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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Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?. SURGERY FIRST. May 30 , 2009. Hepatic resection is the only potentially curable treatment for colorectal liver metastases !!. General Agreement. - PowerPoint PPT Presentation

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Page 1: 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

Page 2: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

General Agreement

Hepatic resection is the only potentially curable treatment for colorectal liver metastases !!

Page 3: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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 .

Page 4: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 5: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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.”

Page 6: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

The Rationale for Systemic Treatment Post Hepatic

Resection:

Based on improved survival results in stage III colon cancer adjuvant

trials!

Page 7: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 8: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 9: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 10: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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)

Page 11: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 12: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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!!

Page 13: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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)

Page 14: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

or CASH

Page 15: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 16: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 17: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 18: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 19: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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.

Page 20: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

ACOSOG, NSABP, NCCTG, ECOG

Phase III Trial Evaluating Perioperative vs Adjuvant Chemotherapy in Patients with Potentially Resectable Hepatic Colorectal

Metastases

Page 21: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 22: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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.

Page 23: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

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

Page 24: Neoadjuvant & Adjuvant Chemotherapy for Hepatic Colorectal Metastases : When to use it ?

Meaningful Progress in Cancer Care Results From Prospective Randomized Trials But Let’s

Make Sure We Don’t Hurt Patients !

THANK YOU