Chemotherapy for Colorectal Cancer

Yong Sang Hong; Tae Won Kim

doi:10.4166/kjg.2009.54.6.355

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Hong and Kim: Chemotherapy for Colorectal Cancer

Review

Korean J Gastroenterol 2009;54(6):355-363.

Published online: 21 February 2009

DOI: https://doi.org/10.4166/kjg.2009.54.6.355

Chemotherapy for Colorectal Cancer

Yong Sang Hong, M.D., Tae Won Kim, M.D.

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

Correspondence to: Tae Won Kim, M.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86, Asanbyeongwon-gil, Pung-nap-dong, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-3910, Fax: +82-2-3010-6961 E-mail: twkimmd@amc.seoul.kr

Abstract

Recent advances in chemotherapy lead to improved survival outcomes in patients with colorectal cancer. The 5-fluorouracil (5-FU) is still one of the important chemotherapeutic agents since 1950s, but the introduction of newer cytotoxic agents, irinotecan and oxaliplatin, or targeted agents, bevacizumab and cetuximab, have changed treatment strategies for these patients. A deliberate choice should be made for adjuvant chemotherapy, because it has became complicated more than ever before. Oxaliplatin plus 5-FU seemed to be superior in terms of disease-free and overall survival than 5-FU alone after curative surgery for colon cancers. However not all of these patients seemed to receive benefit from this intensive adjuvant treatment, and some limitations are present according to the postoperative stage, tumor biology and clinical characteristics. For metastatic disease, there is no doubt that more complicated strategies are present because we have more abundant chemotherapeutic agents available for metastatic setting compared to adjuvant setting. Recently, targeted agents, such as bevacizumab or cetuximab, also took an important place in the treatment of metastatic colorectal cancer, and many efforts are also made to find the biomarkers for predicting treatment responses to these targeted agents. In this review, we intended to sort up the standard strategies of chemotherapy for patients with colorectal cancer according to the latest pivotal publications.

Keywords: Colorectal cancer, Chemotherapy, Targeted agents

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Fig. 1.

Improvement of overall survival in patients with metastatic colorectal cancer according to the recent advances in chemotherapy.

Fig. 2.

Cetuximab and Kras modulate signaling through the epidermal growth factor receptor (EGFR) pathway. (A) Binding of ligand to EGFR triggers signaling through ras/MAPK pathway to multiple targets that may regulate ligand levels. (B) In the presence of cetuximab, ligand binding is prevented, and there is deactivation of EGFR signaling in cells dependent on this pathway. (C) Kras mutations can lead to dysregulation of MAPK pathway and downstream signaling in the absence of ligand-dependent receptor activation.

Table 1.

Survival Outcomes in Patients with Stage II and III Colon Cancer (MOSAIC Trial)

		5 year DFS				6 year OS
	FOLFOX	LV5FU2	HR	p-value	FOLFOX	LV5FU2	HR	p-value
Overall	73.3%	67.4%	0.80	0.003	78.5%	76.0%	0.84	0.046
Stage III	66.4%	58.9%	0.78	0.005	72.9%	68.7%	0.80	0.023
Stage II^∗	83.7%	79.9%	0.84	0.258	86.8%	86.7%	1.00	0.986

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.

FOLFIRI Followed by FOLFOX or the Reverse Sequence in Metastatic Colorectal Cancer, GERCOR Study

	Arm A (n=109) FOLFIRI → FOLFOX	Arm B (n=111) FOLFOX → FOLFIRI	p-value
RR (1^st line)	56%	54%	0.68
PFS (1^st line)	8.5 mo	8.0 mo	0.26
RR (2^nd line)	15%	4%	0.05
PFS (2^nd line)	4.2 mo	2.5 mo	0.003
PFS (2^nd PD)	14.2 mo	10.9 mo	0.64
OS	21.5 mo	20.6 mo	0.99
2-year survival rate	41%	45%	−

RR, response rate; PFS, progression-free survival; OS, overall survival.

Table 3.

Pivotal Randomized Phase III Trials of Bevacizumab in Patients with Metastatic Colorectal Cancers

	Hurwitz et al.²¹			Saltz et al.²²
	IFL	IFL＋Bev	p-value	OxF	OxF＋Bev	p-value
RR	34.8%	44.8%	0.004	49%	47%	0.31
PFS (mo)	6.2	10.6	＜0.001	8.0	9.4	0.0023
OS (mo)	15.6	20.3	＜0.001	19.9	21.3	0.0769

RR, response rate; PFS, progression-free survival; OS, overall survival; IFL, irinotecan＋bolus FL; OxF, FOLFOX or XELOX; Bev, bevacizumab.

Table 4.

Bevacizumab-associated Adverse Events (from the BEAT Study)

	Any grade	Grade 3 or 4
Hypertension	30%	5%
Proteinuria	10%	1%
Bleeding	31%	3%
Wound healing complication	4%	1%
Arterial thromboembolism	2%	1%
GI perforation	2%	2%

Table 5.

Different Efficacy Outcomes according to the Kras Mutation Status (CRYSTAL and OPUS Trial)

	CRYSTAL			OPUS
	FOLFIRI	FOLFIRI＋Cetuximab	p-value	FOLFOX	FOLFOX＋Cetuximab	p-value
Overall patients
RR	38.7%	46.9%	0.004	36%	46%	0.064
PFS (mo)	8.0	8.9	0.048	7.2	7.2
OS (mo)	18.6	19.9
Kras wild-type
RR	43.2%	59.3%	0.03	37%	61%	0.011
PFS (mo)	8.7	9.9	0.07	7.2	7.7	0.0163
OS (mo)	21.0	24.9
Kras mutant
RR	40.2%	36.2%		49%	33%
PFS (mo)	8.1	7.6		8.6	5.5	0.0192
OS (mo)	17.7	17.5

RR, response rate; PFS, progression-free survival; OS, overall survival. p-value: Clinically meaningful values were only recorded.

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