ASCO GU 2010
San Francisco - 4-7 March 2010
Feed back from Ipsen reporters
Each affiliate is responsible for ensuring the subsequent
local approvals (medical and regulatory)
Summary
 EARLY DETECTION AND PREVENTION IN PROSTATE CANCER
 HIGH RISK CANCER IN PROSTATE CANCER
 PROSTATE CANCER FUTURE PATHS
 UROTHELIAL TUMORS
 KIDNEY TUMOR
EARLY DETECTION AND PREVENTION
IN PROSTATE CANCER
Peter R. Caroll, MD, MPH, University of California, San Francisco
Peter Boyle, PhD, International Prevention Research Institute, California
Eric A. Klein, MD, Cleveland Clinic
Otis W. Brawley, MD, American Cancer Society
Early detection: strategic public health options
 Lump screening
 No screening
 Targeted screening
• Agreed with the patient
• Information on the pros and cons
Essential individual questions
 Do I have to be screened?
 If it finds cancer, must I be treated?
 If I wish to be treated, is this treatment really necessary?
 If I am treated, what should I expect:
• Side effects?
• Cure?
2 important clinical studies
 USA: PLCO
•
NEJM 360, 1310-1319, 2009
 Europe: ERSPC
•
NEJM 360, 1320-1328, 2009
 Single study
 Several pooled studies
 Negative study
 Positive study
Arguments in favor of early screening
 The number of deaths from prostate cancer between 50 and 65 years old is not
negligible.
• These patients should have been diagnosed and treated earlier.
 PSA is more specific in young men.
 PSA value at 40 years old > median value.
• predictive for diagnosing prostate cancer before 75
 First dosage earlier
• This can select the men who will need monitoring and some who will not
• could reduce specific mortality
... compared to annual tests starting later.
 Men who are at risk from cancer with a negative biopsy would be good candidates for
chemoprophylaxis
Would it be interesting to give an early first dosage of PSA between
44 and 50 years old?
 Probability of diagnosing prostate cancer
before 75
 PSA measured at age of 44 to 50 years old
Nat Rev Cancer 2008;8:266 Lilja H
Resolving a dilemma?
1.
Offering the possibility of early detection in well informed
healthy men.
2.
Evaluate the how aggressive the diagnosed cancers are.
3.
Selective treatment of well-informed patients after having
been offered several options, then monitoring.
Over-detection /
elective treatment
Reduced
mortality
Mortality from prostate cancer in controlled studies
Study
OR/HR
IC 95%
Quebec
1.16
Norkopping
1.04
PLCO
1.13
(0.75, 1.70)
ERSPC
0.80
(0.65, 0.98)
Impact of PSA dosage (USA)
 In 1985, in the USA, a man had:
• An 8.5% risk of being diagnosed prostate cancer during his lifetime.
• A 2.5% risk of dying from prostate cancer (Seidman et al 1985)
 In 2005, in the USA, a man had:
• A 17.0% risk of being diagnosed prostate cancer during his lifetime.
• A 3.0% risk of dying from prostate cancer (Jemal et al, 2007)
Be careful with the test calibration
(Abstract no. 14)
 Comparison of two calibration standards for PSA dosage: Hybritech( and WHO.
 The WHO calibration gives dosages of 22 to 25% lower than Hybritech®.
 By extrapolating these results to patients from the PCPT (Prostate Cancer
Calculator™), the WHO calibration would not have diagnosed a third of the
patients that have had positive biopsies for prostate cancer.
Prevention
Advantages / Disadvantages
Potential benefits
 Prevent / delay the appearance of
cancer
 Increase life expectancy
 Improve quality of life
 Avoid useless treatment
Potential disadvantages
 Short and long term side effects
 Affecting quality of life
 Becoming a patient
Methods
Prevention and life style
Potential increase of the risk
Potential reduction of the risk
 Red / fatty meat
 Fruit and vegetables
 Dairy / Calcium
 Specific nutriments
 Smoking
 Overweight / Obese
• Vitamin E
• Selenium
• Carotenoids
• Antioxidants
 Fish, omega 3
 Regular physical activity
Negative or not very rigorous studies (SELECT)
Medicine-related prevention
 PCPT
- ↘ 25% risk
 REDUCES:
• ↘ 22.8% risk
• ↘ 31.9% risk if family history
Chemo-prevention: Which patients?
