ASCO GU 2010ASCO GU 2010

San Francisco - 4-7 March 20100

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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

Single study

Negative study

Europe: ERSPC • NEJM 360, 1320-1328, 2009

Several pooled studies

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?

Reduced mortality

Over-detection / elective treatment

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.

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.

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

Prevention Advantages / Disadvantages

Methods

Potential increase of the risk

Red / fatty meat

Dairy / Calcium

Smoking

Overweight / Obese

Potential reduction of the risk

Fruit and vegetables

Specific nutriments

• Vitamin E

• Selenium

• Carotenoids

• Antioxidants

Fish, omega 3

Regular physical activity

Prevention and life style

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

Polymorphism of the androgen receiver gene (CGA repeated sequence) = YES ...in the future

Cut-off

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

threshold, density, velocity

Now

Modeling the risk

Nomograms

Calculator

Future

Predicting the risk

individually

PSA aged 40

Genotyping

Risk of

prostate cancer

Biopsy

Chemo-prevention

± Biopsy

Biopsy

Significant risk of prostate cancer

Significant risk of prostate cancer

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 categoriesD’amico risk group

PSA > 20 orGleason 8 – 10 orT2c

Easy to use/Inaccurate

Probability tablesPartin Tables

PSA, Stage, Biopsy, Gleason Immediate/Relevance

Risk scoresUCSF – CAPRA

Add age, number of positive biopsies Score from1-10 /Not very practical

NomogramKattan

Continuous and categorized data Individualized:Requires a computer

High Risk: a minority of cancers

27,5%32,1%

46,4% 48,0% 45,8%

26,5%25,0%

23,7%27,4% 29,1%

46,0% 42,9%

29,9%24,6% 25,1%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1990 - 1994 1995-1999 2000-2001 2002-2003 2004-2006

Haut risque

Risque intermédaire

Bas risque

High risk

Intermediate risk

Low risk

High Risk: the majority of deaths

Albertsen, JAMA 2005

No treatment for Gleason ≤ 6

S Spe at 20 years old 70-95%

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

Efstahione et al. Eur. Urol Dio: 10.1016 / J. Euro. Uroi. 2009, 10.020

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.

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)

Prostate cancer resistant to

castration (CPRC).

New issues in an old concept.

Intra-tumor

production / conversion

of androgen

Amplification /

Resistance of the AR

Persistence of

serous androgens

CPRC

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 capsulesPost – chemotherapy without prednisone

Pre vs Post docetaxel

Surrenal deficiencyPost – Chemotherapy with prednisone

Corticosteroids necessary

Associating biology and therapy throughout the path leading to AR

Biological event Therapeutic actions Drugs

Production of androgensSCC inhibitorCYP17 inhibitor

KetoconazoleAbirateroneTak 700Tok 001

Circulation / transport of androgens

Blocking transport HE – 3235

Conversion into DHTSAR inhibitorSulphatase inhibitor

DutasterideBN - 83495 sulphatase

Connection to the AR New AR inhibitorsMDV 3100ARN – 509Tok 001 ?

A new landscape for developing systemic therapies in prostate cancer

Multiple (and varied) standards around which the new products must be developed.

A fortunate set of problems.

Clinically Localised Disease

IncreasePSA

MetastasesClinicalCannot be castrated

1Rising PSA:Castration

2CastrationMetastasesAbiraterone

3CastrationMetastases

1st LineDocetaxelStandard

4CastrationMetastases

Post-Cabazitaxel

Abiraterone?MDV 3100

Prostate cancer: New paths non targeted AR (Vm K. Kelly)

Non targeted AR treatments (FDA) (CPCR)

Molecule Indication

Docétaxel 1st line

Mitoxanhrone 2nd line

Estramustine CPCR

Acide Zolendronique CPCR

Strontium89Painful osseous

metastasis

Samarium153Painful osseous

metastasis

Non targeted AR treatments in phase III (CPCR)

Promotor Treatment

Novacea D ± DN101

SWOG D ± atrasentan

CALGB D ± bevacizumab

sanofi-aventis D ± afilbercept

NCI D or KAVEDoxo ± strontium89

Cell Genesys D vs GVAX

Cell Genesys D ± GVAX

Zeneca D ± ZD4054

Bristol D ± dasatinib

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

VEGF

PSMA

IGF-1

EMMPRIN/CD147

MMPs

Androgens

Integrins

Angiopoietines

uPA

FGF-2

TGF-β

PD-ECGF

COX-2

IL-8

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 555% PSA response36% Stable at 12 weeks

Sorafenib Dahut II 22Osseous meta improvement: 2 patients10/19 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

Cytoxics

Immunotherapy

Targeted radio-pharmaceuticals

?

