Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma

Abstract

Background: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study.

Methods: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively.

Results: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%.

Conclusions: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

Keywords: Dose escalation; Improved outcome; Metastatic renal cell cancer; Sunitinib; Toxicity.

Fig. 1

Flowchart of sunitinib dose modifications. (CG – control group, CR – complete remission, DE – dose escalation, DR – dose reduction, LTF – lost to follow-up, N – number of analyzed patients, PD – progressive disease, PR – partial remission, RECIST – Response Evaluation Criteria In Solid Tumors, SD – stable disease, SG – study group)

Fig. 2

Overall survival of patients in four subgroups. Metastasectomy after an effective sunitinib therapy caused the most favorable overall survival (74.3 months). Median survival of patients with slight progression is longer with dose escalation (58.6 months) than without it (27.9 months), or the outcome of all other patients (17.9 months) (p‹0.001). (Cum – cumulative, OS – overall survival)