Target
Chemo-prevention: Targeting by genotyping
 5 genetic variants and prostate cancer = NO
Cut-off
 Polymorphism of the androgen receiver gene (CGA
repeated sequence) = YES ...in the future
Probability of prostate cancer within 4 years according to PSA value
AUC = 0.83
PSA velocity
 PSA evolution
• Between visit 1
• And prostate cancer diagnosis
(JNCI 2006;98:1521 Carter HB)
Death from prostate cancer
Prostate cancer without death
No prostate cancer
Conclusion / Perspectives
 Before
PSA
Risk of
threshold, density, velocity
prostate cancer
Modeling the risk
Significant risk of
prostate cancer
Biopsy
 Now
Biopsy
Nomograms
Calculator
 Future
Predicting the risk
individually
PSA aged 40
Genotyping
Significant risk of
prostate cancer
Chemo-prevention
± Biopsy
HIGH RISK CANCER IN PROSTATE
CANCER
Joel B. Nelson, MD, University of Pittsburgh School of Medicine
Mukesh G. Harisinghani, MD, Dana-Farber Cancer Institute/ Harward Cancer Center
Judd W. Moul, MD, Duke University Medical Center
Mack Roach , III, MD, FACR, University of California, San Francisco
Matthew R. Smith, MD, PhD, Massachusetts General Hospital
High Risk: an unsolvable enigma
Easy to recognize, difficult to define
Tool
Description
Advantages / disadvantages
Risk categories
D’amico risk group
PSA > 20 or
Gleason 8 – 10 or
T2c
Easy to use/
Inaccurate
Probability tables
Partin Tables
PSA, Stage, Biopsy, Gleason
Immediate/
Relevance
Risk scores
UCSF – CAPRA
Add age, number of positive biopsies
Score from1-10 /
Not very practical
Nomogram
Kattan
Continuous and categorized data
Individualized:
Requires a computer
High Risk: a minority of cancers
100%
90%
29,9%
80%
46,0%
24,6%
25,1%
27,4%
29,1%
42,9%
70%
60%
23,7%
Haut
Highrisque
risk
50%
Intermediate
risk
Risque
intermédaire
25,0%
40%
26,5%
Lowrisque
risk
Bas
30%
20%
27,5%
46,4%
48,0%
45,8%
2000-2001
2002-2003
2004-2006
32,1%
10%
0%
1990 - 1994
1995-1999
High Risk: the majority of deaths
No treatment for
Gleason ≤ 6
S Spe at 20 years old 7095%
Albertsen, JAMA 2005
High Risk: improving detection
Lin DW et al. Cancer 115: 2863-2871, 2009
High Risk: genetic markers of tomorrow
Xu J. et al. PNAS 2010, 107: 2136-2140
High Risk: using post-treatment histological classifications
Tumor architecture of preoperatively
treated prostate cancer:
(A) Single cells, cell cords, and cell
clusters;
(B) small glands;
(C) fused glands;
(D) cribriform pattern;
(E) intraductal spread.
Efstahione et al. Eur. Urol Dio: 10.1016 / J. Euro. Uroi. 2009, 10.020
MRI in high risk prostate cancer
 Loco-regional and osseous metastatic evaluation
 Conventional MRI (T1,T2)
 MR-spectroscopy (choline, citrate)
 Dynamic MRI
 Diffusion MRI (tissue excitation)
MRI in high risk prostate cancer
 Endo-rectal probe ++ (extra capsular extension)
 1.5 Tesla vs 3 Tesla antenna
 False positives in T2 (sources of prostatitis)
 Analyzable lymph node status (size N > 5-8 mm)
 Combination of diffusion MRI and dynamic MRI for recidivist diagnosis
Imagery in high risk prostate cancer
Lymph nodes affected
 TEP choline
 VPP 86%
VPN 76%
Bones affected
 Osseous scintigraphy
 Full body MRI
 TEP 18F Fluoride
Surgery in high risk
The "modern" total prostatectomy has its place:
 Blood losses (transfusions from 5 to 15%)
 Definitive incontinence 2 to 10% (age is determining factor)
 Validity of nervous conservation discussed
 Robotics: no proof of superiority over open
 Prime surgical appraisal
High risk and surgery:
different options (multi-mode)
 Total prostatectomy (TP)
 TP + adjuvant (HT) or neoadjuvant (NHT) hormone-therapy
 TP + adjuvant external radiotherapy (ERT) and/or HT
 TP + adjustment ERT+/- HT
 Therapeutic tests with TP + chemotherapy (CT)
 ERT + NHT and/or adjuvant HT
 ERT + brachytherapy ± HT
 only HT...
Surgery in high risk
Phase 1 preoperative ERT (Duke Prostate Center)
 SG 8-10 and/or cT2c+ and/or PSA > 20 ng/ml
 Use of progressive dose levels 40, 45, 50, 54 Gy (pelvis and prostate and VS)
 TP 4 to 8 weeks post-ERT
 2 close protocols (Toronto, Oregon) with different doses and protractions
High Risk: Pre-operative ERT (cont.)
 TORONTO
• 5 Gy x 5 1 to 2 weeks before TP
 OHSU
• 45 Gy in 5 weeks + Docetaxel
• TP in 4-6 weeks
 DUKE
• Increase in dose  54 Gy in 6 weeks
• 45 Gy / pelvic lymph nodes
• TP within 6 weeks
ERT and high risk
 Confirm the need for HT associated with ERT (HT duration to be
modulated according to the number of prognosis factors) [level 1].
 HT + ERT > HT only [level 1].
 Optimum dose not established in association with long HT
 If dose> 72 Gy: IMRT with IGRT [level 1].
ERT and high risk
 Choice of local treatment
 Surgery vs ERT: discordant data in 2 retrospective studies
• Arcangeli: ERT> Surgery?
• Zelefsky: Surgery > ERT?
 Contribution of the pelvic RT? Advantages of IMRT
 Duration of adjuvant HT: long
 To be discussed whether a single prognosis factor present (T and PSA), the age and
co-morbidities (level 3)
PROSTATE CANCER
FUTURE PATHS
Donald J. Tindall, PhD, Mayo Clinic
Charles J. Ryan, MD, University of California, San Francisco
Wm. Kevin Kelly, DO, Yale Cancer Center
Charles G; Drake, MD, PhD, John Hopkins Sidney Kimmel Comprehensive Cancer
Center
LH and paths to synthesize steroids in prostate cancer
 LH and LHRH are expressed in established lines of cancerous cells and in
human prostatic cancerous tissues.
 Depending on time and dose, LH over-regulates the expression of genes and
key enzymes from the steroidogenesis in prostate cancer cells.
 LH stimulates the production of progesterone and testosterone in prostate
cancer cells.
 LH increases the cAMP rates in the prostate cancer cells.
 LH raises the feasibility of prostate cancer cells.
