Targeted therapies in renal cell carcinoma

Geriatric Oncology: Cancer in Senior Adults

Geriatric Oncology: Cancer in Senior Adults

Stéphane OUDARD,
OUDARD
Service de Cancérologie Médicale
Hôpital Georges Pompidou, Paris
Université René Descartes, Paris 5, France
 Introduction
• Renal cancer occurs mostly between age 62 and
67 in Europe (IARC 2007).

• Metastatic renal cancer is observed in 25% of these

patients and median age is slightly higher
higher.

• mRCC patients are often > 65 and 1/3 to ½ are >

70.
 Efficacy of targeted agents,
results
lt off randomized
d i d trials
ti l
Agent Nber Range of benefit Median age Patients > 70 years,
pts (∆ PFS results) (years) %

Sunitinib1 750 6 62 [[27-87]] NR

Sorafenib2 903 2.7 59 [19-86] 16

Bevacizumab 649 & 4.8 61 [30

[30-82]
82] NR
and IFN3,4 732 3.3 61 [56-70]
Temsirolimus5 626 2.4* 58 [32-81] NR
Everolimus6 410 2.1 61 [27-85] NR
Pazopanib7 435 5 59 [25-85] 35 (> 65y)

Not reported 1 Motzer RJ, et al. New Engl J Med 2007; 2 Escudier B, et al. New Engl J Med 2007;
3 Escudier B et al, Lancet 2007 ; 4 Rini B et al, J Clin Oncol 2008
5 Hudes G et al, New Engl J Med
6 Motzer B et al, Lancet 2008
7 Sternberg C et al, J Clin Oncol 2010
Prospective clinical trials : inclusion 
of older patients?
• P
Patients
ti t older
ld ththan 70 representt onlyl a
limited subgroup in Phase III trials.
I f
Information
ti on these
th patients
ti t iis lilimited.
it d

• Subgroup analyses as well as results of

compassionate programs seem to indicate
th same range off efficacy
the ffi in
i elderly
ld l andd
younger patients1
Stadler Cancer 2010, Gore Lancet 2009,
Eisen T et al, JNCI 2008, vol 100:1454-63
Efficacy of different targeted therapies based on the
pivotal trials in metastatic renal cell carcinoma of ≥
65
65-year-old
ld patients
ti t
<65 years sunitinib
>65 years sunitinib
<65 years sorafenib
>65 years sorafenib

<65 years bevacizumab + IFN

>65 years bevacizumab + IFN

<65 years temsirolimus

>65 years temsirolimus
<65 years everolimus
>65 years everolimus

<65 years pazopanib

>65 years pazopanib

0.1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Targeted therapy better Alternative therapy better

 Analysis of sorafenib in older population
f
from the
th TARGET trial
ti l
Retrospective analysis from
TARGET trial
Safety and efficacy of
sorafenib
N= 115 > 70 years old vs 787
younger pts < 70
PFS : 26.3
26 3 weeks older pts vs
23.9 younger pts
Clinical benefit = 84.3 % vs
83.5%
Maintenance of health status
PS: 121 d vs 85 daysy
Eisen T et al, JNCI 2008, vol 100:1454-63
 Analysis of sorafenib in older population
from the TARGET trial
Time to self-reported health status deterioration (FACT–G PWB)*
1 00
1.00 1 00
1.00
Patients > 70 years Patients < 70 years
al distribution function

al distribution function
0.75 0.75

0.50 0.50
Surviva

Surviva
0.25 0.25

0 0
0 100 200 300 400 0 100 200 300 400 500
Time (days) Time (days)

Sorafenib Placebo Eisen T Censored

et al,, JNCI data
2008,, vol 100:1454-63

*Physical Well-Being domain of the

Functional Assessment of Cancer Therapy–General Eisen T et al, JNCI 2008, vol 100:1454-63
 Toxic effects of targeted agents in older
patients
ti t according
di to t subgroup
b analyses:
l

• Sunitinib
S iti ib : more frequent
f t fatigue
f ti
• Beva/IFN : more grade ¾ events (66 vs 58%)
• Sorafenib : no difference in trial
Fatigue and cutaneous symptoms more
frequent in Access program
• Temsirolimus :
No major differences
• Everolimus :
But !
Most comorbidities were exclusion criteria in
controlled trials.
Toxicity in older patients may be underestimated
Which toxicities are you waiting for in the
era of antiangiogenic drugs?

Bellmunt J et al, Critical Rev Oncol Hematol 2009 vol 69:64-72

 Main toxicities of antiangiogenic therapies that 
represent risks for older patients
ik f ld i

• # 1 cardio-vascular effects +++

- Hypertension
- Edema with a certain degree of water
retention
- Arterial thrombosis (heart infarct)
- Venous thrombo-embolism
thrombo embolism
- Cardiac failure
- Cardiac rhythm troubles
troubles.
 Main toxicities of antiangiogenic therapies that 
represent risks for older patients
ik f ld i

• # 2 renal effects +++

- Renal insuffisiency
- Hypertension
- Glomerular thrombotic microangiopathy
- Anemia ((decrease secretion EPO))

