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1 University Hospital Carl Gustav Carus, Dresden, Germany, 2 University Hospital Vienna, Austria

149. Survival with cetuximab / FOLFOX or cetuximab / FOLFIRI of patients with nonresectable colorectal liver metastases in the CELIM study.

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1 University Hospital Carl Gustav Carus, Dresden, Germany, 2 University Hospital Vienna, Austria

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  1. 149 Survival with cetuximab / FOLFOX or cetuximab / FOLFIRI of patients with nonresectable colorectal liver metastases in the CELIM study Gunnar Folprecht,1Thomas Gruenberger,2Wolf Bechstein,3 Florian Lordick,4*HaukeLang,5Juergen Weitz,6Thomas Suedhoff,7Joerg T Hartmann,8*TorstenLiersch,9Claus-Henning Koehne10 1University Hospital Carl Gustav Carus, Dresden, Germany, 2University Hospital Vienna, Austria 3University Hospital Frankfurt, Germany, 4Klinikum Braunschweig, Germany, 5University Hospital Mainz, Germany, 6University Hospital Heidelberg, Germany, 7Klinikum Passau, Germany, 8University Hospital Kiel, Germany, 9University Hospital Goettingen, Germany, 10 Klinikum Oldenburg, Germany*current institution of the author

  2. Background • CELIM study enrolled patients with non-resectable liver metastases • ≥ 5 liver metastases and/or • liver metastases that are technically non-resectable defined by local surgeon in cooperation with local radiologist(amount of functional liver tissue remaining, infiltration of non-resectable structures) • R0 resection in 34% of all patients • Response rates of 70% in k-ras wild type patients • An independent surgical review confirmed that resectability based on CT/MRI images (without clinical data) improved • Current presentation shows survival follow up of June, 2011

  3. Therapy: 8 cycles (~ 4 months) Evaluation of resectability Technically resectable Technically non-resectable 4 additional therapy cycles Resection Therapy continuation for 6 cycles (~ 3 months) Patientswith non-resectable colorectallivermetastases(technically non-resectable / ≥ 5 livermetastases)withoutextrahepaticdisease closedearly, patientswererandomizedto cetuximab arms Biopsy:EGFR screening Randomization EGFR IHC non-detected FOLFOX6 + cetuximab FOLFIRI + cetuximab FOLFOX6 Primary endpoint: Response Folprecht et al, Lancet Oncology 2010

  4. Response andresectionrates Folprecht et al, Lancet Oncology 2010

  5. Overall survivalbytreatmentarms 100% 80% 60% 40% 20% 0% NMedian — FOLFOX/Cet5435.7 (29.9-41.6) — FOLFIRI/Cet5529.0 (18.1-39.8) HR 1.09 (0.69-1.72) 0 12 24 36 48 60 Overall survival in months all patients (%) 100 90 62 47 28 Ptsatrisk 109 98 67 45 14 Median overallsurvival in all patients: 33.1 months(95% CI: 25.8-40.4).

  6. Progression freesurvival 100% 80% 60% 40% 20% 0% NMedian — FOLFOX/Cet5311.2 (7.2-15.3) — FOLFIRI/Cet5310.5 (8.9-12.2) HR 1.15 (0.77-1.70) 0 12 24 36 48 60 Progression freesurvivalin months all patients (%) 100 43 15 6% Ptsatrisk10645 16 5 Median progresisonfreesurvival in all patients: 10.8 months(95% CI: 9.3-12.2).

  7. Survivalby k-ras status Overall survival Progression freesurvival NMedian — K-ras wild type 6936.1 (24.4-47.8) — K-ras mutant2827.4 (15.7-39.1) HR 1.48 (0.88-2.48) NMedian — K-ras wild type 67 11.9 (8.25-15.6) — K-ras mutant27 9.9 (4.5-15.2) HR 1.31 (0.83-2.07) 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 0 12 24 36 48 60 months 0 12 24 36 48 60 months

  8. Survivial in the k-ras wild type subset Overall survival Progression freesurvival NMedian — FOLFOX/Cet3312.1 (5.2-19.1) — FOLFIRI/Cet3411.5 (8.8-14.1) HR 1.09 (0.66-1.79) NMedian — FOLFOX/Cet3435.8 (30.2-41.4) — FOLFIRI/Cet3541.6 (24.8-58.5) HR 1.01 (0.55-1.86) 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 0 12 24 36 48 60 months 0 12 24 36 48 60 months

