Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients

Figures & data

Figure 1. Selection process for the trials included in the meta-analysis.

Table I. Characteristics of trials included in the meta-analysis.

Source	Trial design	No. analyzed	Median age (years)	Underlying malignancy	Dose (once daily)	CTC version	Fatal outcomes (hepatic)
Altorki et al., 2010 [13]	Phase II, single arm	35	64	NSCLC^a	800 mg	3	0
Bible et al., 2010 [16]	Phase II, single arm	37	63	Advanced differentiated thyroid cancers	800 mg	3	0
Friedlander et al., 2010 [12]	Phase II, single arm	36	59.9 (mean)	Ovarian cancer	800 mg	3	0
Hutson et al., 2010 [18]	Phase II, single arm	225	59.8 (mean)	Renal cell carcinoma	800 mg	3	0
Iwamoto et al., 2010 [11]	Phase II, single arm	35	53	Recurrent glioblastoma multiforme	800 mg	3	0
Monk et al., 2010 [8]	Phase II, randomized (pazopanib vs. lapatinib vs. pazopanib with lapatinib)	150^b	49	Metastatic recurrent cervical cancer	Pazopanib only: 800 mg Pazopanib with lapatinib: 400 mg or 800 mg	3	0
Sleijfer et al., 2009 [7]	Phase II, single arm	142	51.4	Soft tissue sarcomas	800 mg	3	0
Sternberg et al., 2010 [5]	Phase III, randomized (pazopanib vs. placebo)	435	59	Renal cell carcinoma	800 mg	3	2/290
Taylor et al., 2010 [9]	Phase II, single arm [5]	21	56	Metastatic breast cancer	800 mg	3	0
Van Der Graaf et al., 2011 [17]	Phase III, randomized (pazopanib vs. placebo)	362^b	56.7	Soft tissue sarcomas	800 mg	N/A	0

^anon-small cell lung carcinoma; ^bnumber used for analysis.

Figure 2. Incidences of high-grade AST, ALT, and bilirubin elevation associated with pazopanib. Summary incidences were calculated using a fixed-effects model for high-grade AST (A), ALT (B), and bilirubin elevation (C). Incidence for each study is displayed numerically on the left and graphically on the right. Total events and sample sizes are also displayed for each study. For study name, the first author's name was used to represent each trial. For each trial: filled-in square, incidence, lines, 95% confidence interval, diamond plot, overall results of the included trials.

Figure 3. Relative risk of high-grade AST, ALT, and bilirubin elevation associated with pazopanib versus placebo. Summary relative risks were calculated using a fixed-effects model for high-grade AST (A), ALT (B), and bilirubin elevation (C). RR for each study is displayed numerically on the left and graphically on the right. Total events and sample sizes are also displayed for each study. For study name, the first author's name was used to represent each trial. For each trial: filled-in square, incidence, lines, 95% confidence interval, diamond plot, overall results of the included trials.

Table II. Incidence and relative risk of liver toxicity with pazopanib.

Categories	Incidence (%, 95% CI)	RR (95% CI), p-value
AST elevation
All grade	39.6% (31.2–48.6)	3.19 (2.24–4.54), p < 0.001
High grade	6.9% (5.5–8.6)	6.56 (2.04–21.07), p < 0.001
ALT elevation
All grade	41.4% (34.1–49.0)	2.38 (1.72–3.29), p < 0.001
High grade	9.4% (7.8–11.4 )	4.33 (1.88–10.0), p = 0.001
Total bilirubin elevation
All grade	24.8% (16.3–35.3)	3.40 (2.05–5.63), p < 0.001
High grade	3.4% (2.3–5.0)	1.31 (0.47–3.64), p = 0.61
Fatal liver toxicity	0.7% (0.2–2.7)	2.51 (0.12–51.91), p = 0.55

ALT, alanine transaminase; AST, aspartate aminotransferase; CI, confidence interval; NSCLC, non-small cell lung cancer; RCC, renal cell cancer; RR, relative risk. The incidence and relative risk were calculated from trials included in this study by meta-analysis as described in the “Methods” section.

Table III. Risk of liver toxicity with VEGFR tyrosine kinase inhibitors.

	Molecular targets	Incidence of high-grade AST elevation (95% CI)	Incidence of high-grade ALT elevation (95% CI)	References
Sunitinib	VEGFR-1,-2; PDGFR, C-Kit, Flt-3, RET	2.0% (0.7–3.5)	3.0% (1.4–4.9)	[37]
Sorafenib	VEGFR-2,-3; Raf, PDGFR, C-Kit, Flt-3, RET	1.0% (0.4–3.0)	2.0% (0.9–4.1)	[38]
Axitinib	VEGFR-1,-2,-3; PDGFR, C-Kit	< 1%	< 1%	[38]
Pazopanib	VEGFR-1, 2, 3; PDGFR; C-Kit	6.9% (5.5–8.6)	9.4% (7.8–11.4 )	This study

PDGFR, platelet derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Targets directly involved in angiogenesis are bolded.

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