IKZ - 7 dec 2006 Adjuvante en Neo-adjuvante Chemotherapie na curatief geopereerd NSCLC

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1 IKZ - 7 dec 2006 Adjuvante en Neo-adjuvante Chemotherapie na curatief geopereerd NSCLC Erik van der Heijden, longarts UMC St Radboud

2 2005 CBS: Kanker belangrijkste doodsoorzaak in NL Longkanker verantwoordelijk voor 25% van de sterfte aan kanker Sterfte Longkanker Aantal sterfgevallen 2005 Persbericht CBS 5 sept data 2006

3 Prognose Mortaliteit longkanker NL Bron: CBS 2005

4 Relatieve overleving longkanker geopereerde patiënten, IKA-regio, % 100% 90% 94% 88% 80% 87% 83% 79% 75% 70% 60% 50% 40% 78% 69% 75% 60% 45% 69% 51% 64% 47% 58% 43% 66% 55% 54% 48% 30% 20% 10% IA IB II III 35% 35% 28% 26% 22% 24% 19% 0% aantal jaar na de diagnose

5 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

6 Neo-adjuvant CT meta-analyse St I-IIIa MET PORT! St IIIa Berghmans, Lung Cancer (2005) 49, 13 23

7 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

8 Neo-adjuvant trials SWOG 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

9 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

10 MRC group - BMJ 1995 meta-analyse N=9387 pat; 52 trials Early disease: 4357 pts; 14 trials 8 cisplatin-based CT: 1394 pts HR = p = 0.08, 5% 5Y OS ns CT with alkylants Other drugs Platinbased CT Surgery + CT better Surgery alone better BMJ 1995; 311(7010):

11 International Adjuvant Lung Cancer Trial (IALT) 2004 N= landen, 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):

12 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):

13 BLT 2004 Waller etal, Eur J Cardio-Thoracic Surgery 2004 (26); Kleine studie: 192 vs 189 pat MVP of cis-vino chemotherapie 27% stage I, 38% stage II, and 34% stage III. Negatief studie ALPI EORTC Scagliotti J Natl Cancer Inst 2003; 95: N=1209 st I IIIA Cisplatin, mitomycin, vindesine vs Observation 5YS 48 vs 45% HR 0 96 ( ) P= RT beide armen, toxisch, 69% volledig behandeld Negatief studie

14 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:

15 Adj CT st Ib/II: vino/cis Winton NEJM 2005;352:

16 Resultaten JBR10 adj Chemotherapie st Ib/II Winton NEJM 2005;352:

17 ANITA trial: Vino/Cis adj CT st Ib / II / IIIa OBS NVB+CDDP Type of surgery n= 433 n= 407 Pneumonectomy 35.8% 38.1% Lobectomy 58.4% 57.2% Stage n= 433 n= 407 I (pt2 N0) 34.2% 35.4% II 30.5% 29.2% IIIA 35.3% 35.4% Histology n= 433 n= 407 Squamous 58.9% 60.0% Non Squamous 41.1% 40.0% PORT 33.3% 21.6% Chemotherapy at relapse 48% 39.2% Douillard, Lancet Oncol 2006; 7:

18 Overall Survival - ITT Population OBS. NVB + CDDP 1.00 Median months P-value Survival Distribution Function Obs NVB + CDDP Hazard Ratio 0.79 [ ] months Douillard, Lancet Oncol 2006; 7:

19 Anita trial: adj CT st Ib / II / IIIa Overall Survival OBS. NVB + CDDP Median months 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 = Douillard, Lancet Oncol 2006; 7:

20 Meta-analyse met nieuwe studies 19 trials in adjuvant (gedeeltelijk abstract data) 7644 pat HR 0.84 (95% CI ) in favour of adjuvant chemotherapy. stages I and II HR 0.88 (95% CI ). stage III HR = 0.85 (95%CI ) NS Berghmans T et al. Lung Cancer 2005;49:13-23.

21 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

22 Meta-analyse LACE Pignon etal J Clin Oncol (Meeting Abstracts) 24: 7008, 2006

23 St Ib? CALGB 9633 Enige trial met carbo Negatief Strauss etal J Clin Oncol 2004: abs 7019 en 2006: abs 7007

24 NVALT 8 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 via pathologie

25 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 ) De Jong WK, Van der Heijden HFM, Pruim J, et al: J Clin Oncol (Meeting Abstracts) 24:7214-, 2006

26 NVALT 8 design S U R G E R Y Stratification: Study center PS (0,1 VS 2) TNM stage Type of resection Prior other malignancy (present vs absent) PET-SUV < 7 PET-SUV 7 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

27 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

28 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

29 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

30 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

31 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

32 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