Giorgio V Scagliotti University of Torino Department of Oncology giorgioscagliottiunitoit Key points of the presentation Incidence Age cut off Comorbidity amp ID: 551454
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Slide1
Optimal treatment for elderly patients with NSCLC
Giorgio V. Scagliotti
University
of
Torino,
Department
of
Oncology
giorgio.scagliotti@unito.itSlide2
Key
points of the presentation
Incidence
Age
cut
-off
Comorbidity
&
geriatric
assessments
Pharmacology
and
toxicity
Treatment
Pragmatic
approach
Personalized
approach
Second-line
OctogenariansSlide3
Elderly
: an
increasing
population
Year Proportion > 65 yrs Projected persons > 65 yrs (ratio) (% population) 1930 1 in 15 - 1990 1 in 8 12.5 2020 1 in 5 17.3 2030 1 in 4 21.1
Yancik R Cancer J 2005; Population BulletinSlide4
SEER Cancer Statistics Review 1975-2008 – National Cancer Institute
US NSCLC
Incidence
Age
at
diagnosis
Median age at diagnosis: 71 yrs
Lung
&
bronchus
Lung
&
bronchusSlide5
Key
points of the presentation
Incidence
Age cut
-offComorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide6
Cut
-off
age
for
elderly
patients in clinical trials and practice
No
agreement
on the
definition of “elderly” (65 – 70 – 75 years?)
Aging is a highly individualized process in which all the changes involved cannot be predicted solely on the basis of chronological age
Many
believe
that
“
biological
age” rather than “chronological age” should guide medical decision To establish the “biological age” is difficult due to the lack of adequate laboratory tests and tools “Chronological age” is the only indicator in defining the elderly 70 years may be the most appropriate threshold because the incidence of age-related changes starts to increase after this cut-off age Balducci L. Eur J Cancer 2000Slide7
Key
points of the presentation
Incidence
Age cut-off
Comorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide8
The
changing
prevalence
of
comorbidity
across the
age
spectrum
Piccirillo JF et al
Crit
Rev
Oncol
Hematol
2008Slide9
Comprehensive
Geriatric
Assessment
Goals
To
improve
diagnosis
accuracy
To
guide the
selection
of
interventions
for
restoring
or
preserving
healthTo recommend an optimal environment for careTo predict outcomesTo monitor clinical changes over timeSalomon D et al. J Am Geriatr Soc
1988 Slide10
Function
Performance status (PS)
Activities of daily living (ADL) Instrumental activities of daily living (IADL) Advanced activities of daily living (AADL) Comorbidity Comorbidity scales (Charlson; CIRS)
QoL
Disease-specific questionnaires
Cognition Folstein Minimental
Status Emotions
Geriatric
Depression
Scale (GDS)
Social
support
network
Polypharmacy NutritionDomains of Geriatric Assessment
Nurse
Oncologist
Dietician
Phisical Therapist
Geriatrician
Social Worker
PharmacistSlide11
Key
points of the presentation
Incidence
Age cut
-offComorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide12
Organ function declines with age
Cardiovascular function
1
decreased elasticity of arterial system
loss of myocytes and atrial pacemaker cellsincreased fibrosis of cardiac fibrous skeleton
Renal function2decreased renal blood flowdecreased glomerular filtration ratedecreased creatinine clearanceHepatic function3reduced hepatic blood flowdecline in cytochrome P450 system
1
Cheitlin MD. Am J
Geriatr
Cardiol 2003;12:9-132Muhlberg W, et al. Gerontology 1999;45:243-53
3
Anantharaju A, et al. Gerontology 2002;48:343-53Slide13
Decrease in lean body mass
Increase percentage body fat
Decrease in serum albumin
Decrease in
haemoglobin levelDecrease in body water
Relevant age-related changes
Increase in volume of distribution for
lipophilic
drugs
Decrease in volume of distribution for
hydrophilic
drugsSlide14
PK changes based on age alone are modest
Changes (variability) are result of:
ComorbidityEnd-organ dysfunction
Physical factors: fat, anemia, albumin, etc.
