Association of renal function with the safety and efficacy of cisplatin plus S-1 therapy and docetaxel plus cisplatin plus S-1 therapy in patients with advanced gastric cancer: an exploratory analysis of JCOG1013.

Abstract

Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer. Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2mg/dL were categorized into A1 (CrCl ≥80mL/min), A2 (60≤CrCl <80) and A3 (CrCl <60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm. The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P=0.006), neutropenia (P=0.002), and grade 3/4 anorexia (P=0.004) and febrile neutropenia (P=0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4months in A1/A2/A3 (P=0.886) and 15.3/13.7/13.7months in B1/B2/B3 (P=0.719)], progression-free survival [median: 7.1/6.8/6.2months in A1/A2/A3 (P=0.884) and 7.5/7.2/7.8months in B1/B2/B3 (P=0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P=0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P=0.362)]. Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy.