A 2/1 sunitinib dosing schedule provides superior antitumor effectiveness and less toxicity than a 4/2 schedule for metastatic renal cell carcinoma: A systematic review and meta-analysis

Abstract

Background The standard sunitinib schedule to treat metastatic renal cell carcinoma (mRCC) is 4 weeks on/2 weeks off (4/2). However, some studies revealed intolerable adverse events (AEs) in patients on this schedule. An alternative schedule, 2 weeks on/1 week off (2/1), may overcome this issue. This meta-analysis was performed to compare the effectiveness and toxicity between the 2/1 and 4/2 sunitinib dosing schedules. Methods We acquired relevant studies by searching PubMed, ScienceDirect, the Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar. Our main endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and AEs. Results We identified 9 medium- and high-quality studies. Both schedules were effective for mRCC, with comparable OS and similar ORR. However, the 2/1 schedule had better PFS (hazard ratio (HR) = 0.81, 95% confidence interval [CI]: 0.66-0.99, P= 0.04), higher DCR (risk rate (RR) = 1.22, 95% CI: 1.01-1.47, P= 0.04) and fewer dosage interruptions (RR= 0.60, 95% CI: 0.43-0.84, P= 0.003). Additionally, the 2/1 schedule elicited fewer specific severe AEs, including thrombocytopenia/platelet disorder, hand-foot syndrome, hypertension and fatigue. In our subanalysis, PFS was better among East Asians using the 2/1 schedule than among other populations (HR= 0.75, 95% CI: 0.58-0.98, P= 0.03), and patients administered an initial dosage of 50 mg/d on the 2/1 schedule had superior PFS (HR= 0.76, 95% CI: 0.59-0.97, P= 0.03) than those others. Conclusions These findings suggest that the 2/1 schedule is more suitable for mRCC than 4/2, due to superior PFS, better DCR and fewer AEs. Nevertheless, more large-scale studies with good quality are needed.

Association of sunitinib concentration and clinical outcome in patients with metastatic renal cell carcinoma treated with a 2‐week‐on and 1‐week‐off schedule

“…This indicates the need to manage the severe adverse effects, although the 2/1 schedule treatment had less sunitinibrelated severe toxicity among patients with metastatic renal cell carcinoma. 7,19 In this study, the median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects. We observed a patient who exhibited a high total sunitinib concentration (sunitinib, 106 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhoea during the 2/1 schedule of sunitinib.…”

“…6 However, a recent meta-analysis demonstrated that the alternative dosing schedule, 2-week-on and 1-week-off schedule (2/1 schedule), is more effective [improved progression-free survival (PFS)] than the 4/2 schedule for the treatment of metastatic renal cell carcinoma. 7 Moreover, the 2/1 schedule is associated with less sunitinib-related severe toxicity and better tolerability among patients with metastatic renal cell carcinoma. 7,8 Sunitinib is primarily metabolized by cytochrome P450 (CYP) 3A4 to its major pharmacologically active metabolite, N-desethyl sunitinib, which is further metabolized to inactive compounds by the same enzyme.…”

“…7 Moreover, the 2/1 schedule is associated with less sunitinib-related severe toxicity and better tolerability among patients with metastatic renal cell carcinoma. 7,8 Sunitinib is primarily metabolized by cytochrome P450 (CYP) 3A4 to its major pharmacologically active metabolite, N-desethyl sunitinib, which is further metabolized to inactive compounds by the same enzyme. 9,10 An in vivo study reported that a total sunitinib (sunitinib plus N-desethyl sunitinib) concentration ≥50 ng/mL is required to achieve an antitumour effect.…”

Systematic review and cost-effectiveness of pharmacokinetically guided sunitinib individualized treatment for patients with metastatic renal cell carcinoma

“…Based on the available evidence, the 2/1 schedule is relatively more effective and safer than the 4/2 schedule, and is feasible way to maintain drug level. 29,30 Comparison of intermittent versus continuous dosing regimens revealed that CDD does not have any advantage over 4/2 schedule in terms of the incidence or severity of AEs or patient-reported outcomes. 18…”

Fatigue and its management in cancer patients undergoing VEGFR-TKI therapy

“…According to a meta-analysis, the 2/1 (2 weeks on, 1 week off) schedule is more suitable than 4/2 (4 weeks on, 2 weeks off) for sunitinib in mRCC, due to superior progression-free survival, better disease control rate, and fewer AEs including fatigue [75,76].…”