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A single tertiary care facility retrospectively analyzed the data from patients with metastatic renal cell carcinoma receiving front-line sunitinib therapy. Improved toxicity and overall response rates were evident, with comparable outcomes observed. These results show that toxicity amelioration using schedule manipulation to maintain an adequate dosage level is a justifiable maneuver.Sunitinib first-line treatment is one of the standards of care in metastatic renal cell carcinoma (mRCC). However, the adverse events associated with its use can hinder adequate dosing and hence have detrimental effects on treatment outcome. Alternative schedules, such as 2-weeks-on treatment and 1-week-off treatment (2/1 schedule), might solve this dilemma. Therefore, an analysis was performed to compare both schedules in terms of toxicity and efficacy.Data regarding first-line sunitinib treatment of mRCC patients using the 4/2 and 2/1 schedules were collected. The data from 56 patients were reviewed. Of the 56 patients, 30 started sunitinib using the 4/2 schedule (group 1) and 26 using the 2/1 schedule (group 2). The primary endpoint was toxicity assessment. The secondary endpoints were the response rate, progression-free survival, and overall survival.The overall incidence of adverse events was less for the 2/1 group, and the difference reached statistical significance for fatigue (P = .018), hand–foot syndrome (P = .008), mucositis (P = .010), hypertension (P = .038), diarrhea (P = .03), and thrombocytopenia (P = .023). The objective response rates were better for group 2 (modified schedule) in the first and subsequent response evaluations. The median progression-free survival was 15 months and 17 months in groups 1 and 2, respectively. The median overall survival was 24 months and 23 months for groups 1 and 2, respectively.The alternative 2/1 schedule of sunitinib demonstrated improved toxicity compared with the traditional 4/2 schedule, with similar survival.