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Optimal Management of Liver Metastases: Present Results and Future Strategies

Highlights in the Management of CRC. Roma, 1-2 febbraio 2007. Mediterranean School of Oncology. Carlo Barone Oncologia Medica Università Cattolica del S. Cuore. Optimal Management of Liver Metastases: Present Results and Future Strategies. CRC liver metastases.

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Optimal Management of Liver Metastases: Present Results and Future Strategies

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  1. Highlights in the Management of CRC Roma, 1-2 febbraio 2007 Mediterranean School of Oncology Carlo Barone Oncologia Medica Università Cattolica del S. Cuore Optimal Management of Liver Metastases: Present Results and Future Strategies Mts epatiche - Roma 2007

  2. CRC liver metastases • 1,025,152 new cases and 528,978 deaths per year in the world: ~ 50% CRC pts develop liver metastases ~ 15% to 25% (118,000) operable ~ 25% to 35% of operated pts alive at 5 years ~ 3% to 4% (40.000) of total can be really cured… Decision Resources, Inc. Globocan for Pharma induustries 2002 Mts epatiche - Roma 2007

  3. Survival in advanced colorectal cancer in 2005 100 1984 overall 1994 overall 2005 chemotherapy 2005 overall 2005 Median survival: Chemotherapy 24 mos. Overall >30 months • 5 year survival: • 1984 2% • 5% • 2005 20% % surviving 50 ? • 1994 2005 • 8 mos 12 mos 27 mos 0 0 1 2 3 4 5 Years after diagnosis of colorectal metastases Dr. G. Poston, Pfizer Satellite Symposium, ECCO 2005 Mts epatiche - Roma 2007

  4. Summary • The role of Surgery in CRC liver mts • Preoperative CT • Resectable mts • Initially not-resectable mts • Hepatotoxicity of CT • The need for a new staging system • The role of targeted agents in the management of liver mts • Adjuvant chemotherapy, HAI o Sys Mts epatiche - Roma 2007

  5. 5-Yr Survival after resection of CRC Liver Mts Mts epatiche - Roma 2007

  6. 5-year survival after resection of CRC liver metastases 30% to 40% Mts epatiche - Roma 2007

  7. 100 90 80 70 60 50 40 30 20 10 Surgery alone versus no surgery *Same survival for non-curative resections % patients 60 pts operated 25% 60 pts not operated* 10 20 30 40 50 60 70 80 Survival (months) 5 years SM Wilson, MA Adson.Arch Surg. 1976;4:330–4. Mts epatiche - Roma 2007

  8. 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - 3 4 5 0.0 1 2 Surgery ± chemotherapy vs no surgery Treatment Resection (n=340) Regional chemotherapy (n=123) Systemic chemotherapy (n=70) No treatment (n=484) Probability of survival Years from diagnosis Stangl R et al. Lancet 1994;343:1405–10. Mts epatiche - Roma 2007

  9. Resection of CRC liver and lung metastases 30% to 40% Mts epatiche - Roma 2007

  10. 1.0 - Complete resection (n = 921) Incomplete resection (n = 62) Non-operated patients (n = 226) 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - 3 4 5 8 9 10 0 1 2 6 7 Patient survival based on level of surgery Probability of survival P < .0001 7 Time from laparotomy /imaging (years) Figure 1. The number at the end of the curve indicates the number of patients surviving beyond 10 years. J.Scheele and coll. Br.J.Surg. 1990, 77:1241. Mts epatiche - Roma 2007

  11. 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0 - Overall Survival with Res. of Multiple (>3) CR Mts with Relation to Response to Neoadj CT 100% 84% Downstaging: 42 Progression: 28 Stabilisation: 57 63% 58% Cumulative survival 45% Log rank: P=.0001 0% 0 1 2 3 4 5 Years Adam R. Ann Oncol. 2003;14 Suppl2:ii13-16. Mts epatiche - Roma 2007