Physiologic changes with agingPolypharmacyGender, ethnicity, genotype
PharmacokineticsSlide15
Pharmacodynamic
Heterogeneity of
effect
Tremendous variability in toxicity
Increased susceptibility
MyelosuppressionMucositisCardiac toxicityNervous system toxicitySlide16
NSCLC in the
elderly
:
barriers
to treatment
Presence of co-morbid conditionsHesitation to treat and/or to treat aggressively
Elderly
have less aggressive cancers
Elderly do not
want aggressive therapy
Elderly
cannot
tolerate
aggressive
therapy
Elderly
have different wishes with respect to prolongation of lifePsycological (“treatment is worse than the disease”)Underrepresented in trialsSocioeconomic Cost of treatment Dependence on othersDecrease in functional statusSlide17
7.1 vs 2.5 months; HR 0.558; p < 0.001
7.7 vs 5.3 months; HR 0.734Slide18
Pretreatment
medical
event
rates were 18.6% for patients younger than 55 years and were only 9.2% for those
age 75 years and
olderIn contrast,
older adults were more likely
to have AEs during
chemotherapySlide19
Key
points of the presentation
Incidence
Age cut-off
Comorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide20
ELVIS
phase
III
randomized
trial: Vinorelbine
vs.
Best
Supportive
Care
Primary endpoint:
QoL
Secondary endpoint: OS, ORR, toxicity
154
pts
>
70
yrs
Vinorelbine 30 mg/m², d 1-8, Q3W
Best Supportive Care
Regimen
No.pts
ORR (%)
OS (
mos
)
Toxicity G3-G4 (%)
Vinorelbine
76
20
6.5
~ 10
BSC
78
NA
4.8
NA
ELVIS
Investigators
JNCI
1999
Estimated effect of vinorelbine with 95% CI
dyspnea
hemoptysis
sore mouth
swallowing troub.
neuropathy
hair loss
pain in chest
pain in shoulder
pain elsewhere
analgesics
cough
-20
-15
-10
-5
0
5
10
15
20
IMPROVEMENT
WORSENING
RSlide21
Primary endpoint: OS
Secondary endpoint: OS, ORR,
QoL
toxicity
180
pts >
70 yrs
Vinorelbine 25 mg/m², d 1-8, Q3W
Docetaxel 60 mg/m², d 1, Q3W
Kudoh
et al JCO 200
6
WJTOG 9904
phase
III
randomized
trial:
Vinorelbine
vs.
Docetaxel
Overal
Survival
: HR 0.78, 95% CI 0.56-1.08; p = 0.13
Regimen
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Vinorelbine
91
9.9
3.1
9.9
Neut
82.9
Docetaxel
89
22.7
5.4
14.3
Neut
69.3
RSlide22
Primary endpoint: OS
Secondary endpoint: OS, ORR,
QoL
toxicity
120 pts
> 70 yrs
Vinorelbine 30 mg/m², d 1-8, Q3W
Vinorelbine 30 mg/m² + Gemcitabine 1200 mg/m², d 1-8, Q3W
Frasci
et al JCO 2000
SICOG
phase
III
randomized
trial: Vinorelbine vs. Vinorelbine +
Gemcitabine
Regimen
No.pts
ORR (%)
OS (
wks
)
Toxicity G3-G4 (%)
Vinorelbine
60
15
18
17
Vinorelbine + Gemcitabine
60
22
29
23
RSlide23
Primary endpoint: OS
698 pts
>
70 yrs
Vinorelbine 30 mg/m²,
d 1-8, Q3W
Vinorelbine 25 mg/m² + Gemcitabine 1000 mg/m²,
d 1-8, Q3W
MILES
phase
III
randomized
trial: Vinorelbine or
Gemcitabine
vs. Vinorelbine +
Gemcitabine
Regimen
No.pts
ORR (%)
OS (
mos
)
Toxicity G3-G4 (%)
Vinorelbine
233
18
8.3
Neut 25
Gemcitabine
233
16
6.5
Neut
8, PLT 3
Vinorelbine + Gemcitabine
232
21
6.9
Neut
18, PLT 4, Constipation 2
Gemcitabine 1200 mg/m²,
d 1-8, Q3W
OR
VS.
