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

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

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

4. 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 .

5. 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

6. 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

7. 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) Pts

8. 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: , 2006

9. 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.”

10. The Rationale: Based on stage III colon cancer adjuvant trials

11. 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; , 2006
Enrolled 173 Pts of planned 200 Pts over 10 yrs. Slow accrual /trial stopped.

12. 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

13. 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)

15. ▼ ▼ 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

16. 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

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

18. ► 2 Group subset analysis ► Criticism here Not Resectable at Surgery*
# Pts % Diff in
Chemo Surg 3 yr DFS P-value
All Patients % P=0.058
All Eligible % P=0.041
All Resected % P=0.025
31 pts (chemo)
30 pts (surgery)
2 Group subset analysis ► Criticism here
EORTC RESULTS ►
Not Resectable at Surgery*

19. 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.

20. 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?

21. 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.

22. 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.

23. 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.

24. CLINICAL TRIALS ► JUST DO IT !
THANK YOU