Risk of hypothyroidism in patients with cancer treated with sunitinib: A systematic review and meta-analysis

Figures & data

Figure 1. CONSORT diagram; selection process for the trials. EAP, expanded access protocol.

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

Author	Year	Phase	Histology	No. of Patients Enrolled	Treatment Arms	Age (years) Median (Range)	Treatment Duration (months) Median (Range)	PFS (months) Median (Range)	No. of Patients for Analysis	No. of hypothyroidism Events		Regular thyroid function monitoring	CTCAE
										All- Grade	High- Grade
Dsmetii [3]	2006	III^a	GIST	312	Sunitinib 50 mg/d, days 1–28, q6w	58 (23–84)	1.9 (0.03–7.9)^b	6 (2.8–7.1)	202	8	1	No	3
					Placebo	55 (23–81)	1.0 (0.06–5.6)^b	1.5 (1.1–2.5)	102	1	0
Motzer [4]	2007	III^a	RCC	750	Sunitinib 50 mg/d, days 1–28, q6w	62 (27–87)	11 (< 1–41)	11 (11–13)	375	61^c	6^c	No	3
					INF 9MIU 3 × weekly	59 (34–84)	4 (< l–40)	5 (4–6)	360	3^c	0^c
Barrios [13]	2010	III^a	HER2- negative BC	482	Sunitinib 37.5 mg daily	53 (25–80)	2 (0.03–16.2)	2.8 (2.4–4.0)	238	29	1	No	3
					Capecitabine 1,250 mg/m^2 BID, days 1–14, q3w	53 (23–80)	2 (0.13–18)	4.2 (3.8–5.5)	240	1	0
Raymond [5]	2011	III^a	PNET	171	Sunitinib 37.5 mg daily	56 (25–84)	4.6 (0.4–17.5)	11.4 (7.4–19.8)	83	6	0	No	3
					Placebo	47 (26–78)	3.7 (0.03–20.2)	5.5 (3.6–7.4)	82	1	0
Robert [15]	2011	III^a	HER2- negative BC	485	Sunitinib 25–37.5 mg daily with paclitaxel 90 mg/m^2 qw for 3w followed by 1w off	57 (27–84)	3.2 (0.03–16.5)	7.4 (6.9–8.5)	235	0^d	0^d	No	3
					Bevacizumab 10 mg/kg q2w with paclitaxel 90 mg/m^2 qw for 3w followed by 1w off	57 (32–92)	0.3 (0.03–1.7)	9.2 (7.7–13.0)	236	0^d	0^d
Bergh [16]	2012	III^a	HER2- negative BC	593	Sunitinib 37.5 mg/d, days 2–15, q3w with docetaxel 75 mg/m^2, day 1, q3w	54 (31–84)	6.5 (5.75–7.25)	8.6 (8.2–10.3)	295	17^d	1^d	No	3
					Docetaxel 100 mg/m^2 q3w	56 (28–78)	4.5 (4.0–4.75)	8.3 (7.7–9.6)	293	2^d	0^d
Rini [28]	2008	II	RCC	61	Sunitinib 50 mg/d, days 1–28, q6w	59 (39–80)	6.7 (0.6–26.5)	7.6 (4.6–9.2)	61	18	0	No	3
