摘要目的: 评价依维莫司序贯给药方案在中国结节性硬化相关肾血管平滑肌脂肪瘤（TSC-RAML）治疗中的疗效,安全性及卫生经济学影响等。方法: 2017年7月–2018年7月开展为期1年的前瞻性队列研究,将47例经临床诊断标准或基因诊断标准明确诊断为的成年TSC-RAML患者纳入研究,患者至少有1个肾血管平滑肌脂肪瘤（RAML）直径≥3 cm。依据患者意愿及经济情况分为标准治疗组(19例)和序贯治疗组(28例),两组初始剂量均为依维莫司10 mg QD,口服,持续服药3个月;标准治疗组维持10 mg QD,口服治疗至第12个月,序贯治疗组从第4个月开始减量为5 mg QD口服至第12个月。随访周期均为12个月,分别于治疗后1、3、6、9、12个月时进行疗效（磁共振影像）、血药浓度及安全性评价（CTCAE v 4.0标准）。主要研究终点是RAML体积相对于基线减少≥50%,没有直径≥1 cm的新发病灶及≥2级的RAML相关出血;主要观察指标包括: 肿瘤体积、血药浓度、不良反应发生率、皮肤病变反应率及卫生经济学指标。结果: 两组治疗1、3、6、9、12个月时肿瘤体积总和较基线减少≥50%的患者比例分别为: 42.1% vs. 39.3%、47.4% vs. 57.1%、63.2% vs. 64.3%、57.9% vs. 64.3%、63.2% vs. 60.7%。两组不同时间皮肤病变反应率分别为: 26.3% vs. 25.0%、36.8% vs. 35.7%、42.1% vs. 39.3%、42.1% vs. 39.3%、42.1% vs. 39.3%。主要不良反应包括: 口腔黏膜炎、皮疹、泌尿系感染、月经失调、贫血、肝功能异常、非感染性肺炎等,多为1~2级,累计3~4级不良反应发生率为27.7%。两组在治疗前3个月总体不良反应发生率及3~4级不良反应发生率差异无统计学意义,治疗12个月时序贯治疗组的总体不良反应发生率和3~4级不良反应发生率均显著低于标准治疗组。两组中药物减量或中断的发生率分别为68.4% vs. 39.3%。给药3个月和12个月时两组依维莫司的血清平均谷浓度分别为（19.63±7.02）μg/L vs. （20.09±8.49）μg/L、（15.45±5.37） vs. (9.07±4.05)μg/L。两组12个月累计平均治疗费用分别为(105 000±10 025)和（75 500±7 582）元。结论: 中国TSC患者的依维莫司血药浓度高于一项多中心随机对照前瞻性临床研究报道的结果,药物治疗疗效显著,但不良反应的发生率更高。相比于传统的依维莫司10 mg持续给药方案,序贯给药方案具有相似的疗效,而患者不良反应发生率及强度显著降低,卫生经济学也更具优势。因此,基于血药浓度监测的个体化给药方案可以使患者获得更好的临床获益和安全性,节约医疗支出。
Abstract：Objective: To evaluate the effect, safety and health economics of administration of Everolimus in the treatment of angiomyolipoma associated with tuberous sclerosis complex. Methods: This was a 1-year prospective cohort study including 47 adult TSC-AML patients from July 2017 to July 2018. All patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of TSC-RAML. The patients were divided into the standard treatment group and the sequential treatment group according to their willingness and economic situation. The initial dose of Everolimus was 10 mg oral per day. After continuous dosing for three months, the standard treatment group maintained 10 mg QD for 12 months, and the sequential treatment group reduced the dose to 5 mg QD from the 4th month to 12th month. The follow-up period was 12 months. The efficacy, serum Everolimus concentration and safety were evaluated at 1st, 3rd, 6th, 9th and 12th month after treatment by CTCAE v 4.0 standard. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline, no new lesion with diameter ≥ 1 cm and RAML-related hemorrhage of ≥ 2 grade. Main outcome measures included tumor volume, blood Everolimus concentration, incidence of adverse reactions, skin lesion response rate and health economics. Result: The 47 patients included 9 males and 38 females with an average age of 32 years old (range from 18 to 63 years). Standard treatment group included 19 cases and sequential treatment group included 28 cases. At the first, third, 6th, 9th and 12th month, the proportion of patients with tumor volume reduction ≥ 50% compared with baseline was 42.1% vs. 39.3%, 47.4% vs. 57.1%, 63.2% vs. 64.3%, 57.9% vs. 64.3%, 63.2% vs. 60.7%. The response rates of skin lesions at different time points in two groups were 26.3% vs. 25.0%, 36.8% vs. 35.7%, 42.1% vs. 39.3%, 42.1% vs. 39.3%, and 42.1% vs. 39.3%. Major adverse effects (AEs) included: oral mucositis, rash, urinary tract infection, menstrual disorders, anemia, abnormal liver function, non-infectious pneumonia. Most AEs were grade 1 or 2, and the cumulative incidence of grade 3 or 4 AE was 27.7%. There was no significant difference between the two groups in the overall incidence of AEs and the incidence of grade 3-4 AE at 3rd month after treatment. The overall incidence of AEs and the incidence of grade 3/4 AEs at 12th month after treatment were significantly