Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?
May 30 , 2009
SURGERY FIRST
General Agreement
Hepatic resection is the only potentially curable treatment for colorectal liver metastases !!
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 .
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; 30-60% chemo; 40-70% cirrhosis
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.”
The Rationale for Systemic Treatment Post Hepatic
Resection:
Based on improved survival results in stage III colon cancer adjuvant
trials!
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
5 Yr DFS : Chemo- 33.5% Surgery- 26.7% p=.028
Enrolled 173 Pts of planned 200 Pts over 10 yrs. Slow accrual /trial stopped.
Dis
ease
Fre
e S
urvi
val (
%) ADJUVANT
No. Patients Randomized Portier et al 173 Adjuvant FU/FA vs ( FCCD Trial)) Surgery alone (JCO 2006) Langer et al 129 SAME (ENG Trial)( Proc ASCO 2002 )
Mitry,E et al, JCO, Vol. 26, No. 30, p.4910, 2008
Mitry,E et al, JCO, Vol. 26, No. 30, p.4909, 2008
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 ChemotherapyFOLFOX ( 6 cycles)
Progression-Free Survival in Resected Patients
HR= 0.73; CI: 0.55-0.97, p=0.025
Surgery only
LV5FU + Oxaliplatin Periop CT
33.2%
42.4%
+9.2%At 3 years
(years)
0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment104 152 85 59 39 24 10
93 151 118 76 45 23 6
Surgery
Pre&Postop CT
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!!
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, 2009. > 9 cycles)
or CASH
Vasodilation & Congestion Peliosis
Hemorrhagic Centrilobular Necrosis Nodular Regenerative Hyperplasia
Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al, J Clin Oncol 24: 4983,2006
Cystic blood filled spaces in hepaticlobules
Sinusoidal Injury /Dilatation
Grade 0 – absent
Grading according to:L. Rubbia-Brandt et al. Ann Oncol. 2004.
Grade 1 – centrilobular Involvement <1/3 lobular surface
Grade 2 – centrilobular 1/3 - 2/3
Grade 3 – complete lobular involvement
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
Complications of Surgery - EORTC 40983Peri-op CT Surgery
Post-operative complications**
40 /159 (25%)
27 / 170 (16%)
Cardio-pulmonary failure 3 2
Bleeding 3 3
Biliary Fistula 13(8%) 7(4%)
(Incl Output > 100ml/d, >10d)
9 2
Hepatic Failure 11(7%) 8(5%)
(Incl. Bilirubin>100mg/d, >3d)
10 5
Wound infection 5 4
Intra-abdominal infection 11(7%) 4(2%)
Need for reoperation 5 (3%) 3(2%)
Other 25
16
Reversible postop complications
40(25%) 27( 16%)
**P=0.04
Annals of Surgical Oncology 16:1247,2009
92 Pts. : 60 Pts. Chemo* before hepatic resection.
32 Pts. - No chemotherapy
* Oxal – 30 Pts; Irinotecan - 15 Pts.
False+ False - PPV Chemo Group 6.4%** 28.4% 93.5%No Chemo 0% 23.6% 100%
Analysis On Per Lesion Basis
Conclusion: Chemo reduces accuracy of CT for preop evaluation of CR LM.
ACOSOG, NSABP, NCCTG, ECOG
Phase III Trial Evaluating Perioperative vs Adjuvant Chemotherapy in Patients with Potentially Resectable Hepatic Colorectal
Metastases
Schema
Pt Population:RESECTABLE
FOLFOX or
FOLFIRI +
Bevacizumab
Liver Resection
FOLFOX or
FOLFIRI +
Bevacizumab6 cycles
Liver Resection
6 cycles
FOLFOX or
FOLFIRI + Bevacizumab
12 cycles
R
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.
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.
CONCLUSIONS
Meaningful Progress in Cancer Care Results From Prospective Randomized Trials But Let’s
Make Sure We Don’t Hurt Patients !
THANK YOU