Kontovinis [29]	2009	II	RCC	42	Sunitinib 50 mg/d, days 1–28, q6w	64 (25–75)	9.0 (1.5–19.5)^b	8.9 (6.5–24.6)	42	5	0	Yes	3
George [30]	2009	II	GIST	61	Sunitinib 37.5 mg daily	59 (24–84)	11.5 (0.5–23.25)‘	8.5 (6–12.3)	60	9	0	No	3
George [31]	2009	II	non-GIST sarcoma	53	Sunitinib 37.5 mg daily	52 (18–79)	NR	1.8	52	16	0	No	3
Gore [32]	2009	EAP	RCC	4564	Sunitinib 50 mg/d, days 1–28, q6w	59 (19–89)	7.5 (1.5–37.5)^b	10.9 (10.3–11.2)	4,371	261	18	No	3
Fountzilas [33]	2010	II	SCCHN	17	Sunitinib 50 mg/d, days 1–28, q6w	61 (45–75)	2.0 (0.65–4.5)	2.3 (0.6–16.6)^e	17	1	0	No	3
MacKay [34]	2010	II	Cervical cancer	19	Sunitinib 50 mg/d, days 1–28, q6w	44 (28–78)	3 (1.5–18)^b	3.5 (2.7–7.0)	19	9	0	No	3
Machiels [35]	2010	II	SCCHN	42	Sunitinib 37.5 mg daily	57 (44–75)	1.8 (0.5–9.8)	2 (1.3–2.7)	38	5	0	No	3
Koeterle [36]	2010	II	HCC	45	Sunitinib 37.5 mg daily	63 (37–83)	2.9 (l–12)^b	1.5 (1.38 –2.83)	45	5	0	Yes	3
Shanafelt [37]	2010	II	CLL	18	Sunitinib 37.5 mg daily	68 (51–89)	2^b	2.7 (1.8–4.6)	18	NR	0	No	3
Mayer [17]	2010	II^a	HER2- negative BC	46	Sunitinib 25 or 37.5 mg daily with bevacizumab 10 mg/kg q2w plus paclitaxel 90 mg/m^2	58 (34–81)	2.8	NR	23	0	0	No	3
					Bevacizumab 10 mg/kg q2w plus paclitaxel 90 mg/m^2	52 (29–80)	3.5	NR	23	0	0
Ping [38]	2011	II	NSCLC	22	Sunitinib 50 mg/d, days 1–28, q6w	55	2.8 (0.5–7.5)	3.0 (2.1–3.8)	22	2	0	No	3
Biagi [39]	2011	II	Epithelial ovarian cancer	31	Sunitinib 50 mg/d, days 1–28, q6w or 37.5 mg daily^f	57 (37–82)	4.5 (1.5–9)^b 4 (l–10)^b	4.1 (1.8–5.4)	16 14	13	0	Yes	3^g
Buckstein [40]	2011	II	DLBCL	19	Sunitinib 37.5 mg daily	65 (34–81)	2 (l–5)^b	2.2 (1.41–3.48)	17	4	0	No	3
Schneider [41]	2011	II	SCLC	16	Sunitinib 50 mg/d, days 1–28, q6w	66 (34–80)	1.0 (0.35–5.0)	2.5 (0.8 –3.1)	16	2	1	No	3
Novello [42]	2011	II	NSCLC	66	Sunitinib 37.5 mg daily	61 (35–77)	2 (1–13)^b	2.4 (1.9–3.3)	64	1	0	No	3
Geivais [43]	2011	II	NSCLC	84	Sunitinib 50 mg/d, days 1–28, q6w	60 (30–81)	2.8 (0.25–33.3)	3.95 (2.6–5.5)	66	2	0	No	3
Motzer [27]	2012	II^a	RCC	292	Sunitinib 50 mg/d, days 1–28, q6w	61 (35–84)	5 (1–26)	9.9 (7.0–13.4)	146	19	0	No	3
					Sunitinib 37.5 mg daily	64 (44–86)	6 (1–25)	7.1 (6.8–9.7)	143	11	0

