Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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