含Pemetrexed化學治療於癌症腎功能不全病人嚴重血液毒性風險與療程影響之探討

Abstract

研究背景 對於晚期（advanced）非鱗狀非小細胞肺癌（non-squamous non-small cell lung cancer, NSCLC），若病人不適用標靶治療或免疫治療時，pemetrexed併用platinum的療程組合作為第一線治療，能增加病人存活率並有較低的血液毒性發生率，此療程組合亦是惡性胸膜間皮瘤（malignant pleural mesothelioma, MPM）的藥物治療首選。仿單不建議pemetrexed用於肌酸酐廓清率（Ccr）小於45 mL/min的病人，並且缺乏腎功能調整劑量的資料。雖有許多回溯性研究探討pemetrexed的安全性與腎功能以及相關危險因子的關聯性，然而研究結果不一致且有諸多研究限制。 研究目的 探討Ccr < 45 mL/min的癌症病人，臨床使用pemetrexed的安全性，比較不同程度腎功能不全者的血液與非血液毒性的發生率，並分析Grade ≥ 3嗜中性球低下的相關危險因子，以及對後續療程的影響。 研究方法 回溯性世代研究以醫學中心病歷資料進行分析，篩選2014年11月‒2016年11月間使用pemetrexed治療之non-squamous NSCLC與MPM病人，收集涵蓋2008/1‒2018/11期間的臨床資料，包含病人基本資料、抗癌療程處方、相關用藥、實驗檢驗值。白血球低下達最低點（WBC nadir）時，以當次療程周期前的Ccr值作為切點基準分組，比較Ccr < 45 mL/min與 Ccr ≥ 45 mL/min兩組間之Grade ≥ 3嗜中性球低下發生率與對接續療程的影響。此外，以基線（baseline）Ccr值45 mL/min為切點分組，比較兩組間嚴重血液毒性與其他藥物不良反應的發生率，透過次族群分析與敏感度分析驗證結果，並採用Cox比例風險迴歸分析鑑別Grade ≥ 3嗜中性球低下的危險因子。研究終止期間另分析整體療程用藥資料與實驗檢驗值。 研究結果 從361位病人中篩選出符合研究條件的研究對象共300位。發生所有程度嗜中性球低下者（n=72）之中，Grade ≥ 3嗜中性球低下者的比例於Ccr < 45 mL/min（WBC nadir）組別為（72.2%, 13/18），相較Ccr ≥ 45 mL/min（WBC nadir）組別的比例（31.5%, 17/54）顯著較高（p=0.002）。 基線Ccr < 45 mL/min組別（n=30）相較Ccr ≥ 45 mL/min組別（n=270），發生率顯著較高為Grade ≥ 3貧血（23.3% vs. 9.3%, p=0.027）與血清肌酸酐異常增加（36.7% vs. 15.2%, p=0.003），然而，Grade ≥ 3嗜中性球低下發生率無顯著差異（13.3% vs. 9.6%, p=0.52）。 基線Ccr < 55 mL/min組別（n=69）相較Ccr ≥ 55 mL/min組別（n=231），顯著高比例發生Grade ≥ 3嗜中性球低下（18.8% vs. 7.4%, p=0.005）、Grade ≥ 3血小板低下（11.6% vs. 3.9%, p=0.029）、血清肌酸酐異常增加（34.8% vs. 12.1%, p< 0.001）與急性腎損傷（5.8% vs. 0.9%, p=0.027）等嚴重血液毒性或腎毒性。 研究對象整體而言，Grade ≥ 3嗜中性球低下的危險因子為首次療程前曾發生白血球低下、高血壓、累積療程周期。基線Ccr < 55 mL/min組別，Grade ≥ 3嗜中性球低下相關危險因子為首次療程併用cisplatin（劑量75 mg/m2以下）、累積療程周期大於6次或累積療程周期10次以下、未依據仿單使用vitamin B12；基線Ccr < 45 mL/min組別，併用carboplatin劑量target AUC 5以下可能降低風險。 因藥物不良反應終止療程的發生率，基線Ccr < 55 mL/min組別，顯著高於Ccr ≥ 55 mL/min組別（15.9% vs. 5.6%, p=0.010）。研究終止期的血紅素相較基線的數值為低，於基線Ccr < 45 mL/min組別（10.1 g/dL vs. 12.3 g/dL, p < 0.001）與Ccr ≥ 45 mL/min組別（10.8 g/dL vs. 13.0 g/dL, p < 0.001）趨勢相近。 結論 醫療人員應注意pemetrexed單一使用或併用platinum時，對於基線Ccr < 55 mL/min病人，容易產生Grade ≥ 3嗜中性球低下、Grade ≥ 3血小板低下與腎毒性、容易因為藥物不良反應終止療程，cisplatin之併用與Grade ≥ 3嗜中性球低下風險有關聯性。相較基線Ccr值，以WBC nadir療程周期前Ccr 45 mL/min分組可能更有效偵測到接受pemetrexed治療的病人，是否容易發生Grade ≥ 3嗜中性球低下或白血球低下的警訊，而本研究發現仍待更多研究以佐證。