Launay Vacher V et al, Anti-Cancer Drugs 2009, 20:81–82

 Main toxicities of antiangiogenic therapies that 
represent risks for older patients
ik f ld i
• # 3 Digestive symptoms:
- Nausea-vomiting
- M
Mucositis
iti Decreased food intake
- Diarrhea

# 4 General symptoms:
- Fatigue
Decreased mobility
- Hand and foot syndrome
Main toxicities of antiangiogenic therapies that 
represent risks for older patients
ik f ld i

• # 5 Biologic disturbances:

- Hyperglycemia
- Hypercholesterolemia
yp
- Anemia
- Neutropenia
- Thrombopenia
- Hypothyroidism
Factors to consider in the ederly mRCC
population

Bellmunt J et al, Critical Rev Oncol Hematol 2009 vol 69:64-72

Absorption and Metabolism change in the
elderly population
Physiological Changes from Aging: Consequence on Drug Absorption:
Decreased gastric motility May lead to slower absorption 
Decreased secretions and delayed onset of effect
Decreased absorptive surface

Ph i l i l Ch
Physiological Changes from Aging:
f A i Consequence on Drug Metabolism:
Consequence on Drug Metabolism:

Decreased Liver Size (Between 18‐44%) Antiangiogenic drugs  that undergo 

“Ph
“Phase 1 
1
Decreased Hepatic  Blood Flow
Metabolism” will result in higher 
concentrations from decreased
metabolism
 How can we manage potential risks in the
geriatric
i t i population?
l ti ?
 Geriatric appraisal
pp
 To help making a decision on whether to
treat cancer in ederly patients
• Geriatric assessment scores based on:
- Functionality (self ability)
- Cognitive status and mood
- Social situation (familial help?)
- C
Comorbidities
biditi and d th
their
i ttreatments.
t t
 To help making a decision on whether to treat 
cancer in elderly patients
i ld l i
• Geriatric algorithm
g ((Balducci-Extermann))
3 categories

Healthy Frail Too sick

al ate life
Evaluate
E Limited
Treat as usual expectancy without interventions,
cancer versus with supportive
treated cancer (onco- care
geriatric assessment)
 Survival probability correlates with individual 
h lh
health status

Independent

Vulnerable
Survival ratio

Higher vulnerability and

frailty are associated with
Fragile
g increased risk of death

Independent
Incontinent
Vulnerable*
Frail** 5 years

Survival (months)

Rockwood K et al. Lancet 1999, 353, 205-206

 Incidence of comorbidities in « frail »
elderly patients (>70) in France (2006)
Type of comorbity %
Cardiovascular
Cardiac failure 29
Coronaropathy 22
Hypertension 47
Cardiac rhythm 23
Thrombo-embolism
Thrombo embolism 15
Digestive system 18
Denutrition 10
Osteoarticular syndrome with impact on mobility 43
Metabolic disturbances
Diabetes 12
Dehydration 9
Thyroid disease 9
Toxic effects of treatments targeted therapies
for mRCC in patients with comorbidities

Type of comorbity Treatment Toxicity

Cardiovascular HTA ….
HTA,
Digestive system Digestive symptoms
Denutrition Weight
g loss
Osteoarticular with mobility impact Hand and foot Syndome, fatigue
Metabolic disturbances hypothyroidism
Renal insufficiency MAT, proteinuria
Diabetes Normalization of glycemia (SU)1

1Billemont B and Medioni J et al, Br J Cancer. 2008 Nov 4;99(9):1380-2

 Example from our institution regarding
older
ld patients
ti t treated
t t d withith TKI
• Clinical Case of a women, 78 years old
Kidney cancer, lung metastasis
HTA, well controlled with 3 medications
Sunitinib given at 37
37.5
5 mg 4w/6
• After 1 cycle,
y , PRES syndome
y
with coma, ocular vision
disturbance, epilepsia and HTA
- sunitinib
iti ib stop
t
- complete recovery in 7 days
g HTA especially
- need to manage p y in
ederly population
Medioni J et al, Targeted Oncol 2007
 Example from our institution regarding
older patients treated with TKI
• Clinical Case of a man, 70 years old
L ft nephrectomy,
Left h t clear
l cellll carcinoma,
i F gr 4
residual GFR = 41 ml/min
lung metastasis
Bevacizumab (B) & IFN
• After
Aft second d iinjection
j ti (B) HTA
HTA,
nephrotic syndrom,
haemolytic-uraemic syndrome
- B stop
- biopsy: glomerular thrombotic microangiopathy
- Response: normalization blood pressure, return to
renal function to previous baseline levels
Frangie C et al. Lancet Oncol 2007, 8:177-78
 If an elderly patient appears to be a
candidate for targeted therapies
• Consider situations at risk:
- Comorbidities >2 = risk ++
- yp
Polypharmacy y >3 = risk ++
- Familial status (alone or with an elderly spouse)

 Think that these risks have potential synergistic

effects:
comorbidities x polypharmacy x familial status =

Very high risk of complications !

 Adjusting targeted therapies in elderly
patients
ti t means

• Estimate the risk of complications

• Reinforce information to general practitioner
and
d family
f il
• Close management with frequent visits & calls

 Hold or decrease treatment doses before

occurrence off severe toxicities
t i iti !!!!