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Risk of mTOR inhibitors induced severe pneumonitis in cancer patients: a meta-analysis of randomized controlled trials

    Xi Zhang

    *Author for correspondence:

    E-mail Address: xizhang1225@foxmail.com

    Department of Radiation Oncology, Affiliated Hospital of Hebei University, Baoding 071000, China

    ,
    Yu-ge Ran

    Department of Radiation Oncology, Affiliated Hospital of Hebei University, Baoding 071000, China

    &
    Kun-jie Wang

    Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding 071000, China

    Published Online:https://doi.org/10.2217/fon-2016-0020

    Background: A meta-analysis of randomized controlled trials was performed to determine the overall risk of noninfectious severe pneumonitis associated with mTOR inhibitors (mTORi) in cancer patients. Materials & methods: PubMed, EMBASE and oncology conference proceedings were searched for relevant studies. Results: A total of 8377 patients from 16 randomized controlled trials were included. The incidence of severe pneumonitis associated with mTORi was 1.7% (95% CI: 1.1–2.5%). The use of mTORi significantly increased the risk of severe pneumonitis compared with controls (odds ratio: 3.36; 95% CI: 2.20–5.12). The analysis was stratified for drug types, tumor types, controlled therapy and mTORi-based regimens, but no significant differences in odds ratios were observed. Conclusion: mTORi significantly increase the risk of severe pneumonitis in cancer patients.

