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Stephen W Fenwick MD FRCS

Aintree University Hospital. Liverpool, UK. Irinotecan Loaded DC Beads as Neoadjuvant Treatment of Resectable Colorectal Liver Metastases. Stephen W Fenwick MD FRCS . Consultant Hepatobiliary Surgeon . Belfast, September 2011. Plan. Systemic chemotherapy in CRLM

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Stephen W Fenwick MD FRCS

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  1. Aintree University Hospital Liverpool, UK Irinotecan Loaded DC Beads as Neoadjuvant Treatment of Resectable Colorectal Liver Metastases Stephen W Fenwick MD FRCS Consultant Hepatobiliary Surgeon Belfast, September 2011

  2. Plan • Systemic chemotherapy in CRLM • Targeted chemotherapy • Phase II trial of targeted chemotherapy in resectable colorectal metastases (Paragon II study) Declaration Stephen Fenwick is a consultant to Biocompatibles UK LTD.

  3. Five-year survival of English colorectal cancer patients 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 All stage 4 resected n=3116 All patients Survival probability All stage 3 All Stage 4 1 2.5 4 0.5 2 3.5 5 0 1.5 3 4.5 Years Patients with resected liver metastases All patients without resected metastases Dukes C Dukes D Morris EJA et al. Brit J Surg 2010; 97: 1110-8

  4. Survival after liver resection for colorectal liver metastases Not due to selection bias Survival stratified by year of surgery (1997–2005) 1.0 0.8 1997 1998 1999 2000 2001 2002 2003 2004 2005 1997-censored 1998-censored 2000-censored 2001-censored 2002-censored 2003-censored 2004-censored 2005-censored 0.6 Cumulative Survival 0.4 So why are we getting better? 0.2 0.0 0 1000 2000 3000 4000 Survival Time

  5. EPOC study Lancet 2008; 371: 1007-1016

  6. Study design Randomize FOLFOX4 Surgery FOLFOX4 6 cycles (3 months) 6 cycles (3 months) Surgery N=364 patients Nordlinger et al. Lancet 2008; 371: 1007-16

  7. Progression-free survival in resected patients 100 HR= 0.73; CI:0.55-0.97, p=0.025 90 80 Periop CT +9.2%At 3 years 70 60 50 42.4% 40 Surgery only 30 33.2% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 104 152 85 59 39 24 10 93 151 118 76 45 23 6 Nordlinger et al. Lancet 2008; 371: 1007-16

  8. Correlation of outcome after hepatectomy to histologic response to neoadjuvant chemotherapy Blazer et al. 2008; 26:5344-51 Complete response Major response Minor response

  9. Secondary liver resection rates of metastases and tumour response 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Resectionrate 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Responserate Studies including selected liver metastases only patients (no extrahepatic disease) (r=0.96; p=0.002) Response rates >70% in unresectable liver only patients equates >40% liver resection rate Studies including non-selected patients with mCRC (solid line) (r=0.74; p<0.001) Phase III studies including non-selected patients with mCRC (dashed line) (r=0.67; p=0.024) Folprecht G, et al. Ann Oncol 2005;16:1311–1319

  10. How to bring more patients to resection? Downstage the disease to make it resectable And / Or “Upstage” the surgical techniques

  11. What are the problems with pre-operative chemotherapy ?

  12. Chemotherapy liver damage Oxaliplatin Irinotecan Steatohepatitis Increased post operative liver failure & 90 day mortality Sinusoidal Obstruction Syndrome Increased peri-operative bleeding ‘Blue’ liver ‘Yellow’ liver

  13. Complications of surgery EPOC Study (EORTC 40983) * * * * * Nordlinger et al. Lancet 2008; 371: 1007-16 *P=0.04

  14. "Complete response" : does it mean cure ? Wait for it to come back? ? Before treatment After 6 cycles of chemotherapy

  15. Macroscopic CR after chemotherapy: ~20% of cells in periphery are viable Dangerous Halo Courtesy of Professors G Mentha and L Rubbia Brandt, University of Geneva

  16. Too much pre-surgery chemotherapy • Problems for the liver surgeon • Excessive Oxaliplatin • Excessive bleeding at surgery • Excessive Irinotecan • Increased risk of post operative liver failure and 90 day mortality • Complete response • “Disappearing” tumours

  17. Targeted chemotherapy?

  18. What would be the advantages of DC bead TACE over conventional therapy? Single administration, so reduced hepatic and systemic toxicity? Targeted, so protecting ‘normal’ liver? Could be combined with metal filings to radio-locate disappearing lesions? Cheaper? Faster action, so possibly shorter delay from treatment to surgery?

  19. Trial proposal Study to evaluate safety/toxicity of targeted neoadjuvant irinotecan DC beads in patients with resectable colorectal liver metastases PARAGON II STUDY

  20. Study Design • Multicentre, open label, single arm phase II study • Primary endpoint – tumour resectability at surgery (% with R0 resection) • Secondary endpoints • Adverse events • Radiological response • Pathological response • Survival Competitive studies: UK: New EPOC EORTC 40051: BOS

  21. Participating Centres • Liverpool • Basingstoke • Paris (Villejuif) • Girona • Vienna Pathology review at a single centre

  22. Paragon II Trial Design • 40 patients with easily resectable colorectal liver metastases • One TACE using Irinotecan loaded beads • Liver resection 4 weeks later

  23. Paragon II Trial Design • 100-300 micron Paragon beads, loaded with irinotecan during manufacture • Aim to give 200mg • Selective embolisation to stasis

