Innovations in the Treatment of Bladder Cancer Douglas S. Scherr, M.D. The Ronald Stanton Clinical Scholar in Urology Associate Professor of Urology Weill Medical College of Cornell University
Innovations • Early Detection - Biomarkers • Diagnosis – Optical Biopsy Techniques • Treatment – Robotic Assisted Radical Cystectomy
BIOMARKERS AND BLADDER CANCER
A Snapshot of Bladder Carcinoma in the US
Bladder Carcinoma Disease Costs and Management Opportunities
•
Major health cost burden per patient: - It is a disease with many events: frequent cystoscopy, high rate of recurrence etc…
- 4 million cystoscopies estimated in the US every year - $4 Billion per year in USA alone; largest cost per pt for any type of tumor
•
Unique amenability to applying molecular detection methods (e.g. UroVysion FISH) and molecular Rx delivery to target
Why is Screening Important • In a study of hematuria screening (Messing et al). Large group of men screened in Wisconsin and compared to a non-screened group
• Significantly higher number of high grade cancers detected in the screened group • At 14 year follow up, NO screened men died of bladder cancer whereas 20% of unscreened bladder cancers died of their disease
Early detection is important!
Shariat et al., J Urol 2006
100
Progression-free Survival Probability
Stage 5-year Survival pT0 92 % pT1 89 % pT2 83 % pT3a 78 % pT3b 62 % pT4 50 % Metastatic 500 cells for accurate reading • FDA approved when used along with cytology for surveillance • Has high negative predictive value to to high number of cells required for test
Urovysion • FISH test to detect increased copies of chromosomes 3,7,17 and homozygous deletions of 9p21 • Low sensitivity for low grade tumors, good for high grade tumors • May have some prognostic value in predicting recurrence • Not accurate in those patients who have already had their bladder removed
Cytokeratins • Intracellular cytoskeletal proteins • CK 8,18,19,20 have been evaluated • Released in urine from dead, exfoliated cells • CYFRA 21-1 test: soluble fragment of CK19 (sens of 75-96% and spec of 67-74%) • Approved in Europe but not USA
Investigated pathways Cell Cycle regulation p53
inhibits G1/S progression
pRb
sequesters E2F, inhibits cell cycle progression
p21/p16/p27
cyclin-dependent kinase inhibitors
Cyclin D1/cyclin E cell cycle control at G1/S transition KI-67
cell proliferation
Apoptotic pathway p53
induces apoptosis or DNA repair
Bcl-2
inhibits caspase activation
Bax
activates cytochrome C release and apoptosis
Caspase 3 Survivin
induces apoptosis protects from apoptosis and regulates mitosis
Angiogenesis pathway TSP1
inhibits angiogenesis
VEGF
promotes angiogenesis through NOS
uPA
degrades extracelullar matrix
bFGF
growth factor stimulating angiogenesis
Tumor Biomarkers Under Investigation •
UBC Rapid Test
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BLCA-1 AND BLCA-4
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Hyaluronic Acid and Hyaluronidase
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Lewis X Antigen
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Microsatellite Analysis
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Soluble Fas
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Quanticyt
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Survivin
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Telomerase
Urinary Bladder Cancer Test (UBC Test) • Point of care test • Measures CK 8 and 18 in the urine • Questionable role – likely inferior to BTA stat and BTA TRAK
BLCA-1 and BLCA-4 • Nuclear transcription Factor • Levels in urine increase with advancing stage
• Very high sensitivity and Specificity • Present in 19% of spinal cord injury patients • Await prospective studies for validation
Hyaluronic Acid and Hyaluronidase • Glycosaminoglycan – when present in tumor promotes mets and interferes with immune surveillance • Hyaluronidase degrades HA into small fragments that promote angiogenesis • Best for detection of high grade tumors
Lewis X Antigen • Expressed in the epithelium of bladder cancer cells • Reasonable specificity and sensitivity • Await large scale testing
Microsatellite Analysis • Polymorphic DNA repeats found throughout the human genome • If a microsatellite undergoes a mutation then microsatellite instability occurs and these can be used for biomarkers • Most common is loss of heterogeneity (LOH) of chromosome 9 in bladder cancer • Data too early for any real recommendations
Quanticyt • Flow cytometry on cells from bladder washings to detect aneuploidy (altered # chromosomes) • Requires a large number of cells (catheterization) of patient for barbatage • Unlikely to be useful
Soluble Fas • Fas signaling is important for apoptosis, immune surveillance • Urinary Fas levels can be independent predictor of recurrence and progression • Higher specificity than NMP22 • Needs validation studies
Survivin • Counter acts cell death and associated with tumor cell invasiveness • Protein and mRNA survivin levels are prognostic
Is one marker optimal?
