Effects of mTOR-Is on malignancy and survival following renal transplantation: A systematic review and meta-analysis of randomized trials with a minimum follow-up of 24 months

Background
mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. The effect of mTOR-Is on the overall incidence of tumors irrespective of their origin is not entirely clear. Furthermore, conflicting data have been shown on mortality under mTOR-Is.
Methods
The current literature was searched for prospective randomized controlled renal transplantation trials. There were 1415 trials screened of which 13 could be included (pts. = 5924). A minimum follow-up of 24 months was mandatory for inclusion. Incidence of malignancies and patient survival was assessed in meta-analyses.
Results
The average follow-up of all trials was 40.6 months. Malignancy was significantly reduced under mTOR-Is compared to CNIs (RR 0.70, CI 0.49–0.99, p = 0.046). This effect remained stable when combined with CNIs (RR 0.58, CI 0.34–1.00, p = 0.05). When NMSCs were excluded the risk for malignancy remained significantly reduced under mTOR-I therapy (mono and combi) (RR 0.43, CI 0.24–0.77, p = 0.0046). Graft survival was minimally decreased under mTOR-Is (RR 0.99, CI 0.98–1.00, p = 0.054). This effect was abrogated when mTOR-Is were combined with CNIs (RR 0.99, CI 0.97–1.02, p = 0.50). Patient survival was not different (RR 1.00, CI 0.99–1.01, p = 0.54).
Conclusions
Posttransplant patients have a lower incidence of malignancy when treated with an mTOR-I no matter if it is used in combination with CNIs or not. This beneficial effect remains significant even when NMSCs are excluded. With currently used mTOR-I-based regimen patient and graft survival is not different compared to CNI therapies.

背景
哺乳动物雷帕霉素靶蛋白抑制剂（mTOR-Is）可对实体器官移植术后部分肿瘤的发生与病程产生正向影响。但无论肿瘤起源如何，mTOR-Is对肿瘤总体发生率的影响尚未完全明确；此外，关于mTOR-Is治疗下的患者死亡率，已有研究呈现出矛盾的结果。
方法
本研究检索当前文献中针对肾移植的前瞻性随机对照试验。经筛选，共纳入13项符合标准的试验（受试者共5924例），初始筛选的试验总数为1415项。纳入标准要求最短随访时长不低于24个月。通过荟萃分析评估恶性肿瘤发生率与患者生存率。
结果
所有试验的平均随访时长为40.6个月。与钙调磷酸酶抑制剂（CNIs）治疗组相比，mTOR-Is治疗组的恶性肿瘤发生率显著降低（相对危险度RR=0.70，95%置信区间CI=0.49–0.99，P=0.046）。当mTOR-Is与CNIs联合使用时，该效应仍保持稳定（RR=0.58，CI=0.34–1.00，P=0.05）。若排除非黑色素瘤皮肤癌（NMSCs），mTOR-I治疗（单药与联合治疗）下的恶性肿瘤风险仍显著降低（RR=0.43，CI=0.24–0.77，P=0.0046）。mTOR-Is治疗组的移植物存活率仅出现小幅下降（RR=0.99，CI=0.98–1.00，P=0.054），但当mTOR-Is与CNIs联合使用时，该效应被抵消（RR=0.99，CI=0.97–1.02，P=0.50）。两组患者生存率无显著差异（RR=1.00，CI=0.99–1.01，P=0.54）。
结论
无论是否联合钙调磷酸酶抑制剂（CNIs），接受mTOR-I治疗的移植后患者的恶性肿瘤发生率均更低。即使排除非黑色素瘤皮肤癌（NMSCs），该有益效应仍具有统计学显著性。就当前临床使用的基于mTOR-I的治疗方案而言，患者生存率与移植物存活率与CNIs治疗方案无显著差异。