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Resectability and agreement between surgeons: Review of CT- and MRI- scans of the CELIM study

Abstract 4091. Resectability and agreement between surgeons: Review of CT- and MRI- scans of the CELIM study (Multicenter randomized trial of cetuximab/FOLFOX versus cetuximab/FOLFIRI in unresectable liver metastases).

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Resectability and agreement between surgeons: Review of CT- and MRI- scans of the CELIM study

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  1. Abstract 4091 Resectability and agreement between surgeons: Review of CT- and MRI- scans of the CELIM study (Multicenter randomized trial of cetuximab/FOLFOX versus cetuximab/FOLFIRI in unresectable liver metastases). Wolf Bechstein,1Hauke Lang,2Claus-Henning Köhne,3 Fabio Parisi,4Hans-Rudolf Raab,3Andrea Frilling,5Ralf Konopke,6Jürgen Weitz,7Christian Stroszczynski,6Gunnar Folprecht6 1University Hospital Frankfurt, Germany, 2University Hospital Mainz, Germany, 3 Klinikum Oldenburg, Oldenburg, Germany, 4New York University, N.Y., U.S., 5University Hospital Essen, Germany, 6University Hospital Carl Gustav Carus, Dresden, Germany, 7University of Heidelberg, Dpt. of Surgery, Heidelberg, Germany

  2. Background • Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004) • Resectability of colorectal liver metastases depends on technical resectability and prognostic factors • Number of liver metastases is an important prognostic factor and pts with > 4 liver met’s were excluded from neoadjuvant trial for resectable liver metastases (Nordlinger, Lancet 2007) • In primary non-resectable liver metastases, resection rate correlates with response to chemotherapy • Few data are available on achievement of resectability due to chemotherapy and on the agreement between surgeons regarding resectabilty • Cetuximab increases response rates when added to FOLFIRI or FOLFOX (Van Cutsem NEJM 2009, Bokemeyer JCO 2009) • The CELIM study compared tumor response and resectability rates in patients with unresected liver metastases receiving neoadjuvant treatment with cetuximab plus FOLFIRI or FOLFOX6

  3. Patient selection • Patients with non-resectable colorectal liver metastases • Definition of non-resectability: • ≥ 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) • Expected resectability after response to chemotherapy was not an inclusion criterion • No extrahepatic disease • Karnofsky PS ≥ 80% and adequate hepatic, renal, and bone marrow function • Metastases histologically confirmed • Patients with simultaneous liver metastases were eligible if the primary tumor was resected ≥ 1 month prior to chemotherapy • Informed consent; no prior chemotherapy (except adjuvant chemotherapy ≥ 6 months ago); no concurrent immunotherapy, chemotherapy or hormone therapy; no previous malignancy other than colorectal cancer, basal cell carcinoma, or pre-invasive carcinoma of the cervix; no inflammatory bowel disease; no relevant coronary heart disease

  4. Biopsy:EGFR screening Randomization EGFR IHC 0 FOLFOX6 + cetuximab FOLFIRI + cetuximab FOLFOX6 Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)without extrahepatic metastases closed early • Stratification: • technically non-resectable / ≥ 5 liver metastases • staging with PET • EGFR IHC • FOLFOX6: oxaliplatin 100 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m² • FOLFIRI:irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m² • Cetuximab: 400 mg/m², then 250 mg/m² weekly 5-FU, 5-fluorouracil; FA, folinic acid; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; PET, positron emission tomography.

  5. 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) Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)without extrahepatic metastases Biopsy:EGFR screening Randomization FOLFOX6 + cetuximab FOLFIRI + cetuximab Primary endpoint: Response EGFR, epidermal growth factor receptor.

  6. Patient characteristics

  7. Patient characteristics NA, not available

  8. Efficacy: confirmed response Responses confirmed by 2nd CT scan according to RECIST or by resection Chi square test for comparison between FOLFOX6+cetuximab vs FOLFIRI+cetuximab: p would be 0.23 CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, CT, computed tomography

  9. Confirmed response by subgroups Responses confirmed by 2nd CT scan according to RECIST or by resection Chi square test for comparison between KRAS wild-type vs KRAS mutant: p < 0.01 CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CT, computed tomography; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; CI, confidence interval

  10. Liver resections Resections in pts with KRAS wild-type tumors: 22/67 pts (33%)

  11. Perioperative morbidity / mortality • Two post-operative deaths (4%): • Gram-negative sepsis – 8 days postop (right hemihepatectomy, FOLFOX + cetuximab arm) • Multiorgan failure – 75 days postop (two-staged liver resection, FOLFOX + cetuximab arm)

  12. CT/MRI scans R S S S S S Blinded surgical review • A blinded surgical review performed for CT/MRI at baseline and at 4 months: • CT / MRI scans were presented by a radiologist to 5-6 liver expert surgeons of participating centers in two workshops. • CT, computed tomography; MRI, magnetic resonance imaging

  13. Surgical review • CT / MRI scans were evaluated by the surgeons without knowing when the scan was taken (before or after chemotherapy) and without clinical data • Surgeons allocated scans to:resection / exploration / chemotherapy preferred / non-resectable • Surgeons were blinded to the votes of the other participants. • 181 scans reviewed / 171 scans evaluable • Paired scans (baseline and follow-up) available for 68/106 ptsActual resection rate in this subgroup 34%, response rate 60% • Following imaging review:22/68 scans (32%) judged resectable at baseline41/68 scans (60%) judged resectable at follow-up (p<0.01)

  14. Waterfall plot of resectability at baseline Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”

  15. Waterfall plot of resectability after chemotherapy Resectability according to imaging increased by 28% (32% → 60%) p<0.01 Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”

  16. Patterns of voting of the individual surgeons Votes for “resectable”/”exploration” are in green, “chemotherapy preferred” in yellow and for “unresectable” in red. Blinded review of patient MRI and CT scans at baseline and follow-up revealed large variation between reviewers in the decision making process.

  17. Agreement and critical disagreement Reviewer Agreement “Critical” disagreement “Agreement” (grey/green) show the percentage of agreement between two individual surgeons with the categories “resection/exploration”, “chemotherapy preferred” and “unresectable”. Total rate in all decisions is 64.5% “Critical disagreement” means the proportion of contrary votes (one surgeon for “resection/exploration”, the other for “unresectable”) The total rate in all pairs is 6.8% The numbers in brackets mean the evaluable images per surgical pair.

  18. Conclusions • High response rates induced by cetuximab plus either FOLFOX or FOLFIRI: • 70% confirmed response in KRAS wild-type patients • Resections among patients with initially non-resectable liver metastases: • 34% R0 liver resection • 46% R0 or R1 liver resection and/or RFA • Perioperative morbidity/mortality comparable to experience from literature • Resectability according to imaging review improved significantly following treatment with cetuximab plus FOLFOX or FOLFIRI • Cetuximab plus FOLFOX or FOLFIRI are good options for conversional chemotherapy for KRAS wild-type patients(Europe, not approved in U.S.) • Although, as demonstrated here, there is heterogeneity between different surgeons in treatment decisions, this rarely results in the need for a surgical second opinion within experienced centers

  19. We thank... • All patients and their relatives • All investigators at the study sitesUniversity 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 companies which supported this studyMerck-Serono, Sanofi-Aventis, and Pfizer

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