Optimal approach to medical management of synchronous colorectal liver metastases

1. MSO, School of Oncology Optimal approach to medical management of synchronous colorectal liver metastases Roma, 4 marzo 2011 Dott.ssa Angela Torsello Angela TORSELLO Oncologia Medica A Istituto Regina Elena, Roma

2. Colorectal cancer liver metastases

3. Colorectalcancerlivermetastases Liver metastases 25% synchronous with the primary tumor 20% metachronous • Mets sinchronous : • More often bilobar and greater in number/size • Poorer survival • Different management (i.e. the resection time of primary tumor and liver metastases represent an important issue) Tan EK et al, Ann Acad Med 2010

4. Treatment of Colorectal Liver Metastases In patientswithlivermetastases the maintopicistoevaluatelesionsresectability or the possibilityof the lesionstobecameresectableafterneoadjuvantchemotherapy: Strangl R et al. Lancet 1994

5. 5-y Survival Resected patients: 25-40% Liver resection= Possibility to cure Adam R.

6. SynchronousColorectalLiverMetastases I • Should primary tumor be resected before starting sistemic treatment? • This could represent a problem in the control of disease (delayed sistemic treatment) • BUT…..Importance of patient symptoms: subocclusion/occlusion, bleeding…

7. SynchronousColorectalLiverMetastases II • Shouldlivermetastasesberesected at the sametimeas the primarytumor? • a) Importanceofprimarytumor site: • - right sidedtumorscouldbebetterresected at the sametimeoflivermetastases in selectedpatients; • leftsidedtumor (especiallyrectalcancer) present more thecnicallydifficulties and post-operative risks • b) A delayed (3-6 months) liverresection and chemotherapyadministrationpermits a “test oftime”: selectionofpatientswhoreallybenefitsofliverresectionwith curative intention

8. Surgery in synchronous colorectal liver metastases The optimal timing of synchronous metastases resction is not well defined Surgical strategy are defined as combined (combined resection of primary and liver), classic (primary before liver) and reverse (liver before primary) These surgical strategies are associated with similar outcomes The combined strategy is considered safe with no different in morbidity and mortality rates or in severity of complications, compared with staged resection

9. Reverse approach • Recently this kind of surgical approach is considered for rectal cancer with synchronous liver metastases • The treatment sequence proposed is the following: • Systemic chemotherapy followed by liver resection • Chemoradiation followed by rectal resection Van der Pool et al, ASCO 2010 abs e14027

10. Postoperative outcome of 142 pts with different surgical strategy for synchronous liver mets Brouquet A et al, J Am Coll Surg 2010

11. The impact of multidisciplinary management 100 2009 chemotherapy Median survival >24 months 5 year survival 9 % 2009 overall (Surgery + Chemo) Median survival ~36 months 5 year survival 20 % % surviving 50 2019? 1999 20% 9% 3% 0 0 1 2 3 4 5 Years after diagnosis of colorectal metastases Poston GJ. EJSO 2005; 31: 325-30

12. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial Nordlinger et al, Lancet 2008

13. Postoperative complications Peri-op Surg Number in group 159 170 Reversible postoperative complications† 40 (25%) 27 (16%) Cardio-pulmonary failure 3 (2%) 2 (1%) Bleeding 3 (2%) 3 (2%) Biliary fistula 13 (8%) 7 (4%) Output >100 mL/day for >10 days 9 (6%) 2 (1%) Hepatic failure 11 (7%) 8 (5%) Bilirubin >100 mg/day for >3 days 10 (6%) 5 (3%) Wound infection 5 (3%) 4 (2%) Intra-abdominal infection 11 (7%) 4 (2%) Need for reoperation 5 (3%) 3 (2%) Urinary infection 4 (3%) 0 Pleural effusion 3 (2%) 1 (1%) Pulmonary embolism/deep-venous thrombosis 2 (1%) 1 (1%) Pneumopathy 2 (1%) 0 Neutropenia 2 (1%) 0 Ascites 1 (1%) 1 (1%) Ileus 2 (1%) 1 (1%) Cardiac arrhythmia 0 1 (1%) Renal failure 0 1 (1%) Other 4 (3%) 4 (2%) Postoperative death 1 (1%) 2 (1%)

14. The timing of chemotherapy and surgery Liver mets resectable at presentation: the perioperative chemotherapy has become the standard treatment in many institutions (to be performed after maximum 6 cycles of chemotherapy) Liver mets initially not resectable: monitoring patients during chemotherapy to perform surgery as soon as the metastases become resectable Nordlinger et al, Clin Colorectal Can 2010 and Ann Oncol 2009

15. Liver metastases treatment Liver metastases 85% non resectable 15% resectable Neoadjuvant chemotherapy • R0 • R0 uncertain Potentially resectable (4-30%) more? FA/OXA/CPT11 (Triplet) FU/OXA o CPT11 FA/FU Target therapies

16. Topics of liver metastases neoadiuvant chemotherapy • Patients selection • Type of treatment (systemic; hepatic intra-arterial) and schedule (new biological drugs) • Liver damage • Respose to treatment (complete vs partial response)

17. PATIENTS SELECTION

18. 50 40 30 48 20 26 10 12 9 large 0 Multi-nodular ill-located extra-hepatic Adam R., et al. Ann Surg Onc 2000 What does it mean “resectable disease”? Traditional controindications: • ≥ 4 metastases • Size • Extrahepatic disease • Ilar disease • Resection margin< 1 cm • Incomplete resection • Now is admitted: • Resection margin≤ 1 cm • Number • Size • Extrahepatic disease • Need standard resection criteria