  12. Pre-operative chemotherapy in resectable CRC liver metastases Oxaliplatin-based regimens Mts epatiche - Roma 2007

  13. Non-resectable liver mts Phase II – non-selected patients (A) Mts epatiche - Roma 2007

  14. Non-resectable liver mts Phase II – non-selected patients (B) Triplets Mts epatiche - Roma 2007

  15. Non-resectable liver mts Phase III – non-selected patients Mts epatiche - Roma 2007

  16. Non-resectable liver mts Phase II – selected patients * + 38.2% resection + RF or CS Mts epatiche - Roma 2007

  17. Neoadju treatment of CRC unresectable liver mts with IRI and 5-FU plus LV • Synchronous mts 67.5% • <3mts/>6 mts 52.5%/27.5% • Largest mts >5 cm 30% • Mts in hilum/bilobar/RL 17.5%55/27.5% U.O.C. di Oncologia Medica Co-operation U.O.C. di Chirurgia Epatobiliare 5FU bolus 400 mg/m² 5FU bolus 400 mg/m² oxaliplatin 85 mg/m2 2 h 5FU 1,200 mg/m² CI 46 h FA 200 mg/m² 2 h FA 200 mg/m² 2 h DAY 1 DAY 2 Annals of Oncology 2004;15:933–9. Mts epatiche - Roma 2007

  18. Criteria for unresectabilityUCSC experience *Major hepatectomy (more than 4 segments resection, according to Coineau) needed Pozzo C, et al. Ann Oncol. 2004;15:933-39. Mts epatiche - Roma 2007

  19. Primary Endpoints Response Resection Rate Neoadjuvant chemotherapy % 40 % • 2 carcinosis • 1 N+ 16 RR Candidates for Surgery 40 24 3 RC RP SD • R0 • 10 multiple segmental res. • 3 right lobectomies PD 16 13 33% Pozzo C, et al. Ann Oncol. 2004;15:933-39. Mts epatiche - Roma 2007

  20. 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Resection rate by response and main cause of unresectability By Main Cause of Unresectability By Response 60% 58% 36% Resection rate (%) CR + PR Size of mts 18% 14% Liver Reserve = 0 Location SD PD=0% N° Pozzo C, et al. Ann Oncol. 2004;15:933-39. Mts epatiche - Roma 2007

  21. 1,0 - 0,9 - 0,8 - 0,7 - 0,6 - 0,5 - 0,4 - Non resected Resected 0,3 - 0,2 - 0,1 - 0,0 - 0 10 20 30 40 50 60 70 Secondary Endpoints • Median Follow-up: 30 m (6-54) • TTP (all) = 14.3 m • Median OS = 30.6 m • Not resected = 24 m • Resected = not reached Overall Survival Patients% Months Pozzo C, et al. Ann Oncol. 2004;15:933-39. Mts epatiche - Roma 2007

  22. FOLFIRINOX as induction CT in pts with previously unresectable CRC liver mts Reason for un-resectability • Invasion of hilum 6 pts • Contact with inferior VC 16 pts • Invasion of >2 hepatic veins 4 pts • Remnant liver <25% 12 pts • Unlikely R0 4 pts 5FU bolus 400 mg/m² FA 400 mg/m² 2 h 5FU 2,400 mg/m² CI 46 h oxaliplatin 85 mg/m2 2 h irinotecan 180 mg/m2 1 h 30 Ychou M, et al. ESMO 2004, Abs 273. Mts epatiche - Roma 2007

  23. Primary Endpoints Response Resection Rate Neoadjuvant chemotherapy % • 13 Res+ RF/CS • 1 R2 82 % Candidates for Surgery RR • 13 Res+ RF/CS • 1 R2 14 28 34 RC RP SD PD 14 41% 28 • 9 R0 • 5 R1 6 Ychou M, et al. ESMO 2004, Abs 273. Mts epatiche - Roma 2007

  24. Secondary Endpoints • Median Follow-up = 30.9 m (26.4-35.6) • TTP (resected and non-resected) = 11.9 m • Median OS = 35.5 m • MS RC post-surgery = not reached • Survival (2 yrs) = 70% Median Survival RC post-surgery (n = 27) 1.00 0.75 0.50 Overall Survival (n = 34) 0.25 0.00 Ychou M, et al. ESMO 2004, Abs 273. Mts epatiche - Roma 2007

  25. FOLFOX4 for Pts with Unresectable Liver-only Mts from CRC: a NCCTG Phase II Study Reasons for Unresectability • Number 19 pts (45%) • Localization 3 pts (7%) • Size 3 pts (7%) • Combination 15 pts (36%) • Not available 2 pts (5%) 5FU bolus 400 mg/m² 5FU bolus 400 mg/m² oxaliplatin 85 mg/m2 2 h 5FU 1,200 mg/m² CI 46 h FA 200 mg/m² 2 h FA 200 mg/m² 2 h DAY 1 DAY 2 Alberts, JCO 2005; 23:9243–9. Mts epatiche - Roma 2007