Paths of steroidogenesis in prostate cancer
Cancer Res 2008; 68: (15). August 1, 2008
Bone Flare (transitory raising the osseous scintigraphy)
(S. Shah et al.)
 Osteoblastic response linked to curing bones after antineoplasic treatment.
 Early appearance in response to new treatment.
 Frequent phenomenon (study on 33 patients):
• 30.0% of patients included.
• 43.5% of PSA responder patients.
 Can easily be interpreted as a progression of the illness.
Bone Flare: Mechanism
 Scarring of the osteosclerosis metastases
• Increase in density of osteoblasts.
• Appearance of new dense zones.
 These 2 phenomena can be accompanied by an increase in the absorption
of the radioisotope from the scintillation camera.
Androgen receptors (AR) and prostate cancer:
State of the art (J. Tindall)
 AR plays a critical role in
maintaining the functions of
prostate cancer cells in the CPRC.
 An AR splicing variant can
generate an active protein that
induces androgen-independent
activity.
 AR variants are potential
therapeutic targets.
AR targeted therapeutic strategies
(C. J. Ryan)
Amplification /
 Prostate cancer resistant to
Resistance of the AR
castration (CPRC).
 New issues in an old concept.
CPRC
Intra-tumor
production / conversion
of androgen
Persistence of
serous androgens
Abiraterone - What have we learnt after 4 years?
Phase I
Phase II
Phase III
Toxicities, action / PSA
Efficacy / longevity
Efficacy / Longevity
On an empty stomach/ food
Pre - chemotherapy with prednisone
Survival vs Prednisone
Tablets / gel capsules
Post – chemotherapy without
prednisone
Pre vs Post docetaxel
Surrenal deficiency
Post – Chemotherapy with
prednisone
Corticosteroids necessary
Associating biology and therapy throughout the path leading to AR
Biological event
Therapeutic actions
Drugs
Production of androgens
SCC inhibitor
CYP17 inhibitor
Ketoconazole
Abiraterone
Tak 700
Tok 001
Circulation / transport of
androgens
Blocking transport
HE – 3235
Conversion into DHT
SAR inhibitor
Sulphatase inhibitor
Dutasteride
BN - 83495 sulphatase
Connection to the AR
New AR inhibitors
MDV 3100
ARN – 509
Tok 001 ?
A new landscape for developing systemic therapies in prostate
cancer
Metastases
Clinical
Cannot be castrated
Clinically
Localised
Disease
Increase
PSA
1
Rising PSA:
Castration
2
Castration
Metastases
Abiraterone
3
Castration
Metastases
1st Line
Docetaxel
Standard
4
Castration
Metastases
PostCabazitaxel
Abiraterone?
MDV 3100
 Multiple (and varied) standards around which the new products must be developed.
 A fortunate set of problems.
Prostate cancer: New paths non targeted AR (Vm K. Kelly)
Non targeted AR treatments (FDA)
(CPCR)
Molecule
Indication
Docétaxel
1st line
Mitoxanhrone
CPCR
Acide Zolendronique
CPCR
Treatment
Novacea
D ± DN101
SWOG
D ± atrasentan
CALGB
D ± bevacizumab
sanofi-aventis
D ± afilbercept
NCI
D or KAVE
Doxo ± strontium89
Cell Genesys
D vs GVAX
Cell Genesys
D ± GVAX
Zeneca
D ± ZD4054
Bristol
D ± dasatinib
Painful osseous
metastasis
Samarium153
Promotor
2nd line
Estramustine
Strontium89
Non targeted AR treatments in phase III
(CPCR)
Painful osseous
metastasis
Study on phase III TROPIC: Results:
 Cabazitaxel: new taxane active on tumor cell descendants resistant to docetaxel
 Design: patients were pre-treated with docetaxel at random 1/1 between:
cabazitaxel (C)(25 mg/m²) + prednisone vs mitoxantrone (M) (12mg/m²) +
prednisone
 Results: 755 pts in 132 centers, 26 countries
- Median number of cycles: 6 C vs 4 M
- Tolerance: neutropenics gr3/4: 82% C vs 58% M
- Effectiveness: improvement of global survival (ITT)
C > M: median global survival: 15.1 vs 12. 7 months
(HR = 0.70; IC 95%: [0.59 – 0.83], p < 0.0001)
TROPIC: ITT overall survival
New approach to escaping castration:
autologous dendritic cell immunotherapy
 Reminder: 2 types of active cell immunotherapy
- autologous dendritic cells + fusion P (Sipuleucel-T)
- allogenic cells for tumor descendants transfected by GM-CSF (G-VAX):
approach abandoned
 Design of the phase III IMPACT study:
- randomization 2/1 – three IV doses every 2 weeks vs placebo – double blind
 Results updated at 36 months:
- 341 pts having received Sipuleucel vs 171 pts for placebo
- Tolerance: Low intensity AEs with Sipuleucel (Gr ½)
transitory (<48h), flu-like symptoms
- Effectiveness: reduction of death risk by 23%
Median survival: 25.8 months vs 21.7 months with Sipuleucel
Angiogenesis stimulator in prostate cancer metastases
 HIF-α
 Angiopoietines
 VEGF
 uPA
 PSMA
 FGF-2
 IGF-1
 TGF-β
 EMMPRIN/CD147
 PD-ECGF
 MMPs
 COX-2
 Androgens
 IL-8
 Integrins
 MUC1
Li et al., Medicinal Research Reviews DOI 10.1002/med
Anti-angiogenesis agents in the CPCR
Agent
Author
Phase
# patients
Result
Bevacizumab
Reese
II
15
↘ PSA > 25%: 1 patient
Sorafenib
Steinbild
II
55
5% PSA response
36% Stable at 12 weeks
Sorafenib
Dahut
II
22
Osseous meta improvement: 2
patients
10/19 POD (based on PSA)
SU5416 + Dex
Stadler
II
36
No clinical activity
SU101
Ko
II
35
↘ PSA > 50%: 3 patients
Cediranib and CPCR: phase II
 Cediranib bioavailable orally
 Inhibitor of TK-FLt-1 and KDR receptors for the VEGF (vascular endothelium
growing factor)
 Cediranib 20 mg/J (C) ± pred. 10 mg/J (P)
 Results:
• C (n=24)
53% tumor regression
RP: 4 patients (17%)
• C+P (n = 10)
60% tumor regression
RP: 2 patients (20%)
AR non targeted therapies:
the last (?) square
Angiogenesis
inhibitors
Immunotherapy
?
