Toxicities and outcome in elderly

patients treated with targeted

therapies for metastatic renal

cell carcinoma

François-Xavier Nouhaud, Christian Pfister, Claire

Lenormand, Frédéric Di Fiore, Olivier RigalRouen University Hospital, Normandy, France

Antenne

d’Onco-Gériatrie Haute-Normandie

• None

Disclosures

Renal carcinoma

• Favourable overall prognosis

• Recurence: 20-40 %

Context• 2-3% of all new cancer cases

• 14th most common worldwide

• Renal Cell Carcinoma : 75-90%

• 20-30% initially metastatic

• Target therapies

– Since 2005

– Median overall survival : 24 months

Overall prognosis

• 1-year survival = 80%

• 5-year survival = 65%

Metastatic renal carcinomaLocalized renal carcinoma

Background (I)

Temsirolimus

Everolimus

Pazopanib

Axitinib

Sorafenib

Sunitinib

Bevacizumab

VEGF therapy

TKI & Anti

VEGF therapy

mTOR

inhibitors

L3?L3?

L2?L2?L1?L1?

Escudier et al, Cancer 2009

Background (III)

• Older patients and mRCC

• In randomized trials (pooled analysis)

• Patients ≥ 70 years were underrepresented

� Less than 20% of included patients

� In contrast, 50% of diagnosis occured in patients > 65 years

• Patients have been carefuly selectionned

� ECOG 0-1

� Adequate renal, hepaticet cardiac function

• No evidence for difference in outcome between younger

and older patients

Background (IV)

Hutson et al, Br J Cancer 2014

Toxicities all grades <70 yrs ≥ 70 yrs p

Fatigue 60 69 0.01

Cough 20 29 0.005

Peripheral edema 17 27 0.001

Weight decresed 16 24 0.005

Appetite decreased 13 29 <0.0001

Anemia 18 25 0.01

Thrombopenia 16 25 0.003

Background (IV)

• Older patients and mRCC

• In randomized trials (pooled analysis)

• Some TKI-induced toxicities were more frequent

Hutson et al, Br J Cancer 2014

+15% of severe

TKI-induced toxicities

Older vs young

mRCC patients

Derbel Miled et al, J Geriatr Oncol 2013

Brunello et al, Ann Oncol 2012

De Giorgi et al, Clin Genitourin Cancer 2014

Background (IV)

• Older patients and mRCC

• A few retrospective « real-life » analysis

• Sample size varies from 30 to 200 pts

• Some issues are yet not clearly established in non-selected

older patients

�The rates of severe TKI-induced toxicities?

�The rates of dose interruptions/modifications?

�The impact of baseline co-factors?

�If there is any difference with younger patients?

Aim

The aim the study was to assess the characteristics

and the outcome of patients ≥ 70 years treated withtargeted therapies for a mRCC

• Retrospective single center study conducted from

January 2006 to June 2012

• All consecutive patients treated with a first-line TT for a

mRCC

• Data were analysed according two groups of patients

� ≥ or < 70 years

• Patient characteristics at treatment initiation as well as

progression-free survival (PFS) and overall survival (OS)

were collected

Patients and methods

• Analysis of toxicities with the Common Terminology

Criteria for Adverse Events (v3.0) and categorized in

grade III-IV versus I-II

• Exploratory univariate and multivariate analysis

including main baseline factors (sex, age, ECOG, hb,

plat, neutrophil, albumin, renal function, ca+, LDH, type

of treatment, time since diagnosis) in order to identify

parameters associated:• with PFS (Cox proportional hazard model)

• with severe toxicities (logistic regression)

Patients and methods

Results

• Patients characteristics (I)

Results

< 70 years

N=69

≥ 70 years

N=33

p

Age (mean, SD) 56,2 +/- 8,2 75,1 +/- 4 <0.001

Age > 75 years - 39% -

Clear cell histology

ECOG ≤ 1

Previous nephrectomy

Time < 1 year since diagnosis

Charlson score (mean, SD)

First-line therapy

Sunitinib

Sorafenib

mTOR inhibitor

• Patients characteristics (I)

Results

< 70 years

N=69

≥ 70 years

N=33

p

Age (mean, SD) 56,2 +/- 8,2 75,1 +/- 4 <0.001

Age > 75 years - 39% -

Clear cell histology 88% 82% 0.37

ECOG ≤ 1 36% 27% 0.37

Previous nephrectomy 90% 91% 0.99

Time < 1 year since diagnosis 68% 52% 0.10

Charlson score (mean, SD) 6,74 ± 1,1 7,11 ± 1 0.14

First-line therapy

Sunitinib

Sorafenib

mTOR inhibitor

58%

28%

14%

82%

15%

3%

0.065

• Patients characteristics (II)