Gridelli et al JNCI 2003
RSlide24
Author
Treatment
Age
No.pts
ORR (%)
OS (months)
Toxicity
Langer, 2003
CDDP+PAC
CDDP+TXT
CDDP+GEM
CBDCA+PAC
>
70
< 70
227
912
25
22
8.3
8.2
No differences
Hensing, 2003
CBDCA+PAC
>
70
< 70
67
163
27
20
7.1
7.8
No differences
Belani, 2005
CDDP+TXT
>
65
< 65
149
259
NR
NR
12.6
11.0
Elderly experienced slight more toxicity than younger patients
CDDP+VNR
>
65
< 65
134
270
NR
NR
9.9
10.1
CBDCA+TXT
>
65
< 65
118
288
NR
NR
9.0
9.7
Ramalingam, 2008
CBDCA+PACw
>
70
< 70
72
147
26
29
37*
39°
A trend toward higher incidence of fatigue,
hyperglycemia
, and dehydration for elderly over younger
pts
in both arms
CBDCA+PAC
>
70
< 70
64
151
19
19
31*
46*
Blanchard, 2011
CDDP+VNR or CBDCA+PAC
>
70
< 70
122
494
30
27
7.0
9.0
Higher grade 3-5 toxicity in elderly
pts
Main
retrospective
analyses
of
elderly
from
phase
III
randomized
trials with
platinum-based
regimensSlide25Slide26
Characteristics
Age < 65
n = 815 (%)
Age ≥ 65
n = 398 (%)
Age < 70
n = 1,060 (%)
Age ≥ 70
n = 153 (%)
Pem+Cis
(n = 390)
Gem+Cis
(n = 425)
Pem+Cis
(n = 215)
Gem+Cis
(n = 183)
Pem+Cis
(n = 521)
Gem+Cis
(n = 539)
Pem+Cis
(n = 84)
Gem+Cis
(n = 69)
OS in NSQ
(HR, 95% CI)
0.89 (0.76-1.05)
0.75 (0.59-0.94)
0.83 (0.72-0.95)
0.85 (0.59-1.22)
PLT
2.8
8.0
5.1
17.5
3.1
9.3
7.2
23.2
Neutropenia
11.5
25.2
20.9
26.8
13.6
25.4
22.6
27.5
Anemia
5.9
10.1
3.3
10.4
5.4
10.6
2.4
7.2
Leukopenia
3.8
8.0
5.1
6.6
4.2
7.6
4.8
7.2
Fatigue
6.7
3.5
6.5
6.6
6.0
3.5
10.7
11.6
Febrile neutropenia
0.5
2.8
2.8
4.4
1.2
3.2
2.4
4.3
Nausea
8.2
4.0
7.9
5.5
8.1
3.9
8.3
8.7
Vomiting
6.9
6.8
5.1
4.9
6.3
6.3
6.0
5.8
Retrospective
age
subgroups
analysis
of first-line Cisplatin + Pemetrexed or
Gemcitabine
in non-
squamous
NSCLC
patients
Gridelli et al
Clin
Lung
Cancer
2011Slide27
Primary endpoint: OS
Secondary endpoint: PFS, ORR,
QoL
, toxicity
Carboplatin AUC 6, d 1 +
Paclitaxel
90 mg/m², d 1-8-15, Q4W
451
patients
70-89
years
Quoix
et al Lancet
Oncol
2011
Regimen
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxic Deaths (n, %)
Carboplatin + Paclitaxel
225
27.1
6.0
10.3
10 (4.4)
Vinorelbine
OR Gemcitabine
226
10.2
2.8
6.2
3 (1.3)
Vinorelbine 25 mg/m², d 1-8 OR Gemcitabine 1150 mg/m², d 1-8, Q3W
IFCT-0501
phase
III
randomized
trial:
Carboplatin
+
Paclitaxel
vs. Vinorelbine or
Gemcitabine
RSlide28
Primary endpoint: OS
Secondary endpoint: PFS, ORR,
QoL
, toxicity
Cisplatin 25 mg/m² + Docetaxel 20 mg/m², d 1-8-15, Q4W
Abe et al ASCO 2011
Regimen
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxicity (%)
Cisplatin
+
Docetaxel
138
34.4
4.7
13.3
HypoNa
15, Anorexia 11,
Infec
8, TD 2.2
Docetaxel
134
24.6
4.4
14.8
Neut
89, Feb
Neut
15
Docetaxel 60 mg/m², d 1, Q3W
JCOG-0803/WJOG4307L
Phase
III
randomized
trial:Cisplatin
+ Docetaxel vs. Docetaxel
272
patients
>
70
years
RSlide29
NVALT-3
phase
III
randomized
trial:
Carboplatin
+ Gemcitabine
vs.
