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Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris

The multimodal treatment of liver metastases : FREQUENTLY ASKED QUESTIONS. Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris. Questions. What is resectable ? Chemotherapy before or after resection ? Indications for immediate surgery ?

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Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris

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  1. The multimodal treatment of livermetastases: FREQUENTLY ASKED QUESTIONS Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris

  2. Questions Whatis resectable? Chemotherapybefore or afterresection? Indications for immediatesurgery? How to manage metastaseswhichdisappearfromimaging? Doesneoadjuvantchemotherapyincrease the risks of surgery? Targeted agents before surgery for liver metastases ? Should all patients withlivermetastasesbeconsidered for resection?

  3. Question Whatis a resectablemetastasis?

  4. A resectablemetastasis: a principle • Complete resection of tumor is feasible • Free resection clearance: R0 • Preservation of hepatic vein(s) and portal pedicle to remnant liver • Remnant liver parenchyma 25 % • Resectability does not depend on the number of metastases

  5. Resectablemetastases • Categories: - Easilyresectable - More difficult to resect; need for specificskills - Resectable + RFA - Potentiallyresectableafterresponse to chemotherapy - Unresectable and unlikely to everberesected • Do not deny the potentialbenefit of major liverresection; if local surgeon does not have the expertise,refer to an expert institution

  6. Complete local treatmentwithresection and radio frequency ablation right lobectomy + RFA Bilobardisease

  7. Message: • Discuss all cases in multidisciplinary meetings

  8. Question: • Chemotherapy combined with surgery for resectable metastases: before or after?

  9. Aim and design Demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone Randomize FOLFOX4 Surgery FOLFOX4 6 cycles (3months) 6 cycles (3 months) Main Eligibility criteria • Potentially resectable liver metastases of colorectal cancer • Up to 4 deposits (on CT-scan, at randomization) Surgery N=364 patients

  10. Progression-free survival in eligible patients Nordlinger et al. Lancet 2008 HR= 0.77; CI:0.60-1.00, p=0.041 LV5FU + OxaliplatinPeriop CT +8.1%At 3 years 36.2% Surgery only 28.1%

  11. Overall survival in eligible patientsNordlinger et al. ASCO 2012 HR= 0.87; CI:0.66 -1.14, p=0.303 median OS: +8.7 months 5 years OS:+4.1 % LV5FU + OxaliplatinPeriop CT 52.4.% 48.3% Surgery only 55M 63.7M 5

  12. Message: • Peri-operativechemotherapywith FOLFOX considered the treatment of reference in patients withresectablemetastases

  13. Question: • Are there indications for immediatesurgery of resectablemetastases?

  14. Is this « good risk »case an indication for surgeryonly? • Metastasisiseasilyresectablewithadequatmargin • Risk of cancer relapse is 50%: surgery alone is not sufficient

  15. Post-operative chemotherapypooled-analysis of two 5-FU studies 1.0 0.8 p=0.058 0.6 Survival 0.4 0.2 Adjuvant chemotherapy Surgery alone 0.0 0 20 40 60 80 Months Mitry E, et al. J Clin Oncol 2008;26:4906-11.

  16. Post-operativechemotherapyonly? • No sufficientevidence to be standard treatmentat the moment • 1/3 patients do not receiveplannedpost-optreatment, althoughalmost all canreceivepre-optreatment ( EORTC study ) • No trials availablecomparingpre vs post • Post-operativechemotherapyis an option in patients whodid not receiveperi-operativechemotherapy: • - Small and poorlylocatedmetastasiswhichmaydisappearafterchemotherapy • - Small synchronousmetastasiswith indication to resect the primary

  17. Question: How to manage metastaseswhichdisappearfromimagingduringchemotherapy?

  18. « Complete response » on imaging • Complete responsedoes not mean cure in up to 80% of cases • It ispreferableto resectlivermetastasesbeforecomplete response when surgeons can see them,and not overtreat patients with chemotherapy 1Benoist et al. JCO 2006 2Tan et al. J GastroIntestSurg 2007 3Adam et al. JCO 2008 4Elias et al. Ann SurgOncol 2007

  19. « Complete response » on imaging:lookingforlostmetastases Try other imaging methods: - MRI - FDG Pet scan probably unhelpful ( Tan, J GastrointestSurg 2007 Covas ASCO 2008) - Contrast Enhanced US If they are no longer visible - resect the site - hepaticartery infusion - follow up for recurrence

  20. Localisation of small lesions which may be lost • Evaluate patients every 3-4 cycles and resectbeforemetastasesdisappear • Localisation is not a problem if an indication for anatomicalresection • Percutaneousradiofrequency ablation and resection of scar • Coilsbeforechemotherapy to mark smalllesions Zalinski et al, Ann SurgOncol 2009

  21. Question: • Doesneoadjuvantchemotherapyincrease the morbidity or mortality of surgery?

  22. Clinical significance: impact on surgery • Mortality rate not increased • Morbidity rate related to the number of cycles of CT • Karoui Nordlinger et al, Ann.Surg. 2006 • Aloia Adam et al, 2006: Morbidityincreasedafter 12 cycles • Nakano Jaeck et al, 2008: Morbidityincreasedafter 6 cycles

  23. EORTC 40983 : complications of surgery *P=0.04 Nordlinger et al., Lancet 2008

  24. Risks of surgerydepend on the number of cycles Message:

  25. Optimal duration of pre-operativechemotherapy? Question:

  26. Optimal duration of pre-operativechemotherapy Different - whenmetastases are resectable - whenmetastases are not resectable

  27. Duration of pre-operativechemotherapy in resectablemetastases - 6 cycles according to EORTC 40983- Couldfewer cycles besufficient?

