P2.03a-012 Nephrotoxicity in Patients with Advanced NSCLC Receiving Pemetrexed-Based Chemotherapy

Abstract

In patients with advanced non-small cell lung cancer (NSCLC) pemetrexed (PEM) is increasingly used as maintenance therapy after induction PEM/platinum treatment. Despite the extensive use of PEM, the incidence of nephrotoxicity during (maintenance) PEM therapy has not been systematically evaluated. Knowledge about nephrotoxicity during PEM-based treatment could determine the need for adapted renal protective strategies. We assessed the occurrence of nephrotoxicity and its influence on treatment continuation in NSCLC patients receiving PEM-based therapy. In a prospective observational multi-center study, treatment-naive patients with stage IIIB or IV NSCLC were enrolled. Patients were treated with PEM-cisplatin (PEMCIS; PEM 500mg/m2 and CIS 75mg/m2) or PEM-carboplatin (PEMCAR; CAR AUC=5). Patients with at least disease stabilization after four cycles and a favorable toxicity profile were eligible for PEM maintenance therapy. Prior to the initial PEM/platinum cycle, baseline serum creatinine (μmol/l) was obtained. Subsequently, prior to and weekly after each administration of PEM(/platinum) serum creatinine was measured. Glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboriation (CKD-EPI) formula. Acute kidney disease (AKD) was defined as >1.5-fold increase of serum creatinine and/or decrease in GFR >35% or GFR<60mL/min within 3 months (KDIGO). Of the 151 patients starting PEM-based therapy, the majority of patients had stage IV disease (86.8%) and they were treated with PEMCIS (64.2%) or PEMCAR (35.8%). During the first four cycles, treatment was discontinued in four patients (2.6%) due to AKD. Patients starting maintenance therapy (n=44, 29.1%) received a median number of 4 PEM cycles. During maintenance treatment with PEM, 12 patients developed AKD (27.3%): three patients could continue treatment after recovery of renal function and in one patient AKD was a part of septic shock. The remaining eight patients (18.2%) stopped treatment due to renal impairment. From patients with a decreased renal function at baseline (eGFR<90mL/min) a significantly higher proportion of patients stopped maintenance therapy due to renal impairment compared to patients with an eGFR≥90mL/min at baseline (6/11 vs. 2/33, p<0.05). Patients have a significant risk of developing nephrotoxicity leading to treatment discontinuation during maintenance therapy, especially if the renal clearance is impaired at the start of induction PEM/platinum therapy. In those patients a cumulative systemic dose of PEM or increased susceptibility may play a role in the development of nephrotoxicity. Patients might benefit from altered renal protective strategies, like continuation of hydration during maintenance therapy or dose-adjustment based on renal function. This study was funded by ZonMw, the Netherlands.