Cytoxics
Targeted radiopharmaceuticals
Brachytherapy by 125I for prostate cancer: Going back 15 years
 Biochemical relapse-free survival (BRFS) excellent and lasting long term after
prostate brachytherapy by 125I only for patients with low and intermediate risk.
 BRFS if PSA < 20 ng/ml: 85% over 15 years
 Overall survival at same rate as general population broken down by age.
Conclusions
 Excellent and durable long term BRFS is achieved with I-125
prostate Brachytherapy alone in low and intermediate risk
patients
 85% 15-yrs BRFS if iPSA < 20 ng/ml
 OS is similar to age matched population at large
 CSS tracks with BRFS after 11?7 yrs of tight cohort follow-up
Cell cycle progression (CCP) genes and recurrence after TP
 A signature of expression defining the risk of recurrence after TP was
developed and validated.
 Associated with classic clinical criteria for post-operative monitoring, this
signature spectacularly improves the risk of recurrence in patients with a
low risk prostate cancer.
Survival without recurrence and CCP
Evolution of the trend to use more expensive treatments in prostate
cancer treatment
Surgery
Increase in the proportion of
Minimally invasive radical prostatectomy
(MIRP)
% Open
1.5% in 2002
8.7% in 2005
Radiotherapy
Increase in the proportion of
Intensity-Modulated Radiotherapy (IMRT)
% 3D-CRT
% MIRP
% IMRT
28.7% in 2002
81.7% in 2005
Mixed histological (MH) characteristics and survival post MVAC
neoadjuvant CT in locally advanced bladder cancer
 Survival after just cystectomy
• MH < UC: HR = 1.28 [0.80, 2.06], p=0.30
 Response to MVAC
• MH> UC:
– Downstaging to pT0: 28% vs 25%
– Survival: HR = 0.46 [0.28, 0.87], p = 0.02 for MH
HR = 0.90 [0.67, 1.21], p = 0.48 for UC
 UC + SCC and UC + ACa respond to MVAC
 The benefit of neoadjuvant MVAC in SWOG is obtained in MH patients
Abbreviations:
MVAC = methotrexate, vinblastine, doxorubicin, cisplatin,
UC = urothelial carcinoma; MH = Mixed histology
HR = Hazard ratio; SCC = squamous cell cancer
Aca = Adenocarcinoma; SWOG = South West Oncology group
UROTHELIAL TUMORS
Stuart G. Silverman, MD, Brigham and Women’s Hospital
Ashish M. Kamat, MD, M.D. Anderson Cancer Center
Seth P. Lerner, MD, Baylor College of Medicine
Joaquim Bellmunt, MD, PhD, University Hospital del Mar
Imagery of the high urinary apparatus
 The uroscanner today has definitively
replaced the UIV.
 3-phases imagery protocol:
• No injection: abdomen and pelvis
• Nephrogram injection
• Excretory phase with furosemide 10 mg: VE
examination
 2 Constraints
• Dose of radiation
• Cost
Evolution of the number of IUVs between 1999 and 2006 at the
Montefiore Medical Center
Indications for UroTDM
 Multiple indications for the scanner but search for risk factors to justify
the UroTDM
• Age > 40 years old
• Smokers
• Macroscopic hematuria
 Recommendations from the AUA if there is hematuria
• UroTDM + Urinary cytology + cystoscopy
• The UPR is still valid...
23% of urological cancers
(kidney or excretory paths)
Counter-indications for UroTDM
 4 main counter-indications:
• Allergy
• Pregnancy
• Renal deficiency
• Child
 In the event of counter-indications: 2 phase MRI
– T2 Static
– T1 excretive phase
How can we optimize BCG therapy?
Optimization of BCG therapy
Factors predicting the therapeutic response?
 Dosage of IL2 in urine = bladder inflammation marker and predicts
therapeutic response
De Reijke J Urol 1999, Saint I J C 2003
 Genotype IL6 = defines an individual response profile for patients from
the first instillations
Lebovici J C O 2005
BCG therapy: anticipating relapse
 Calculation of relapse
probability
 A nomogram is more practical!
Optimize the BCG therapy
2 objectives +++
 Identify a profile that can differentiate responders from non responders
 Identify the dose and the administration schedule to obtain the optimum
profile (that might vary from one patient to another)
Advantages of lymph node curage in cystectomy
Lymph node invasion remains the major prognostic factor for 5 year survival
N
P1
P2
P3
P4
Stein et al.
1054
7
18
23-46
42
Leissner et al.
290
2
11-22
40-46
40-80
Vazina et al.
176
4
16
40
50
Steven et al.
263
5
14-24
40
33-42
Ghoneim et al.
