1. Adjuvant chemotherapy in resectable liver-limited metastasis colorectal cancer
指導VS: 鄧豪偉
財團法人台灣癌症臨床研究發展基金會

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 JCO
Outcome After Hepatectomy for Multiple (Four or More) Colorectal Metastases in the Era of Effective Chemotherapy Annals of Surgical Oncology
Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials Annals of Surgical Oncology 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 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 Annals of oncology
Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases Int J Colorectal Dis
NCCN guidline 2012 version 3.

3. Introduction Colorectal cancer when diagnosis 50%-60%: metastases
20%-34% synchronous liver metastases
Frequent metachronously following treatment.
大約有50-60% 的大腸癌在診斷的時候已經有遠端轉移，其中有20-34% 的病人是同時合併肝轉移，稱為同步轉移。另外，在肝轉移的部分，有許多病人是在接受治療後才發生，稱之為非同步轉移。

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%.
肝轉移的病人如果沒接受治療，五年存活率很低，約只有0.4-4%， 如果給予姑息性 5-FU治療，3年存活率也只有5-10%。所以在特定的病人，施與肝腫瘤切除，五年存活率可以達到25-40%，甚至有少部分的人可以痊癒。

5. Poor prognostic factor: The synchronous group :
>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 ?!
在2007年的這篇研究中發現，若肝轉移有下列情況，屬於預後不好的因子，包括: 超過三個病灶、兩葉肝轉移、大腸原發病灶屬於晚期。 另外，同步合併肝轉移的病人，表示腫瘤的轉移狀況較廣泛，因此比起非同步轉移的病人有較差的預後。大多這類肝轉移的病人在接受過手術之後，最容易發生的復發位置在肝及肺部，而且常常在兩年內發生，是不是暗示著開完刀後需要更積極的化學藥物治療就不可而知。
Clinicopathological features and prognosis in
resectable synchronous and metachronous colorectal
liver metastasis
Ann Surg Oncol 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.
術前化療有其優點及缺點，優點包括:及早治療潛在性的轉移腫瘤，可以預先知道化學藥物的反應。缺點包括: 可能引起肝毒性而導致肝功能下降，或化學藥物治療效果不佳的狀況下，反而延誤開始的時機。若效果太好，反而在開刀的時候無法準確的知道腫瘤的位置。

7. Method: Chemo-regiment:
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.
收納了171個病人，隨機分配單獨接受開刀手術或合併術後化療，追蹤時間為87個月。
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH AURC 9002 Trial 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
結果顯示: 術後接受化療的這組病人在DFS這部分有明顯的好處，但在存活率發現並無顯著意義。
Overall survival
Disease free survival
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH AURC 9002 Trial JCO

9. Conclusion:
Adjuvant intravenous systemic chemotherapy (5-FU+ LV) provided a significant disease-free survival.
結論: 在可切除的大腸癌合併肝轉移的病人，術後接受5-FU的化學治療，可以有較好的disease free survival.
Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver metastases: FFCD ACHBTH AURC 9002 Trial 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%.
2007年這個研究，收集了98個病人，在開刀前後分別接受化學治療。
Outcome After Hepatectomy for Multiple (Four or More)
Colorectal Metastases in the Era of Effective Chemotherapy
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.
其五年的存活率約33%，儘管病患為超過四個以上的肝轉移，但在完全切除且接受輔助性化學藥物治療之後，仍然可以得到長期的存活率。
Outcome After Hepatectomy for Multiple (Four or More)
Colorectal Metastases in the Era of Effective Chemotherapy
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
2008年這篇研究收集了278個病人，開刀之後隨機分配接受輔助性化療或觀察。
Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials 2007 Annals of Surgical Oncology JCO.

13. Conclusion: marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus–based regimen after complete resection of colorectal cancer metastases
結果顯示，術後給予輔助性化療雖然在統計上不夠有意義，但似乎可以增加disease frees survival及overall survival.
Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials 2007 Annals of Surgical Oncology 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.
2008年這篇研究收集了364個病人，隨機分配於僅接受開刀或開刀前後接受化學藥物治療兩組，其化療配方選用FOLFOX4.
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

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.
結果顯示手術前後使用FOLFOX可以增加病人的disease free survival.
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

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)
2009這個研究收集了306個病人，隨機分配於使用FL或FOLFIRI兩種不同化療配方的組別。
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer2009 Annals of oncology

17. Conclusion: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.
結果顯示: Irinotecan 合併5-FU 使用，在diseae free survival 或overall survival上，並沒有比單用5-FU有險處上的差異。
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal 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.
但在2010這個回溯性的研究收集了52個病人，一組使用Oxaliplatin 或Irinotecan合併5-FU，一組單獨使用5-FU.
Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases
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.
結果顯示: 5-FU合併使用Oxaliplatin 或irinotecan比單用5-FU的組別，有較好的disease free survival及overall survival.
Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases
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
目前正在進行中的臨床試驗，是比較大腸癌合併肝轉移在手術切除之後，隨機分配於輔助性單獨使用Xelox或合併Bevacizumab.

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.

22. 目前NCCN guideline 的建議，在大腸癌同步肝或肺轉移的病人，切除之後的治療建議。

23. 可以在手術前接受化學藥物治療，可以考慮選用FOLFIRI、FOLFOX、XELOX單獨或合併標靶藥物治療，或是手術後接受上述輔助性化學藥物合併標靶藥物治療。

24. Thanks for your attention~