  9. Survival and R0 resection Overall survival Progression freesurvival 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% — R0 resected — Not R0 resected — R0 resected — Not R0 resected HR 2.07 (1.35-3.16) p=0.001 HR 2.34 (1.37-4.01) p=0.002 • Median PFS: 15.4 • 95%CI: 11.4-19.5 • Median PFS: 8.9 • 95%CI: 6.7-11.0 • Median OS: 46.7 • 95%CI: 30.7-62.7 • Median OS: 27.3 • 95%CI: 21.2-33.3 0 12 24 36 48 60 0 12 24 36 48 60 100 89 78 64 49% 10091 54 37 16% 10091825946% 10089624722% R0 resected, N=36 not R0 resected, N=70 R0 resected (k-ras wtsubset, N=22) not R0 resected (k-ras wtsubset, N=45)

  10. Disease free survival after R0 resection All R0 resectedpts. Bynumberofmetastases atrandomization 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% N Median DFS 36 9.9 mo. (5.8-14.0) NMedian < 5 met.1116.8 5-10 met.228.2 >10 met.3 2.5 p<0.001 0 12 24 36 48 60 months 0 12 24 36 48 60 months DFS 100 47 19 8% k-ras wt 100 50 18 5% subset median DFS in k-ras wtpts: 11.5 mo. DFS was measuredfromresectiontorecurrenceordeath

  11. CELIM: Blinded surgical review Baseline Follow-up 32% 60%, p<0.01 As defined in theinclusioncriteria, all patientswereinitiallytechnically non-resectable and/orhad ≥ 5 metastases. CT/MRI imagesofpatientswereretrospectivelyreviewedby a groupofsurgeonswhowereblindedto all clinicaldataandtotheimaging time (before / after treatment). Surgeonsvotedfor non-resectable (red), borderline resectable withchemotherapypreferredfirst (yellow) and resectable/exploratorylaparotomywithaimofresection (green/light green). Folprecht et al, Lancet Oncology 2010

  12. Survival by surgical review After chemotherapy and cetuximab Imaging atbaseline „non-resectable“ (N=34) „resectable“(N=41) „non-resectable“ (N=53) „resectable“(N=22) 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% HR 0.81 (0.44-1.50) p=0.5 HR 0.47 (0.27-0.83) p=0.007 0 12 24 36 48 60 0 12 24 36 48 60 months As inclusioncriteria, all patientsweretechnically non-resectable and/orhad ≥ 5 metastases. Surgicalreviewbased on CT/MRI imagesonly (withoutanyclinicalinformation).

  13. Summary and Conclusions • Multidisciplinary treatment including cetuximab plus FOLFOX6 or FOLFIRI resulted in a median overall survival of 33.1 months and a 4-year OS-rate of 28% • Patient with R0 resection lived significantly longer than patients with medical treatment alone (HR 2.34 [1.37-4.01] p=0.002). • In R0 resected patients, 3-year- and 4-year- OS-rates are 64% and 49%. • Cetuximab/FOLFOX and cetuximab/FOLFIRI showed similar progression-free and overall survival • With cetuximab plus FOLFOX or FOLFIRI, k-ras wild type had by numbers a longer OS and PFS compared to k-ras mutant patients • Despite favorable long term survival, median DFS after R0-resection of ~ 10 months demonstrates the need for multidisciplinary cooperation and patient selection, especially in patients with high number of metastases • Resectability after treatment with cetuximab and FOLFOX or FOLFIRI but not at baseline was associated with longer survival(based on independent surgical review of CT/MRI images without clinical data)

  14. We thank... • All patientsandtheir relatives • All investigatorsatthestudysitesUniversity Hospital Dresden Klinikum Oldenburg University Hospital Vienna University Hospital Tübingen University Hospital Göttingen University Hospital Munich Rechts der IsarKlinikum Passau Krankenhaus der Barmherzigen Brüder TrierUniversity Hospital / NCT Heidelberg University Hospital Würzburg University Hospital Frankfurt Klinikum CelleUniversity Hospital Essen Klinikum Magdeburg University Hospital Mannheim Klinikum AscherslebenKlinikum Essen-Mitte • The companieswhichsupportedthisstudyMerck KGaA, Sanofi-Aventis, and Pfizer

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