Results

< 70 years

N=69

≥ 70 years

N=33

p

Hemoglobin level < UNL 38% 24% 0.18

Platelet count < UNL 17% 3% 0.06

Neutrophil count > UNL 25% 9% 0.11

Albumin level < UNL 41% 36% 0.68

Calcium level > UNL 4% 3% 0.99

Renal function < 60 ml/min 30% 64% 0.0024

MSKCC prognostic score

Good

Intermediate

Poor

19%

51%

30%

33%

52%

15%

0.13

• TKI-induced toxicities

Results

< 70 ans

N=69

≥ 70 ans

N=33

p

Overall toxicity (grades I-IV) 89% 96% 0.20

Severe toxicity (grades III-IV)

Dose reduction

Discontinuation for toxicity

• TKI-induced toxicities

Results

< 70 ans

N=69

≥ 70 ans

N=33

p

Overall toxicity (grades I-IV) 89% 96% 0.20

Severe toxicity (grades III-IV) 41% 73% 0.02

Dose reduction 51% 79% 0.006

Discontinuation for toxicity 21% 50% 0.004

• TKI-induced toxicities

� Renal function was the only factor associated with severe TKI-induced toxicities

� ECOG, age, hb, platelet, neutrophil, albumin, delay since diag. < 0.05 in univ. analysis

Results

< 70 ans

N=69

≥ 70 ans

N=33

p

Overall toxicity (grades I-IV) 89% 96% 0.20

Severe toxicity (grades III-IV) 41% 73% 0.02

Dose reduction 51% 79% 0.006

Discontinuation for toxicity 21% 50% 0.004

OR 95IC p

Renal function < 60 ml/min 5.5 1.70-17.38 0.003

Time (months)

Su

rviv

al ra

te (

%)

0 20 40 60 800

50

100

Time (months)0 20 40 60 80

0

50

100

Results

• Progression-free and overall survival

PFS OS

Median 11 vs 6 months,

p=0.02

Median 30 vs 18 months,

p=0.15

≥70 years<70 years

≥70 years<70 years

Time (months)

Su

rviv

al ra

te (

%)

0 20 40 60 800

50

100

Time (months)0 20 40 60 80

0

50

100

Results

• Progression-free and overall survival

� No factors were identified in multivariate analysis � ECOG, age, hb, platelet, neutrophil, albumin, renal function, time since diagnosis < 0.05 in

univariate analysis

PFS OS

Median 11 vs 6 months,

p=0.02

Median 30 vs 18 months,

p=0.15

≥70 years<70 years

≥70 years<70 years

Conclusions

• In the present retrospective study comparing

older to younger patients treated for a mRCC :

• There was no statistical difference in overall baseline

characteristics

• However, we observed a trend for a higher

proportion of better prognosis parameters in older

patients at presentation

• Poor MSKCC score in 15% vs 30% in younger

• With, in consequence, a trend for better survival

Conclusions

• Impact of prognostic score in older patients

Presentstudy

Hutson et al. BJC 2014

De Giorgi et al.Clin Gen Cancer 2014

Derbel et al.J Geriatr Oncol 2013

Khambati et al.Clin Gen Cancer 2014

Design Retrosp. Prosp.

Pool analysis

Retrosp. Retrosp. Retrosp.

Nb older patients 33 202 185 48 144

Heng/MSKCC score

Good

Intermediate

Poor

33%

52%

15%

37%

44%

4%

24%

59%

18%

23%

43%

33%

4%

69%

27%

Survival

PFS

OS

11 m

30 m

11 m

25 m

12 m

30 m

6 m

16 m

5 m

17 m

Conclusions

• Impact of prognostic score in older patients

Presentstudy

Hutson et al. BJC 2014

De Giorgi et al.Clin Gen Cancer 2014

Derbel et al.J Geriatr Oncol 2013

Khambati et al.Clin Gen Cancer 2014

Design Retrosp. Prosp.

Pool analysis

Retrosp. Retrosp. Retrosp.

Nb older patients 33 202 185 48 144

Heng/MSKCC score

Good

Intermediate

Poor

33%

52%

15%

37%

44%

4%

24%

59%

18%

23%

43%

33%

4%

69%

27%

Survival

PFS

OS

11 m

30 m

11 m

25 m

12 m

30 m

6 m

16 m

5 m

17 m

Conclusions

• TKI-induced toxicities including:

• Grade ¾ side effects

• Dose reduction

• Treatment discontinuation

� Were significantly increased in older than in younger patients

� In a similar proportion than previously reported

� Baseline renal function impairment was associated with TKI-

induced toxicities in the whole population

� Specific strategies need to be investigated in mRCC, particularly in

older patients who are more exposed to side effects

Conclusions

Thank you for your attention