  26. FOLFOX4 for Patients with Unresectable Liver-Only Mts from CRC: Primary Endpoints Response Resection Rate Neoadjuvant chemotherapy % 40.5 % • 2 unresect. • 1 part. Res. RR 17 Candidates for Surgery 42 3 25 PD SD RP RE RC 16 14 33% • R0 Alberts SR, et al. JCO. 2005;23:9243-9 Mts epatiche - Roma 2007

  27. FOLFOX4 for Pts with Unresectable Liver-Only Mts from CRC: Secondary Endpoints Resected pts Resected pts Time to Recurrence (from surgery) Time to Progression (from registration) • Median follow-up: 36 m • Median OS: 26 m (95% C.I. 19-34 m) • Resected pts: not reached • 3 yrs Surv. of res. pts: 67% OS Mts epatiche - Roma 2007

  28. Neoadj CT for Pts with CRC Unresectable Liver-Only Mts: phase II studies Mts epatiche - Roma 2007

  29. Liver metastases 85% unresectable 15% resectable • 10%-30% potentially resectable • 70%-90% never resectable Resection Resectability in pts with CRC liver metastases – where are we now? CT 30%? Mts epatiche - Roma 2007

  30. in 29 pts : 46 LM sites (76%) There no evidence residual macroscopic disease 15 initially resectable pts had surgery – viable tumor cells at LM sites in 12 (80%) pts 14 initially unresectable pts had surgery – after 1 year 74% of LMs had recurred in 11 (79%) pts Does complete response mean cure? 38 pts with 183 LMs received CTx CT scan 66 (36%) LMs disappeared laparotomy, liver exam and ultrasound in 9 pts : 20 LM sites (24%) There was residual macroscopic disease Persistent macro- or microscopic disease or early recurrence in situ in 55/66 LMs (83%) = 32/38 pts Benoist et al. JCO 2006;24:3939-45 Mts epatiche - Roma 2007

  31. 66 LM disappeared on CT scan after chemotherapy Surgery : Macroscopic cancer : 20 LM No lesion : 46 LM 15 sites resected 31 sites left in place In situ recurrence : 23 Viable tumor cells : 12 55/66 (83%) of metastases were not « cured » Mts epatiche - Roma 2007

  32. Chemotherapy-induced liver changes Sinusoidal distention and obstruction (oxaliplatin) Steatohepatitis (Irinotecan) Vauthey et al. JCO 2006 Mts epatiche - Roma 2007

  33. Relation between type of liver damage and clinical outcome • Steatosis associated with higher infection rate(Kooby et al. 2003) • Steatohepatitis associated with higher mortality rate due to liver failure after surgery (Vauthey et al.,2006) • Vascular injury associated with higher rate of operative bleeding and transfusion requirement(Vauthey et al. 2006; Adam et al. 2005) Mts epatiche - Roma 2007

  34. Type of CT prior to resection • 44/87 pts (51%) who received CT exhibited centrolobular lesions Rubbia-Brandt, Ann Oncol 2004 Mts epatiche - Roma 2007

  35. Incidence of steatohepatitis with modern CT regimens Leonard et al ASCO 2005 Mts epatiche - Roma 2007

  36. Preoperative (neoadjuvant) CT • Adam et al ASCO 2005 • 92 patients resected for liver metastases • 17 pts no CT • 23 pts FUFOL • 52 pts FOLFOX • FOLFOX-treated patients had < steatosis and fibrosis than FUFOL-treated patients • No clinically relevant impact on outcome following resection Adam et al. ASCO 2005; #3529 Mts epatiche - Roma 2007

  37. EORTC 40983 study: Resectable liver mts • FOLFOX4  Surgery  FOLFOX4 • R • (N = 363) • Surgery alone 6 cycles 6 cycles Endpoints DFS and safety More post-operative complications in FOLFOX arm (21.1% vs 9.7%): not definitive results Mts epatiche - Roma 2007

  38. Resectable liver mts: CT vs Surgery aloneKaroui/Nordlinger (2006) Postoperative morbidity was correlated with no. cycles but not type of chemotherapy Karoui et al. Annals Surgery 2006 Mts epatiche - Roma 2007

  39. Hepatoxicity of preoperative CT Vauthey et al. JCO 2006 Mts epatiche - Roma 2007

  40. Hepatoxicity of preoperative CTSummary • Both Oxa and IRI may induce hepatotoxicity • Oxa induces a prevalenty vascular damage (sinusoidal obstruction or distention), whreas IRI induces a steatohepatitis • The clinical impact of this toxicity is not clear, but it could be a concern in pts with resectable liver mts • Post-operative morbidity seems correlate with the number of cycles, not with the type of CT Mts epatiche - Roma 2007

