Stomatitis and VEGFR-Tyrosine Kinase Inhibitors (VR-TKIs): A Review of Current Literature in 4369 Patients

Table 1

Report on all papers about sunitinib and stomatitis.

	Authors	Year	Neoplasia	Number of cases	Stomatitis; number	Stomatitis; grade 1	Stomatitis grade 2	Stomatitis grade 3	Stomatitis grade 4
(1)	Arakawa-Todo et al. [18]	2013	Metastatic renal cell carcinoma; A: sunitinib 50 mg once daily was given in repeated 6-week cycles of 4 weeks followed by 2 weeks off	A: 15	TOT: 9 (60%)	A: 9 (60%)		A: 0
(2)	Armstrong et al. [19]	2016	Metastatic nonclear renal cell carcinoma; A: sunitinib 50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment	A: 51	A: 14 (27.45%)	A: 14 (27%)		A: 0
(3)	Bang et al. [20]	2011	Advanced gastric cancer; A: sunitinib 50 mg/day for 4 weeks on treatment and 2 weeks off	A: 78	A: 28 (35.9%)	A: 27 (34.6%)		A: 1 (1.3%)
(4)	Cardoso et al. [21]	2012	HER2-positive metastatic breast cancer; A: sunitinib 37.5 mg (starting dose across sunitinib combination studies) once daily by oral capsule on schedule 2/1	A: 25	A: 12 (48%)	A: 9 (36%)		A: 3 (12%)
(5)	Carrato et al. [22]	2013	Metastatic colorectal cancer randomized phase III trial; A: sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan)	A: 386	A: 35 (9%)	Not reported		A: 35 (9%)
(6)	Dirican et al. [23]	2013	Metastatic renal cell carcinoma; A: sunitinib: 50 mg per day was administered in repeated 6-week cycles of daily therapy for 4 weeks, followed by 2 weeks off	A: 23	A: 6 (26.1%)	A: 4 (17.4%)		A: 2 (8.7%)
(7)	Domagala-Haduch et al. [24]	2016	Advanced renal cell carcinoma; A: sunitinib: 50 mg/day for 4 weeks, and then it is stopped for 2 weeks	A: 39	A: 13 (33.3%)	A: 11 (28.2%)		A: 2 (5.1%)
(8)	Goodman et al. [25]	2007	Refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma; A: sunitinib: 50 mg given daily for 4 weeks followed by a 2-week rest period (schedule 4/2)	A: 202	A: 58 (29%)	A: 56 (27.7%)		A: 2 (1%)
(9)	Grünwald et al. [26]	2011	Metastatic renal cell carcinoma (RCC); IL-21 administered subcutaneously (s.c.) in combination with sunitinib 50 mg once daily (OD) orally at the 4 weeks on/2 weeks off; A: rIL-21 3 μg/kg; B: rIL-21 10 μg/kg	A: 5; B: 4	TOT: 4 (80%); TOT: 1 (25%)	A: 4 (80%); B: 1 (25%)		A: 0; B: 0
(10)	Hong et al. [27]	2009	Advanced renal cell carcinoma patients; A: sunitinib (50 mg for 4 weeks on/2 weeks off schedule); B: sunitinib 37.5 mg daily continuous dosing	A: 62; B: 14	TOT: 48 (63.2%)	TOT: 40 (64.5%)		TOT: 8 (10.5%)
(11)	O’Donnell [28]	2011	Advanced renal cell carcinoma (RCC); A: sunitinib; Seven patients started at a dose of 50 mg daily and nine patients started at a dose of 37.5 mg daily. The remaining three patients started at 25 mg daily	TOT: 19	A: 8 (42.1%)	A: 7 (36.9%)		A: 1 (5.26%)
(12)	Kim et al. [29]	2014	The starting sunitinib dose was 37.5 and 50 mg for 12 and 22 patients, respectively. A 4 weeks on/2 weeks off regimen was followed for 31 patients; a 2 weeks on/2 weeks off regimen for one patient; and a daily regimen for two patients	A: 34	A: 13 (39%)	A: 10 (30%)		A: 3 (9%)
(13)	Lee et al. [30]	2010	Metastatic renal cell carcinoma; A: 6-week cycles of sunitinib treatment (50 mg once daily for 4 weeks on and 2 weeks off schedule)	A: 21	A: 9 (42.8%)	A: 5 (23.8%)		A: 4 (19%)
(14)	Lee et al. [31]	2015	treatment-naïve patients with clear cell type metastatic renal cell carcinoma (mRCC); A: sunitinib 50 mg, “2 weeks on, 1 week off”; B: sunitinib 50 mg, 4 weeks on, 2 weeks off	A: 38; B: 36	A: 27 (71%); B: 31 (86%)	A: 26 (68.4%); B: 27 (75%)		A: 1 (3%); B: 4 (11%)
