A Perspective: Role of Targeted Therapy in Colon Cancer

Hyun Hee Chung; Byung Ik Jang

doi:10.4166/kjg.2013.61.3.128

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Chung and Jang: A Perspective: Role of Targeted Therapy in Colon Cancer

Review Article

Korean J Gastroenterol 2013;61(3):128-135.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.61.3.128

A Perspective: Role of Targeted Therapy in Colon Cancer

Hyun Hee Chung, Byung Ik Jang

Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

Correspondence to: Byung Ik Jang, Department of Internal Medicine, Yeungnam University Hospital, 170 Hyeonchung-ro, Nam-gu, Daegu 705-717, Korea. Tel: +82-53-620-3831, Fax: +82-53-654-8386, E-mail: JBI@MED.YU.AC.KR

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

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10–15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.

Keywords: Colorectal neoplasms, Targeted molecular therapy

References

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Table 1.

Trial of Bevacizumab in the Treatment of Metastatic Colorectal Cancer

Trial	Group	Patient (n)	Response rate (%)	PFS (month)	OS (month)
Hurwitz⁶	IFL	411	34.8	6.2	15.6
	IFL＋ BV	402	44.8 ^a	10.6 ^a	20.3 ^a
BICC-C study⁷	mIFL＋ BV	60		8.3
	FOLFIRI＋ BV	57		11.2
TREE study⁸	TREE 1 (FOLFOX/bFOL/CapOx)	147	41/20/27	8.7/6.9/5.9	18.2
	TREE 2 (with BV)	213	52/39/46	9.9/8.3/10.3	24.4
NO16966⁹	XELOX or FOLFOX	701		8.0
	(XELOX or FOLFOX)＋ BV	699		9.4 ^a
E3200¹⁰	FOLFOX4	290	9.2	4.8	10.8
(2nd line)	FOLFOX4＋ BV 10 mg	289	21.8 ^a	7.2 ^a	12.9 ^a

PFS, progression free survival (median); OS, overall survival (median); BV, bevacizumab; IFL, irinotecan+bolus 5-fluorouracil (5-FU)＋ leucovorin; mIFL, modified IFL; FOLFIRI, irinotecan＋ infusional 5-FU＋ leucovorin; FOLFOX, oxaliplatin＋ infusional 5-FU＋ leucovorin; bFOL, oxaliplatin＋ bolus 5-FU＋ leucovorin; CapOx, capcitabine＋ oxaliplatin; XELOX, capcitabine＋ oxaliplatin.

^a p＜0.05.

Table 2.

Side-effects of Bevacizumab with Chemotherapy

Adverse event (%)	Saltz et al.¹¹		Hurwitz et al.⁶
Adverse event (%)	FOLFOX/XELOX (n=675)	Bevacizumab＋ FOLFOX/XELOX (n=600)	Placebo＋ IFL (n=397)	Bevacizumab＋ IFL (n=393)
Patients with any event	75	80	74	85 ^a
Hypertension	1	4	2	11 ^a
Proteinuria	0	＜1	1	1
Leukopaenia	NR	NR	31	37
Diarrhea	NR	NR	25	32
Any thrombotic event	NR	NR	16	19
VTE	5	8	NR	NR
ATE ^b	1	2	NR	NR
Pulmonary embolism	NR	NR	5	4
Bleeding	1	2	3	3
Gastrointestinal perforation	＜1	＜1	0	2

FOLFOX, oxaliplatin+infusional 5-fluorouracil (5-FU)＋ leucovorin; IFL, irinotecan＋ bolus 5-FU＋ leucovorin; XELOX, capcitabine＋ oxaliplatin; VTE, venous thromboembolism; ATE, arterial thromboembolism; NR, not rated.

^a p＜0.01.

^b Also includes ischemic cardiac events.

Table 3.

Trial of Cetuximab in the Treatment of Metastatic Colorectal Cancer

Trial	Inclusion criteria	Group	Patient (n) R	Response rate (%)	PFS (month)	OS (month)
Saltz¹⁶	EGFR (＋) MCRC,	Cetuximab only	57	10.5	1.4	6.4
BOND trial¹⁷	irinotecan refractory ⁷ EGFR (＋) MCRC,	Cetuximab	111	10.8	1.5	6.9
	irinotecan refractory	IFL＋ cetuximab	218	22.9 ^a	4.1 ^a	8.6
BOND-2 tria	al¹⁸ Irinotecan refractory	Cetuximab＋ BV	40	20.0	5.6
	MCRC, Naї ve to BV and etuxim	mab Cetuximab＋ BV＋ irinotecan	41	37.0 ^a	7.9 ^a
Andre²³	EGFR (＋) MCRC, 1st line	FOLFOX4＋ cetuximab	43	81	12.3	30.0
CACLGB	1st line	FOLFOX or FOLFIRI	116	38
80203²⁴		FOLFOX or FOLFIRI＋ cetuximab	108	52 ^a
CRYSTAL²⁵	EGFR (＋) MCRC, 1st line	FOLFIRI	609	38.7	8.9
		FOLFIRI＋ cetuximab	608	46.9 ^a	9.5

PFS, progression free survival (median); OS, overall survival (median); EGFR, epidermal growth factor receptor; MCRC, metastatic colorectal cancer; IFL, irinotecan＋ bolus 5-fluorouracil (5-FU)＋ leucovorin; BV, bevacizumab; FOLFOX, oxaliplatin＋ infusional 5-FU＋ leucovorin; FOLFIRI, irinotecan＋ infusional 5-FU＋ leucovorin.

^a p＜0.05.

Table 4.

Clinical Trials of New Target Therapy

Inhibition of Src tyrosine kinase	AZD0530 (phase II), SKI-606 (bosutinib), SU6656, AP23464, BMS-354825
	(dasatinib) – phase I/II
mTOR inhibitor	Temsirolimus (NCT00593060), everolimus (NCT00522665)
PI3K/Akt signalling pathway	BEZ235, BGT226, XL147, BKM120, GDC-0941, XL765
Induction of apoptosis
Smac	GDC-0152
Death receptor 5 (DR5)	AMG 655 (NCT00813605)
Aurora kinase (AK) inhibitors	ZM447439, VX-680, AZD1152, MLN8054, MLN 8237
Proteasome inhibitors	Bortezomib
Targeting epithelial cell adhesion molecule (EpCAM)	Edrecolomab (phase III), MT201, EMD 273066, tucotuzumab celmoleukin
Antisense and small interfering RNA (siRNA)	Antisense strategies against Bcl2, survivin, XIAP
Radioimmunotherapy using cancer-specific antibody	huA33 (NTC00291486)

Src, sarcoma; mTOR, mammalian target of rapamycin; PI3K, Phosphatidylinositide 3-kinases; Smac, second mitochondrial activator of cas-pases; XIAP, X-linked inhibitor of apoptosis protein.

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