2720
2
8-19
39
36
Incidence of pelvic lymph node metastases during radical cystectomies
in selected contemporary series (2000 – 20009)
Extension of lymph node curage
Importance of node density
 No. of positive nodes /No. of nodes
sampled
Use of presacral curage and/or
aortic bifurcation?
Lymph node invasion at this level
↗ depending on stage
 Positive in 30% of T3
Bruins J Urol 2009
Roth et al Eur. UroL; 57:205; 2010
Rational for extended lymph node curage
Capitanio et al. BJU 2008
And real life!!
 SEER 9:
1998 – 1996
• 53% of patients: < 4 nodes removed
• 40% of patients:
 SEER 17:
no lymph node curage
1998 – 2004
Minimum improvement if less than 10 nodes removed
Advantages of a randomized study
SWOG S1011 LND
Prospective study comparing pelvic and iliac lymph node curage extended to standard pelvic curage during
cystectomy for cancer.
T2, T3, T4
Radical
cystectomy
R
a
n
d
o
Standard curage
Int/ext iliac
Obturator
Extended curage
Standard + Presacral,
Aortic bifurcation
N+ Chemo
adjuvant
KIDNEY TUMOR
Evolution of the anatomopathological analysis with integration of molecular markers
Integration of these markers into functional imagery
Tackling small renal lumps
Victor E. Reuter, MD, Memorial Sloan-Kettering Cancer Center
Chaitanya R. Divgi, MD, University of Pennsylvania
David Y.T. Chen, MD,Princess margaret Hospital / University of Toronto
Debra A. Gervais, MD, Massachusetts General Hospital
Histological classification: evolution
 Clear cell RC
Clear cell RC (conventional)
Chromophobe RC
Renal Oncocytoma
 Granular RC
Chromophobe RC
Clear cell RC (conventional)
Papillary RC
Collecting tubule carcinoma
Epithelioid angiomyolipoma
Papillary RC
Collecting tubule carcinoma
 Papillary / tubulopapillary RC
Carcinoma via Xp11 translocation
Tubular Mucineux and spindle cell
Clear cell RC (conventional)
Chromophobe RC
Papillary RC
 Sarcommatoid RC
Collecting tubule carcinoma
Unclassifiable RC
Sub-division of clear cell cancer
 Clear cell RC, conventional type
 Clear cell RC, multilocular cyst
• Apparently benign
 Clear cell RC, associated with translocation
• Aggressive
 Clear cell RC, papillary
• No vHL mutation
• Benign?
Numerous markers
Clear cell RC
Papillary RC
Vimentin
Diffuse Cytoplasmic
Absent
CAIX
Diffuse Membranous
Cytoplasmic
Focal cytoplasmic
Necrosis tips
Focal cytoplasmic
(rare)
Absent
CD10
Diffuse Membranous
Cytoplasmic
Apical membranous
Focal or diffuse
Diffuse Cytoplasmic
Focal cytoplasmic
AMACR
Diffuse or focal
Cytoplasmic
Cytoplasmique finement
granulaire diffus
Focal cytoplasmic
Focal cytoplasmic
CK7
Focal cytoplasmic
Diffuse Membranous
Diffuse Membranous
Focal cytoplasmic
(rare)
CD117
Focal cytoplasmic
Focal cytoplasmic
(rare)
Diffuse Membranous
Diffuse Cytoplasmic
*
Chromophobe RC
Absent
*
Oncocytoma
Absent
Non classified tumors: aggressive
Non classified RC: a diagnostic category to which an RC should be assigned when it cannot be
classified in another category... includes composites of known types... and unrecognizable
cellular types
(Heidelberg classification, J. Pathol, 1997; 183:131)
Classification of tumors by the WHO 2004
Non classified RC: a diagnostic category to which an RC should be assigned when it cannot be
classified in another category... includes composites of known types... sarcomatoid morphologies
without recognizable epithelials ... and unrecognizable cellular types
Integration into functional imagery
 Hypothesis
•
124I-cG250
will provide in vivo confirmation of clear cell cancer
• The pre-operative diagnosis of clear cell RC can guide the surgical technique and the
patient's subsequent care.
• Patients with renal lumps programmed for a nephrectomy
• 90% detection accuracy
"Industrial" application with development of a specific CA IX antibody
 Girentuximab (eG250) is specifically linked to CAIX
• CAIX is hyper-expressed in > 95% of ccRC
• Rarely expressed in indolent RC
• Not expressed by benign tumors (oncocytomas, angiomyolipomas)
 Positive "Proof-of-Concept" study
 Protocol for a pivot study (REDECT) developed in collaboration with FDA
 PET/CT sensitivity
≈ 86%
(IC 95%: 79-91%)
 PET/CT specificity
≈ 87%
(IC 95%: 75- 95%)
 REDECTANE®: it works!
Small kidney tumors
 40% of renal lumps < 2cm are benign (25% 2-4 cm)
(Steinberg et al J.
 46% of 1 cm lumps are benign
(Frank et al. J. Urol. 169A, 2003)
 Most small lumps are low grade ccRC and other types.
Biopsies
 80% of diagnosis during first biopsy
• 80% at second
 Very low morbidity
 Why forego a biopsy if it can influence the patient's care?
– See Prostate
3 therapy options
Treatment method
No of studies
No of institutions
No of tumors
Partial nephrectomy
50
50
5037 (77.8%)
Cryoablation
19
19
496 (7.7%)
RFA
21
21
607 (9.4%)
Active surveillance
10
10
331 (5.1%)
Total
99 *
87
6471
* The study data was taken into account in partial nephrectomies and in cryoablations
Active surveillance: a developing concept
 Active surveillance with delayed treatment
• Most small RC grow slowly, and if they undergo metastasis, they do so late.
