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)