Lessons Learned.
Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short‐term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin‐associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient‐reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring “at least rarely” after cycle 1, prior to objective high‐frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long‐term toxicity are needed.Background.Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole.Materials and Methods.Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6–19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle.Results.Pantoprazole had no impact on decrements in hearing threshold at 4–8 kHz, post‐treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died.Conclusion.Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N‐acetyl‐ß‐glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.
Methotrexate (MTX) is an antimetabolite, widely used in the practice of pediatric oncology. It plays a major role, along with other drugs, in the treatment of children with acute lymphoblastic leukemia, B-cell lymphomas, and osteogenic sarcomas. In these diseases, MTX is used in high doses (HD), ranging from 5 g/m 2 to 12 g/m 2 . MTX exerts its antineoplastic effect by inhibiting activity of dihydrofolate reductase, an enzyme that plays a central role in the metabolism of folic acid. The main side effects of HDMTX are mucositis and renal and hepatic damage. Allergic reactions to HDMTX have been reported rarely, especially in children [1]. Our successful management of this problem might therefore be instructive.Our patient was a 16-year-old boy previously in excellent health who had an osteogenic sarcoma of the right proximal tibia with multiple metastases to bones, bone marrow, brain, and lung. There was no previous history of allergic reactions to drugs or a history of allergic diseases in the patient or his first-degree relatives. The child was started on three courses of HDMTX (12 g/m 2 ) for 4 hr weekly. He developed an urticarial rash on his trunk and lower extremities approximately 30 min after beginning the first dose of MTX. The drug was stopped and the child was given diphenylhydramine intravenously (0.5 mg/kg). The rash disappeared approximately 20 min after the antihistamine was given, and MTX was resumed. Its infusion this time was uneventful, and no other symptoms or signs of anaphylactic reaction were seen.Before starting MTX, the child was given 5% glucose solution and ondansetron (Zofran) for the first time. Subsequent doses of MTX were given with a premedication of diphenyldramine IV and were not accompanied by any signs of allergic reaction.
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