Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Lancet Oncol. 2021 Sep;22(9):1333-1340. doi: 10.1016/S1470-2045(21)00377-6. Epub 2021 Aug 13.
Kidney function assessment by estimated glomerular filtration rate (eGFR) equations, such as the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, is important to determine dosing and eligibility for anticancer drugs. Inclusion of race in eGFR equations calculates a higher eGFR at a given serum creatinine concentration for Black patients versus non-Black patients. We aimed to characterise the effect of removing race from the CKD-EPI equation on dosing and eligibility of anticancer drugs with kidney function cutoffs.
We did a retrospective analysis of patients enrolled in phase 1 studies sponsored by the Cancer Therapy Evaluation Program between January, 1995, and October, 2010. eGFR based on creatinine (eGFR) was calculated by the CKD-EPI equation and a version of the CKD-EPI equation without the race term (CKD-EPI). Estimated creatinine clearance (eCl) was calculated by the Cockcroft-Gault equation. Dosing simulations based on each assessment of kidney function were done for ten anticancer drugs with kidney function cutoffs for dosing (oxaliplatin, capecitabine, etoposide, topotecan, fludarabine, and bleomycin) or eligibility (cisplatin, pemetrexed, bendamustine, and mitomycin) based on labelling approved by the US Food and Drug Administration or consensus guidelines. The absolute proportion of patients eligible or in each renal dosing range was calculated for each drug. Eligibility and dosing discordance rates were also calculated.
Demographics and laboratory values from 340 Black patients (172 men and 168 women) were used. Median age was 57 years (IQR 47-64), median bodyweight was 78·1 kg (67·0-89·8), median body surface area was 1·91 m (1·77-2·09), and median serum creatinine concentration was 0·9 mg/dL (0·8-1·1). Median eGFR or eCl was 103 mL/min (85-122) calculated by CKD-EPI, 89 mL/min (73-105) by CKD-EPI, and 90 mL/min (72-120) by Cockcroft-Gault. Black patients were recommended to receive dose reductions or were rendered ineligible to receive drug more frequently when using CKD-EPI than when using CKD-EPI, but at a similar rate as when using Cockcroft-Gault. The number of patients ineligible for therapy or recommended to receive any renal dose adjustment when CKD-EPI versus CKD-EPI was used increased by 72% (from 25 of 340 to 43 of 340 patients) for cisplatin, by 120% (from five to 11) for pemetrexed, by 67% (from three to five) for bendamustine, by 150% (from ten to 25) for capecitabine, by 150% (from ten to 25) for etoposide, by 67% (from three to five) for topotecan, by 61% (from 74 to 119) for fludarabine, and by 163% (from eight to 21) for bleomycin. Up to 18% of patients had discordant recommendations using CKD-EPI versus CKD-EPI.
Removing race from the CKD-EPI equation will calculate a lower eGFR for Black patients and exclude more patients from receiving anticancer therapy, which could lead to undertreatment of Black patients with cancer and adversely affect their outcomes.
National Institutes of Health.
通过估算肾小球滤过率(eGFR)方程(如慢性肾脏病-流行病学合作组(CKD-EPI)方程)评估肾功能对于确定抗癌药物的剂量和资格非常重要。在 eGFR 方程中纳入种族因素会导致黑种人患者在给定血清肌酐浓度下计算出的 eGFR 高于非黑种人患者。我们旨在描述从 CKD-EPI 方程中去除种族因素对具有肾功能截止值的抗癌药物剂量和资格的影响。
我们对 1995 年 1 月至 2010 年 10 月间由癌症治疗评估计划赞助的 I 期研究中的患者进行了回顾性分析。基于肌酐的 eGFR(eGFR)通过 CKD-EPI 方程和不包含种族项的 CKD-EPI 方程版本(CKD-EPI)计算。通过 Cockcroft-Gault 方程计算估计的肌酐清除率(eCl)。根据美国食品和药物管理局或共识指南批准的标签,对十种具有肾功能截止值的抗癌药物进行剂量模拟,这些药物用于剂量(奥沙利铂、卡培他滨、依托泊苷、拓扑替康、氟达拉滨和博来霉素)或资格(顺铂、培美曲塞、苯达莫司汀和丝裂霉素)。对于每种药物,计算每个肾功能评估中合格或处于每个肾脏剂量范围内的患者的绝对比例。还计算了合格和剂量不一致的比率。
使用了 340 名黑种患者(172 名男性和 168 名女性)的人口统计学和实验室值。中位年龄为 57 岁(IQR 47-64),中位体重为 78.1 公斤(67-89.8),中位体表面积为 1.91 平方米(1.77-2.09),中位血清肌酐浓度为 0.9 毫克/分升(0.8-1.1)。使用 CKD-EPI 计算的中位 eGFR 或 eCl 为 103 毫升/分钟(85-122),使用 CKD-EPI 计算的为 89 毫升/分钟(73-105),使用 Cockcroft-Gault 计算的为 90 毫升/分钟(72-120)。与使用 CKD-EPI 相比,使用 CKD-EPI 时,黑种患者更频繁地被建议减少剂量或被判定不符合接受药物治疗的资格,但与使用 Cockcroft-Gault 时的比例相似。当使用 CKD-EPI 与 CKD-EPI 相比时,不符合治疗或建议接受任何肾脏剂量调整的患者数量增加了 72%(从 340 名患者中的 25 名增加到 43 名),顺铂增加了 120%(从 5 名增加到 11 名),培美曲塞增加了 67%(从 3 名增加到 5 名),卡培他滨增加了 150%(从 10 名增加到 25 名),依托泊苷增加了 150%(从 10 名增加到 25 名),拓扑替康增加了 67%(从 3 名增加到 5 名),氟达拉滨增加了 61%(从 74 名增加到 119 名),博来霉素增加了 163%(从 8 名增加到 21 名)。多达 18%的患者使用 CKD-EPI 与 CKD-EPI 之间存在不一致的建议。
从 CKD-EPI 方程中去除种族因素会导致黑种人患者的 eGFR 计算值降低,并使更多的患者无法接受抗癌治疗,这可能导致黑种癌症患者的治疗不足,并对其结果产生不利影响。
美国国立卫生研究院。