lower in the sequential treatment group. The incidence of drug reduction or interruption in two groups was 68.4% and 39.3% respectively. At 3rd month and 12th month, the mean serum Everolimus valley concentrations in two groups were (19.63±7.02) μg/L vs. (20.09±8.49) μg/L, and (15.45±5.37) vs. (9.07±4.05) μg/L respectively. The cumulative average treatment costs for 12 months in two groups were (105 000±10 025) RMB and (75 500±7 582) RMB respectively. Conclusions: The serum concentration of Everolimus in Chinese TSC patients was higher than that reported by EXSIT2, and the drug treatment was significantly effective, but the incidence of AEs was higher. Compared with the previous regimen of Everolimus (10 mg continuous administration), the sequential administration regimen had similar efficacy, significantly reduced the incidence and intensity of AEs, and had more advantages in health economics. Therefore, individualized drug administration program based on blood concentration monitoring can make patients obtain better clinical benefits and safety, and save medical expenses.
[1] CURATOLO P, BOMBARDIERI R, JOZWIAK S. Tuberous sclerosis. Lancet, 2008,372(9639):657-668.
[2] BASKIN J. The pathogenesis and imaging of the tuberous sclerosis complex. Pediatr Radiol, 2008,38(9):936-952.
[3] BISSLER JJ, KINGSWOOD JC, RADZIKOWSKA E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, 2013,381(9869):817-824.
[4] NORTHRUP H, KRUEGER D, NORTHRUP H, et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol, 2013,49(4):243-254.
[5] DASGUPTA A, MORENO V, BALARK S, et al. Rapid estimation of whole blood everolimus concentrations using architect sirolimus immunoassay and mathematical equations: comparison with everolimus values determined by liquid chromatography/mass spectrometry. J Clin Lab Anal, 2011,25(3):207-211.
[6] HALPENNY D, SNOW A, MCNEILL G, et al. The radiological diagnosis and treatment of renal angiomyolipoma-current status. Clin Radiol, 2010,65(2):99-108.
[7] NELSON CP, SANDA MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol, 2002,168(4 Pt 1):1315-1325.
[8] YAMAKADO K, TANAKA N, NAKAGAWA T, et al. Renal angiomyolipoma: Relationships between tumor size, aneurysm formation, and rupture. Radiology, 2002,225(1):78-82.
[9] YI C, HAO G, WENDA W, et al. Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial. Orphanet J Rare Dis, 2018,13:43.
[10] WEI CC, TSAI JJ. Continuous low-dose everolimus shrinkage tuberous sclerosis complex-associated renal angiomyolipoma: a 48-month follow-up study. J Investig Med, 2019,67(3):686-690.
[11] TAKASHI H, HIROYUKI I, KATSUHISA E, et al. Intermittent everolimus administration for renal angiomyolipoma associated with tuberous sclerosis complex. Int J Uro, 2017,24(11):780-785.
[12] ZHANG X, SUN G, ZHAO J, et al. Improved long-term clinical outcomes and safety profile of Sunitinib dosing schedule with 4/2 switched to 2/1 in patients with metastatic renal cell carcinoma. J Cancer, 2018,9(18):3303-3310.
[13] HE Z, GUO G, ZHANG C, et al. Efficacy of sunitinib in patients with metastatic renal cell carcinoma: initial experience in two Chinese centers. Chin Med J (Engl), 2014,127(8):1450-1453.
[14] SIROKY BJ, YIN H, BISSLER JJ. Clinical and molecular insights into tuberous sclerosis complex renal disease. PediatrNephrol, 2011,26(6):839-852.
[15] DAVIES M, SAXENA A, KINGSWOOD JC. Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide Orphanet J Rare Dis, 2017,12(1):35.
[16] PALAVRA F, ROBALO C, REIS F. Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex. Oxid Med Cell Longev, 2017:9820181.
