RESUMO
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200-800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2-15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0-12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0-12 h decreased by 27% (90% CI: -38% to -14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.
RESUMO
Many patients have advanced esophageal cancer at diagnosis. However, the most optimal treatment has not been identified. Therefore, we evaluated a weekly regimen of carboplatin (area under the curve (AUC)) of 4 and paclitaxel at 100 mg/m2 as an induction or palliative treatment. All patients with advanced (gastro)esophageal cancer treated with this regimen between 2002-2018 were included. Exclusion criteria were previous radiotherapy or treatment elsewhere. Data on toxicity, response, and survival were collected. Analyses were performed in two groups: induction (iCT) or palliative chemotherapy (pCT). Median progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. A total of 291 patients was included (iCT: 122; pCT: 169). Most patients had T3 carcinoma (iCT: 54%; pCT: 66%) and stage IV disease (iCT: 42%; pCT: 91%). A toxicity grade ≥3 occurred mainly as hematological toxicity (iCT: 71%; pCT: 73%) and gastrointestinal toxicity (iCT: 3%; pCT: 5%). Response rates were 48% (iCT) and 44% (pCT). Esophagectomy or definitive chemoradiotherapy followed in 42% of iCT, resulting in a PFS of 22.1 months (interquartile range (IQR): 12.4-114.2) and OS of 26.8 months (IQR: 15.4-91.7). For pCT, PFS was 8.2 months (IQR: 5.1-14.5) and OS 10.9 months (IQR: 6.5-18.3). This retrospective cohort study demonstrated that weekly carboplatin (AUC4) and paclitaxel (100 mg/m2) is a well-tolerated and effective induction or palliative treatment regimen for patients with locally advanced or metastatic disease. Future research should directly compare this treatment regimen with other first-line treatment options to determine its true value for clinical practice.
