michele milella oncologia medica a istituto nazionale tumori regina elena roma n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma PowerPoint Presentation
Download Presentation
Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma

Loading in 2 Seconds...

play fullscreen
1 / 51

Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma - PowerPoint PPT Presentation


  • 97 Views
  • Uploaded on

Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma. Disclosures. I have very strong opinions on this talk’s topic and will try to force and bend available evidence to convince you that I’m right. …In the beginning was Motzer !. Poor risk (20%)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma' - yair


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
michele milella oncologia medica a istituto nazionale tumori regina elena roma
Michele Milella

Oncologia Medica A

Istituto Nazionale Tumori Regina Elena

Roma

disclosures
Disclosures

I havevery strong opinions on this talk’s topic and willtrytoforce and bendavailableevidenceto convince youthat I’m right.

in the beginning was motzer
…In the beginningwasMotzer!

Poorrisk (20%)

Median PFS: 2.5 mos

Median OS: 5 mos

1-yr OS: 20%

2-yr OS: 6%

3-yr OS: 2%

the ccf extension
The CCF extension

Poorrisk (28%)

Median OS: 7.3 mos

1-yr OS: 23%

what do we really know i mean high quality scientific evidence
What do weREALLYknow?(I mean: high-qualityscientificevidence…)
slide7

The Global ARCC Study:Trial Design

RANDOMIZE

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide8

Main Inclusion Criteria:Poor Prognostic Factors

Patients had at least 3 of 6 “poor prognostic factors” for shortened survival listed below:

  • Karnofsky performance status 60 or 70
  • Hemoglobin less than the lower limit of normal (LLN)
  • Less than 1 year from time of initial RCC diagnosis to randomization
  • Corrected serum calcium > 10 mg/dL
  • Lactate dehydrogenase > 1.5 times the upper limit of normal (ULN)
  • More than 1 metastatic organ site of disease (sites defined as different tissues with metastasis: lung, liver, bone, kidney, lymph node, etc.)

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide9

Baseline Characteristics /Subgroups (ITT Patient Population)

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide10

Baseline CharacteristicsPoor Prognostic Factors (ITT Population)

  • Treatment arms generally well balanced for prognostic factors

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide11

Primary EndpointMedian Overall Survival

Treatment with TORISEL was associated with a 49% increase in median OS compared with IFN-α

1.00

0.75

Probability of Survival

0.50

0.25

0.00

0

5

10

15

20

25

30

Time From Registration, Months

TORISEL (N=209)

TORISEL + IFN-α (N=207)

IFN-α (N=207)

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide12

Secondary Endpoints

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide13

Overall Survival

Across Patient Subgroups

Subgroup

No. of Patients

Hazard Ratio (95% CI)

Age <65 y 287 ≥65 y 129

Sex Male 287 Female 129

Karnofsky performance status ≤70 340 >70 75

Nephrectomy Yes 278 No 138

Histology Clear cell 339 Other 73

Diagnosis to randomization

<1 y 338 ≥1 y 78

Hemoglobin level <1 x LLN 340 ≥1 x LLN 76

LDH level ≤1.5 x ULN 315 >1.5 x ULN 84

Corrected serum calcium level

≤10 mg/mL 276 >10 mg/mL 126

Geographic area US 122 W EU, Canada, Australia 87 Asia-Pacific, E EU, Africa, S Amer 207

0.0 0.5 1.0 1.5 2.0

TORISEL Better

Interferon- Better

Hudes et al. N Engl J Med. 2007;356:2271-2281.

slide14

OS by Prognostic Factors (ITT Population)

1 Median Overall Survival in months

2 95% Confidence Interval

Hudes et al. N Engl J Med. 2007;356:2271-2281.

poor prognosis patients who are they
Poorprognosispatients:Who are they????

50 yr-old male

mRCC (synchronous)

Nefrectomized

Hb 13.8

LN and pulmonarynodules

KPS 100%

80 yr-oldfemale

mRCC (synchronous)

No nefrectomy

Hb 9.8

Corrected Ca++ 3.45

LN, lung, bone, pancreas

KPS 60%

Are they the same???

Wouldyoutreatthem the same???

but based on which data
…but, based on which data?

