Treatment should start with Chemotherapy before Surgery: Answer no 3 Bernard NORDLINGER M.D. Hôpital Ambroise Paré – Boulogne Assistance Publique Hôpitaux de Paris

Metastasis is resectable with adequat margin Case no 1 56-year old male had resection of a T3N0M0 sigmoid colon cancer CT scan 12 months : 4 cm metachronous solitary metastasis in left liver Metastasis is resectable with adequat margin

Survival after surgery of CR liver metastases 22% 35% 25% 33% 39% 26% 32% 37% 38% 34% 58% 41% 5% 0% 3% - 4% 2% 2.8% 0.8% 1% 259 60 80 141 859 219 280 1818 204 1001 235 257 133 615 190 1981 1986 1987 1988 1991 1992 1994 1999 2000 2002 2003 2004 Foster Iwatsuki Nordlinger Adson Hughes Scheele Rosen Nordlinger - Jaeck Gayowski Fong Minigawa Ercolani Choti Adam Abdalla 5yr Survival Op. Mort. Patients Year Authors

This patient has a « good risk » metastasis With surgery only - Cancer relapses in 2/3 of patients Nordlinger et al Cancer 1994 - Life expectancy Fong et al, Ann Surg 1999

Treatment options Surgery first +/- post-operative chemotherapy Chemotherapy before surgery

Postoperative chemotherapy after resection of liver metastasis?

Post-operative chemotherapy Very few trials available Hepatic arterial infusion (M. Lorenz 1998, N. Kemeny 1999, M. Kemeny 2002) Systemic chemotherapy (Langer 2002, Portier 2006) Most studies are underpowered ,show a trend toward a survival benefit of 5 FU based chemotherapy, combined with surgery

Meta-analysis of the two 5FU studies DFS P=0,058 Mitry, JCO 2008 In multivariable analysis, adjuvant chemotherapy was independently associated with both progression-free survival and overall survival.

CPT-GMA 301 Phase III study Adjuvant chemotherapy with more active regimen than 5FU only CPT-GMA 301 Phase III study 5-FU / FA (6 months) R0 resection of liver metastases R FOLFIRI (6 months) N=324, Ychou et al.ASCO 2008

Disease-Free Survival 1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51%

Post-operative chemotherapy No sufficient data to be the standard of care at the moment We need clear results from future trials 30 to 40% of patients do not, or can not receive chemotherapy within a few weeks after surgery Nordlinger et al. Lancet 2008

Perioperative chemotherapy (before and after)

EORTC 40983: Peri-operative chemotherapy Randomi Ze d FOLFOX4 Surgery FOLFOX4 6 cycles (3 months) 6 cycles (3 months) Surgery N=364 patients With CR UK, ALM CAO, AGITG, FFCD

Aim of this study To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone, but not to compare pre vs post-operative chemotherapy

Size of lesions after pre-operative chemotherapy * Before 50 mm (20-255) After 33 mm (0-230) Relative reduction - 25.6 % * SUM of the largest diameters 1. CT-scan measurements were consistent with the measurements performed at pathological examination Pre-op CT with 6 cycles of FOLFOX4 decreased the diameter of lesions

Case no 1 - 4 cm metachronous solitary metastasis in left liver - Easily resectable with adequat margin

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

Results Nordlinger et al. Lancet 2008 N pts CT N pts Surgery % absolute difference in 3-year PFS Hazard Ratio (Confidence Interval) P-value All patients 182 +7.2% (28.1% to 35.4%) 0.79 (0.62-1.02) P=0.058 All eligible Patients 171 +8.1% (28.1% to 36.2%) 0.77 (0.60-1.00) P=0.041 All resected 151 152 +9.2% (33.2% to 42.4%) 0.73 (0.55-0.97) P=0.025

Progression-free survival EORTC 40983: progression free survival, all patients: update May25, 2009 Progression-free survival Treatment Patients (N) Observed Events (O) Hazard  Ratio (95% CI) P-Value (Log-Rank) Median (95% CI) (Months) % at  3 Year(s) (95% CI) Surgery 182 134 1.00 0.0473 11.73 (9.63, 18.23) 29.58 (22.96, 36.48) Pre&Postop CT 126 0.79 (0.62, 1.01) 18.66 (15.41, 25.76) 36.37 (29.34, 43.42)

EORTC 40983: progression free survival, all patients: update May25, 2009

Progression free survival / irrespective of resection EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009 Progression free survival / irrespective of resection Treatment Patients (N) Observed Events (O) Hazard  Ratio (95% CI) P-Value (Log-Rank) Median  (95% CI) (Months) % at  3 Year(s) (95% CI) Surgery 182 133 1.00 0.0259 14.32 (11.04, 18.76) 30.07 (23.41, 36.99) Pre&Postop CT 123 0.76 (0.59, 0.97) 20.11 (16.46, 28.94) 38.50 (31.31, 45.63)

EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009

EORTC 40983 Peri-operative chemotherapy with FOLFOX4 reduces the risk of relapse of cancer after surgery by one quarter.