  41. In 2006: A clear separation between resectable and unresectable? • Definition of resectability has evolved • Many pts may be now considered resectable, as a result of novel treatment strategies • Resectability rates for liver only metastases after chemotherapy 6%-60% • Resection rates correlate with response to chemotherapy • 5-year survival rates after secondary liver resection (possible after chemotherapy) are in line with those following primary liver resectionat 35%-50% 1. Folprecht et al. Ann Oncol, 2005; 2. Bismuth et al. Ann Surg, 1996; 3. Giacchetti et al. Ann Oncol, 1999 Mts epatiche - Roma 2007

  42. Which liver mts are resectable? OncoSurge Strategy • Absolute Controindications • - Unresectable extrahepatic disease • - More than 70% liver involvement • - Liver failure • Surgically unfit • Not influencing factors • - Age/Primary tumor stage • - Timing of mts detection • - Past blood transfusion • Liver resection type • Preresection CEA • Previous hepatectomy • Immediate resection appropriate • - Adequate resection margins • - No portal adenopathy • ≤ 4 mts and unilobar involvement • Post-CT resection appropriate • - Independent of tumor response in the case of ≤ 4 mts and unilobar involvement • After tumour shrinkage for > 4 mts or bilobar liver involvement Poston GJ, JCO 2005 Mts epatiche - Roma 2007

  43. French guidelines (2003) Resectable patients Class 1Easily resectable: involvement of ≤4 of 8 liver segments, vena cava clear, ≥ 1 hepatic vein, contra-lateral portal pedicle Class 2Potentially resectable: involvement of 5-6 segments, ±contra-lateral major named vascular structures within liver Gastroenterologie Clinique et Biologique 2003;Special issue II Mts epatiche - Roma 2007

  44. ,6 - ,5 - ,4 - ,3 - ,2 - ,1 - 0,0 - ,3 ,4 ,5 ,6 ,7 ,8 ,9 Resection rate of metastases and tumour response Studies with selected patients Liver metastases only, no extra-hepatic disease R=0.96, P=0.002 Studies with all patients with metastatic CRC (solid line) R=0.74, P<0.001 Phase III studies in metastatic CRC (dashed line) R=0.67, P=0.024 Resection rate Response rate Folprecht et al, Ann Oncol 2005 Mts epatiche - Roma 2007

  45. Limitations of present Stage IV • Does not: • allow stratification of patients according to prognosis • guide therapeutic decision making • permit comparison of results from radical/non-radical treatments Mts epatiche - Roma 2007

  46. Incurable Unresectable Prognosis: ≈6 months Potentially curable Resectable Prognosis: long-term survival Stage 4 – the catch-all STAGE 4 CRC spread beyond N2 A new system is needed to differentiate between these Stage 4 patients according to prognosis for the appropriate decision-making process Mts epatiche - Roma 2007

  47. Staging: why a new staging? • Our perceptions of ‘resectable’ and ‘unresectable’ disease has been altered • The developments in the field of liver resection are not reflected in our approach to staging • Patients with mCRC no longer form a homogeneous group • We need a staging system which • Can differentiate between the patient sub-groups with different prognosis (resectable, initially unresectable, never resectable) • Provides guidancefor therapeutic decision making • Provides clear indication for surgery or chemotherapy Mts epatiche - Roma 2007

  48. Guidance from Second Workshop, November 2005 • Consensus for a proposed stratification of Stage 4 (IV) patients: Stage 4a: easily resectable liver metastases Stage 4b: resectable liver metastases Stage 4c: liver metastases that are resectable after downsizing Stage 4d: liver metastases that will never be resectable Stage 5a: resectable extrahepatic disease Stage 5b: unresectable extrahepatic disease Mts epatiche - Roma 2007

  49. Guidance from Second Workshop, November 2005 • Makes the distinction between: • Resectable • Easy • Difficult • Initially unresectable • Never resectable • Defines disease outside of the liver Mts epatiche - Roma 2007

  50. The compromise from the third workshop: may 2006 (1) • Consensus for a proposed stratification of Stage 4 (IV) patients: Stage 4a: Resectable liver only metastases Stage 4b: Initially unresectable liver only mts Stage 4c: Liver only metastases that will never be resectable Stage 5a: Resectable liver and extrahepatic disease Stage 5b: Resectable extrahepatic disease only Stage 5c: Unresectable extrahepatic disease Mts epatiche - Roma 2007

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