19. French Recommendations 2003 • Potentially resectable= class I (involvement max 4 anatomic segments; non-involvement of cava vein, almost one of hepatic veins and controlateral portal pedunculus)* • Potentially resectable= classe II (involvement of 5-6 anatomic segments and/or major controlateral vascular structures)* • Not resectble that became resectable= classe III • Never resectable= classe IV *Classe I = easily resectable Classe II= resectable with difficult

21. Criteri di non resecabilità (IRE): • Size • Multinodular • Ilar location • Extraepatic disease • Patients with >3 metastases who receive chemotherapy in order to stabilize liver disease before surgery • Patients who present with huge resectable liver metastases at the time of resection of the primary tumor and need extended liver surgery

22. CRC Staging: IV Stage (Consensus 2006) • Stage IVa: “easily resectable liver metastases” • Stage IVb: “resectable liver metastases” • Stage IVc: “liver metastases thet may become resectable after downsizing” • Stage IVd: “liver metastases that are unlikely to become resectable”* • Stage Va: “resectable disease outside the liver” • Stage Vb: “unresectable disease outside the liver”* • *never resectable EJC, 2006

23. It is important: • Staging of metastastic patients (TC, US, RMN, PET) • Resection criteria • Prognostic factors (outcome predictors)

24. NEOADJUVANT CHEMOTHERAPY

25. Response rate and surgery of metastases (First line 5-FU, LV and l-OHP) 40 93-94 Chrono 4-10 30 90-93 94-96 20 Complete resection of metastases (%) Chrono 5-16 90-93 10 Flat 5-16 r = 0.96 ; p = 0.0007 0 0 30 40 50 70 60 Objective responses (%) Secondary surgery of metastases : major prognostic factor of survival

26. Resection rate of metastases and tumor response Folprecht G, et al. Ann Oncol 2005;16:1311–1319 Studies including selected patients(liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) 0.6 0.5 0.4 Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) Resection rate 0.3 0.2 0.1 Phase III studies including nonselected patientswith mCRC (dashed line) (r=0.67; p=0.024) 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate

27. Which Regimen: doublets or triplets? Pozzo C. et al Cancer Treat Rev, 2008

28. Triplets 1) Activity and efficacy increase 2) Resection rate increase 3) Balance between activity and toxicity 4) Acute toxicity acceptable

29. Treatment of metastatic CRC New drugs and new combinations • Oral 5-FUs (capecitabine, UFT) • Irinotecan • Oxaliplatin • Cetuximab • Bevacizumab Tumor response rates typically >50−60% …and even 72%

30. Cetuximab and resection rate in first-line FOLFIRI-based regimen A Patients in ERBITUX arm; b5 patients became eligible for resection, 4 underwent surgery; cR0 resection rate in patients with liver limited disease

31. FOLFIRI FOLFIRI ERBITUX + FOLFIRI ERBITUX + FOLFIRI CRYSTAL: resection rate ITT Cetuximab raddoppia i pazienti portati alla chirurgia e triplica le % di R0 Curative liver resections Response rates Response rate (%) R R0 7 Resection rate (%) 4.8 3.7 1.8 CRYSTAL CRYSTAL

32. Cetuximab and resection rate in first-line FOLFOX-based regimen aPatients in ERBITUX arm; bR0 resection rate in patients with liver limited disease; NR, not reported

33. OPUS: resection rate ITT Cetuximab raddoppia i pazienti portati a resezione e le % di resezioni R0

34. Panitumumab (pmab) with FOLFIRI as first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): Resections and curative surgery in a phase II single arm, multicenter study (20060314). R. Hofheinz, L. Mineur, R. Greil, C. Kohne, H. Letocha, J. Thaler, E. Fernebro, E. Gamelin, L. DeCosta, M. Karthaus KRAS/MT KRAS/WT Response rate 56% 38% Resection rate 15% 7% ASCO 2010, abs 3545

35. CETUXIMAB and resection rate in pretreated patients IFO=irinotecan/5-FU/FA/oxaliplatin; NR=not reported

36. Studio EMR 604-CELIM Patients with technically unresectable/≥5 liver metastases without extrahepatic disease RESECTION Adjuvant therapy for 6 cycles (same schedule as pre-operatively) ERBITUX + FOLFOX (n=54) Technically resectable R ERBITUX + FOLFIRI (n=54) Technically unresectable 4 further treatment cycles Primary endpoint: Response rate 8 cycles (~4 months) Started December 2004

37. Patient characteristics

38. Resections by patient subgroup Comparison of R0 resections between strata technically non-resectable and ≥ 5 liver mets: p=0.4

39. POCHER STUDY Patients with unresectableliver metastases +/- extrahepatic disease RESECTION Adjuvant therapy for 4-6 courses (same schedule as pre-operatively) Technically resectable ERBITUX + CPT-FFL ~ (n=43) for 4-6 courses Technically unresectable 4 further treatment cycles Primary endpoint: Response rate 8 cycles (~4 months) Started December 2004

41. POCHER RESULTS

45. Bevacizumab + CAPOX BEV ACIZUMAB+ Capecitabine + L-OHP: ORR = 78% Patient with colorectal liver metastases± primary tumor • Surgery: • Resection rate 40%in pts with metachronous mets • - Reasection rate 67% in pts with synchronous mets Wong R et al, Ann oncol 2011 ESMO 2006

50. Bevacizumab in synchronous metastases In patients with asimptomatic primary tumour and synchronous metastases, Bevacizumab (plus FOLFOX6) can be used without increased risks of bleeding/perforation (McCahill et al, ASCO 2010 abs 3527) In neoadjuvant setting of liver metastases, Bevacizumab (plus Xelox) can be used safely without increased risks and with efficacy also in patients with primary insitu (Gruenberger T et al, ASCO 2010 abs e14032)