Background Pemetrexed and platinum combination therapy is first-line treatment for patients with either unresectable malignant pleural mesothelioma (MPM) or advanced non-squamous non-small cell lung cancer (NSCLC) if not suitable for targeted therapy or immunotherapy. Patients with creatinine clearance (Ccr) less than 45 mL/min are not recommended for pemetrexed treatment according to the label. From a few observational studies, there are inconsistent results of whether pemetrexed could be safely used in patients with renal impairment, especially Ccr < 45 mL/min. Objective The study aims at the safety of pemetrexed in cancer patients with Ccr < 45 mL/min, incidence rate of hematologic and non-hematologic toxicities, and the risk factors of Grade ≥ 3 neutropenia as well as impact on regimen of treatment. Methods This cohort study retrospectively collected data from medical records in a medical center. Patients receiving pemetrexed-based regimens for non-squamous NSCLC or MPM from 2014/11‒2016/11 were screened, whose clinical data within the range of 2008/1‒2018/11 were collected. Incidence of Grade ≥ 3 neutropenia and regimen change were compared between patient groups according to the cut-off value of Ccr 45 mL/min prior to the cycle of WBC nadir (Ccr, WBC nadir). Besides, incidence rate of severe hematologic toxicities and other adverse drug events were compared between groups according to baseline Ccr. Subgroup and sensitivity analysis were adopted to examine above findings. Cox regression analysis was used to investigate factors related to Grade ≥ 3 neutropenia. Regimen of treatment and laboratory data at the end of study were analyzed. Results 300 patients in analysis were screened from 361 patients. Proportion of Grade ≥ 3 neutropenia in all-grade neutropenia in patients with Ccr < 45 mL/min (WBC nadir) (2.2%, 13/18) was significantly higher than that in patients with Ccr ≥ 45 mL/min (WBC nadir) (31.5%, 17/54) (p=0.002). Patients with baseline Ccr < 45 mL/min (n=30) had significantly higher rate of Grade ≥ 3 anemia (23.3% vs. 9.3%, p=0.027) and all-grade Scr (serum creatinine) elevation (36.7% vs. 15.2%, p=0.003), compared to those of Ccr ≥ 45 mL/min (n=270). No discrepancy of Grade ≥ 3 neutropenia was found between the two groups. However, patients with baseline Ccr < 55 mL/min (n=69) had significantly higher rate of severe hematologic toxicities and renal toxicity compared to those of Ccr ≥ 55 mL/min (n=231), such as Grade ≥ 3 neutropenia (18.8% vs. 7.4%, p=0.005), Grade ≥ 3 thrombocytopenia (11.6% vs. 3.9%, p=0.029), all-grade SCr elevation (34.8% vs. 12.1%, p< 0.001) and acute kidney injury (5.8% vs. 0.9%, p=0.027). Those risk factors significantly associated with Grade ≥ 3 neutropenia include previous neutropenia before start-up of pemetrexed treatment, hypertension, and number of treatment cycles; nevertheless, cumulative dose of pemetrexed is of significantly lower risk. As for patients with baseline Ccr < 55 mL/min, those risk factors significantly associated with Grade ≥ 3 neutropenia include combined cisplatin use in the first treatment cycle, number of treatment cycles longer than 6 or below 10, off-label or never use of vitamin B12; in contrast, patients with baseline Ccr < 45 mL/min had significantly lower risk when initial dose of carboplatin is below 5 AUC. Incidence of treatment discontinuation by adverse drug event was higher in patients with baseline Ccr < 55 mL/min, compared to those of Ccr ≥ 55 mL/min (15.9% vs. 5.6%, p=0.01). At the end of study, median hemoglobin was significantly lowered than the value at baseline, which was both seen in patients with baseline Ccr < 45 mL/min (10.1 g/dL vs. 12.3 g/dL, p<0.001) and those of Ccr ≥ 45 mL/min (10.8 g/dL vs. 13.0 g/dL, p<0.001). Conclusion Cautions are required in that patients with baseline Ccr < 55 mL/min receiving pemetrexed-based regimens either single agent or combined with platinum are prone to severe hematologic toxicities, renal toxicity, and treatment discontinuation by adverse drug events; moreover, combined with cisplatin is significantly associated with Grade ≥ 3 neutropenia. Ccr < 45 mL/min (WBC nadir), compared to the value at baseline, may be better to distinguish victims of Grade ≥ 3 neutropenia or leukopenia, though further studies are needed.