J Korean Surg Soc.  2013 Oct;85(4):154-160. 10.4174/jkss.2013.85.4.154.

Prospective multicenter phase II clinical trial of FOLFIRI chemotherapy as a neoadjuvant treatment for colorectal cancer with multiple liver metastases

• Kim JY
• Kim JS
• Baek MJ
• Kim CN
• Choi WJ
• Park DK
• Namgung H
• Lee SC
• Lee SJ

• KMID: 2096705
• DOI: http://doi.org/10.4174/jkss.2013.85.4.154

Abstract

PURPOSE
This study evaluated the efficacy of neoadjuvant chemotherapy combining 5-flurouracil/folinic acid with irinotecan (FOLFIRI) in colorectal multiple liver metastases regardless of resectability.
METHODS
Forty-four patients with multiple (at least two) colorectal liver metastases were enrolled at seven tertiary referral hospitals between May 2007 and September 2010. All patients received the FOLFIRI chemotherapeutic regimen. Response to chemotherapy was assessed after three cycles (6 weeks) and once more after six cycles (12 weeks) of treatment.
RESULTS
Objective response was noted in 27 patients (61.4%) and 4 patients (9.1%) had progressive disease. Of 44 patients, 10 patients (22.7%) underwent curative surgery (R0 resection) and 34 patients did not receive R0 resection. Grades 3 to 4 hematological toxicity was noted in 12 patients (27.3%) and grades 3 to 4 nonhematologic toxicity was identified in 5 patients (11.4%).
CONCLUSION
FOLFIRI chemotherapy as a neoadjuvant chemotherapy for multiple colorectal liver metastases regardless of resectability demonstrated the possibility of R0 resection, high rate of objective response, and tolerable toxicities in this study.

Keyword

Colorectal cancer; Neoadjuvant therapy; Metastasis; Chemotherapy

MeSH Terms

Camptothecin
Colorectal Neoplasms
Humans
Liver
Neoadjuvant Therapy
Neoplasm Metastasis
Prospective Studies
Tertiary Care Centers
Camptothecin

Figure

• 

  Fig. 1 Study design. SD, stable disease; PD, progressive disease; FOLFIRI, 5-flurouracil/leucovorin with irinotecan; CTx, chemotherapy.

• 

  Fig. 2 Flowchart. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Reference

1. Boyle P, Langman JS. ABC of colorectal cancer: Epidemiology. BMJ. 2000; 321:805–808.

2. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin. 1999; 49:8–31. 1

3. Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg. 1989; 210:127–138.

4. Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004; 239:818–825.

5. Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002; 235:759–766.

6. Fong Y, Blumgart LH. Hepatic colorectal metastasis: current status of surgical therapy. Oncology (Williston Park). 1998; 12:1489–1498.

7. Pozzo C, Basso M, Cassano A, Quirino M, Schinzari G, Trigila N, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol. 2004; 15:933–939.

8. Bismuth H, Adam R, Levi F, Farabos C, Waechter F, Castaing D, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg. 1996; 224:509–520.

9. Chua TC, Saxena A, Liauw W, Kokandi A, Morris DL. Systematic review of randomized and nonrandomized trials of the clinical response and outcomes of neoadjuvant systemic chemotherapy for resectable colorectal liver metastases. Ann Surg Oncol. 2010; 17:492–501.

10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): Colon/rectal cancer. ver. 1. 2010 [Internet]. Fort Wathington: NCCN;c2012. cited 2013 Apr 24. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

11. Ho WM, Ma B, Mok T, Yeo W, Lai P, Lim R, et al. Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases: a multicenter phase II study by the Cancer Therapeutic Research Group. Med Oncol. 2005; 22:303–312.

12. Zelek L, Bugat R, Cherqui D, Ganem G, Valleur P, Guimbaud R, et al. Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial). Ann Oncol. 2003; 14:1537–1542.

13. Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997; 350:681–686.

14. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22:229–237.

15. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000; 343:905–914.

16. Wein A, Riedel C, Bruckl W, Merkel S, Ott R, Hanke B, et al. Neoadjuvant treatment with weekly high-dose 5-Fluorouracil as 24-hour infusion, folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer. Oncology. 2003; 64:131–138.

17. Taïeb J, Artru P, Paye F, Louvet C, Perez N, Andre T, et al. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study. J Clin Oncol. 2005; 23:502–509.

18. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. 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. 2008; 371:1007–1016.

19. Peppercorn PD, Reznek RH, Wilson P, Slevin ML, Gupta RK. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer. 1998; 77:2008–2011.

20. Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004; 15:460–466.

21. Aloia T, Sebagh M, Plasse M, Karam V, Levi F, Giacchetti S, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006; 24:4983–4990.

22. Kooby DA, Fong Y, Suriawinata A, Gonen M, Allen PJ, Klimstra DS, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003; 7:1034–1044.

23. Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005; 200:845–853.

24. Benoist S, Brouquet A, Penna C, Julie C, El Hajjam M, Chagnon S, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol. 2006; 24:3939–3945.

25. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007; 25:4779–4786.

26. Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005; 23:4866–4875.

27. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360:1408–1417.

28. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335–2342.

29. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009; 20:1964–1970.

30. Bathe OF, Ernst S, Sutherland FR, Dixon E, Butts C, Bigam D, et al. A phase II experience with neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for colorectal liver metastases. BMC Cancer. 2009; 9:156.