    Papers of special note have been highlighted as: • of interest

    References

    • 1 Fasolo A, Sessa C. Targeting mTOR pathways in human malignancies. Curr. Pharm. Des. 18(19), 2766–2777 (2012).
    • 2 Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol. Med. 11(8), 353–361 (2005).
    • 3 Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br. J. Cancer 91(8), 1420–1424 (2004).
    • 4 Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356(22), 2271–2281 (2007).
    • 5 Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(22), 520–529 (2012).
    • 6 Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 514–523 (2011).
    • 7 Motzer RJ, Escudier B, Oudard S et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116(18), 4256–4265 (2010).
    • 8 Krueger DA, Care MM, Holland K et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363(19), 1801–1811 (2010).
    • 9 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 381(9869), 817–824 (2013).
    • 10 Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann. Oncol. 19(8), 1387–1392 (2008).
    • 11 Gartrell BA, Ying J, Sivendran S et al. Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: a systematic review and meta-analysis. Target Oncol. 9(3), 195–204 (2014).• In this study, the incidence of grade 3–4 pneumonitis was 0.03 (95% CI: 0.01–00.04) per patient.
    • 12 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann. Intern. Med. 151(4), 264–269 (2009).
    • 13 ClinicalTrials.gov. www.clinicaltrials.gov
    • 14 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control. Clin. Trials 17(1), 1–12 (1996).
    • 15 The Cancer Therapy Evaluation Program. http://ctep.cancer.gov
    • 16 Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat. Med. 23(9), 1351–1375 (2004).
    • 17 Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet. Epidemiol. 28(2), 123–137 (2005).
    • 18 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4), 1088–1101 (1994).
    • 19 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109), 629–634 (1997).
    • 20 Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, Phase 3 study. Lancet 378(9808), 2005–2012 (2011).
    • 21 André F, O’Regan R, Ozguroglu M et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled Phase 3 trial. Lancet Oncol. 15(6), 580–591 (2014).
    • 22 Hurvitz SA, Andre F, Jiang Z et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a Phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 16(7), 816–829 (2015).
    • 23 Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol. 27(16), 2630–2637 (2009).
    • 24 Gonzalez-Angulo AM, Akcakanat A, Liu S et al. Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer. Ann. Oncol. 25(6), 1122–1127 (2014).
    • 25 Bachelot T, Bourgier C, Cropet C et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J. Clin. Oncol. 30(22), 2718–2724 (2012).
    • 26 Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1814–1823 (2015).
    • 27 Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1803–1813 (2015).
    • 28 Demetri GD, Chawla SP, Ray-Coquard I et al. Results of an international randomized Phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J. Clin. Oncol. 31(19), 2485–2492 (2013).
    • 29 Ohtsu A, Ajani JA, Bai YX et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, Phase III GRANITE-1 study. J. Clin. Oncol. 31(31), 3935–3943 (2013).
    • 30 Hutson TE, Escudier B, Esteban E et al. Randomized Phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 32(8), 760–767 (2014).
    • 31 Rini BI, Bellmunt J, Clancy J et al. Randomized Phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J. Clin. Oncol. 32(8), 752–759 (2014).
    • 32 Morelon E, Stern M, Israël-Biet D et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 72(5), 787–790 (2001).
    • 33 Duran I, Siu LL, Oza AM et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur. J. Cancer 42(12), 1875–1880 (2006).
    • 34 Albiges L, Chamming’s F, Duclos B et al. Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann. Oncol. 23(8), 1943–1953 (2012).
    • 35 White DA, Schwartz LH, Dimitrijevic S, Scala LD, Hayes W, Gross SH. Characterization of pneumonitis in patients with advanced non-small cell lung cancer treated with everolimus (RAD001). J. Thorac. Oncol. 4(11), 1357–1363 (2009).
    • 36 Nozawa M, Ohzeki T, Tamada S et al. Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma. Int. J. Clin. Oncol. 20(4), 790–795 (2015).• In this respective study, there was a trend for increased grade 3 or higher non-infectious pneumonitis in the everolimus group (14.6 vs 6.8%; p = 0.102) when compared with temsirolimus group.
    • 37 Noguchi S, Masuda N, Iwata H et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer 21(6), 703–714 (2014).
    • 38 Bouabdallah K, Ribrag V, Terriou L, Soria JC, Delarue R. Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects. Curr. Opin. Oncol. 25(Suppl 2), S1–12 (2013).
    • 39 Sakamoto S, Kikuchi N, Ichikawa A et al. Everolimus-induced pneumonitis after drug-eluting stent implantation: a case report. Cardiovasc. Intervent. Radiol. 36(4), 1151–1154 (2013).
    • 40 Chiba T, Ishizuka T, Ogata T et al. Case report: a case of drug-induced interstitial pneumonitis by everolimus-eluting coronary stent. Nihon Ganka Gakkai Zasshi 101(12), 3522–3524 (2012).
    • 41 Howard L, Gopalan D, Griffiths M, Mahadeva R. Sirolimus-induced pulmonary hypersensitivity associated with a CD4 T-cell infiltrate. Chest 129(6), 1718–1721 (2006).
    • 42 Schmitz F, Heit A, Dreher S et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur. J. Immunol. 38(11), 2981–2992 (2008).
    • 43 Weichhart T, Costantino G, Poglitsch M et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29(4), 565–577 (2008).
    • 44 Säemann MD, Haidinger M, Hecking M, Hörl WH, Weichhart T. The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am. J. Transplant. 9(12), 2655–2661 (2009).
    • 45 Pham PT, Pham PC, Danovitch GM et al. Sirolimus-associated pulmonary toxicity. Transplantation 77(8), 1215–1220 (2004).
    • 46 Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
    • 47 Nishino M, Brais LK, Brooks NV, Hatabu H, Kulke MH, Ramaiya NH. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach. Eur. J. Cancer 53, 163–170 (2016).
    • 48 Nishino M, Boswell EN, Hatabu H, Ghobrial IM, Ramaiya NH. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy: radiographic pattern-based approach in Waldenström macroglobulinemia as a paradigm. Oncologist 20(9), 1077–1083 (2015).
    • 49 Porta C, Osanto S, Ravaud A et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur. J. Cancer 47(7), 1287–1298 (2011).
    • 50 White DA, Camus P, Endo M et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am. J. Respir. Crit. Care Med. 182(3), 396–403 (2010).
    • 51 Duran I, Goebell PJ, Papazisis K et al. Drug-induced pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms. Expert Opin. Drug Saf. 13(3), 361–372 (2014).
    • 52 Willemsen AE, Grutters JC, Gerritsen WR, van Erp NP, van Herpen CM, Tol J. mTOR inhibitor-induced interstitial lung disease in cancer patients: comprehensive review and a practical management algorithm. Int. J. Cancer 138(10), 2312–2321 (2016).