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Stephen W Fenwick MD FRCS Aintree University Hospital Liverpool, UK Consultant Hepatobiliary Surgeon Belfast, September 2011 Irinotecan Loaded DC Beads.

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Presentation on theme: "Stephen W Fenwick MD FRCS Aintree University Hospital Liverpool, UK Consultant Hepatobiliary Surgeon Belfast, September 2011 Irinotecan Loaded DC Beads."— Presentation transcript:

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

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

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

4 Survival after liver resection for colorectal liver metastases 0.0 0.2 0.4 0.6 0.8 1.0 40003000200010000 Survival Time Cumulative Survival Survival stratified by year of surgery (1997–2005) 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 Not due to selection bias So why are we getting better?

5 Lancet 2008; 371: 1007-1016 EPOC study

6 Study design R a n d o m iz e SurgeryFOLFOX4 Surgery 6 cycles (3 months) N=364 patients 6 cycles (3 months) Nordlinger et al. Lancet 2008; 371: 1007-16

7 Progression-free survival in resected patients HR= 0.73; CI: 0.55-0.97, p=0.025 Surgery only Periop CT 33.2% 42.4% +9.2% At 3 years (years) 0123456 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 1041528559392410 931511187645236 Nordlinger et al. Lancet 2008; 371: 1007-16

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

9 Secondary liver resection rates of metastases and tumour response Studies including non-selected patients with mCRC (solid line) (r=0.74; p<0.001) Studies including selected liver metastases only patients (no extrahepatic disease) (r=0.96; p=0.002) 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 Resection rate Response rate 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.30.40.50.60.70.80.9 Response rates >70% in unresectable liver only patients equates >40% liver resection rate

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

11 What are the problems with pre- operative chemotherapy ?

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

13 Complications of surgery Peri-op CT Surgery Post-operative complications* 40 /159 (25.2%) 40 /159 (25.2%) 27 / 170 (15.9%) 27 / 170 (15.9%) Cardio-pulmonary failure 3 2 Bleeding 3 3 Biliary Fistula 12 12 5 (Incl Output > 100ml/d, >10d) (Incl Output > 100ml/d, >10d) (9) (9) (2) (2) Hepatic Failure 11 11 8 (Incl. Bilirubin>10mg/dl, >3d) (Incl. Bilirubin>10mg/dl, >3d) (10) (10) (5) (5) Wound infection 4 4 Intra-abdominal infection 8 2 Need for reoperation 5 3 Other 25 2516 Incl. post-operative death 1 patient 2 patients *P=0.04 Nordlinger et al. Lancet 2008; 371: 1007-16 EPOC Study (EORTC 40983) **********

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

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

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 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 Inclusion Criteria

25 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 Inclusion Criteria

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

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

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 so far CentreRecruitedEmbolizedLaparotomy Basingstoke 111 Girona 333 Liverpool 26 25 Paris 111 Vienna 888 39 patients 26/08/2011 1 st patient 11/02/2009 1.3 patients/month Recruitment

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

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-W Progressive 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 Serious Adverse Events 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

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

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

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

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 Treated metastasis Untreated 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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