BC, breast cancer; CLL, chronic lymphocytic leukemia; CTCAE, Common Terminology Criteria for Adverse Events; EAP, expanded access protocol; GIST, GI stromal tumor; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; INF, interferon immunotherapy; MIU, million international units; NR, not reported; NSCLC, non–small cell lung cancer; PFS, progression–free survival; PNET, pancreatic neuroendocrine tumor; RCC, renal cell cancer; SCCHN, squamous cell carcinoma of the head and neck; SCLC, small cell lung cancer.

^aRandomized trial; ^bCalculated from the number of cycles administered and the length of each cycle; ^cData retrieved from drug package insert; ^dData provided by Pfizer; ^eTime to tumor progression; ^fOf the 31 patients entered, 17 were treated on sunitinib 50 mg/d days 1–28, q6w in stage 1 of accrual and 14 were treated on Sunitinib 37.5 mg daily in stage 2 of accrual; ^gData provided by the author.

Table II. Incidence of all- and high-grade hypothyroidism events from all included trials.

Author	Year	Phase	Sample Size	No. of Events	Incidence (95% CI)
All-grade
Demetri [3]	2006	III	202	8	0.040 (0.013–0.066)
Motzer [4]	2007	III	375	61	0.163 (0.125–0.200)
Barrios [13]	2010	III	238	29	0.122 (0.080–0.163)
Raymond [5]	2011	III	83	6	0.072 (0.017–0.128)
Robert [15]	2011	III	235	0	0
Bergh [16]	2012	III	295	17	0.058 (0.031–0.084)
Rini [28]	2008	II	61	18	0.295 (0.181–0.410)
Kontovinis [29]	2009	II	42	5	0.119 (0.021–0.217)
George [30]	2009	II	60	9	0.150 (0.060–0.240)
George [31]	2009	II	52	16	0.308 (0.182–0.433)
Gore [32]	2009	EAP	4371	261	0.060 (0.053–0.067)
Fountzilas [33]	2010	II	17	1	0.059 (0–0.171)
MacKay [34]	2010	II	19	9	0.474 (0.249–0.698)
Machiels [35]	2010	II	38	5	0.132 (0.024–0.239)
Koeberle [36]	2010	II	45	5	0.111 (0.019–0.203)
Mayer [17]	2010	II RCT	23	0	0
Ping [38]	2011	II	22	2	0.091 (0–0.211)
Biagi [39]	2011	II	30	13	0.433 (0.256–0.611)
Buckstein [40]	2011	II	17	4	0.235 (0.034–0.437)
Schneider [41]	2011	II	16	2	0.125 (0–0.287)
Novello [42]	2011	II	64	1	0.016 (0–0.046)
Gervais [43]	2011	II	66	2	0.030 (0–0.072)
Motzer [27]	2012	II RCT	289	30	0.104 (0.069–0.139)
Total			6660	504	0.098 (0.073–0.124)
Test for heterogeneity: Q = 412.07; p < .001; I^2 = 94.7%
High-grade
Demetri [3]	2006	III	202	1	0.005 (0–0.015)
Motzer [4]	2007	III	375	6	0.016 (0.003–0.029)
Barrios [13]	2010	III	238	1	0.004 (0–0.012)
Raymond [5]	2011	III	83	0	0
Robert [15]	2011	III	235	0	0
Bergh [16]	2012	III	295	1	0.003 (0–0.010)
Rini [28]	2008	II	61	0	0
Kontovinis [29]	2009	II	42	0	0
George [30]	2009	II	60	0	0
George [31]	2009	II	52	0	0
Gore [32]	2009	EAP	4371	18	0.004 (0.002–0.006)
Fountzilas [33]	2010	II	17	0	0
MacKay [34]	2010	II	19	0	0
Machiels [35]	2010	II	38	0	0
Koeberle [36]	2010	II	45	0	0
Shanafelt [37]	2010	II	18	0	0
Mayer [17]	2010	II RCT	23	0	0
Ping [38]	2011	II	22	0	0
Biagi [39]	2011	II	30	0	0
Buckstein [40]	2011	II	17	0	0
Schneider [41]	2011	II	16	1	0.063 (0–0.181)
Novello [42]	2011	II	64	0	0
Gervais [43]	2011	II	66	0	0
Motzer [27]	2012	II RCT	289	0	0
Total			6678	28	0 0.004 (0.003–0.005)
Test for heterogeneity: Q = 14.75; p = 0.903; I^2 = 0.0%

EAP, expanded access protocol; RCT, randomized controlled trial.

Figure 2. Forest plots of relative risk (RR) of all- and high-grade hypothyroidism events associated with sunitinib versus control. The size of squares corresponds to the weight of the study in the meta-analysis. RR of all- and high-grade hypothyroidism was calculated using the fixed-effects model.

Table III. Relative risk and incidence of all- and high-grade hypothyroidism events stratified by underlying malignancy, monitoring, sunitinib dosing schedule or duration of treatment with sunitinib.

	Incidence (95% CI)	P difference	Relative Risk (95% CI)	P difference
All-grade
RCC	13.4% (7.4–19.4)	0.21	19.3 (6.2–61.7)	0.43
Non-RCC	9.1% (5.9–12.2)		10.8 (4.4–26.2)
Regular monitoring (+)	20.2% (4.6–35.8)	0.17	5.9 (0.7–48.2)	0.42
Regular monitoring (−)	9.0% (6.4–11.6)		15.0 (7.1–31.8)
Continuous dosing	8.3% (4.7–11.9)	0.33	17.5 (4.3–72.2)	0.71
Intermittent dosing	10.9% (7.1–14.7)		12.8 (5.7–28.8)
Long treatment duration	12.5% (8.6–16.4)	0.02	13.6 (6.0–31.0)	0.91
Short treatment duration	6.5% (3.3–9.7)		14.8 (3.9–56.9)
High-grade
RCC	0.4% (0.1–0.7)	1.00	12.5 (0.71–220.8)	0.34
Non-RCC	0.4% (0.3–0.5)		2.4 (0.4–14.9)
Regular monitoring (+)	1.2% (0–2.7)	0.25	NA	NA
Regular monitoring (−)	0.4% (0.3–0.5)		4.8 (1.1–20.8)
Continuous dosing	0.4% (0.1–0.7)	0.56	3.0 (0.3–28.8)	0.63
Intermittent dosing	0.5% (0.3–0.6)		6.3 (0.9– 45.1)
Long treatment duration	0.4% (0.2–0.5)	1.00	7.7 (1.0–62.3)	0.41
Short treatment duration	0.4% (0.1–0.7)		2.2 (0.2–20.1)

RCC, renal cell cancer.

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