BACKGROUND: mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS: Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION: The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.
BACKGROUND:mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS: Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION: The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.
Authors: Ahmad Tarhini; Athanasios Kotsakis; William Gooding; Yongli Shuai; Daniel Petro; David Friedland; Chandra P Belani; Sanja Dacic; Athanassios Argiris Journal: Clin Cancer Res Date: 2010-11-02 Impact factor: 12.531
Authors: Brian M Slomovitz; Karen H Lu; Taren Johnston; Robert L Coleman; Mark Munsell; Russell R Broaddus; Cheryl Walker; Lois M Ramondetta; Thomas W Burke; David M Gershenson; Judith Wolf Journal: Cancer Date: 2010-08-02 Impact factor: 6.860
Authors: James C Yao; Catherine Lombard-Bohas; Eric Baudin; Larry K Kvols; Philippe Rougier; Philippe Ruszniewski; Sakina Hoosen; Jessica St Peter; Tomas Haas; David Lebwohl; Eric Van Cutsem; Matthew H Kulke; Timothy J Hobday; Thomas M O'Dorisio; Manisha H Shah; Guillaume Cadiot; Gabriele Luppi; James A Posey; Bertram Wiedenmann Journal: J Clin Oncol Date: 2009-11-23 Impact factor: 44.544
Authors: José Baselga; Vladimir Semiglazov; Peter van Dam; Alexey Manikhas; Meritxell Bellet; José Mayordomo; Mario Campone; Ernst Kubista; Richard Greil; Giulia Bianchi; Jutta Steinseifer; Betty Molloy; Erika Tokaji; Humphrey Gardner; Penny Phillips; Michael Stumm; Heidi A Lane; J Michael Dixon; Walter Jonat; Hope S Rugo Journal: J Clin Oncol Date: 2009-04-20 Impact factor: 44.544
Authors: Susan L Ellard; Mark Clemons; Karen A Gelmon; Brian Norris; Hagen Kennecke; Stephen Chia; Kathleen Pritchard; Andrea Eisen; Ted Vandenberg; Marianne Taylor; Eric Sauerbrei; Moshe Mishaeli; David Huntsman; Wendy Walsh; Martin Olivo; Lynn McIntosh; Lesley Seymour Journal: J Clin Oncol Date: 2009-08-17 Impact factor: 44.544
Authors: Milind M Javle; Rachna T Shroff; Henry Xiong; Gauri A Varadhachary; David Fogelman; Shrikanth A Reddy; Darren Davis; Yujian Zhang; Robert A Wolff; James L Abbruzzese Journal: BMC Cancer Date: 2010-07-14 Impact factor: 4.430
Authors: Kenta Masui; Kazuhiro Tanaka; Shiro Ikegami; Genaro R Villa; Huijun Yang; William H Yong; Timothy F Cloughesy; Kanato Yamagata; Nobutaka Arai; Webster K Cavenee; Paul S Mischel Journal: Proc Natl Acad Sci U S A Date: 2015-07-13 Impact factor: 11.205
Authors: Eric J Chow; Kasey J Leger; Neel S Bhatt; Daniel A Mulrooney; Colin J Ross; Sanjeev Aggarwal; Neha Bansal; Matthew J Ehrhardt; Saro H Armenian; Jessica M Scott; Borah Hong Journal: Cardiovasc Res Date: 2019-04-15 Impact factor: 10.787
Authors: André P Fay; Aymen Elfiky; Gabriela H Teló; Rana R McKay; Marina Kaymakcalan; Paul L Nguyen; Anand Vaidya; Daniel T Ruan; Joaquim Bellmunt; Toni K Choueiri Journal: Crit Rev Oncol Hematol Date: 2014-06-04 Impact factor: 6.312
Authors: Eric J Chow; Zoltan Antal; Louis S Constine; Rebecca Gardner; W Hamish Wallace; Brent R Weil; Jennifer M Yeh; Elizabeth Fox Journal: J Clin Oncol Date: 2018-06-06 Impact factor: 44.544
Authors: Jordan B Jahrling; Ai-Ling Lin; Nicholas DeRosa; Stacy A Hussong; Candice E Van Skike; Milena Girotti; Martin Javors; Qingwei Zhao; Leigh Ann Maslin; Reto Asmis; Veronica Galvan Journal: J Cereb Blood Flow Metab Date: 2017-05-17 Impact factor: 6.200