Abstract
BackgroundPemetrexed (PEM) is administered over a long term to patients with non-squamous cell lung cancer as a maintenance therapy after platinum combination induction chemotherapy. Although decreased renal function owing to long-term PEM exposure has been reported, changes in the renal function of individual patients have not been reported. This study aimed to evaluate serum creatinine (Scr) in individual patients over time and determine whether long-term PEM exposure contributed to increased Scr.MethodsA retrospective study was performed using 90 non-squamous cell lung cancer patients, who had received maintenance therapy with PEM ± bevacizumab (BEV) after carboplatin + PEM ± BEV therapy at the Sapporo Minami-Sanjo Hospital from February 2012 to February 2019. Using Scr at the start of induction chemotherapy as the baseline, we calculated the correlation coefficient (r) of the rate of Scr change in an individual patient and the number of treatment courses to divide patients into two groups for comparison: patients with + 0.4 < r ≦ + 1.0 and an observed positive correlation (the r+0.4< group), and patients with − 1.0 ≦ r ≦ + 0.4 and no observed positive correlation (the r+0.4≧ group).ResultsStatistically significant differences between the r+0.4< group and the r+0.4≧ group were observed for the following parameters: the median cumulative dose of PEM (interquartile range) [9100 (6365, 12,260) mg/body vs. 5600 (4140, 7440) mg/body, P < 0.01]; the number of patients taking nonsteroidal anti-inflammatory drugs at the start of treatment [15 patients (31%) vs. 3 patients (7%), P < 0.01]; and the median number of treatment courses starting from induction chemotherapy [11 (8, 14) courses vs. 8 (6, 11) courses, P < 0.01]. Next, the results of univariate and multivariate analyses demonstrated that the cumulative dose of PEM (≧ 7000 mg/body vs < 7000 mg/body, OR 2.40; 95% CI, 1.22–4.75, P = 0.01) was an independent explanatory variable of the r+0.4< group.ConclusionsLong-term PEM exposure may induce chronic renal dysfunction. Hence, maintaining kidney function during PEM treatment by reducing the use of combination drugs and the risk of other renal dysfunctions, such as dehydration, may help patients continue therapy and contribute to their long-term survival.
Highlights
Pemetrexed (PEM) is administered over a long term to patients with non-squamous cell lung cancer as a maintenance therapy after platinum combination induction chemotherapy
Paz-Ares et al have reported that the continued administration of PEM as a maintenance therapy significantly extended progression-free survival in patients who have efficaciously been treated with PEM + cisplatin induction chemotherapy in the PARAMOUNT trial [4]
Patients demonstrating decreased renal function are at a risk of increased blood PEM concentrations associated with decreased PEM clearance [6], as well as exacerbated side effects related to PEM, including liver dysfunction, rash, leukopenia, neutropenia, loss of appetite, decreased hemoglobin, and nausea [7]
Summary
Pemetrexed (PEM) is administered over a long term to patients with non-squamous cell lung cancer as a maintenance therapy after platinum combination induction chemotherapy. This study aimed to evaluate serum creatinine (Scr) in individual patients over time and determine whether long-term PEM exposure contributed to increased Scr. The antifolate drug pemetrexed (PEM) is known to demonstrate a powerful antitumor effect against tumor cells in mesothelioma and non-small-cell lung cancer by inhibiting multiple folate-metabolizing enzymes simultaneously [1]. Paz-Ares et al have reported that the continued administration of PEM as a maintenance therapy significantly extended progression-free survival in patients who have efficaciously been treated with PEM + cisplatin induction chemotherapy in the PARAMOUNT trial [4]. The final report of the PARAMOUNT trial in 2013 has stated that PEM maintenance therapy for advanced nonsquamous non-small-cell lung cancer extends overall survival [5]. Reports of renal dysfunctions due to PEM administration include acute kidney injury, due to acute tubular necrosis [10], as well as nephrogenic diabetes insipidus and renal tubular acidosis [11]
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