kinase inhibitors in localized and metastatic kidney cancers ...kinase inhibitors in localized and...
TRANSCRIPT
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Kinase inhibitors in localized and metastatic kidney cancers inmetastatic kidney cancers in
senior adult patientssenior adult patients.Jean-Pierre Droz, MD, PhD, ,
Professor of Medical Oncology, Claude-Bernard Lyon 1 University Geriatric Oncology Program
PROLOG program of the French National Cancer Institute Centre Léon-Bérard, Lyon, France
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Three major pathological subgroupsThree major pathological subgroups.
Clear cell Papillary Chromophobe cell
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VEGF receptor blockade.
VEGFBevacizumab
VEGF
VEGFR-2
Vascular endothelial cellplasma membrane
PI3K RafP PSorafenib
AxitinibSorafenib
Akt/PKB MEKP PVascular permeability
SorafenibSunitinib
p38MAPKErkEndothelial cell
survival
Endothelial cell
Temsirolimus
Rini B, et al. J Clin Oncl. 2005;23:1028-1043.
Endothelial cell migration
Endothelial cell proliferation
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0.80.91.0
0 50.60.70.8
0 20.30.40.5
Sunitinib (n=375)M di t h d
00.10.2 Median not reached
IFN-α (N=375)Median not reached
Hazard Ratio = 0.65(95% CI: 0.449–0.942)P = 0.0219*
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Durée (Mois)
Overall survival= S(ASCO 2008)
Progression-freeSurvival= SSurvival= S
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Hypertension 24%/8%
Hand /foot syndrom 20%/5% Trials’inclusion criteriaNausea /vomiting 44%/3%Diarrhea 53%/5%
Rash 19%/1%
Trials inclusion criteriaand toxicities.
Anemia 71%/3%
Leucopenia /neutro 78%/5%
Thrombocytopenia 65%/8%Median age 62 years (27-87)
y p
Asthenia 51%/7%
Pain 11%/1%
Anorexia NR
Age > 70 years ?
Perform. status ≥ 80 (100= 62%)Anorexia NR
Hyperglycemia NR
Lipids /lipase 30-40%/1%
Edema NR
Creatinine clear. + ???
Cardiac comorb. significant < 1y?Edema NR
Creatinine increase 66%/1%
Weight loss NR
Hypertension controlled
Haematological +Stomatitis 25%/1%
Liver toxicity # 50%/2%
Cardiac toxicity 10%/2% (EVF)
Liver +
Lipids Proteinuria NR
Thrombosis NR
Perforation NR
Coagulation +
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NEJM 2007;356:125-134
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O ll i l NSOverall survival= NS
Progression-free Survival= S
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Hypertension 17%/4%
Hand /foot syndrom 30%/1%
Trials’inclusion criteriaNausea /vomiting 20%/0%Diarrhea 43%/2%
Rash 40%/1%
Trials’inclusion criteriaand toxicities.
Anemia 34%/3%
Leucopenia /neutro NR
Thrombocytopenia NR
Median age 58 years (19-86)
Age > 70 years ?y p
Asthenia 35%/5%
Pain 10%/0%
Anorexia NR
Perform. status ≥ 60 (100= 49%)
Creatinine clear. ?
Anorexia NR
Hyperglycemia NR
Lipids /lipase 12%/7%
Edema NR
Cardiac comorb. ?
Hypertension ?Edema NRCreatinine increase NR
Weight loss 10%/0%
yp
Haematological +Liver +Stomatitis NR
Liver toxicity NR
Cardiac toxicity 1 pt
Liver +Lipids ?
Proteinuria NR
Thrombosis 1 pt
Perforation NR
Coagulation +
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Overall and Progression-free survivalsare significantly improved.
Temsirolimus > combination > IFN.
Overall survival= S
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Hypertension NR
Hand /foot syndrom NR
Nausea /vomiting 37%/2% Trials’inclusion criteriagDiarrhea 27% /1%
Rash 47%/4%
Anemia 45%/20%
Trials inclusion criteriaand toxicities.
Median age 59 years (23-86)
A > 70 30% (> 65 )
Anemia 45%/20%
Leucopenia /neutro 6%/1%
Thrombocytopenia 14%/1%
A th i 51%/11 % Age > 70 years 30% (> 65 y)
Perform. status ≥ 60
Asthenia 51%/11 %
Pain 28%/5%
Anorexia 32%/3%
Creatinine clear. # ≥ 60 (< 80= 82%)
Cardiac comorb. ?
Hyperglycemia 26%/11%
Lipids /lipase 24%/1%
Edema 27%/2%
Hypertension ?
