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

Abstract

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.

Fig 1. Flowchart of the selection of articles.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Itemsfor Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 For more information, visit www.prisma-statement.org.

Fig 2. Malignancies on mTOR-I vs. CNI treatment post transplantation.

(A) Forest plot indicating the relative risk of the occurence of malignancies. ¹ Latest update by Gatault et al. in 2016. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Guba et al. in 2012. ⁵ Latest update by Lebranchu et al. in 2011. (B) Forest plot indicating the relative risk of the occurence of malignancies excluding NMSC’s. ¹ Last update by Gatault et al. in 2016. ² Last update by Felchner et al. in 2007. ³ Last update by Guba et al. in 2012. ⁴ Last update by Lebranchu et al. in 2011.

Fig 3. Malignancies on mTOR-I+CNI vs. CNI treatment post transplantation.

(A) Forest plot indicating the relative risk of the occurence of malignancies. ¹ Last update by Kumar et al. in 2008. ² Last update by Cibrik et al. 2013. ³ Last update by Vitko in 2005. (B) Forest plot indicating the relative risk of the occurence of malignancies excluding NMSC’s. ¹ Latest update by Kumar et al. in 2008.

Fig 4. Malignancies on mTOR-I (monotherapy or combined with CNIs) versus CNI treatment post transplantation.

(A) Forest plot indicating the relative risk of the occurence of malignancies. ¹ Latest update by Fischer et al. in 2015. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Guba et al. in 2012. ⁵ Latest update by Kumar et al. in 2008. ⁶ Latest update by Lebranchu et al. in 2011. ⁷ Last update by Cibrik et al. 2013. ⁸ Latest update by Vitko et al. in 2005. (B) Forest plot indicating the relative risk of the occurence of malignancies excluding NMSC’s. ¹ Last update by Gatault et al. in 2016. ² Last update by Flechner et al. in 2007. ³ Last update by Guba et al. in 2012. ⁴ Last update by Kumar et al. in 2008. ⁵ Last update by Lebranchu et al. in 2011.

Fig 5. Graft survival censored for death post transplantation.

(A) Forest plot indicating the graft survival censored for death on mTOR-I vs. CNI treatment. ¹ Latest update by Gatault et al. in 2016. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Lebranchu et al. in 2011. (B) Forest plot indicating the graft survival censored for death on mTOR-I+CNI vs. CNI. ¹ Last update by Cibrik et al. 2013. ² Latest update by Vitko et al. in 2005. (C) Forest plot indicating the graft survival censored for death on mTOR-I (all) vs. CNI. ¹ Latest update by Gatault et al. in 2016. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Lebranchu et al. in 2011. ⁵ Last update by Cibrik et al. 2013. ⁶ Latest update by Vitko et al. in 2005.

Fig 6. Overall patient survival post transplantation.

(A) Forest plot indicating the overall patient survival on mTOR-I vs. CNI treatment. ¹ Latest update by Gatault et al. in 2016. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Guba et al. in 2012. ⁵ Latest update by Lebranchu et al. in 2011. (B) Forest plot indicating the overall patient survival on mTOR-I+CNI vs. CNI treatment. ¹ Latest update by Kumar et al. in 2008. ² Last update by Cibrik et al. 2013. ³ Latest update by Vitko et al. in 2005. (C) Forest plot indicating the overall patient survival on mTOR-I (all) vs. CNI treatment. ¹ Latest update by Gatault et al. in 2016. ² Latest update by Ekberg et al. in 2009. ³ Latest update by Flechner et al. in 2007. ⁴ Latest update by Guba et al. in 2012. ⁵ Latest update by Kumar et al. in 2008. ⁶ Latest update by Lebranchu et al. in 2011. ⁷ Last update by Cibrik et al. 2013. ⁸ Latest update by Vitko et al. in 2005.