EORTC INTERGROUP 40983 : Perioperative FOLFOX4 for Potentially Resectable Colorectal Liver Metastases, Nordlinger,B et al June 4, 2007 Discussant Nicholas Petrelli, MD Helen F Graham Cancer Center

No Financial Interests to Disclose Nicholas Petrelli, M.D. No Financial Interests to Disclose

Is perioperative treatment with FOLFOX4 the first choice for resectable colorectal hepatic metastases? NOT YET Will some oncologists use the results of EORTC 40983 to reinforce what they have been doing anyway? YES

DEFINITIONS: ASCO 2006 LIVER THINK TANK Neoadjuvant Therapy - Preoperative systemic therapy for resectable hepatic metastases followed by post resection therapy. Adjuvant Therapy - Systemic/regional therapy post hepatic resection. Conversion Therapy – Systemic/regional therapy utilized for patients with unresectable hepatic metastases in an attempt to make the metastases resectable .

NSABP C-09 Phase III Hepatic Resection/Ablation L. Wagman, MD ELIGIBILITY  6 Metastases No Extrahepatic ↓ Stratify: Surgical intent, Type chemo ±Oxal. Randomize Surgery ADJUVANT Capecitabine ↓ Oxaliplatin ↓ Capecitabine + Oxaliplatin IA FUDR

Oxaliplatin+5-FU/LV (FOLFOX6) + C225 NCCTG Phase II: Resection of Unresectable CRC Limited to the Liver Using FOLFOX6 + Cetuximab S. Alberts, MD CR/PR resectable Surgery Chemo PR, unresectable Rx to Prog/Tolerability Prog Off Study, Rx per M.D. Oxaliplatin+5-FU/LV (FOLFOX6) + C225 Conversion Chemotherapy Evaluation

Phase III Trial Resectable Hepatic Only Metastases NEOADJUVANT European Organization for Research & Treatment of Cancer (EORTC 40983) Resectable Hepatic Metastases ( 364 Pts) ↓ Randomize Pre(6 cycles) & Postop Surgery alone 182Pts FOLFOX(6 cycles) 182 Pts

General Agreement Hepatic resection is the only potentially curable treatment for colorectal liver metastases! “Chemotherapy alone offers the potential for control & improved survival but not potential cure. Surgery can offer potential cure.” S.Alberts, J Clin Oncol 24:4952-4953, 2006

NCCN GUIDELINES 2007 “Patients who have completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy… observation or a shortened course of chemotherapy is considered for patients who have completed neoadjuvant chemotherapy.”

The Rationale: Based on stage III colon cancer adjuvant trials

ADJUVANT 5 Yr DFS : Chemo- 33.5% Surgery- 26.7% p=.028 Disease free Portier et al, Multicenter Randomized Trial of Adjuvant Fluorouracil & Folinic Acid Compared with Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial, J Clin Oncol 24; 4976-4981, 2006 Enrolled 173 Pts of planned 200 Pts over 10 yrs. Slow accrual /trial stopped.

Resected Liver Mets –No Evidence Sargent DJ et al, Disease free survival versus overall survival as a primary endpoint for adjuvant colon cancer studies: 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664,2005 Disease free survival an excellent predictor of overall survival Meets formal definitions of surrogacy Model allows prediction of OS effect based on DFS effect Resected Liver Mets –No Evidence

Specific Chemotherapy Associated Hepatic Toxicity Irinotecan – Steatohepatitis Oxaliplatin – Sinusoidal/vascular injury Acute & chronic clinical sequelae Biologics - ???? Bevacizumab – 6 to 8 wks before resection Liver regeneration & hemorrhage Morbidity is increased with prolonged course of chemotherapy (Aloia et al, J Clin Oncol, 2006)

▼ ▼ Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al, J Clin Oncol 24: 4983,2006 Peliosis: Vasodilation & Congestion Hepatic atrophy & sinusoidal congestion ▼ ▼ Hemorrhagic Centrilobular Necrosis Nodular Regenerative Hyperplasia

Complications of Surgery Peri-op CT Surgery Post-operative complications** 40 /159 (25.2%) 27 / 170 (15.9%) Cardio-pulmonary failure 3 2 Bleeding Biliary Fistula 12 5 (Incl Output > 100ml/d, >10d) (9) (2) Hepatic Failure 11 8 (Incl. Bilirubin>10mg/dl, >3d) (10) (5) Wound infection 4 Intra-abdominal infection Need for reoperation Other 25 16 Incl. post-op death ** p=0.04 1 patient 2 patients

DISSECTION OF EORTC 40983 # Pts % Diff in Chemo Surg 3 yr DFS P-value All Patients 182 182 +7.2% P=0.058 All Eligible 171 171 +8.1% P=0.041 ↓ 11 pts. (each arm) ineligible -advanced disease

► 2 Group subset analysis ► Criticism here Not Resectable at Surgery* # Pts % Diff in Chemo Surg 3 yr DFS P-value All Patients 182 182 +7.2% P=0.058 All Eligible 171 171 +8.1% P=0.041 All Resected 151 152 +9.2% P=0.025 31 pts (chemo) 30 pts (surgery) 2 Group subset analysis ► Criticism here EORTC RESULTS ► Not Resectable at Surgery*

A Surgeon’s Statistical Analysis A range of 7%-9% difference in the % absolute difference in PFS is minimal. There is little difference in the HR’s for the 3 groups especially when considering the CI’s. The resected group is the more homogeneous group and thus more likely to show less variation in response other than that attributed to the chemotherapy.

QUESTIONS FOR THE MANUSCRIPT In those patients who underwent hepatic resection, how many additional metastases were found on Pathology ? Were the number of metastases resected in each group balanced after pathologic examination of the resected liver?

CONCLUSIONS EORTC 40983 The results of neoadjuvant chemotherapy with FOLFOX4 in addition to surgical resection are encouraging but additional questions remain and subgroup analysis weakens the results. Hepatic resection first is still a good option for resectable metastases.

CONCLUSIONS EORTC 40983 3) The next Phase III Trial should compare neoadjuvant to adjuvant therapy. More chemotherapy is not necessarily better. This is not just a matter of chemotherapy timing. It’s a matter of maintaining healthy non tumor bearing liver parenchyma prior to surgery.

Sometimes we harm patients to get them better! CONCLUSIONS EORTC 40983 4) Chemotherapy induced liver injury is real; patient selection, drug type and duration of chemotherapy must be taken into consideration in the adjuvant and neoadjuvant hepatic resection clinical trial setting. Sometimes we harm patients to get them better! 5) In order to run good clinical trials, there needs to be more coordination and “buy in” for high priority trials among Cooperative Groups.

CLINICAL TRIALS ► JUST DO IT ! THANK YOU