Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?
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Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?
May 30 , 2009
SURGERY FIRST
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General Agreement
Hepatic resection is the only potentially curable treatment for colorectal liver metastases !!
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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 .
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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
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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.”
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The Rationale for Systemic Treatment Post Hepatic
Resection:
Based on improved survival results in stage III colon cancer adjuvant
trials!
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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
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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
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Mitry,E et al, JCO, Vol. 26, No. 30, p.4909, 2008
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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)
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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
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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!!
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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)
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or CASH
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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
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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
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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
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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
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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.
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ACOSOG, NSABP, NCCTG, ECOG
Phase III Trial Evaluating Perioperative vs Adjuvant Chemotherapy in Patients with Potentially Resectable Hepatic Colorectal
Metastases
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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
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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.
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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
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Meaningful Progress in Cancer Care Results From Prospective Randomized Trials But Let’s
Make Sure We Don’t Hurt Patients !
THANK YOU