Efficacy and Safety of Individualized Schedule of Sunitinib by Drug Monitoring in Patients with Metastatic Renal Cell Carcinoma

Abstract

Purpose

To investigate the survival benefit and safety of individualized schedules for sunitinib in patients with metastatic renal cell carcinoma (mRCC) through plasma concentration monitoring.

Methods

A total of 105 patients with mRCC were enrolled. The schedule was adjusted in two ways: therapeutic drug monitoring (TDM) and toxicity-adjusted schedule (TAS). One group of patients were without any schedule adjustment (maintained schedule, MAS). Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared. The relationship between AEs and steady-state concentration or consecutive monitoring curves was explored. Further monitoring of individualized schedules was also conducted.

Results

Based on the plasma concentration, the schedules of 18 patients were adjusted in the TDM group. The schedules were adjusted in 37 patients due to severe AEs in the TAS group, while 50 patients were without any schedule adjustment. The median PFS and OS were better in the TDM group than the other two groups (p = 0.001 and p = 0.004, respectively). Univariate and multivariate analyses indicated that TDM could decrease the risk of death independently (p = 0.026). Moreover, the incidence of grades 3/4 AEs decreased from 88.9% to 33.3% in the TDM group (p = 0.001). Sunitinib concentration in 150–200ng/mL was regarded as a “transitional zone” due to severe AEs mainly happened when concentration elevated over it. After TDM, further plasma concentration monitoring indicated that individualized schedules enabled sunitinib concentration to fluctuate in a much safer range.

Conclusion

Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with adjusted schedules by therapeutic drug monitoring could achieve better survival benefits.

Keywords:

• sunitinib
• plasma concentration
• metastatic renal cell carcinoma
• individualized schedule adjustment
• clinical outcomes

Abbreviations

VEGFR, Vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; mRCC, metastatic renal cell carcinoma; IMDC, International mRCC Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; AEs, adverse events; TDM, therapeutic drug monitoring; TAS, toxicity-adjusted schedule; MAS, maintained schedule; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; C_SS, steady-state concentration; LC-MS/MS, liquid chromatography/mass spectrometry; PFS, progression-free survival; OS, overall survival; CTCAE, Common Terminology Criteria for Adverse Events; CR, complete response; PR, partial response; PD, progression of the disease; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; QoL, quality of life; HR, hazard ratio; CI, confidence interval.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical Statement

This study was conducted according to the principles expressed in the Declaration of Helsinki and had been reviewed and approved by a responsible Institutional Review Board (IRB) of West China Hospital, Sichuan University, The approval ID was: 2012 clinical trial approval No. 15. Every relevant detail has been explained to the patient himself, and written consent forms were obtained from each patient.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

All authors declared that there were no potential conflicts of interest.