1. Adjuvant chemotherapy in
resectable liver-limited metastasis
colorectal cancer
R4 陳三奇
指導VS: 鄧豪偉 1

2. Reference
• Clinicopathological features and prognosis in resectable synchronous and metachronous colorectal liver metastasis
Ann Surg Oncol 2007
• Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After
Resection of Colorectal Liver metastases: FFCD ACHBTH AURC 9002 Trial
2006 JCO
• Outcome After Hepatectomy for Multiple (Four or More) Colorectal Metastases in the Era of Effective
Chemotherapy
2007 Annals of Surgical Oncology
• Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled
Analysis of Two Randomized Trials 2007 Annals of Surgical Oncology
2008 JCO.
• Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from
colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial 2008 Lancet
• A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following
complete resection of liver metastases from colorectal cancer
2009 Annals of oncology
• Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of
metachronous colorectal liver metastases
2010 Int J Colorectal Dis
• NCCN guidline 2012 version 3.
2

3. Introduction
• Colorectal cancer when diagnosis
– 50%-60%: metastases
– 20%-34% synchronous liver metastases
– Frequent metachronously following treatment.
3

4. • Prognosis of liver metastasis :
– no treatment : 5-year survival- 0.4%-4%.
– Palliative CT( fluorouracil ): 3-year survival -5-10%.
• Surgery in selected patients:
– remove colorectal liver metastases
– cure is possible in this population
– 5-y-s : 25-40%.
4

5. • Poor prognostic factor:
– >3 metastases, bilobar distribution, an advanced stage of the primary tumor.
• The synchronous group :
– indicate a more disseminated disease status
– a shorter disease-free survival than metachronous metastasis.
• Most treatment failures are due to :
– local hepatic recurrences
– lung metastases
• occur within the first 2 years
=> may need more aggressive chemotherapy ?!
Clinicopathological features and prognosis in
resectable synchronous and metachronous colorectal
liver metastasis 5
Ann Surg Oncol. 2007 Feb;14(2):786-94

6. Neoadjuvant or adjuvant
chemotherpay
• Potential advantages of preoperative CT:
– Earlier treatment of micrometastatic disease
– Determination of responsiveness to chemotherapy
(as a prognostic factor and postoperation treatment)
• Disadvantages :
– liver steatohepatitis and sinusoidal liver injury
(irinotecan- and oxaliplatin-based chemotherapeutic
regimens)
– missing the “window of opportunity” for resection
– achievement of a complete response, thereby making
it difficult to identify areas for resection.
6

7. • Method:
– Patients: eligible for complete resection of liver
metastasis. (n=171)
– Randomised sugery alone or combine with
adjuvant chemotherapy.
– Follow up time: 87m.
• Chemo-regiment:
– Leucovorin 200 mg/m2 bolus then
– 5-FU 400mg/m2, QD x 5days, monthly, 6 cycles.
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared
With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH
7
AURC 9002 Trial 2006 JCO

8. • DFS: 5-y-s: 33.5% vs 26.7% (P=0.028 )
• OS : 5-y-s: 51% vs 41% , (P=0.13)
P=0.13
P=0.028
Disease free survival Overall survival
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared
With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH
8
AURC 9002 Trial 2006 JCO

9. • Conclusion:
– Adjuvant intravenous systemic chemotherapy (5-
FU+ LV) provided a significant disease-free
survival.
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared
With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH
9
AURC 9002 Trial 2006 JCO

10. • Method:
– 98 patients with four or more colorectal hepatic
metastases were resected.
– Neoadjuvant C/T: 57%. 5-FU+ LV, (irinotecan 48% ,
oxaliplatin 12%)
– Adjuvant: 92%.
Outcome After Hepatectomy for Multiple (Four or More)
Colorectal Metastases in the Era of Effective Chemotherapy 10
2007 Annals of Surgical Oncology