Sunitinib

ASCO 2008; abstr 16057

but based on which data1
…but, based on which data?

Bevacizumab/IFNa

AVOREN

CALGB

but based on which data2
…but, based on which data?

Sorafenib

Pazopanib

No data available

No data available

JCO 2009

Cancer 2011

AnnOncol 2011

JCO 2010

slide21

mTTP: 5.0 mos (3.5-6.5)

mOS: 9.3 mos (7.3-11.5)

slide22

Median OS (with 95% CI) for mRCC patients classified as poor-risk by classical MSKCC criteria upon treatment with selected targeted agents

Temsirolimus

Sunitinib

Bevacizumab/IFN

so sunitinib would be the only alternative but in which patients
So, Sunitinibwouldbe the ONLYalternative…but in whichpatients???

Poorriskbyclassical MSKCC criteria

Poorriskbybothcriteria

Poorriskbymodified MSKCC criteria

Intermediate riskbyclassical MSKCC criteria

validation of the idc model
Validation of the IDC model

Poorrisk(30%)

Median OS: 7.8 mos

cytoreductive surgery
Cytoreductive Surgery

SWOG 8949 n=246

EORTC Trial n=85

OS= 17 vs 7 months

OS=11 vs 8.1 months

IFN

Nephrectomy + IFN

Flanigan RC, NEJM 345:1655, 2001 Mickisch, Lancet 358:966, 2001

cytoreductive surgery1
Cytoreductive Surgery

31% decrease in risk of death with nephrectomy

  • Eligibility data: ECOG PS 0-1, clear cell histology, primary resectable
  • lack of CNS, liver or extensive bone metastases
  • Absolute benefit diminishes in poor risk groups
  • We don’t know what mechanism underlies the improvement in survival

Flanigan RC J Urol 171:1071, 2004

rcc consortium database n 314 37 poor risk by heng
RCC Consortium Database N= 314 (37% PoorRisk by Heng)
  • Pts treated with Sunitinib, Sorafenib, Bevacizumab
  • Retrospective data

Benefit of cytoreductive nephrectomy seems to be marginal in poor risk group

Choueiri TK, JUrol 185: 60-66, 2011

upfront nephrectomy in poor risk
UpfrontNephrectomy in PoorRisk?

PoorRisk

Poor Performance status

Unresectable

PrimayTumor

Upfront Systemic

Therapy

Upfront Therapy

Improvement in Overall

Patient Status

PoorRisk

Resectable

PrimayTumor

Nephrectomy??

slide43

Overall Survival by Histologic Subtype (ITT Population)

1 Median Overall Survival in months

2 95% Confidence Interval

Data on file, Wyeth Pharmaceuticals Inc.

tem vs ifn in ncc rcc
Tem vs IFN in ncc-RCC

Dutcher, Med Oncol 2009

tem vs ifn in ncc rcc1
Tem vs IFN in ncc-RCC

Dutcher, Med Oncol 2009

ldh levels are predictive of tem benefit over ifn in poor risk mrcc patients
LDH levels are predictive of Tem benefit over IFN in poorriskmRCCpatients

Low LDH

IFNa

High LDH

Tem

Armstrong, JCO 2012

still a peculiarity of mtor inhibitors
…still a peculiarity of mTOR inhibitors?

Modified from Heng, JCO 2009

conclusions
Conclusions
  • Temsirolimusis the most appropriate therapeuticchoice in the vastmajorityofpts w at least 3/6 poorriskfeatures(and, by the way, the onlyonesupportedbyevidence….)
  • In selectedpts w intermediate risk by strict MSKCC criteria, Sunitinibis a reasonablechoice
  • However, in a fraction of poorriskpts VEGF inhibitorsdramatically alter diseasenaturalhistory(…buthow do weidentifythem???)
  • Otherfactors, suchasnefrectomystatus, histology, LDHlevels, or the necessitytoobtainanobjectiveresponseshouldbetakeninto account
open questions
Open questions
  • How willnew prognosticclassifications impact on theseresults?
  • Isthere a life afterfirst-lineforpoorriskpatients?
  • Will weeverunderstand the biologybehindclinicalclassifications (ifthereisany…)?