• Many small RC appear in elderly or ill subjects
• Most small RC that cause death appear in an advanced state.
Canadian study (RC4)
 Methodology
• 209 small sized tumors, detected by chance in 178 patients in 8 centers.
• Eligible
– Elderly subject
– Co-morbidity
– Refuses treatment
• Ineligible
– Life expectancy > 2 years
– Aware of tumor for over 12 months
– Treatment for another cancer
– Hereditary renal cancer syndrome
Results
 Early results confirm that the majority
 The rate of delayed treatment for tumor
of the pRC grow at negligible speed,
progression must be determined with
even if the RC is confirmed by biopsy.
prolonged monitoring.
 Surveillance with delayed treatment
 2 pRC have undergone metastasis,
seems to be a reasonable option for
suggesting that size is just one of the
selected patients.
prognostic factors and that other
markers are necessary.
Ablative treatment
 Thermal ablation is still valid.
 Preferable for patients with co-morbidity, surgical risk, elderly subject
 Surveillance becomes more important
• The lumps are going to grow bigger
• The patients are going to get older, become anxious in the event of change
• ????????? 3cm surveillance anxiety point is good for TA ????
• Patients request less invasive treatments
 The balance between excessive and insufficient treatment has not been
achieved yet
As a conclusion
Small RC
"Healthy"
"Ill"
Potentially malign
Moderate risk
Targeted resection
Sparing the nephrons
Molecular Imagery
Biopsy
Risk
Null /minimal
Ablation
Active Surveillance
KIDNEY TUMOR
Rational for partial nephrectomy (PN) compared to radical nephrectomy (RN)
Care strategy in kidney cancer: affecting the IVCand affecting the lymph nodes
Targeted therapies
Paul Russo ,MD, Memorial Sloan-Kettering Cancer Center, New York, New York
Michael L Blute , Mayo Medical School and Mayo Clinic, Rochester, Minnesota
H Van Poppel MD, PHD, University Hospital K.U. Leuven, Leuven
Rational for partial nephrectomy (PN) compared to radical
nephrectomy (RN)
Paul Russo ,MD, Memorial Sloan-Kettering Cancer Center, New York, New York
1 - 30% of kidney cancers are M+ at diagnosis
2 - 70% of renal tumors are < 4 cm at diagnosis (and 80% have a RN in the USA…)
3 - variable potential evolution
20% = benign
25% = indolent (chromophobe…)
54% = RCC being responsible for 90% of later M+
4 - PN = RN for t. < 7 cm for the oncological result
5 RN is associated with a higher risk than PN of affecting the renal function (Mayo clinic 2000 &MSKCC2002)(4,5)
6 - notion of "pre-existing CKD (chronic kidney disease)"
RN is a factor that is independent of the appearance of a CKD (6)
RN (compared to PN) is associated with an increase in the risk of death (after adjustment over the year of
surgery, diabetes, Charlson-Romano index and histology (7)
RN is associated with an X1.38 risk of overall mortality and X1.4 risk of cardiovascular accidents (8)
CONCLUSION
1) RN is more recommendable for T. < 4 cm
2) PN must be envisaged each time that < 7cm and/or technically possible
Partial Versus Radical Nephrectomy for 4 to 7 cm Renal Cortical Tumors
R. Houston Thompson, Sameer Siddiqui, Christine M. Lohse, Bradley C. Leibovich, Paul Russo and Michael L.
Blute*
From the Departments of Urology (RHT, SS, BCL, MLB) and Health Sciences Research (CML), Mayo Medical School and Mayo Clinic, Rochester,
Minnesota, and Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center (RHT, PR), New York, New York
A, overall survival in 873 patients treated with RN (dotted curve) and 286 treated with PN (solid curve) (p 0.8). B,
cancer specific survival in 704 patients treated with RN and 239 treated with PN (p 0.039).
J Urol. 2009 December ; 182(6): 2601-6
Chronic kidney disease after nephrectomy in patients with renal cortical
tumours: a retrospective cohort study
William C Huang, Andrew S Levey, Angel M Serio, Mark Snyder, Andrew J Vickers, Ganesh V Raj, Peter T Scardino,
and Paul Russo
(W C Huang MD, A M Serio MS, M Snyder, G V Raj MD, Prof P T Scardino MD, Prof P Russo MD) and Department of Epidemiology and Biostatistics
(A J Vickers PhD), Memorial Sloan Kettering Cancer Center, New York, NY, USA; and Division of Nephrology, Tufts-New England Medical Center,
Boston, MA, USA (Prof A S Levey MD)
26% of patients undergoing
elective PN had eGFR <60
c/w CKD
Lancet Oncol. 2006 September ; 7(9): 735–740.
Figure 3.
Probability of freedom from new onset of GFR lower than 45 mL/min per
1·72 m2, by operation type
Radical Nephrectomy for pT1a Renal Masses May be Associated With
Decreased Overall Survival Compared With Partial Nephrectomy
R. Houston Thompson,* Stephen A. Boorjian, Christine M. Lohse, Bradley C. Leibovich, Eugene D. Kwon, John C.
Cheville and Michael L. Blute
From the Departments of Urology (RHT, SAB, BCL, EDK, MLB), Health Sciences Research (CML) and Laboratory Medicine and Pathology (JCC),
Mayo Medical School and Mayo Clinic, Rochester, Minnesota
J Urol. 2008 February ; 179(2): 468-473
Partial Nephrectomy vs. Radical Nephrectomy in Patients With Small Renal
Tumors: Is There a Difference in Mortality and Cardiovascular Outcomes?