Potential negative impacts Risk that metastases progress during chemotherapy Liver damage induced by chemotherapy

Risk of progression during pre-operative chemotherapy: EORTC 40983 Progressive disease 12/182 pts (7%) 4 were resected 8 were not resected 4: appearance of new lesions: preoperative chemotherapy permitted to avoid unnecessary surgery 4: progression of known metastases (2%)…

Survival according to response to neoadjuvant CT (multiple metastases) Outcome after resection when metastases progress during chemotherapy Survival according to response to neoadjuvant CT (multiple metastases) 95% 100 Stabilization: 39 Progression: 34 Downstaging: 58 92% 80 60 55% 63% 44% Survival (%) 40 37% 30% Replace mine 20 12% Log–rank: p<0.0001 8% 1 2 3 4 5 Years Updated from: Adam R, et al. Ann Surg 2004;240:644–658

Risk of progression during pre-operative CT Risk is low ( total: 7%; known metastases: 2%) It is better to know before surgery because this is a biological marker for poor prognosis Indication for second line chemotherapy, Before surgery Evaluate every 3 cycles

Risk of liver damage induced by chemotherapy The type of liver injury depends on the drug administered Vascular lesions : Oxaliplatin (Rubbia-Brandt et al, 2004) Steatosis : 5FU, Irinotecan ? (Parikh et al, 2003) Steatohepatitis : Irinotecan (Vauthey et al, 2006)

Clinical significance: impact on surgery Karoui Nordlinger et al, Ann.Surg. 2006 Mortality rate not increased Morbidity rate related to the number of cycles of CT Aloia Adam et al, Ann.Surg. 2006 : Morbidity increased after 12 cycles Nakano Jaeck et al, Ann.Surg. 2008 : Morbidity increased after 6 cycles

EORTC 40983 : complications of surgery Peri-op CT Surgery Reversible complications (pts) * 40 /159 (25%) 27 / 170 (16%) Cardio-pulmonary failure 3 2 Bleeding Biliary Fistula 13 7 (Incl Output > 100ml/d, >10d) (9) (2) Hepatic Failure 11 8 (Incl. Bilirubin>10mg/dl, >3d) (10) (5) Wound infection 5 4 Intra-abdominal infection Need for reoperation Other (lung, urinary, ascites, etc…) 20 10 Post-operative deaths 1 patient 2 patients Other :… *P=0.04 Nordlinger et al., Lancet 2008

Liver damage Damage induced to liver by neoadjuvant chemotherapy is limited and has few clinical consequences if patients are not overtreated Damage induced to tumor has a major impact on survival

Complete pathological response after preoperative chemotherapy Tumor is replaced by fibrosis

Impact of pathological response after chemotherapy on survival 75% 56% 33% Complete response : 29/738 (4%) Adam et al, JCO 2008 Complete response : 25/271 (9%) Blazer et al, JCO 2008

Preoperative treatment of GI cancers in general: the present and the future Benefits outweigh potential disadvantages Has become the standard of care for most patients with cancers of the rectum Prolongs survival in patients with stomach cancer Cunningham,NEJM,2006. - Reduces the risk of relapse after resection of colorectal cancer liver metastases.

The patient Received FOLFOX4 6 cycles before surgery and 6 cycles after surgery Post-operative course was uneventful Pathologic examination showed: - major response : 15% residual cancer cells - large part of tumor was replaced by major fibrosis reflecting the effect of chemotherapy

Future trials can go two ways Perspectives Future trials can go two ways 1- Simplify treatment: make it easier for patients - Compare preop CT to postop CT - Reduce the number of cycles of CT given before surgery 2- Intensify treatment to further reduce the risk of relapse of cancer - Combine cytotoxics and targeted agents - Combine several cytotoxics -

R EORTC 40091:BOS2 (Biologics,Oxaliplatin,Surgery) Resectable FOLFOX + EGFR blocker R Resectable Liver Metastases from CRC n < 10 KRAS WT +/- Lung Mets < 2 + VEGF inhibitor + EGFR blocker follow up SURGERY

Previously untreated patients with resectable mCRC CRUK phase III study: CRC liver metastases: Previously untreated patients with resectable mCRC KRAS WT Randomized (expected n=340) Oxaliplatin + fluoropyrimidine + Cetuximab Oxaliplatin + fluoropyrimidine 2 weeks preoperative 12 weeks postoperative PFS