IKZ - 7 dec 2006
Adjuvante en Neo-adjuvante Chemotherapie na curatief geopereerd NSCLC
Erik van der Heijden, longarts UMC St Radboud
2005 CBS: Kanker belangrijkste doodsoorzaak in NL Longkanker verantwoordelijk voor 25% van de sterfte aan kanker
Sterfte Longkanker 2000-2004
Aantal sterfgevallen 2005 Persbericht CBS 5 sept 2005 - data 2006
Prognose Mortaliteit longkanker NL
Bron: CBS 2005
Relatieve overleving longkanker geopereerde patiënten, IKA-regio, 1988-2001 100% 100% 90%
94% 88% 83% 87%
80%
78%
70%
66% 69% 64%
60% 50% 45%
30%
47%
55% 48%
43%
24%
35%
35%
IA IB II III
20%
54% 58%
51%
40%
75%
75%
69%
60%
79%
28%
26%
22%
19%
10% 0% 0
1
2
3
4 5 6 aantal jaar na de diagnose
7
8
9
10
Is elk stadium van NSCLC een systeemziekte?
• Recidief percentage na curatieve ok ~60% • Chemotherapie voor eradicatie micrometastasen • Neo-adjuvant (inductie) vs Adjuvant PRO • Fittere patiënt • Minder chemo-resistente cellijnen? • Beperktere resectie (weefselsparend)? CON • Onvolledige stadiering voor start chemo • Minder evidence
Neo-adjuvant CT – meta-analyse
St I-IIIa
MET PORT!
Berghmans, Lung Cancer (2005) 49, 13—23
St IIIa
Neo-adjuvante chemotherapie
• randomised study NSCLC, n=373, T2N0, T1-2N1, T3N0-1 • arm A: CT – S – adj CT • arm B: primary surgery • Cddp/ifosfamide/mitomycin: 2 x pre + 2x postop; RT voor T4, N2/3, >R0 • relative risk of death: PCT N0/1: 0.68; p=0.027, PCT N2: 1.04; p=0.85
Depierre A et al. J Clin Oncol 2001;20:247-53
Neo-adjuvant trials SWOG 9900 600 pat nodig, accruel gestopt in juli 04 bij 354 patiënten na bekend worden abstracts adjuvante trials JBR10 en CALGB op ASCO 2004
•
NVALT-2 (LU-22) Data worden verwacht
•
Adjuvante chemotherapie
• Meta-analyse in 1995 (BMJ) • Sindsdien 19 trials adjuvant • 9 studies met > 200 patienten • Cisplatin-based arms : n= 10 • UFT trials : n=6. The last one (2004) included 999 pts • Carboplatin-based : 1 (CALGB 9633) • 3 meta-analyses
MRC group - BMJ 1995 meta-analyse
• N=9387 pat; 52 trials • Early disease: 4357 pts; 14 trials • 8 cisplatin-based CT: 1394 pts • HR = 0.87 - p = 0.08, • 5% 5Y OS ns
CT with alkylants Other drugs
Platinbased CT 0.0
0.5
Surgery + CT better
BMJ 1995; 311(7010):899-909
1.0
1.5
2.0
Surgery alone better
International Adjuvant Lung Cancer Trial (IALT) 2004
• N=1867 33 landen, 1995-2000 • Cisplatin based adj CT: n = 932 vs • Observation: n = 935 • st I: 36.5%, st II: 24.2%, st III: 39.3% • 74% tenminste 240 mg/m2 cisplatin • 7 sterfgevallen tgv CT (0.8%) • Mediane OS 50,8 vs 44.4 m • 5YS 44,5 vs 40,4% • OS HR: 0.86 (95%CI: .76–.98; p< 0.03). • Powered voor een 5%OS verschil met n=3300 pat.
N Engl J Med 2004; 350(4):351-360
Hotta – meta-analyse adj CT
• 5716 pat in 11 trials • cisplatinum houdende CT: HR 0.89, p= 0,015 • UFT (single agent Japan): HR 0.80, p= 0,012 J Clin Oncol 2004; 22(19):3860-3867
BLT 2004 Waller etal, Eur J Cardio-Thoracic Surgery 2004 (26); 173-182
• Kleine studie: 192 vs 189 pat • MVP of cis-vino chemotherapie • 27% stage I, 38% stage II, and 34% stage III. ÆNegatief studie ALPI – EORTC Scagliotti J Natl Cancer Inst 2003; 95: 1453–61
• N=1209 st I–IIIA • Cisplatin, mitomycin, vindesine vs Observation • 5YS 48 vs 45% HR 0·96 (0·81–1·13) P= 0·59. • 13 RT beide armen, toxisch, 69% volledig behandeld • ÆNegatief studie
NCIC-JBR10 Completely Resected Early Stage NSCLC Stage IB - II
482
Randomized to Standard of Care Observation Only 239
VS
Chemotherapy Cisplatin –Vinorelbine 243
Winton NEJM 2005;352:2589-97
Adj CT st Ib/II: vino/cis
Winton NEJM 2005;352:2589-97
Resultaten JBR10 adj Chemotherapie st Ib/II
Winton NEJM 2005;352:2589-97
‘ANITA’ trial: Vino/Cis adj CT st Ib / II / IIIa OBS
NVB+CDDP
n= 433
n= 407
Pneumonectomy
35.8%
38.1%
Lobectomy
58.4%
57.2%
n= 433
n= 407
I (pT2 N0)
34.2%
35.4%
II
30.5%
29.2%
IIIA
35.3%
35.4%
n= 433
n= 407
Squamous
58.9%
60.0%
Non Squamous
41.1%
40.0%
33.3%
21.6%
48%
39.2%
Type of surgery
Stage
Histology
PORT Chemotherapy at relapse
Douillard, Lancet Oncol 2006; 7: 719–27
Overall Survival - ITT Population
Median months
1.00
Survival Distribution Function
P-value
OBS.
