chemo options?
1) MVAC
2) Gem-CDDP
- or Gem-Carbo
What is the expected RR with MVAC
About 70% with CR 50%
But very toxic
Sternberg J Urol 1985
Not as tolerable as cf CDDP/Gem
Other series show MVAC>CDDP
RR about 40% vs 10% with OS 12.5m vs 8m
Between HDMVAC and MVAC. Which is better?
HDMVAC >MVAC in terms of increased RR by 1.5x.
But OS seems equivalent.
Any rose for ddMVAC as opposed to MVAC?
Yes. Borderline statistically significant relative reduction in risk of PD and death
EORTC 30924 by Sternberg Eur J Cancer
- updated 2006
Differences show up in 7y update.
N=260
Met
Unresectable T3-4
Chemo-naive
RESULTS: CR 20% vs 10% PR ~40% 5y OS 22% vs 13.5% (MVAC) Med Survival 15.1m vs 14.9m (MVAC) 7y med PFS 9.5m vs 8m
Gem/CDDP vs MVAC. What is the result?
GC=MVAC
Von dear Maase JCO 2000
T4b N2-3 Muscle invasive No prior chemo N=400
2 arms: 1) Gem/CDDP - Gem (1000 D1,8,15) Q28d - CDDP (70) D2 Q28d 2) MVAC - MTX (30) D1, 15, 22 - Vinblastine (3) D2, 15, 22 - Doxorubicin (30) D2 - CDDP (70) D2 Q28days
RESULTS:
- no substantial difference in Overall RR ~45%
- no difference in OS 15m (MVAC) vs GC 14m (trend)
- 5y OS 13% vs 15% (MVAC) (trend)
- med PFS 7.7m vs 8.3m (MVAC)
- no diff in TTP/Tx failure either
- Gem/CDDP has fewer side effects than MVAC
Any value in addition of Paclitaxel to met Bladder CA chemo?
ORR improved 55% vs 45%
MOS no different 15m vs 12m (trend)
FN rate 13% vs 4%
Bellmunt JCO 2012 2 arms: 1) Gem (1000) D1,8,15, CDDP (70) D2 - Q28days 2) Pac (80) D1,8 CDDP (70) D1 Gem (1000) D1,8 - Q21.
How about ddMVAC and ddGC?
Bamias JCO 2011
Outcomes almost the same. ddGC = better tolerated - Gemcitabine 2500 - CDDP 70 - Q14d
RESULTS:
ORR 47% (ddMVAC) vs 47% (ddGC)
OS 18.5m vs 21m (ddGC)
Is Carbo = CDDP in Bladder CA?
No
Data suggests CDDP > Carbo in terms of efficacy
- MA Galsky Annals 2011 CDDP>Carbo in terms of CR, ORR
What is the definition of those unfit for CDDP?
ECOG 2
CCT
What are possible 2nd line chemotherapy?
No standard
1) Taxanes
2) Pemetrexed
3) ?Eribulin
4) Vinflunine
RR 10-20%
Tell me the evidence for Vinflunine
Bellmunt JCO 2009
Phase 3 study with 370 patients
Vinflunine > BSC
320mg/m2 Q21days
RR 10% vs 0%
PFS 3m vs 1.5m
Med OS 7m vs 4m
Significant hematological toxicities
Vinflunine is a vinca alkaloid, inhibits micro tubules
How about the evidence for Gem-Pac as 2nd line
Albers in Ann Onco 2011
N=100
6# Gem/Pac > vs Gem/Pac until PD
ORR 40% with PFS 3.5m and OS 8m
Why in first line do we elect to use Gem/CDDP?
MVAC >CDDP
MVAC = ddMVAC
MVAC = GC (Von der Masse JCO 2000)
PGC = GC