William C. Huang, M.D., Elena B. Elkin, Ph.D., Andrew S. Levey, M.D., Thomas L. Jang, M.D., and Paul Russo, M.D.
Department of Urology, New York University Medical Center, New York, New York, USA (W.C.H.); the Department of Epidemiology and Biostatistics
(E.B.E.) and the Department Surgery, Division of Urology (T.J., P.R.), Memorial Sloan-Kettering Cancer Center, New York, New York, USA; and the
Department of Medicine, Division of Nephrology, Tufts-New England Medical Center, Boston, Massachusetts, USA (A.S.L.)
J Urol. 2009 January ; 181(1): 55–62. doi:10.1016/j.juro.2008.09.017
MSKCC 2010/PARTIAL NEPHRECTOMY
 PN planned and attemped for all tumors <7cm, considered for >7cm if
technically feasible.
 Technique (lap & open) less important than safety achieving PN
 Active extension of limits of partial nephrectomy to routinely resect hilar
and endophytic tumors.
 Use of intra-operative ultrasound, Gil-Vernet maneuver, complex vascular
and collecting system repairs, mini-flank surgical incision, iced slush.
 Routine pre-op calculation of eGFR using the MDRD or CKD-epi equation.
 Judicious use of careful observation in patients that are elderly or have
significant pre-existing CVD or CKD
Care strategy in kidney cancer:
-Affecting the IVC
-Affecting the lymph nodes
Michael L Blute , Mayo Medical School and Mayo Clinic, Rochester, Minnesota
1. In 20 years, mortality from kidney cancer has doubled
2. 30% of kidney cancers are diagnosed locally advanced or M+
3. Managing caval thrombus:
Repeat imagery in pre-op immediately
No longer do arterial embolization (1)
Proposed pre-op classification
4. Managing adenopathies:
Definition of candidates at risk from being N+: criteria
Diagram of distribution of lymph nodes depending on the side:
- message 1: if we do curage, it must go from the pillars of the diaphragm to
the iliac bifurcation
- message 2: if there is an interaortocaval lymph node, it MUST be cured
contralaterally
Mayo clinic Register ( 2006)
Mayo clinic CSS for tumor thrombus level (n=650)
A contemporary case for LND as management for RCC
 Role of LND for RCC remains controversial
• No survival benefit noted in low-stage disease
• Potential benefit in patients with N+ disease and advanced disease
 Need for improved ability in predicting N+ disease
• Avoid over treatment
• Avoid complications associated with LND
Cancer-Specific Survival for 1,652 Patients according Lymph
Node Status for Clear Cell RCC
J Urol. 2004 August ; 172(2): 465-469
Who needs lymphadenectomy?
Blute, J urol 2004
 Reviewed 1652 radical nephrectomy cases for non-metastatic
ccRCC
 Determined features predictive of node positivity:
•
•
•
•
•
Nuclear grade 3 or 4
Sarcomatoid component
Tumor >10cm
Stage pT3 or pT4
Tumor necrosis
 If 0-1 features only 0.6% node positive
 If ≥2 features 10% node positive
 5 features 53% node positive
Recommendations
 Right tumors paracaval and interaortocaval
 Left tumors paraaortic (?interaortocaval)
 From crus of diaphragm to bifurcation of aorta
• Parker, An J anat 1935
 Clean out completely to assure resection and improve staging
Targeted therapies
H Van Poppel MD, PHD, University Hospital K.U. Leuven, Leuven
1. Targeted therapies: drugs currently available: 6
2. Adjuvant treatments: 3 tests in progress: ASSURE, SORCE, S-TRAC
3. Neo-adjuvant treatment:
a few small retrospective series
Need for randomized tests
4. Prospective studies planned:
phase II (Cleveland)
EORTC: phase II future: sunitinib + Nx vs NX + sunitinib
Targeted molecular therapies
 Sunitinib1, sorafenib2, temsirolimus3, bevacizumab4 in combination with
IFN-α, everolimus5 and pazopanib6 are approved for treatment of advanced
RCC
 Responses seen at the level of the primary tumour and systemic
metastases
 Improvement in time to progresion and overall survival
 Relatively favourable toxicity profile
 Interest in their use in the adjuvant/ neoadjuvant setting
1.
2.
3.
4.
5.
6.
Escudier B et al. N Engl J Med 2007
Motzer RJ et al. N Engl J Med 2007
Hudes G et al. N Engl J Med 2007
Escudier B et al. Lancet 2007
Motzer RJ et al. Lancet 2008
Limvoransak S et al. Expert Opin Pharmacother 2009
Adjuvant therapies in high-risk surgical resected RCC
3 ongoing randomisd double-blind phase III trials
 ASSURE
• Adjuvant Sorafenib or Sunitinib for unfavourable REnal cell carcinoma
 SORCE
• Comparing Sorefenib and placebo in patients with Resected primary renal CEll
carcinoma at high or intermediate risk of relapse
 S-TRAC
• Sunitinib and placebo Treatment of Renal Adjuvant Cancer
Note : Encouraging results with (non-toxic) vaccines
Adjuvant therapies in high-risk surgically resected RCC
Trail Name
Interventions
Arm A : oral sunitinib malate OD for 4wk – rest for
2 wk – Oral placebo for sorafenib BID for 6 wk
ASSURE
Arm B : oral sorafenib BID for 6 wk – placebo for
sunitinib malate OD for 4 wk – rest for 2 wk
Primary
Outcome
Disease free
Survival
Secondary
Outcome
Overall survival
Quality of life
Arm C : oral placebo as in arm A and as in arm B
Arm I : 3 yrs of oral placebo
SORCE
Arm II : 1 yr of oral sorafenib followed by 2 yrs of
oral placebo
Disease free
Arm III : 3 yrs of oral sorafenib
Survival
Patients in arm I and II with progressive disease
may cross over and receive treatment in arm III
S-TRAC
Arm A : oral sunitinib malate 50 mg for 1yr : 4 wk
on, 2 wk off
Arm B : oral placebo for 1 yr : 4 wk on, 2 wk off
Disease free
Survival
Metastasis-free
Survival
Disease-specific
Survival time
Overall survival
Cost effectiveness
Toxicity
Overall survival
Safety
Tolerability
Patient-reported
Outcomes
Neoadjuvant therapies in advanced RCC
 Opponents1
• No well-defined endpoints that determine the optimal time of surgery once neoadjuvant
therapy has started
• Impaired wound healing and perioperative bleeding or thromboembolic events
 Proponents2
• Neoadjuvant therapy could facilitate patient selection for nephrectomy (no response –
no nephrectomy)
• If response
Downstaging/downsizing of tumour may facilitate surgical debulking
1.
