Chemotherapy for Colorectal Cancer

Yong Sang Hong; Tae Won Kim

doi:10.5124/jkma.2010.53.7.582

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Hong and Kim: Chemotherapy for Colorectal Cancer

Focused Issue of This Month

Colorectal Cancer

Journal of the Korean Medical Association

Journal of the Korean Medical Association 2010; 53(7): 582-591.

Published online: 6 July 2010

DOI: https://doi.org/10.5124/jkma.2010.53.7.582

Chemotherapy for Colorectal Cancer

Yong Sang Hong, MD, Tae Won Kim, MD

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Corresponding author: Tae Won Kim. twkimmd@amc.seoul.kr

Received 16 June 2010 Accepted 27 June 2010

(open-access):

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Survival outcomes have been steadily improving for last 50 years in patients with colorectal cancer. The 5-fluorouracil (5-FU) is still one of the major chemotherapeutic agents. New cytotoxic agents, irinotecan and oxaliplatin, or targeted agents, bevacizumab and cetuximab, have been studied in the treatment of colon cancer. Adjuvant chemotherapy is indicated in patients with colon cancer at high-risk stage II and III, and after complete resection. Oxaliplatin-based regimens, FOLFOX, are considered as the standard adjuvant chemotherapy. If there are contraindications for oxaliplatin, the best alternatives are capecitabine or 5FU/LV. In rectal cancer, adjuvant chemotheradiotherapy is indicated in patients who had curative resection with stage II and III cancer. Adjuvant chemotherapy is necessary after neoadjuvant chemoradiotherapy in rectal cancer. The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-fluorouracil-based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil-based chemotherapy eliminates irinotecan resistance. Interestingly, there has been no clear association between the expression of epidermal growth factor receptor (EGFR) and response to the EGFR inhibitors. Instead, KRAS mutation has been accepted as a negative predictive factor for the treatment of cetuximab. In contrast, no valid biomarkers for bevacizimab were found so far. More studies are necessary to identify biomarkers of targeted agents. Recent advancement of chemotherapeutic agents extended survival in colorectal cancer.

Keywords: Colorectal cancer, Chemotherapy, Targeted agents

Figures and Tables

Figure 1

Recent improvement of overall survival in patients with metastatic colorectal cancer.

Table 1

Survival outcomes in patients with stage II and III colon cancer (MOSAIC trial)[13]

^*DFS: disease-free survival, OS: overall survival, HR: hazard ratio

^†FOLFOX did not result in survival benefit in patients with high-risk stage II colon cancers (T4 lesion, perforated, obstructive, poorly differentiated grade of tumor, positive venous invasion, harvested less than 10 lymph nodes during surgery).

Table 2

Pivotal randomized phase III trials of bevacizumab in patients with metastatic colorectal cancers

^*RR: response rate, PFS: progression-free survival, OS: overall survival

^*IFL: irinotecan+bolus FL, OxF: FOLFOX or XELOX, Bev: bevacizumab

Table 3

Bevacizumab-associated adverse events (from the BEAT study)[22]

Table 4

Different efficacy outcomes according to the KRAS mutation status (CRYSTAL and OPUS trial)

^*p value: clinically meaningful values were recorded only.

^*RR: response rate, PFS: progression-free survival, OS: overall survival

References

1. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997. 15:246–250.

2. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial. J Clin Oncol. 2009. 27:3109–3116.

3. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004. 350:2343–2351.

4. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005. 352:2696–2704.

5. Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2+irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNC-LCC Accord02/FFCD9802). Ann Oncol. 2009. 20:674–680.

6. Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007. 25:3456–3461.

7. Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009. 27:3117–3125.

8. Wolmark N, Yothers G, O'Connell MJ, Sharif S, Atkins JN, Seay TE, Feherenbacher L, O'Reilly S, Allegra CJ. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08. J Clin Oncol (Meeting Abstracts). 2009. 27:LBA4.

9. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R. German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004. 351:1731–1740.

10. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006. 24:4620–4625.

11. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC. EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006. 355:1114–1123.

12. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000. 355:1041–1047.

13. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000. 18:2938–2947.

14. Tournigand C, Andér T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004. 22:229–237.

15. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008. 26:3523–3529.

16. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorou-racil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008. 19:1720–1726.

17. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irino-tecan 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.

18. Fuchs CS, Marshall J, Barrueco J, Barrueco . Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008. 26:689–690.

19. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004. 350:2335–2342.

20. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén , Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008. 26:2013–2019.

21. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd. Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Onco-logy Group Study E3200. J Clin Oncol. 2007. 25:1539–1544.

22. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D. First BEAT investigators. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009. 20:1842–1847.

23. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004. 351:337–345.

24. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irino-tecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008. 26:2311–2319.

25. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemo-therapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009. 360:1408–1417.

26. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Koralewski, Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009. 27:663–671.

27. Han HS, Chang HJ, Hong YS, Kim SY, Lee KS, Jung KH. Epidermal growth factor receptor expression discrepancies in metastatic colorectal cancer patients treated with cetuximab plus irinotecan-based chemotherapy refractory to irinotecan and oxaliplatin. Dis Colon Rectum. 2009. 52:1144–1151. discussion 1152-1153.

28. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, Klimstra DS, Fridman D, Kelsen DP, Saltz LB. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005. 23:1803–1810.

29. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S, Peeters M, Humblet Y, Van Cutsem E, Tejpar S. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008. 19:508–515.

30. Liévre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006. 66:3992–3995.

31. Dieterle CP, Conzelmann M, Linnemann U, Berger MR. Detection of isolated tumor cells by polymerase chain reaction-restriction fragment length polymorphism for K-ras mutations in tissue samples of 199 colorectal cancer patients. Clin Cancer Res. 2004. 10:641–650.

32. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007. 25:3230–3237.

33. Sohn BS, Kim TW, Lee JL, Ryu MH, Chang HM, Kang YK, Park HS, Na YS, Jang SJ, Kim JC, Lee JS. The Role of KRAS Mutations in Predicting the Efficacy of Cetuximab-Plus-Irinotecan Therapy in Irinotecan-Refractory Korean Metastatic Colorectal Cancer Patients. Oncology. 2009. 77:224–230.

34. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008. 26:5705–5712.

35. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A. PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2009.

36. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009. 69:1851–1857.

37. Hong YS, Cho HJ, Kim SY, Jung KH, Park JW, Choi HS, Oh JH, Kim BC, Sohn DK, Kim DY, Chang HJ. Carbonic anhydrase 9 is a predictive marker of survival benefit from lower dose of bevacizumab in patients with previously treated metastatic colorectal cancer. BMC Cancer. 2009. 9:246.

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