NVB + CDDP
43.8
65.8 0.013
Hazard Ratio
0.79 [0.66 - 0.95]
0.75
0.50
Obs 0.25
NVB + CDDP 0 0
20
40
60
80
100
months Douillard, Lancet Oncol 2006; 7: 719–27
120
‘Anita’ trial: adj CT st Ib / II / IIIa
Overall Survival Median months
OBS.
NVB + CDDP
43.8
65.8
1-year survival
+ 3.1%
80.4%
83.5%
2-year survival
+ 5.1%
62.8%
67.9%
5-year survival
+ 8.6%
42.6%
51.2%
7-year survival
+ 8.4%
36.8%
45.2%
logrank p value = 0.013 Douillard, Lancet Oncol 2006; 7: 719–27
Meta-analyse met nieuwe studies
• 19 trials in adjuvant (gedeeltelijk abstract data) • 7644 pat • HR 0.84 (95% CI 0.78—0.89) in favour of adjuvant chemotherapy. • stages I and II HR 0.88 (95% CI 0.83—0.94). • stage III HR = 0.85 (95%CI 0.69—1.04) NS
Berghmans T et al. Lung Cancer 2005;49:13-23.
Meta-analyse Lung Adj Cisplat Evaluation (LACE)
• 5 trials • ALPI, ANITA, BLT, IALT, JBR10 • including 4584 pts----Median follow-up : 5.1 years • 80% male • Median age : 59 years (9% >=70 years) • Pathological stage: • IA : 8% / IB : 30% / II : 35% / III : 27% • Surgery : 31% pneumonectomies • Pathology : 49% squamous cell, 39% adenocarcinoma
Pignon etal J Clin Oncol (Meeting Abstracts) 24: 7008, 2006
Meta-analyse LACE
Pignon etal J Clin Oncol (Meeting Abstracts) 24: 7008, 2006
St Ib ? – CALGB 9633
• Enige trial met carbo • Negatief Strauss etal J Clin Oncol 2004: abs 7019 en 2006: abs 7007
NVALT – 8
• Æ PAT SELECTIE • PET-SUV meeting • Eenmalig ijking dmv fantoom • Standaardisatie PET-protocol en SUV meting • Reguliere diagnostische PETscan • Chirurgie • Ro resectie • Stadiering • Laag-toxisch schema – betere compliance? • Weefselbank Æ via pathologie
NVALT – 8: PET-SUV max
• N=84 pat UMCG en UMC St Radboud • St Ia - IIIa • Overall survival according to SUVmax • dichotomized at median value (6.9), • Hazard Ratio 2.3 (95% CI 1.1-4.7)
•
De Jong WK, Van der Heijden HFM, Pruim J, et al: J Clin Oncol (Meeting Abstracts) 24:7214-, 2006
NVALT – 8 design PET-SUV < 7 S U R G E R Y
PET-SUV ≥ 7
Stratification: Study center PS (0,1 VS 2) TNM stage Type of resection Prior other malignancy (present vs absent)
NVALT 8A
NVALT 8B
Observation only versus 4 cycles cisplatin-based chemotherapy
4 cycles Cisplatin/Pemetrexed versus 4 cycles Cisplatin/Pemetrexed + Nadroparin for 16 weeks
NVALT 8 Power berekening Arm A n = 432 per arm, 4 jr accrual 5 jr FU Arm B n = 300 per arm, 3 jr accrual, 2 jr en 3 mnd FU NL: ~1500 thoracotomie per jr Zoveel mogelijk centra in NL
• •
• •
Primary Objective: Disease free survival Secondary Objective(s): Overall survival Dose intensity of subsequent cycles QoL Toxicity Health economics Exploratory endpoints: Analysis of tumor and blood samples for prognostic markers, genomics/proteomics
• • • • •
NVALT – 8 ARM A – LAAG risico groep
• Observatie versus adj chemo • Hypothese: voorkomen van onnodige behandeling • Één van de volgende cis gebaseerde schema’s gedurende hele studie in het deelnemende centrum • Cis/docetaxel • Cis/ gem • Cis/ vino • Cis/ pemetrexed
NVALT – 8 ARM B – HOOG risico groep
• Pem/cis vs Pem/cis + LMWH • LMWH: FAMOUS / MALT / CLOT trials • Nadroparine, start dag 1 kuur 1 • 2 weken therapeutisch • 14 weken half-therapeutische dosis
NVALT – 8 Bijkomende voordelen
• State of the art PET-scan in dagelijkse routine • State of the art chirurgische stadiering • State of the art PA beoordeling / verslaglegging
Conclusie
• Cisplatinum gebaseerd schema • Plaats Neo-adjuvant nog niet duidelijk • Adjuvant CT is ‘standard’ na R0 resectie St II • St Ib geen adjuvant buiten studieverband • St IIIa minder data Blum, NEJM 2004;350 (4): 404-5
Pulmonary Oncology Unit Heart-Lung Centre Nijmegen Radboud University Nijmegen Medical Centre The Netherlands
Miep van der Drift, longarts Erik van der Heijden, longarts Olga Schuurbiers, longarts Anja Timmer, med oncoloog
