Targeted therapies in the management of colorectal carcinoma: role of bevacizumab

Figures & data

Figure 1 The major mediator of tumor angiogenesis is the vascular endothelial growth factor (VEGF) family of growth factors. The VEGF family binds to the VEGF receptors (VEGFR)-R1, VEGFR-2, VEGFR-3 tyrosine kinase as shown in figure. Neuropilin (NRP 1 and 2) are co-receptors for the VEGFRs and lack tyrosine kinase activity. The binding of VEGF to the VEGF receptors results in activation of the intracellular pathways. Activation of the PLC-PKC-raf kinase-MEK-mitogen activated protein kinase pathway results in increased cell proliferation. Activation of the phosphatidylinositol 3′-kinase (P13K), akt pathway leads to increased cell survival.

Table 1 Initial phase II trials of bevacizumab in metastatic colorectal cancer

Phase II studies	Chemotherapy regimen	n	Time to progression (months)	Response rate	Median survival (months)
Kabbinavar et al^Citation47	5-FU/LV	36	5.2	6 (17%)	13.8
	5-FU/LV + BV 5 mg/kg	35	9	14 (40%)	21.5
	5-FU/LV + BV 10 mg/kg	33	7.2	8 (24%)	16.1
Kabbinavar et al^Citation57	5-FU/LV	105	5.5	15.2%	12.9
	5-FU/LV + BV 5 mg/kg	104	9.2	26%	16.6

Abbreviation: BV, bevacizumab.

Table 2 Selected randomized studies of bevacizumab in first-line metastatic colorectal cancer

Studies	Phase	Chemotherapy regimen	n	Time to progression (months)	Response rate (%)	Median survival (months)
Hurwitz^Citation9	III	IFL + BV 5 mg/kg	402	10.6	44.8	20.3
BICC-C^Citation8	III	FOLFIRI + BV 5 mg/kg	57	11.2	57.9	28
		mIFL + BV 5 mg/kg	60	8.3	53.3	19.2
AVIRI^Citation52	IV	FOLFIRI + BV 5 mg/kg	209	11.1	44	NRa
TREE-2^Citation54	II	FOLFOX + BV 5 mg/kg	71	9.9	52	26.1
		bFOL + BV 5 mg/kg	70	8.3	39	20.4
		CapeOX + BV 5 mg/kg	72	10.3	46	24.6
N16966^Citation55	III	FOLFOX or XELOX + BV 5 mg/kg	699	9.4	49	21.3

a NR, not reported.

Table 3 Current adjuvant studies utilizing bevacizumab in colorectal cancer

Adjuvant studies	Chemotherapy regimen	n
AVANT^Citation74	FOLFOX-4 vs FOLFOX-4 plus bevacizumab vs XELOX plus bevacizumab	3450
NSABP C-08^Citation78	mFOLFOX6 with and without bevacizumab	2632
E 5202^Citation76	FOLFOX with and without bevacizumab	3610
QUASAR 2^Citation78	Capecitabine with and without bevacizumab	2240

Table 4 Adverse events in selected trial of bevacizumab in colorectal cancer

	Kabbinavar 2003^Citation47		Hurwitz 2004^Citation9	Kabbinavar 2005^Citation57	AVIRI 2008^Citation52	TREE 2^Citation54			ECOG 3200^Citation56		Saltz 2008^Citation55	First BEAT^Citation60	BRITE (long term f/u)^Citation96,Citation97,Citation101,Citation102
	BV 5 mg/kg	BV 10 mg/kg	BV 5 mg/kg	BV 5 mg/kg	Irinotecan + LV + 5-FU + BV 5 mg/kg	FOLFOX + BV 5 mg/kg	bFOL + BV 5 mg/kg	CapOX + BV 5 mg/kg	FOLFOX4 + BV 10 mg/kg	BV 10 mg/kg	BV 7.5 mg/kg + FOLFOX4 or XELOX	FOLFOX/FOLFIRI/XELOX/5FU/Cap + BV 5–7.5 mg/kg
HTN – any grade (%)	11	28	22.4	32	NR	NR	NR	NR	NR	NR	NR	29.9	27.5
Grade 3 or 4 HTN (%)	8.6	25	11	16	3.8	5.82			6.2	7.3	4	5.3	NR
Proteinuria – any grade (%)	22.8	28.1	26.5	38	NR	NR	NR	NR	NR	NR	NR	10.4	NR
Grade 3 or 4 Proteinuria (%)	NR	NR	0.8/0	1/0	NR	0.89			0.7	0	<1	1.1	NR
ATE (%)	2.85	6.25	NR	10	4.3	0	0	5.55	NS	2	1.5	2
Grade 3 or 4 bleeding (%)	0	9.4	3.1	5	3.8	3	0	0	3.4	2.1	2	3.4	2.5
GI perforation (%)	NR	NR	1.5	2	NR	2.24			1.04	1.04	<1	1.8	2
Wound healing (%)	NR	NR	NR	NR	NR	1.34			NR	NR	<1	1.1	3.7

Abbreviations: HTN, hypertension; ATE, arterial thrombo embolic events; GI, gastrointestinal; NR, not reported, NS, non-significant; BV, bevacizumab.

Table 5 Common terminology criteria for adverse events v3.0 (CTCAE)¹⁰⁹

	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Hypertension	Asymptomatic, transient (<24 h) increase by >20 mmHg (diastolic) or to >150/100 if previously within normal limits	Recurrent or persistent (>24 h) or symptomatic increase by >20 mmHg (diastolic) or to >150/100 if previously within normal limits	Requiring more then one drug or more intensive therapy than previously	Life-threatening consequences (hypertensive crisis)	Death
Proteinuria	1+ or 0.15–1.0 g/24 h	2+ to 3+ or >1.0–3.5 g/24 h	4+ or >3.5 g/24 h	Nephrotic syndrome	Death
Thrombo-embolism	–	DVT or cardiac thrombosis	DVT or thrombosis	Embolic event including PE or life-threatening thrombus	Death

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