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

Abstract

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 (GFR _cysC) in patients receiving cisplatin with and without pantoprazole.

Materials and Methods.

Cisplatin (60 mg/m ² × 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 GFR _cysC (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 GFR _cysC 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.

Translated abstract

经验总结

• 使用随机交叉设计并以连续变量(如听力阈值和急性肾损伤生物标志物变化)作为短期终点,确定有机阳离子转运蛋白2抑制剂泮托拉唑并未减轻与顺铂相关的肾毒性或耳毒性。

• 胱抑素C是用于估计癌症患者肾小球滤过率的有力方法。使用患者报告结果调查,在通过听力图测得客观高频听力损失之前,所有患者均发现在第1周期后“至少很少”发生耳鸣和主观听力损失。

• 需要可改善结果且急性和长期毒性较低的新治疗方法。

摘要

背景. 有机阳离子转运蛋白2(OCT2)是一种在肾小管和耳蜗毛细胞上表达但不在骨肉瘤细胞上表达的顺铂摄取转运体,可介导顺铂摄取。泮托拉唑可抑制OCT2并减轻顺铂耳毒性和肾毒性。我们使用随机交叉设计,在接受顺铂联合和不联合泮托拉唑治疗的患者中评价了听力图、尿液急性肾损伤(AKI)生物标志物和根据胱抑素C估计得出的肾小球滤过率(GFR;GFR _cysC)。

材料和方法. 12例中位(范围)年龄为12.8(5.6–19)岁的骨肉瘤(OS)患者接受顺铂(60 mg/m ² X 2天/周期)给药,同时在第1和2周期或第3和4周期接受泮托拉唑给药[静脉输注(IV),4小时给予1.6 mg/kg]。在每个周期中监测听力图、尿液AKI生物标志物和血清胱抑素C。

结果. 泮托拉唑对4‐8 kHz听力阈值递减、尿液AKI生物标志物治疗后升高或GFR _cysC无影响(图1、表1)。在联合或不联合泮托拉唑治疗的情况下,两个周期后的组织学缓解(坏死百分比)相似。所有八例确诊为局部OS的患者均存活且缓解;确诊时3/4例转移患者已死亡。

结论. 泮托拉唑并未减轻顺铂耳毒性或肾毒性。GFR _cysC降低以及N‐乙酰‐β‐氨基葡萄糖苷酶(NAG)和肌酐升高表明这些生物标志物可以量化顺铂的肾小球和近端肾小管毒性。泮托拉唑的OCT2抑制作用似乎不会改变抗肿瘤应答或生存情况。