11. • Actuarial 5-year survival
was 33%.
• Long-term survival can
be achieved after
resection of multiple
colorectal metastases;
however, because most
patients will experience
recurrence of disease,
effective adjuvant
therapy and close
follow-up is necessary.
Outcome After Hepatectomy for Multiple (Four or More)
Colorectal Metastases in the Era of Effective Chemotherapy 11
2007 Annals of Surgical Oncology

12. • 278 patients(CT:138, S:140), complete
resection of liver or lung metastasis.
– FFCD- Leucovorin 200 mg/m2 bolus then
5-FU 400mg/m2, QD x 5days, monthly, 6 cycles
– ENG trial: Leucovorin 100mg/m2, then
5-FU 370mg/m2, QD x 5days, monthly, 6 cycles
Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From
Colorectal Cancer: A Pooled Analysis of Two Randomized Trials 2007 Annals12of
Surgical Oncology 2008 JCO.

13. Conclusion: marginal statistical significance in favor of
adjuvant chemotherapy with an FU bolus–based regimen
after complete resection of colorectal cancer metastases
Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From
Colorectal Cancer: A Pooled Analysis of Two Randomized Trials 2007 Annals13of
Surgical Oncology 2008 JCO.

14. • 364 patients with resectable liver metastases
from colorectal cancer.
– Randomised 182 patients in perioperative
chemotherapy group, 182 in surgery group.
– Regimen: FOLFOX4 6cycles before and after
surgery.
Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for
resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983):
14
a randomised controlled trial 2008 Lancet

15. • Perioperative chemotherapy with FOLFOX4 is compatible with
major liver surgery and reduces the risk of events of
progression-free survival in eligible and resected patients.
Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for
resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983):
15
a randomised controlled trial 2008 Lancet

16. • 306 patients, completely resectable liver-
limited metastases colorectal cancer.
– FA, 400 mg/m2 infused over 2h
– 5-FU as a 400 mg/m2 i.v. bolus
– 5-FU continuous infusion, 2400 mg/m2 over 46 h.
• with or without irinotecan: 180 mg/m2 infusion
(FOLFIRI)
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with
FOLFIRI in patients following complete resection of liver metastases from colorectal
16
cancer2009 Annals of oncology

17. • Conclusion: FOLFIRI in the adjuvant treatment of LMCRC
showed no significant improvement in DFS compared with
LV5FUs.
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with
FOLFIRI in patients following complete resection of liver metastases from colorectal
17
cancer2009 Annals of oncology

18. • Between 2000 and 2007, in Taipei Veterans
General Hospital hospitalization.
• 52 patients having undertaken resection of
metachronous colorectal liver disease with
curative intent.
– 31 patients: FOLFOX or FOLFIRI x 6-12 cycles
– 19 patients: 5-FU/leucovorin (LV)-based
chemotherapy.
Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall
survival following resection of metachronous colorectal liver metastases 18
2010 Int J Colorectal Dis

19. • Conclusions: Adjuvant FOLFOX/FOLFIRI chemotherapy
following resection of metachronous CLMs is demonstrated to
have better DFS and OS than 5-FU/LV chemotherapy.
Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall
survival following resection of metachronous colorectal liver metastases 19
2010 Int J Colorectal Dis

20. Ongoing trial
• HEPATICA study
– two-arm, multicenter, randomized, comparative
efficacy and safety study.
– Randomized after resection or resection combined
with RFA
– CT: CAPOX + Bevacizumab or CAPOX alone
– Follow up 5yrs
– The primary endpoint : disease free survival.
– Secondary endpoints are overall survival, safety and
quality of life
20

21. • Arm A (CAPOX+Bevacizumab) consists of
– 8 cycles of CAPOX (either all cycles postoperatively
or 3 cycles preoperatively followed by 5 cycles
postoperatively)
• Oxaliplatin: 130 mg/m2, day 1, every 3 weeks
• Capecitabine: orally ,1000 mg/m2 twice-daily. Day1-14,
every 3 weeks.
• bevacizumab at 7.5 mg/kg, maximum of 48 weeks.
• Arm B : CAPOX only.
21

22. 22

23. 23

24. Thanks for your attention~
24