adjuvant therapy in older adults: nsclc
TRANSCRIPT
ADJUVANT THERAPY IN
OLDER ADULTS: NSCLC
Andrea Luciani, MD, PhD
Medical Oncology Unit
Ospedale S. Paolo- Polo Universitario
Milano
1. Poor 5y-survival after surgery (IB 57%, IIA 55%, IIB 38%, IIIA 25%)
2. Positive 5 y-S from clinical trials (+4-15%)
3. Positive results (at 5 ys) from meta-analysis (+3-5%)
4. Follow-up confirmation (after 8-12 ys)
5. Positive comparison with other adjuvant setting
6. Easy patients selection
7. Well established treatment strategy (CDDP-based CTx)
8. Cheaper treatment in lung cancer
9. Strongly recommended by international guidelines
Why adjuvant CT….
NSCLC Collaborative Group, BMJ 1995NSCLC Collaborative Group, BMJ 1995
1995 Meta-analysis and Clinical Practice
Post Meta-analysis Timeline 1995-2008
A Wozniak, ASCO 2006
INT 0115
NEJM 2000
ALPI
JNCI 2003
NSCLCCG
BMJ 1995
JLCRG
NEJM 2004
IALT
NEJM 2004
JBR.10
NEJM 2005
ANITA 01
Lancet 2006
BLT
2004
NEGATIVE
POSITIVE
CALGB 9633
ASCO 2006
LACE
JCO 2008
Trial StageN
ptsCT 5y-S % HR [95%CI] p
IALT(1995-2000)
NEJM 2004
I-II-III 1867
CIS+VP16 (56%)/
+VNB(27%)/
+VBL/VDS (17%)
+/- RT
+4.1 0.86
[0.76-0.98] <.03
JBR.10(1994-2001)
NEJM 2005
IB-II 482CIS+VNB
No RT+15
0.70 [0.53-0.92] .022
ANITA(1994-2000)
Lancet 2006
IB-II IIIA
840CIS+VNB
+/- RT+8.6 0.79
[0.66-0.95].013
Positive Trials
JL Pignon et al, JCO 2008
ADJUVANT CT IN EARLY NSCLC
Meta-analyses Results
65.7 months
43.7 months
Observation NVB + CDDP
Median months Gain 43.8 65.8
1-year survival + 2.8% 80.7% 83.5%
2-year survival + 4.7% 63.2% 67.9%
5-year survival + 8.6% 42.7% 51.3%
7-year survival + 8.4% 36.8% 45.2%
ANITA OVERALL SURVIVAL
Logrank p-value = 0.017 Douillard JY, Lancet Oncol 2006
ANITA OVERALL TOXICITY
Douillard JY, Lancet Oncol
2006
LONG TERM OBSERVATION IN JBR10
ADJUVANT TRIAL
MD Vincent et al, P ASCO 2009
Trial Cisplatinmg/mq
Vinorelbine mg/mq
Compliance%
Main toxicity
JBR10 Winton 2005
50 d 1,8 q 4 wks up to 4 cycles
25 weekly x 16
45 73%Neu G 3-4
0.8% TD
ANITA Douillard2006
100 d1 q 4 wksup to 4 cycles
30 weekly
up to 16 wks
56 92%Neu G 3-49% FN2% TD
IALTLe Chevalier 2004
80–120 d 1 q 4 wks up to 3 – 4 cycles
30 weekly 74 17.5%
Neu G3-4 0.8% TD
CISPLATIN AND VINORELBINE:
Schedule
The use of adjuvant cisplatin-based doublet chemotherapy after surgery for stages II and III
NSCLC, originating from 23 randomised trials published between 1992 and 2005 [I, A].
Efficacy in stage IB remains controversial since the results are inconsistent in this subgroup [II,
B]. There is no overall survival (OS) benefit, except for patients with tumours >4 cm in the CALGB
9633 study, or patients with tumours >5 cm in the JBR.10 study.
PORT in completely resected early-stage NSCLC is not recommended [I, A].
Routine use of PORT may be considered in N2 patients after resection.
PORT is indicated after incomplete surgery [III, B].
Patient Selection Criteria
• >70 vs < 70 Karnofsky PS
• Early vs Late postop. recovery
• Absence vs presence of multimorbidity
• < 70 vs > 70 years
• Non-smokers vs Smokers
• Female vs Male
PROBLEMS AND OPEN QUESTIONS
• No formal analysis of outcome in elderlyNSCLC
• Under-representation of elderly patientsin adjuvant trials
• IALT and ANITA excluded patients over75
ANITA Trial Retrospective Results
C Langer, ASCO 2006
ANITA Trial Retrospective Doses and Tox
C Langer, ASCO 2006
Retrospective analysis to examine the elderly population of patients treated in National Cancer
Institute of Canada Clinical TrialsGroup (NCICCTG) study JBR.10
Elderly patients were defined as age more than 65 and young patients as age 65 or younger
Mean dose-intensities:
18.0 versus 14.1 mg/m2/wk for cisplatin (P
.001) and 13.2 versus 9.9 mg/m2/wk for
vinorelbine (P.0004)
More elderly patients discontinued
chemotherapy treatment due to refusal
compared with younger patients (40% v
23%; P.01)
EARLY STAGE NSCLC ERCC1 Role (Bio-IALT)
Olaussen KA et al, NEJM 2006
ERCC1- : benefit of adjuvant chemotherapy (HR for death 0.65, CI95% 0.50-0.86, p=0.002).
MS=56 vs 42 mos.5yS= 47 vs 39%.
Adequate information and participation of the patient and
family members is important for elderly NSCLC patients.
Treatment decisions should be taken after clear information
is given to the patient regarding prognosis of the disease,
treatment options, benefit-risk ratio of the proposed
treatment and the potential negative effect of over- and
under-treatment.
M Weinmann et al, Lung Cancer 2003
patients aged ≥ 70 years
stage IIIB/IV NSCLC
therapy naïve,
WHO PS of 0–2
randomized 1:1: vandetanib plus gemcitabine
(V/G) or placebo plus gemcitabine (P/G)
Vandetanib or placebo was administered as
single oral 100 mg daily doses.
Gemcitabine was administered at a
1200 mg/m2 dose as an intravenous infusion
on day 1 and day 8 of each 21-day cycle
Primary endpoint of the study was PFS.
Secondary endpoints were OS
183 days; 95% CI, 116–214
169 days; 95% CI: 95–
194
p = 0.047
The significant benefit in the V/G
group was obtained despite the PFS in the
control group was
longer than expected.
However, our assumption of a 50% PFS
prolongation was not reached.
PFS was significantly prolonged in
the V/G arm compared with the P/G arm for the following
covariates: patients with all combined types of histological
tumors except squamous cell carcinoma, never/past smokers and female patients
International, multicenter, randomized, phase
III study
Patients were randomly assigned (1:1) to nab-
P/C or sb-P/C and stratified by age (<70 versus
≥70 years)
ORR in the nab-P/C versus sb-P/C arms
(34% versus 24%, P = 0.196)
Docetaxel (75 mg/m2) plus ramucirumab (10
mg/kg) (Arm A) or docetaxel (75 mg/m2) plus
placebo (Arm B)
The primary end point of this study is overall
survival (OS)
NEMO EST TAM SENEX QUI SE ANNUM NON PUTET POSSE VIVERE
(Cicero, De Senectute, VII, 24)