2.
Margulis V et al. Eur Urol 2008 ; 54 ; 489-92
Biswas S et al. The
Neoadjuvant therpies in advanced RCC
 In cases contraindicated for surgery
• Neoadjuvant (presurgical) treatment with TT
– Resulted in reduction of
> Primary tumour size1
> Tumour thrombus 1,2,3
> Bulky lymphadenopathy1
> Metastatic lesions1
• Reduced the surgical risks and facilitates surgery
1.
2.
3.
Shuch B et al. BJU int 2008
Karakiewicz PI et al. Eur Urol 2008
Robert G et al. Eur Urol 2009
Neoadjuvant sunitinib in advanced RCC
 Retrospective analysis (Cleveland Clinic)
• 19 patients with advanced RCC deemed unsuitable for surgery
– 12 with unresectable primary tumour
– 7 with large burden of metestatic disease
• 50 mg sunitinib daily for 4 wk on / 2 wk off
• Tumour responses assessed by RECIST every 2 cycles
Primary tumor
response
Secondary tumor
response
Partial response
3 (16%)
2 (11%)
Stable disease
7 (37%)
7 (37%)
Disease progression
9 (47%)
10 (53%)
Neoadjuvant sunitinib in advanced RCC
 Most common treatment-related toxicities :
• Fatigue (74%), dysgeusia (43%), diarrhea (31%) ans hand foot skin reaction
(32%)
 At median follow-up of 6 months :
• Shrinkage of primary tumour : 8 (42%)
• Average decrease in primary tumour size : 24%
Neoadjuvant sunitinib in advanced RCC
 Neoadjuvant sunitinib
• can lead to a reduction in tumour burden
• can facilitate subsequent nephrectomy
• no significant surgical morbidity : no issues with wound healing, bleeding or
thromboembolic events
 A larger, prospective phase II study of neoadjuvant sunitinib in patients
with RCC with unresectable primary tumours (with or without metastases)
is underway at the Cleveland Clinic
Thomas AA et all. J Urol 2009
Neoadjuvant Sorafenib in ≥ satge II RCC
 30 patients (17 M0, 13 M+)
 Median 32 days Sorafenib
 Median decrease primary tumour size 9.6%
 Median loss intratumoral enhancement (Choi) 13%
 RECIST : 26 SD, 2 PR, 0 PD
 No surgical complications
Safe and feasible
Cowey CL et al. JCO 2010
Neoadjuvant targeted drugs M+ or locally recurrent RCC
Early report from M.D. Anderson Cancer
 44 patients : preoperative bevacizumab, sorafenib or sunitinib before CN or
resection
 Bevacizuman discontinued at least 4 wks and sorafenib or sunitinib
discontinued up to 1 day before surgery
 Possible selection bias, small numbers of patients, heterogeneity in
preoperative therapy…
 Neoadjuvant therapy is safe with no increase in surgical morbidity or
perioperative complications
Margulis V et al. J Urol 2008
Rationale for CN in mRCC patients in the TKIs era
 2 questions :
• Is CN clinically beneficial in treatment of mRCC with TKIs ?
Carmina phase III trial
• If nephrectomy is necessary, which intervention should be performed first
(surgery or TKIs) ?
Phase III EORTC trial
• 440 pts with mRCC will be randomised to nephrectomy followed by
sunitinib or sunitinib followed by nephrectomy, with PFS as primary
endpoint
CARMINA trial
 Randomised, open label, phase II study evaluating the importance of
nephrectomy in mRCC patients treated with sunitinib
•
•
•
•
•
Estimated enrollment : 576
Arm A : nephrectomy followed by sunitinib
Arm B : sunitinib alone (50 mg/day – 4wks/2 wks rest)
Primary outcome : overall survival
Secondary outcome :
– Objective response (complete or partial) according to RECIST criteria
– Clinical benefit (complete response, partial or stable for at least 12 wks)
– Progession-free survival
• Start may 2009 – primary completion date : May 2015
Conclusions
 Targeted molecular agents are active at the level of the primary tumour and
of systemic metastases and have manageable adverse events
 Randomised trials are needed to further study the toxicity of targeted drugs
and identify the exact role of targeted drugs as neoadjuvant and adjuvant
therapy in both localized and advanced RCC
 Integration of surgery and systemic therapy requires the identification of
the optimal targeted drugs and optimal time of therapy, and the
development of reliable prognostic biomarkers
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