1. Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?
SURGERY FIRST
May 30 , 2009

2. General Agreement
Hepatic resection is the only potentially curable treatment for colorectal liver metastases !!

3. DEFINITIONS: ASCO 2006 LIVER THINK TANK
Neoadjuvant Therapy - Preoperative systemic therapy for resectable hepatic metastases. (Perioperative)
Adjuvant Therapy – Systemic therapy post hepatic resection.
**Conversion Therapy – Systemic therapy utilized for patients with unresectable hepatic metastases in an attempt to make the metastases resectable .

4. New Criteria of Resectability
An R0 resection.
Minimally 2 adjacent liver segments spared.
Vascular inflow & outflow, biliary drainage preserved.
Remaining liver volume must be adequate. 20% normal; % chemo; % cirrhosis

5. NCCN GUIDELINES 2009
“…limited data exists regarding the efficacy of adjuvant chemotherapy following resection for metastatic CR liver disease. Nevertheless, the panel recommends a course of active systemic chemotherapy … to increase the likelihood that residual microscopic disease will be eradicated.”

6. The Rationale for Systemic Treatment Post Hepatic Resection: Based on improved survival results in stage III colon cancer adjuvant trials!

7. ADJUVANT
5 Yr DFS : Chemo- 33.5%
Surgery- 26.7%
p=.028
Disease Free Survival ( %)
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.

8. Mitry,E et al, JCO, Vol. 26, No. 30, p.4910, 2008
No. Patients Randomized
Portier et al Adjuvant FU/FA vs
( FCCD Trial)) Surgery alone
(JCO 2006)
Langer et al SAME
(ENG Trial)
( Proc ASCO 2002 )

9. Mitry,E et al, JCO, Vol. 26, No. 30, p.4909, 2008

10. Phase III Trial Resectable Hepatic Only Metastases
European Organization for Research & Treatment of Cancer (EORTC 40983) ASCO 2007; Lancet 371:1007,2008
Resectable Hepatic Metastases 1-4 ( 364 Pts) ↓
Randomize
Pre ( 6 cycles) & Postop No Chemotherapy
FOLFOX ( 6 cycles)

11. Progression-Free Survival in Resected Patients
HR= 0.73; CI: , p=0.025
100 90
+9.2% At 3 years 80
LV5FU + Oxaliplatin 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 :
Treatment
104
152 85 59 39 24 10
Surgery 93
151
118 76 45 23 6
Pre&Postop CT

12. ISSUES WITH PERIOPERATIVE TREATMENT ( EORTC)
EORTC results based on sub population of patients randomized.
A highly selected group of patients ( 1-4 metastases) Would patients with more metastases have the same results?
Issue of post operative morbidity with chemotherapy before hepatic resection. MY MAIN DEFENSE!!

13. Specific Chemotherapy Associated Hepatic Toxicity
Irinotecan – Steatohepatitis
Oxaliplatin – Sinusoidal/vascular injury
Acute & chronic clinical sequelae
Biologics - ???? short & long term effects
Bevacizumab – 6 to 8 wks before resection
Liver regeneration (VEGF mediates hepatocyte & sinusoidal endothelial cell proliferation)
Hemorrhage
Morbidity is increased with prolonged course(>6 cycles) of chemotherapy (Nakano et al, Annals Surgery) (ASCO GI ,Abst# 295, > 9 cycles)

14. or CASH

15. Vascular Changes in Liver Post Systemic Chemotherapy
Aloia et al, J Clin Oncol 24: 4983,2006
Vasodilation & Congestion
Peliosis
Cystic blood filled spaces in hepatic
lobules
Hemorrhagic Centrilobular Necrosis
Nodular Regenerative Hyperplasia

16. Sinusoidal Injury /Dilatation
Grade 0 – absent
Grade 1 – centrilobular Involvement <1/3 lobular surface
Grade 2 – centrilobular 1/3 - 2/3
Grade 3 – complete lobular involvement
Grading according to:
L. Rubbia-Brandt et al.
Ann Oncol

17. 90 Pts –hepatectomy after preop chemotherapy. (Oxaliplatin - 62 Pts)
Sinusoidal Injury (SI) Secondary To Preoperative Chemotherapy Increases Post Hepatectomy Morbidity Nakano et al, Annals Surgery ,2008
90 Pts –hepatectomy after preop chemotherapy (Oxaliplatin - 62 Pts)
Incidence of SI was significantly higher in the Oxal. group ( 52%) vs other chemo (21%).
The morbidity of Gr. 3 & 4 was higher in pts with SI ( 29%) than no SI (17%). (ns)
Post op complications:
transitory liver failure ,biliary fistula, cholangitis, intra abdominal collections ► increased LOS

18. Complications of Surgery - EORTC 40983
Peri-op CT
Surgery
Post-operative complications**
40 /159 (25%)
27 / 170 (16%)
Cardio-pulmonary failure 3 2
Bleeding
Biliary Fistula
13(8%)
7(4%)
(Incl Output > 100ml/d, >10d) 9
Hepatic Failure
11(7%)
8(5%)
(Incl. Bilirubin>100mg/d, >3d) 10 5
Wound infection 4
Intra-abdominal infection
4(2%)
Need for reoperation
5 (3%)
3(2%)
Other 25 16
Reversible postop complications
40(25%)
27( 16%)
Other :…
**P=0.04

19. * Oxal – 30 Pts; Irinotecan - 15 Pts.
Annals of Surgical Oncology 16:1247,2009
92 Pts. : 60 Pts. Chemo* before hepatic resection Pts. - No chemotherapy
Analysis On Per Lesion Basis
False False PPV
Chemo Group %** % %
No Chemo % % %
Conclusion: Chemo reduces accuracy of CT for preop evaluation of CR LM.
* Oxal – 30 Pts; Irinotecan - 15 Pts.

20. ACOSOG, NSABP, NCCTG, ECOG
Phase III Trial Evaluating Perioperative vs Adjuvant Chemotherapy in Patients with Potentially Resectable Hepatic Colorectal Metastases

21. Schema R Pt Population: RESECTABLE FOLFOX or FOLFIRI + Bevacizumab
Liver Resection R
6 cycles
6 cycles
FOLFOX or
FOLFIRI + Bevacizumab
Liver Resection
12 cycles

22. RESECTABLE COLORECTAL HEPATIC METASTASES Conclusions
1) The results of perioperative chemotherapy with FOLFOX4 in addition to surgical resection are encouraging( 1-4 mets , good risk pts. ) but there is a better option ► Hepatic resection first then chemotherapy!!!
2) Chemotherapy induced liver injury is real; patient selection, drug type & duration of chemotherapy must be taken into consideration.

23. CONCLUSIONS
4) Surgeon / medical oncologist / pathologist must follow the patient as a multidisciplinary team.
5) Perioperative vs adjuvant - It is not just a matter of chemotherapy timing; It’s a matter of maintaining healthy liver parenchyma prior to surgery to minimize post op complications and maximize QOL.

24. Meaningful Progress in Cancer Care Results From Prospective Randomized Trials But Let’s Make Sure We Don’t Hurt Patients !
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