  28. Duration of pre-operativechemotherapy in initiallyunresectablemetastases? • Aim: convert patients to resection with a hope for cure • Chemotherapy should be discontinued when metastases have become resectable and not givenuntil best responseisobserved • Overtreatment can damage the liver and preclude surgery

  29. Question: If resectablemetastasesprogressduringpre-operativechemotherapy?

  30. Progression duringpre-operative CT • A biological marker for poorprognosis • No surgery if metastasesprogress • Change chemotherapy,

  31. Question: Targeted agents before liver surgery for metastases ?

  32. Cetuximab:1st-line mCRC treatment in KRAS wild-type OxFp, Oxaliplatin + fluoropyrimidine; p-value for primary endpoint only The methodologies applied in the studies shown are not identical and studies should therefore not be compared 1Van Cutsem E, et al. J ClinOncol 2010; 28(15s):3570; 2Bokemeyer C, et al. ASCO-GI 2010, #428; 3Maughan TS, et al. J ClinOncol 2010; 28(15s):3502.

  33. Panitumumab:1st-line mCRC treatment in KRAS wild-type 1Siena S, et al. ASCO-GI 2010, #283;.

  34. Bevacizumab:1st-line mCRC treatment p-value for primary endpoint only The methodologies applied in the studies shown are not identical and studies should therefore not be compared 1Saltz LB, et al. J Clin Oncol 2008; 26:2013-9; 2Hurwitz H, et al. N Engl J Med 2004; 350:2335-42.

  35. RECIST criteria may not fully evaluate the efficacy of bevacizumab in CLM Major response Interobserver variation: κ=0.78 Chun & Vauthey. JAMA 2009

  36. Response and resection; phase 2 trials:Cetuximab and Bevacizumab * Bechstein WO, et al. J ClinOncol 2009;27(Suppl. 15): Abstract No. 4091** GarufiC, et al. ASCO GI 2008. Abstract No. 367; ***Wong R. ESMO34th-ECCO15th

  37. Targetedtherapies and risk of surgicalcomplications - EGFR blockers: no interferencewithsurgery - VEGF inhibitors: surgery delayed 6 – 8 weeks

  38. Targeted agents in resectablemetastases • Standard treatmentis FOLFOX4 • Shouldweextrapolatethat « the most effective regimen » is the best? • Whichreference? Metastatic or adjuvant treatment?

  39. Ongoing and future trials in resectable metastasis • CRUK 06/031: FOLFOX ± cetuximab in KRAS WT • EORTC: 2 trials

  40. EORTC 40091: BOS2 (Biologics, Oxaliplatin, Surgery) KRAS Wild type SURGERY FOLFOX • FOLFOX Follow up Resectable Liver Metastases from CRC n < 8 KRAS WT R SURGERY • FOLFOX + Panitumu mab FOLFOX + Panitumu mab Follow up FOLFOX+ Bevacizumab SURGERY • FOLFOX • + Bevacizu mab Follow up Endpoints: PFS; Pathological Response

  41. EORTC 1207: BOS3 (Biologics, Oxaliplatin, Surgery) KRAS Mutated SURGERY mFOLFOX6 mFOLFOX6 Follow up Resectable liver metastases (n° ≤ 8) from CRC KRASmutant Randomization SURGERY mFOLFOX6+ Aflibercept mFOLFOX6+ Aflibercept Follow up

  42. Targeted agents in unresectablemetastases • Aimisresection • Regimenwithhighresponse rate - intensified chemotherapy - addition of biologics to chemotherapy

  43. Question: Should all patients presentingwithlivermetastasesbeconsidered for resection?

  44. Patients usuallydivided in 3 groups: • Resectable • Never resectable • Potentiallyresectable in case of good response to chemotherapy

  45. Some patients have such a major response to chemotherapythatitallows to considersurgeryalthough not expectedinitially

  46. GONO study: FOLFOXIRI – PFS in R0 patients 1.0 0.8 0.6 0.4 0.2 0 R0 patients Median PFS: 17.8 months 5-years PFS: 16% OS estimate n=37 Events (n)=31 Median Follow up: 60.5 months 0 12 24 36 48 60 Time (months) Falcone, et al. Ann Surg 2009

  47. Resectionafterchemotherapy Resectionafterchemotherapy: Never saynever; keepeyes open Be awarethatresectiondoes not solve all the problems Discuss all patients in multidisciplinary meetings

  48. Anyother question?

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