Role of loco-regional treatment in the medical and surgical management strategy of metastatic colorectal cancer

Transcription

1 Role of loco-regional treatment in the medical and surgical management strategy of metastatic colorectal cancer M Ducreux, MD, PhD Gustave Roussy Villejuif, FRANCE M Ducreux is a consultant to Biocompatibles UK Ltd, a BTG International group company Because people depend on us

2 Rationale for Intra-arterial Approach Hematogenous spread of tumor cells from colorectal cancer via portal vein Liver = first site of metastases Goal of locoregional therapy to liver = STOP STEPWISE SPREAD TO OTHER ORGANS Blood supply to liver metastases = hepatic artery once size >2-3 mm Intra-tumoral concentration with IA = 16 x IV Ideal agent: high dose response curve, high extraction rate, rapid total body clearance 2

3 Classical intra-arterial treatment: IAHC - rationale Ideal drug : High hepatic extraction at the first passage High systemic clearance Current practice Fluoropyrimidines : (FUDR,5FU) : x 10 to 300 THP-adriamycin : x 20 Mitomycin C : x 6 à 8 Cisplatin : x 4 à 7 Decrease of toxicity Better therapeutic index Oxaliplatin : x 4 4

4 IAHC: Technical aspects Catheter implantation needed 5

5 IAHC: Technical aspects 6

6 Percutaneous placement of hepatic arterial catheter 7

7 Palliative IAHC Meta-analysis

8 Palliative IAHC Meta-analysis

9 Palliative IAHC Meta-analysis

10 Modern IAHC IA oxaliplatin + IV LV5FU2 Phase II trial Oxaliplatin :100 mg/m² IA 2 hours infusion d1 + IV LVFU2, 1st line Treatment repeated every 2 weeks 28 patients (17 M, 11 F), median age = 60 years, ECOG 0-1 : 24 pts ORR: 64%, CR: 7% Disease control growth: 100% after 8 cycles Secondary resections: 18% Survival (%) Progression-free survival Overall survival 27 months N. at risk Months Ducreux M,et al. J Clin Oncol 2005;23:

11 Palliative IAHC with targeted therapies B Best résponse (%) CHOICE phase II trial Oxali IA + LV5FU2 AND cetuximab IV 35 patients, 1 st line Wild type Kras: 30 (86%) ORR: 87% (CR = 3%) KRAS/BRAF WT : 96% Disease control rate: 97% KRAS/BRAF WT : 100% Secondary resection: 66% Malka D., et al. JFHOD 2012 K : KRAS muté B : BRAF muté? : inconnu C : chirurgie K B K K? N. at risk DC Bead, DC BeadM1, DEBDOX and DEBIRI are trademarks and/or registered trademarks of Biocompatibles UK Ltd. 25 DC Bead 18 and DC 9 BeadM1 4 are not 3 cleared 2 by the % C K C C C C C C C C C C C C C C C C C C C Progression-free survival Overall survival 29.0 B RP SD PD Not reached C C Follow-up : 48 months Months

12 An example of efficacy: a patient alive 4 years later Before After 13

13 Active also as a rescue after failure of conventional treatments Retrospective series Gustave Roussy 44 pre-treated patients Folfox or Folfiri 98% Both 64% ORR 62% ORR refractory 35% Second resection 18% Median PFS 7.0 m Liver median PFS 11.5 m Survival (%) N. at risk Progression-free survival Overall survival Months Boige V, et al. Ann Surg Oncol 2008;15:

14 Secondary Resectability Experience of the MSKCC 55 patients 49 IAHC IAH FUDR + IV oxaliplatin et irinotecan 92% of responses 39% secondary resection Kemeny N et al. J Clin Oncol 2009;27:

15 Adjuvant treatment after resection of liver metastases A first «positive» publication in pts randomized IAHC (FUDR + dexamethasone) + 5FU /FA IV or 5FU/FA alone for 6 months or continuous infusion of 5FU in patients who previously received 5FU/FA N pts hepatic DFS 2-year S. 2-year DFS margin + survival IAHC + systemic % 90 % 85 % Systemic % 44 % 69 % p Kemeny N et al N Engl J Med 1999;341:

16 Modern adjuvant treatment - Prospective basis IGR ( ) - 98 patients RO/SD with preoperative CT 4 resection of liver metastases 1 cycle of adjuvant CT Treatment Oxaliplatin IAH : n = 44 FOLFOX or FOLFIRI IV : n = 54 - Median follow-up: 45 months % OS Months RFS 53% Chimio systémique CIAH Logrank: chi2 à 1 ddl = 1.843, p = Logrank: chi2 à 1 ddl = , p < % 96 Chimio systémique CIAH Goéré D.,et al. Ann Surg 2013;257: Months

17 TACE in liver metastases High selectivity but more interesting in HCC than in liver metastases Less data 18

18 TACE for CRC Mets: Results Study Pts Sessions Anticancer drug Embolizing material ORR. Median survival Wasser (2005) Muller (2003) Popov (2002) Altamira (1997) Mitomycin Starch (DSM) 14% 14 months Melphalan (5-FU &GM- CSF) Lipiodol, Gelfoam 77% Not reached 11 1 Mitomycin C Gelfoam NA 9 months Mitomycin, 5-FU Lipiodol, Gelfoam 66% 10 months Tellez (1998) Cisplatin, Doxorubicin, Mitomycin C Angiostat 63% 29 months 19

19 LUF-L-E/H LUF-F-E/H LUF-LH/E LUF-F-H/E LF-L-E/H LF-L-H/E LUF Pure LF Unclear role of Lipiodol Tumoral selectivity: Tumor / normal liver = ratio 4 to 10 (Raoul, Radiology 1996, de Baere, Radiology 2006 Water in oil > oil in water (propensity for large vessels) Artery Vein Lipidol concentrataion afer injection of various emuslsion Healthy liver Tumor Lipiodol is a trademark of Guerbet société anonyme (sa) FRANCE 19

20 Locoregional treatment for liver metastases of colorectal cancer: WHERE ARE WE? Local treatment are an option for liver-confined metastatic colorectal cancer Few prospective randomized trials New intra-arterial treatments have been developed including : Radioembolization with yttrium-90 microspheres DC Bead loaded with irinotecan (DEBIRI ) 20

21 Irinotecan loaded DC Bead DEBIRI DC Bead is a new drug delivery embolization system capable of uniform loading and controlled local and sustained elution of irinotecan Compared to IV or IAH injection in animal models, DEBIRI has shown*: Lower systemic exposure to irinotecan Lower early serum levels of irinotecan High and prolonged intratumoral level of irinotecan A greater rate of tumor necrosis Recent clinical studies have produced promising and encouraging results (Fiorentini 2012, Martin 2012) Based on these results, several studies are currently ongoing to confirm the benefit of DEBIRI in the treatment of liver metastases from CRC * Rao PP et al Cardiovasc Intervent Radiol Dec;35(6): company. BTG and the BTG roundel logo are registered trademarks of BTG International Ltd. Copyright 2013 Biocompatibles UK Ltd. GxUS-DCB