Combined cell-cycle biomarkers J Clin Oncol 2003
Combined apoptosis biomarkers Lancet Oncol 2007
UCB Molecular Pathways- Opportunities for Targeted Therapies Non Invasive LG UCB pathway: HRAS or FGFR3 mutant proteins Inhibition of RTK-as signaling pathway e.g. Receptor tyrosine kinase inhibitors: gefitinib, erlotinib ErbB2 blocker: trastuzumab EGFR blocker: cetuximab Invasive High Grade UCB pathway: Restoration p53/RB function: gene therapy/small molecules Inhibition VEGF/VEGFR: Sorafenib, sunitinib, pazopanib, bevacizumab Inhibition of anti-apoptotic molecules (survivin)
The Future: integration of molecular panels • Improve prognosis of heterogeneous disease (UCB)
e.g. early cystectomy in pT1HG • Improve selection and thereby increase use of current chemotherapy
• Prediction of response to current chemoRx • Therapeutic response indicator e.g. select patients who achieve pT0 after neoadjuvant
chemotherapy for bladder preservation • Target for therapy (combination therapies)
Evolution of the Surgeon-Scientist Applied Anatomist Applied Pathophysiologist
Evolution of the Surgeon-Scientist Applied Anatomist Applied Pathophysiologist Integration of Anatomy and Biology Molecular PathologyBiologist Applied Molecular
NEW METHODS OF BLADDER CANCER DETECTION
Fluorescence Cystoscopy Hexaminolevulinate (trade name of Hexvix) is approved for bladder cancer diagnosis in Europe, and now recently approved in the US.
Hexvix is converted into a fluorescent porphyrin (Protoporphyrin IX), which is an intermediate in the heme biosynthetic pathway. These fluorescent porphyrins will accumulate preferentially in rapidly dividing cells.
They can be excited with blue light, and cells containing high amounts of this porphyrin will fluoresce red.
Problem: low specificity
Ref: http://www.hexvix.com/start.shtml
Fluorescence Cystoscopy • Resection of a papillary pTaG2 carcinoma
The Optical Biopsy The Holy Grail of Medical Endoscopy
Etiology of our problem “Standard Diagnostic Practice”
3-5 Business Days
Bladder biopsy
Pathological Processing
• Expensive • High patient morbidity • Probability of missed tumor or incomplete resection •Patient wait time and recovery
Histopathological diagnosis
High mag. Showing malignant cells with high N:C ratio and necrotic-fibrotic areas (red)
Minimally Invasive Bladder Cancer Surgery • Efforts to reduce the operative morbidity of RC have fostered interest in minimally invasive approaches.
• Laparoscopic RC • Robot-assisted laparoscopic RC
Introduction - Robotic Cystectomy • Robotic / laparoscopic radical cystectomy can be performed safely. (Parro 1992, Sanchez de Badajoz 1995, Gill 2000,) • Robotic radical cystectomy has been shown to reduce blood loss and length of stay. (Menon 2003, Balaji 2004, Wang 2007, Pruthi 2007, Galich 2006) • But So What? (Skinner 2007, Herr 2007, Soloway 2007…)
Three Questions • Can it be done? • Should it be done? • Does it provide oncologic control? • Does it provide any benefits over the old way of doing things? • Can everyone do it?
Complications after cystectomy • Complication rate after cystectomy was previously reported at 28% to 39%. (Stein 2001, Hautmann 1999, Lee 2004) • However, recent studies have shown that the true complication rate may be higher.
• Vanderbilt reported a 30-day postoperative complication rate of 41%, and MSKCC reported a 90-day postoperative complication rate of 64%. (Lowrance 2008, Shabsigh 2008)
Table 4: Patients with complications 30 days
90 days
Open
Robotic
P-value
Open
Robotic
P-value
# of patients with complications
61 (58.7%)
34 (41.0%)
0.04
64 (61.5%)
37 (48.1%)
0.07
# of patients with major complications
31 (29.8%)
8 (9.6%)
0.007
32 (30.8%)
13 (16.9%)
0.03
Grade 0
43 (41.3%)
39 (59.0%)
40 (38.5%)
41 (53.2%)
Grade 1
7 (6.7%)
10 (12.0%)
8 (7.7%)
10 (13.0%)
Grade 2
23 (22.1%)
16 (19.3%)
24 (23.1%)
13 (16.9%)
Grade 3a
13 (12.5%)
7 (8.4%)
15 (14.4%)
8 (10.4%)
Grade 3b
7 (6.7%)
0 (0%)
5 (4.8%)
4 (5.2%)
Grade 4
6 (5.8%)
1 (1.2%)
6 (5.8%)
1 (1.3%)
Grade 5
5 (4.8%)
0 (0%)
6 (5.8%)
0 (0%)
Highest grade of complication
Robotic Assisted Radical Cystectomy • Robotic cystectomy is associated with fewer overall and major complications at 30 days. • Robotic cystectomy is associated with fewer major complications at 90 days. • This reduction in complication rate may be explained in part by lower blood loss in robotic cystectomies.
Conclusion • Bladder cancer is an ideal disease for a screening biomarker • Ongoing studies are important for biomarker validation • New technologies seek to improve treatment strategies