  24. Inclusion Criteria • 18-80 yrs, not pregnant or lactating • Potentially resectable disease, confined to liver • Unilobar disease, <4 lesions • No chemotherapy up to 1 month previously • No other primary cancer within past 10 yrs • Not enrolled in another trial within 30 days • Adequate liver, and bone marrow function • WCC>3, Platelets >100, Bilirubin<1.5x normal • Prothrombin time not more than>50% of normal

  25. Inclusion Criteria • 18-80 yrs, not pregnant or lactating • Potentially resectable disease, confined to liver • Unilobar disease, <4 lesions • No chemotherapy up to 1 month previously • No other primary cancer within past 10 yrs • Not enrolled in another trial within 30 days • Adequate liver, and bone marrow function • WCC>3, Platelets >100, Bilirubin<1.5x normal • Prothrombin time not more than>50% of normal

  26. Exclusion Criteria • Extra-hepatic disease • Contraindications to Irinotecan • Active infection • Allergy to Contrast media • Contraindications to Hepatic Artery embolisation • Severe atherosclerosis

  27. Trial Schedule Baseline (PET)CT within 1 month of procedure TACE 4 weeks CT followed by liver resection Follow up CT at 3, 6, 9 & 12 months.

  28. Technical considerations • PARAGON beads are easy to use • 4 hour “life” • Small tumours more difficulty to localise • Contrast enhanced US • C arm CT

  29. Post embolization • Pain and nausea expected • Pre procedure NSAIDs • Manage with IV anti-emetics at time of embolisation • Post procedure IV Narcotics, Morphine via PCA, IV paracetemol, NSAIDs, and occasionally Entonox • Intra arterial lidocaine

  30. Recruitment 39 patients 26/08/2011 1st patient 11/02/2009 1.3 patients/month • Recruitment so far

  31. Recruitment Included Patients (n = 48, intention to treat population) Ineligible for TACE after inclusion (n = 9) Patients treated with TACE (n = 39) Ineligible for resection after TACE (n = 2) Patients treated with surgery (n = 36, one patient is waiting for surgery) Withdrawn after surgery (n = 11) 12 months follow-up (n = 18)

  32. Patients excluded before TACE • 9 patients excluded • Bilobar metastases (2) • Withdrew consent (2) • Pulmonary metastases • Suspected HCC • Allergy to contrast • Unable to canulate segmental artery • Tumour vessels not seen at angiography

  33. Patients excluded before resection • 2 patients excluded • Peritoneal disease at laparotomy

  34. Paragon II Patient characteristics n = 48, 10 female (21%), 38 male (79%) Age ±SD at TACE visit: 62 ±11 years (range 36-78) 1-3 tumours at screening, average 1.33 1-4 tumours prior to TACE, average 1.4 Longest diameter pre TACE 44 mm (range 9-100)

  35. Withdrawn During 12M Follow-up 01-001 B-L Progressive disease (new lesions, p.hepatis, lung nodules) 02-001 W-WProgressive disease (new lesion) 01-007 JOD Progressive disease (new lesions) 01-010 JHO Progressive at 12 months (target+non-trgt) 01-014 V-L Progressive disease (new lesion) 04-001 AMR Diagnosed as HCC by histology 04-004 RAA Unrelated death (pneumomediastinum) 01-016 C-G Progressive disease (new lesions) 01-017 G-W Unrelated death (aspiration, organ failure) 04-003 JAB Outcome after 12 months to be confirmed

  36. Primary Endpoint: tumour resectability of targeted tumours (% of patients with R0 resection, i.e. >2mm clearance margin) Patients: R0 16/25 (64%), R1 (<2mm) 9/25 (36%) Paragon II R0 Resection

  37. Two patient deaths Acute pneumomediastinum, during surgery Aspiration pneumonitis, post surgery in-patient stay Eleven Serious Adverse Events Post embolisation syndrome in 4 patients (15%, expected) Pancreatitis (expected, TACE related, non-target embol.) Biloma (expected, surgical complication, MHRA: TACE) Urinoma (expected, surgical complication, not TACE related) Paroxysmal atrial fibrillation (not TACE related) Jaundice (due to recurrence, not TACE related) Neck haematoma (anaesthetic line complication) Aspiration pneumonitis (not TACE related) No serious and unexpected events Serious Adverse Events

  38. Outcomes Histological tumour response (n=26) 16% 23% 61%

  39. Surgical findings • Often marked capsular ischaemia • Increased inflammatory reaction around tumour • Areas of ischaemia difficult to differentiate from tumour • Ischaemic cholecystitis

  40. Patient 1 • 62 year old male • Previous Segment VIII resection in 2005, with recurrence at site

  41. Patient 1 - TACE • Treated with 70mg Irinotecan • Discharged at 48 hrs post procedure

  42. Patient 1 - 4 weeks post TACE • Right anterior sectionectomy • R0 resection • Complete tumour necrosis • Background steatosis, portal chronic inflammatory change

  43. Patient 6 Known lesion segment 8 Pre-treatment 1 month post PET-CT pre-treatment Positive segment 8 Negative segment 4A

  44. Patient 6 histopathology Untreated metastasis Treated metastasis

  45. Conclusion • Neoadjuvant TACE with Paragon beads is feasible and safe, with acceptable adverse events • R0 resection and tumour necrosis rates are encouraging • No negative effects seen at surgery

  46. Conclusion • Future work – explore differential tumour response • Future trials combining DC bead therapy with systemic chemotherapy are now awaited

  47. Future trials? Resctable disease Randomized phase III study with neoadjuvant irinotecan DC bead TACE and perioperative systemic chemotherapy (primary endpoint being PFS) Unresectable patients Randomized phase II study looking at benefit of addition of irinotecan DC bead TACE to systemic FOLFOX (primary endpoint being liver resection rate)

  48. Thank you

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