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

% Open

% MIRP

1.5% in 20028.7% in 2005

SurgeryIncrease in the proportion ofMinimally invasive radical prostatectomy (MIRP)

RadiotherapyIncrease in the proportion ofIntensity-Modulated Radiotherapy (IMRT)

% 3D-CRT

% IMRT

28.7% in 200281.7% 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 histologyHR = Hazard ratio; SCC = squamous cell cancerAca = 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 therapyFactors 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 therapy2 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 cystectomiesin selected contemporary series (2000 – 20009)

Extension of lymph node curage

Roth et al Eur. UroL; 57:205; 2010

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 T3Bruins J Urol 2009

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: no lymph node curage

SEER 17: 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, T4Radical

cystectomy

Rando

Standard curage Int/ext iliacObturator

Extended curageStandard + 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

Granular RC

Papillary / tubulopapillary RC

Sarcommatoid RC

Clear cell RC (conventional)

Chromophobe RC

Renal Oncocytoma

Chromophobe RC

Clear cell RC (conventional)

Papillary RC

Collecting tubule carcinoma

Epithelioid angiomyolipoma

Papillary RC

Collecting tubule carcinoma

Carcinoma via Xp11 translocation

Tubular Mucineux and spindle cell

Clear cell RC (conventional)

Chromophobe RC

Papillary 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 Chromophobe RC Oncocytoma

Vimentin Diffuse Cytoplasmic Absent * Absent * Absent

CAIX Diffuse MembranousCytoplasmic

Focal cytoplasmicNecrosis tips

Focal cytoplasmic(rare)

Absent

CD10 Diffuse MembranousCytoplasmic

Apical membranousFocal 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

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 anti-body  

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

of the pRC grow at negligible speed,

even if the RC is confirmed by biopsy.

Surveillance with delayed treatment

seems to be a reasonable option for

selected patients.

The rate of delayed treatment for tumor

progression must be determined with

prolonged monitoring.

2 pRC have undergone metastasis,

suggesting that size is just one of the

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"  

Targeted resection Sparing the nephrons

Potentially malign

Moderate risk RiskNull /minimal

Ablation Active Surveillance

Molecular Imagery Biopsy

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 TumorsR. 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 studyWilliam 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)

Figure 3.

Probability of freedom from new onset of GFR lower than 45 mL/min per 1·72 m2, by operation type

26% of patients undergoing elective PN had eGFR <60 c/w CKD

Lancet Oncol. 2006 September ; 7(9): 735–740.

Radical Nephrectomy for pT1a Renal Masses May be Associated With Decreased Overall Survival Compared With Partial NephrectomyR. Houston Thompson,* Stephen A. Boorjian, Christine M. Lohse, Bradley C. Leibovich, Eugene D. Kwon, John C. Cheville and Michael L. BluteFrom 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. Escudier B et al. N Engl J Med 20072. Motzer RJ et al. N Engl J Med 20073. Hudes G et al. N Engl J Med 20074. Escudier B et al. Lancet 20075. Motzer RJ et al. Lancet 20086. 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 InterventionsPrimary

OutcomeSecondary Outcome

ASSURE

Arm A : oral sunitinib malate OD for 4wk – rest for 2 wk – Oral placebo for sorafenib BID for 6 wk

Arm B : oral sorafenib BID for 6 wk – placebo for sunitinib malate OD for 4 wk – rest for 2 wk

Arm C : oral placebo as in arm A and as in arm B

Disease free

Survival

Overall survival

Quality of life

SORCE

Arm I : 3 yrs of oral placebo

Arm II : 1 yr of oral sorafenib followed by 2 yrs of oral placebo

Arm III : 3 yrs of oral sorafenib

Patients in arm I and II with progressive disease may cross over and receive treatment in arm III

Disease free

Survival

Metastasis-freeSurvivalDisease-specificSurvival timeOverall survivalCost effectiveness

Toxicity

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

Overall survivalSafetyTolerabilityPatient-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. Margulis V et al. Eur Urol 2008 ; 54 ; 489-922. 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. Shuch B et al. BJU int 20082. Karakiewicz PI et al. Eur Urol 20083. 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

Special thanks from Ipsen to our reporters!

F. Bladou

O. Chapet

J-M Cosset

S. Culine

J-L Davin

R. De Crevoisier

J-L Descotes

J-C Eymard

O. Haillot

G. Kouri

P. Lande

I. Latorzeff

P. Mongiat Artus

G. Pasticier

C. Pfister

V. Ravery

X. Rebillard

P. Richaud

J. Rigaud

M. Soulie

M. Zerbib