Table 1 -.

Detailed data of the three randomized controlled trials included in the pooled analysis

Source	Trial phase	Disease stage	Follow-up(yr)	Additional criteria	Study groups	Treatment design	Dosage^a	Median time to DFS	No. of patients	No. of events
										DFS	Any death	G3/4 AE
Haas et al [4] (ASSURE)	III	Pt1b high-grade N0M0 or N + M0, clear cell and non-clear cell RCC	4	ECOG 0–1, normal liver and hematological function; creatinine clearance of >30 ml/min	Exp.	Sunitinib/ sorafenib	Sunitinib: 50 mg/d for the first 28 d of each 6-wk cycle Sorafenib: 400 mg twice per day throughout all cycles	5.8/6.1 yr	647/649	284/284	156/138	390/449
					Con.	Placebo		6.6 yr	647	287	141	159
Ravaud et al [5] (S-TRAC)	III	Stage III-IV M0 (UISS modified criteria), clear cell RCC	4	ECOG 0–2	Exp.	Sunitinib	50 mg/d on a 4-wk-on, 2-wk-off schedule for 1 yr	6.8 yr	309	113	67	185
					Con.	Placebo		5.6 yr	306	144	74	59
Motzer et al [6] (PROTECT)	III	pT2 high-grade, pT3–4 N0M0 or N + M0, clear cell RCC	5	KPS ≥80%	Exp.	Pazopanib	Starting 600 mg/d for 1 yr, with optional dose escalation to 800 mg/d after 8–12 wk	30.4 mo	571	188	65	338
					Con.	Placebo		30.7 mo	564	203	83	119

Con. = control; DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; Exp. = experimental; G3/4 AE = grade 3/4 adverse events; KPS = Karnofsky performance status; RCC = renal cell carcinoma; UISS = UCLA Integrated Staging System.

Dosage: For ASSURE, given that high rates of toxicity-related discontinuation occurred after 1323 patients had enrolled (treatment discontinued by in 44% (193/438) and 45% (199/441) of sunitinib- and sorafenib-treated patients, respectively), the starting does for each drug was reduced compared with individually titrated up to the original full doses. Specifically, the starting dose was amended to 37.5 mg for sunitinib or 400 mg for sorafenib for the first one to cycles of therapy. For PROTECT, the trial was originally designed with pazopanib 800 mg once daily as the starting dose. An amendment to the protocol was introduced to reduce the starting dose to 600 mg once daily due to a higher than expected treatment discontinuation. This resulted in 568 patients being recruited, which served as the group for primary analysis. Previously, 198 patients received 800 mg as the starting dose, where 53% experienced adverse events and had their dosage reduced, and 51% discontinued treatment. For S-TRAC, dose interruptions occurred in 54% (166/309) of sunitinib patients, while dose reductions (to 37.5 mg/d) occurred in 46% (140/309).