Carboplatin
+
Paclitaxel
Primary endpoint:
QoL
Secondary endpoint: OS, ORR, toxicity
Carboplatin AUC 5, d 1 + Gemcitabine 1250 mg/m²,
d
1-8, Q3W
181
patients
>
70
years
Biesma
et al
Ann
Oncol
2011
Regimen
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Carboplatin + Gemcitabine
90
27
4.7
8.6
75
Carboplatin + Paclitaxel
91
19
4.5
6.9
60
Carboplatin AUC 5, d 1 + Paclitaxel 175 mg/m², d 1-8, Q3W
RSlide30
MILES-2
phase
II
randomized
trial:
Cisplatin
+ Vinorelbine
vs.
Cisplatin + Gemcitabine
Primary endpoint: Unacceptable toxicity
Secondary endpoint: OS, PFS, ORR
Cisplatin 40 mg/m², d 1 + Vinorelbine 25 mg/m²,
d
1-8, Q3W
R
121
pts
>
70
yrs
Gridelli et al JCO 2007
Regimen
No.pts
ORR (%)
PFS (
wks
)
OS (
wks
)
Toxicity G3-G4 (%)
Cisplatin
+
Vinorelbine
61
36
21
33
18
Cisplatin + Gemcitabine
60
43
25
43
16
Cisplatin 60 mg/m², d 1 + Gemcitabine 1000 mg/m²,
d
1-8, Q3WSlide31
Characteristics
Age < 65
n = 319 (%)
Age ≥ 65
n = 157 (%)
Age < 70n = 400 (%)
Age ≥ 70
n = 76 (%)
Pem
(n = 217)
Placebo
(n = 102)
Pem
(n = 103)
Placebo
(n = 54)
Pem
(n = 272)
Placebo
(n = 128)
Pem
(n = 48)
Placebo
(n = 28)
OS in NSQ
(HR, 95% CI)
0.62 (0.46-0.83)
0.87 (0.58-1.28)
0.63 (0.49-0.81)
0.81 (0.44-1.50)
Neutropenia
2.7
0
2.9
0
2.5
0
4.1
0
Anemia
1.8
0
3.8
0
2.5
0
2.0
0
Fatigue
2.7
0
6.7
1.9
3.6
0
6.1
3.6
Neuropathy sensory
0.5
0
1.9
0
0.4
0
4.1
0
Constipation
0.5
0
0
1.9
0.4
0
0
3.6
Distention bloating, abdominal
0.5
0
0
1.9
0.4
0
0
3.6
Retrospective
age
subgroup
analysis
of
maintenance
Pemetrexed vs. Placebo
after
Platinum-
based
induction
chemotherapy
in non-
squamous
NSCLC
patients
Gridelli et al
Clin
Lung
Cancer
2011Slide32
Key
points of the presentation
Incidence
Age cut-off
Comorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide33
Erlotinib
as first-line treatment for elderly (> 70
years
) patients with advanced NSCLC
Jackman, et al. JCO 2007
Therapy
No.pts
ORR (%)
TTP (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Erlotinib
80
10
3.5
10.9
19Slide34
INVITE phase II randomized trial: Gefitinib
vs.
Vinorelbine
Primary endpoint: PFS
Secondary endpoint: ORR, OS,
QoL
, toxicity
Gefitinib 250 mg/
daily
Vinorelbine 30 mg/m², d 1-8, Q3W
Crinò L et al, JCO 2008
196
patients
>
70
years
Regimen
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Vinorelbine
99
5.1
2.9
8.0
41.7
Gefitinib
97
3.1
2.7
5.9
12.8
RSlide35
NEJ 003 phase II trial: Gefitinib in EGFR-mutated elderly patients (
>
75
years
)
Therapy
No.pts
ORR (%)
PFS (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Gefitinib
31
74.2
13.8
1-yr S 77.4%
AST/ALT 19, TD 3
Minegishi Y et al, ASCO 2010Slide36
Author
Age
Treatment
No.pts
ORR (%)
PFS (mos)OS (mos)
Toxicity
Ramalingam
, 2008
>
70
CBDCA+PAC+BEV 15 mg/kg
vs
CBDCA+PAC
111
113
29
27
5.9
4.9
11.3
12.1
TD 6.8% and 1.8% in BEV and placebo arms. Higher toxicity with BEV in elderly
Leighl, 2010
>
65
CDDP+GEM+BEV 7.5 mg/kg
or
CDDP+GEM+BEV 15 mg/kg
vs
CDDP+GEM
89
103
112
40
29
30
HR 0.71
HR 0.84
-
HR 0.84
HR 0.88
-
Only grade > 3 PLT more frequent in BEV arms
Griesinger, 2009
<
65
> 65
BEV+CT
1,557
609
NR
7.6
TTP
8.3
15.2
15.3
No differences
Retrospective
analysis
of Bevacizumab-
based
therapy
in non-
