Transcript EORTC INTERGROUP 40983 : Perioperative FOLFOX4 for Potentially Resectable Colorectal

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
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
Capecitabine ↓
↓ Capecitabine
Oxaliplatin
+
Oxaliplatin
+
IA FUDR
NCCTG Phase II: Resection of Unresectable CRC
Limited to the Liver Using FOLFOX6 + Cetuximab
S. Alberts, MD
Oxaliplatin+5-FU/LV (FOLFOX6) + C225
CR/PR resectable
Evaluation
PR, unresectable
Prog
Surgery
Chemo
Rx to Prog/Tolerability
Off Study, Rx per M.D.
Phase III Trial Resectable Hepatic Only
Metastases
European Organization for Research & Treatment of Cancer
(EORTC 40983)
Resectable Hepatic Metastases ( 364 Pts)
↓
Randomize
182Pts
Pre(6 cycles) & Postop
FOLFOX(6 cycles)
Surgery alone
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
Disease free
5 Yr DFS : Chemo- 33.5%
Surgery- 26.7%
p=.028
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.
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
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
Post-operative complications**
Peri-op CT
Surgery
40 /159 (25.2%)
27 / 170 (15.9%)
Cardio-pulmonary failure
3
2
Bleeding
3
3
Biliary Fistula
12
5
(Incl Output > 100ml/d,
>10d)
(9)
Hepatic Failure
11
(Incl. Bilirubin>10mg/dl,
>3d)
(10)
Wound infection
4
4
Intra-abdominal infection
8
2
Need for reoperation
5
3
Other
25
Incl. post-op death ** p=0.04
(2)
8
(5)
16
1 patient
2 patients
DISSECTION OF EORTC 40983
All Patients
All Eligible
# Pts
Chemo Surg
182
182
171
171
% Diff in
3 yr DFS
+7.2%
+8.1%
↓
11 pts. (each arm)
ineligible
-advanced disease
P-value
P=0.058
P=0.041
All Patients
All Eligible
All Resected
# Pts
% Diff in
Chemo Surg 3 yr DFS
182
182 +7.2%
171
171 +8.1%
151
152 +9.2%
31 pts (chemo)
30 pts (surgery)
►
P-value
P=0.058
P=0.041
P=0.025
Not Resectable at
Surgery*
2 Group subset analysis ► Criticism here
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
1) The results of neoadjuvant chemotherapy with
FOLFOX4 in addition to surgical resection are
encouraging but additional questions remain and
subgroup analysis weakens the results.
2) 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.
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