(15)	Lee et al. [32]	2013	A: SU: 37.5 mg/die + oral capecitabine 800 mg/m^2 + cisplatin 60 mg/m^2; B: SU: 37.5 mg/die + oral capecitabine 1,000 mg/m^2 + cisplatin 60 mg/m^2; C: SU: 25 mg/die + oral capecitabine 1,000 mg/m^2 + cisplatin 80 mg/m^2; D: SU: 37.5 mg/die + oral capecitabine 800 mg/m^2 + oxaliplatin 110 mg/m^2; E: SU: 37.5 mg/die + oral capecitabine 1,000 mg/m^2 + oxaliplatin 110 mg/m^2; F: SU: 25 mg/die + oral capecitabine 1,000 mg/m^2 + oxaliplatin 110 mg/m^2	A: 6; B: 7; C: 15; D: 23; E: 3; F: 22	A: 5 (83.3%); B: 3 (42.9%); C: 8 (53.3%); D: 10 (43.5%); E: 1 (33.3%); F: 7 (31.8%)	A: 5 (83.3%); B: 3 (42.9%); C: 6 (40%); D: 10 (43.5%); E: 1 (33.3%); F: 7 (31.8%)		A: 0; B: 0; C: 2 (13.3%); D: 0; E: 0; F: 0
(16)	Lee et al. [6]	2009	Retrospective study; A: sorafenib 400 mg twice daily for RCC and HCC; B: sunitinib 50 mg daily, consisting of 4 weeks of treatment followed by a 2-week rest period in cycles of 6 weeks for RCC and GIST	A: 109; B: 119	A: 28 (26%); B: 43 (36%)	Not reported		Not reported
(17)	Marschner et al. [33]	2017	mRCC; A: sorafenib; B: sunitinib	A: 25; B: 152	A: 3 (12.0%); B: 29 (23.2%)	A: 2 (8%); B: 27 (17.7%)		A: 1 (4.0%); B: 2 (1.6%)
(18)	Mir et al. [34]	2016	mRCC; A: sunitinib 50 mg once daily for 4 weeks	A: 50	A: 24 (12%)	A: 20 (40%)		A: 4 (2%)
(19)	Patel et al. [35]	2009	Advanced renal cell carcinoma; A: temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period.	A: 3	A: 1	A: 1 (33.3%)		A: 0
(20)	Porta et al. [36]	2011	mRCC; A: sunitinib; B: sorafenib	A: 85; B: 60	A: 50 (58.8%); B: 16 (26.7%)	A: 48 (56.4%); B: 16 (26.7%)		A: 2 (2.4%); B: 0
(21)	Rock et al. [37]	2007	GIST; A: sunitinib 50 mg	A: 202	A: 58 (29%)	A: 56 (27.7%)		A: 2 (1%)
(22)	Socinski et al. [38]	2008	Advanced non-small cell lung cancer; A: sunitinib 50 mg/d for 4 weeks followed by 2 weeks of no treatment in a 6-week cycle	A: 63	A: 27 (43%)	A: 27 (43%)		A: 0
(23)	Sonpavde et al. [39]	2010	Metastatic castration-resistant prostate cancer; A: sunitinib 50 mg/day: 4 weeks on followed by 2 weeks off	A: 36	A: 2 (5.7%)	A: 1		A: 1
(24)	Sternberg et al. [40]	2015	Metastatic renal cell carcinoma (mRCC); A: oral sunitinib 50 mg/day on a 4 weeks on/2 weeks off schedule	A: 521	A: 192 (37%)	A: 159 (31%)		A: 33 (6%)
(25)	Van Der Veldt et al. [41]	2008	Advanced RCC; A: sunitinib 50 mg daily for 4-week treatment followed by 2-week rest period in a cycle of 6 weeks	A: 82	A: 58 (70.73%)	A: 51 (62%)		A: 7 (9%)
(26)	Yildiz et al. [42]	2011	Advanced renal cell carcinoma; A: sunitinib 37.5 mg daily; B: sunitinib 25 mg	A: 67	A: 36 (51%)	A: 36 (51%)		A: 0
(27)	Yoo et al. [43]	2010	Renal cell carcinoma; A: sunitinib 50 and 37.5 mg daily	A: 65	A: 37 (57%)	A: 31 (50%)		A: 6 (10%)
(28)	Zhao et al. [44]	2013	Locally advanced clear cell renal carcinoma; A: sorafenib 400 mg orally twice daily for a 4-week cycle; B: sunitinib 50 mg orally daily for a 6-week cycle	A: 20; B: 23	A: 8 (40%); B: 7 (30%)	Not reported		Not reported
	Total			2.596	914 (35.2%)
	Total with grade			2.068	829 (40.08%)	739 (35.73%)		90 (5.35%)
	Total not reporting grade			142	50 (3.52%)	Not reported		Not reported
	Total reporting only grade >2			386	35 (0.06%)	Not reported		35 (0.06%)

Note. Carrato et al. (2013) [22] did not report the grade of stomatitis; Lee et al. (2009) [6] and Zhao et al. (2013) [44] reported the incidence rates limited to grade 3 and grade 4 treatment-related toxicities; for this reason, data about cases of stomatitis and stomatitis grades 1 and 2 are lower than real.