squamous
NSCLC
elderly
patients
Slide37
Phase
II
randomized
trial of Pemetrexed +
Gemcitabine
+ Bevacizumab or Pemetrexed +
Carboplatin
+ Bevacizumab in
elderly
patients
with
non-
squamous
NSCLC
Primary endpoint: TTP
Secondary endpoint: ORR, toxicity, OS
Pemetrexed 500 mg/m² + Gemcitabine 1500 mg/m² + Bevacizumab 10 mg/kg, d 1-15 Q4W
110
patients
>
70
years
Spigel
et al JTO 2011
Regimen
No.pts
ORR (%)
TTP (
mos
)
OS (
mos
)
Toxicity G3-G4 (%)
Pemetrexed
+ Gemcitabine +
Bevacizumab
55
35
4.7
7.5
Treatment-related interruption 23
Pemetrexed + Carboplatin + Bevacizumab
55
35
10.2
14.8
Treatment-related interruption 9
Pemetrexed 500 mg/m² + Carboplatin AUC 5 + Bevacizumab 15 mg/kg, d 1, Q3W
RSlide38
EPIC Trial
E
lderly Patients Individualized Chemotherapy Trial2:1 RandomizationIndividualized Arm
Control
ArmSquamous Cell Carcinoma
YesNoEGFR Mut +Off StudyERCC1 lowRRM1 highERCC1 highRRM1 lowERCC1 lowRRM1 low
ERCC1 high
RRM1 highCarboplatin
Gemcitabine
Carbo/Gem
Taxane
ERCC1 low
TS high
ERCC1 high
TS low
ERCC1 low
TS low
ERCC1 high
TS high
Carboplatin
PemetrexedCarbo/PemYesNoRRM1 lowRRM1 highGemcitabineTaxane
Treatment
based
on
Investigators
’
Preference
EGFR
Mut
+
YesSlide39
Key
points of the presentation
Incidence
Age cut-off
Comorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide40
Author
Age
Treatment
No.pts
ORR (%)
TTP (
mos
)
OS (
mos
)
Toxicity
Weiss, 2006
>
70
Pemetrexed
vs
Docetaxel
47
39
5.0
5.6
4.6
2.9
9.5
7.7
Febrile neutropenia greater in the elderly. Docetaxel more toxic than pemetrexed in elderly
< 70
Pemetrexed
vs
Docetaxel
224
238
9.8
9.2
3.0
3.9
7.8
8.0
Wheatley-Price, 2008
>
70
Erlotinib
vs
Placebo
112
51
7.6
NA
3.0
PFS
2.1
7.6
5.0
Grade
>
3 were significantly more frequent in elderly than younger (p < 0.001). Elderly discontinued therapy more frequently than younger (p < 0.0001)
< 70
Erlotinib
vs
Placebo
376
192
9.3
NA
2.1
PFS
1.8
6.4
4.7
Tibaldi, 2007
>
70
Docetaxel
33
21.2
4.0
6.0
Grade
>
3 was reported in less than 10% of
pts
Second-line
data in
elderly
patients
with NSCLC
Considering the available results, age alone should not prevent the administration of second-line therapy, which should be chosen on the basis of life expectancy, expected benefit, comorbidities and patient’s preferences
Slide41
Key
points of the presentation
Incidence
Age cut-off
Comorbidity & geriatric assessmentsPharmacology and toxicityTreatmentPragmatic approachPersonalized approachSecond-line
OctogenariansSlide42
Altundag
O e al, JTO 2007Slide43
Conclusions
Elderly
patients
are a
specific population. Data from
younger population
cannot be applied.
Specifically designed clinical trials with adequate
CGA are needed.Single
third
generation
agents
is
a
reasonable
choice
.
Platinum
-based regimen with attenuated dose or weekly schedule could be considered for good PS elderly patients without significant comorbidities.Gefitinib is well tolerated and has to be considered as first choice for EGFR-mutated patients. Other targeted therapies, i.e. bevacizumab, still required
further prospective evaluations.
Robust second-line data are still lacking
.
Octogenarians
deserve
specifically
designed
studies
.