Cisplatin-Induced Adverse Events in Osteosarcoma Not Improved With Pantoprazole

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Ototoxicity and nephrotoxicity are common adverse events observed in patients treated with methotrexate, doxorubicin, cisplatin.
Ototoxicity and nephrotoxicity are common adverse events observed in patients treated with methotrexate, doxorubicin, cisplatin.

Pantoprazole does not improve cisplatin-induced ototoxicity or nephrotoxicity in younger patients with newly diagnosed osteosarcoma, according to a study published in The Oncologist.

Ototoxicity and nephrotoxicity, caused by organic cation transporter 2 (OCT2)-mediated cisplatin uptake into cochlear hair cells and renal tubular cells, are common adverse events (AEs) observed in patients treated with methotrexate, doxorubicin, cisplatin. Investigators hypothesized pantoprazole could be used as a rescue agent for these AEs.

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For this phase 2 study, researchers concurrently administered intravenous pantoprazole with cisplatin to 12 young patients with osteosarcoma on cycles 1 and 2 or cycles 3 and 4. A randomized crossover study design was used to evaluate audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate estimated by serum cystatin C (GFRcysC) during each treatment cycle.

No differences in high-frequency hearing threshold at 4 to 8 kHz or nephrotoxicity were observed between patients treated with pantoprazole plus cisplatin compared with historical controls.

Analysis revealed that measuring the GFR by serum creatinine (GFRcr) was not as sensitive as GFRcysC; GFRcr was shown to be insensitive to GFR changes associated with nephrotoxicity while GFRcysC consistently reflected decreases in GFR after cisplatin administration. Researchers also noted that N-acetyl-ß-glucosaminidase (NAG), a urinary biomarker of AKI, could also be a useful measurement of cisplatin renal tubular toxicity.

Results of the study showed that pantoprazole-mediated OCT2 inhibition by pantoprazole does not improve nephrotoxicity or ototoxicity, but the authors concluded that “this trial design and acute endpoints may be useful to screen the growing number of antioxidant, anti-inflammatory, and other agents with potential to ameliorate of cisplatin toxicity.”

Reference

Fox E, Levin K, Zhu Y, et al. Pantoprazole, an inhibitor of the organic cation transporter 2, does not ameliorate cisplatin-related ototoxicity or nephrotoxicity in children and adolescents with newly diagnosed osteosarcoma treated with methotrexate, doxorubicin, and cisplatin [published online February 14, 2018]. Oncologist. doi: 10.1634/theoncologist.2018-0037

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