Haematological +
Creatinine increase 14%/3%
Weight loss 19%/1%
Stomatitis NR
Liver +
Lipids +
Liver toxicity NR
Cardiac toxicity NR
Proteinuria NR
Coagulation Proteinuria NR
Thrombosis NR
Perforation NR
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Overall survival= NSOverall survival= NS
Progression-freeSurvival= SSurvival S
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Hypertension 26%/3%
Hand /foot syndrom NR Trials’inclusion criteriaNausea /vomiting NRDiarrhea 20%/2%
Rash NR
and toxicities.
Anemia NRLeucopenia /neutro 7%/4%
Thrombocytopenia 6%/2% bleeding 33% Median age 61 years (18-81)y p g
Asthenia 33%/12%
Pain NRAnorexia NR
Age > 70 years +
Perform. status ≥ 70(70-80= 23%)
Creatinine clear. +??Anorexia NRHyperglycemia NRLipids /lipase NREdema NR
Cardiac comorb. ?
Edema NRCreatinine increase NRWeight loss NR
Hypertension Not controlled
Haematological +Stomatitis NR
Liver toxicity NR
Cardiac toxicity 1 pt
Liver +Lipids
Proteinuria 18%/7%
Thrombosis 3%/2%
Perforation 5 (1%)
Coagulation +
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Summary: standard management.y g
MSKCC Treatment optionsgroups
First- line Second- line
Standard Option Standard Option
favorable Sunitinib Beva+IFNIL2 ?IL2 ?
Sorafenib SunitinibT i
Intermediate-i k
Sunitinib Beva+IFN Temsiro-limus ?
riskPoor- risk Temsiro- Sunitinib
limus
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Major treatment limits in elderlyMajor treatment limits in elderly.Sunitinib Sorafenib Temsirolimus Bevacizumab
Median age 62 years (27-87) 58 years (19-86) 59 years (23-86) 61 years (18-81)Age > 70 years ? ? 30% (> 65 y) +Perform. status ≥ 80 (100= 62%) ≥ 60 (100= 49%) ≥ 60 ≥ 70(70-80= 23%)Creatinine clear. + ??? # ≥ 60 (< 80= 82%) +??
Cardiac comorb. significant < 1y? ? ?
Hypertension t ll d ? t ll dHypertension controlled ? controlled
Haematological + + + +Liver + + + +Lipids +Coagulation + + +
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Comparative side effects (1)Comparative side effects (1).Sunitinib Sorafenib Temsirolimus Bevacizumab
Hypertension 24%/8% 17%/4% NR 26%/3%
Hand /foot syndrom 20%/5% 30%/1% NR NRNausea /vomiting 44%/3% 20%/0% 37%/2% NRDiarrhea 53%/5% 43%/2% 27% /1% 20%/2%Diarrhea 53%/5% 43%/2% 27% /1% 20%/2%
Rash 19%/1% 40%/1% 47%/4% NRAnemia 71%/3% 34%/3% 45%/20% NRLeucopenia /neutro 78%/5% NR 6%/1% 7%/4%
Thrombocytopenia 65%/8% NR 14%/1% 6%/2% bleeding33%
Asthenia 51%/7% 35%/5% 51%/11 % 33%/12%
Pain 11%/1% 10%/0% 28%/5% NR
= very frequent = frequent
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Comparative side effects (2).Sunitinib Sorafenib Temsirolimus Bevacizumab
p ( )
Anorexia NR NR 32%/3% NR
H l i NR NR 26%/11% NRHyperglycemia NR NR 26%/11% NR
Lipids /lipase 30-40%/1% 12%/7% 24%/1% NR
Edema NR NR 27%/2% NR
Creatinine increase 66%/1% NR 14%/3% NR
Weight loss NR 10%/0% 19%/1% NRStomatitis 25%/1% NR NR NRLiver toxicity # 50%/2% NR NR NRCardiac toxicity 10%/2% (EVF) 1 pt NR 1 ptProteinuria NR NR NR 18%/7%Proteinuria NR NR NR 18%/7%Thrombosis NR 1 pt NR 3%/2%Perforation NR NR NR 5 (1%)
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Conclusions: difficult to treat elderly!!Conclusions: difficult to treat elderly!!• Few patients included in trials; no specificFew patients included in trials; no specific
reports in elderly.• Inclusion criteria do not allow to include elderly• Inclusion criteria do not allow to include elderly
patients: what behind?M i i i hi h i i ld l• Many toxicities which are important in elderly: HTA, CxVx, anorexia, fatigue /asthenia, hand /foot syndrom, anemia, neutropenia, renal toxicity.
• The need for retrospective /prospective cohort studies.studies.