Patterns of Interstitial Lung Disease During Everolimus Treatment in Patients with Metastatic Renal Cell Carcinoma

Mizuno, Ryuichi; Asano, Koichiro; Mikami, Shuji; Nagata, Hirohiko; Kaneko, Gou; Oya, Mototsugu

doi:10.1093/jjco/hys033

Cited by 25 publications

(32 citation statements)

References 16 publications

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“…In vivo studies have also shown that rapamycin treatment augments lung injury induced by BLM or lipopolysaccharide in mice with acute lung injury (17,28). Clinically, serum Krebs von den Lungen 6, which is a biomarker of interstitial lung disease and is associated with epithelial cell injury and capillary-alveolar permeability changes, is elevated in patients with everolimus-induced ILD (24,34). Based on these data, it is speculated that mTOR inhibitors have the potential to cause alveolar epithelial injury, which could, in turn, initiate and/or augment lung injury (as shown in the left pathway in Fig.…”

Section: Discussionmentioning

confidence: 99%

Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice

Washino

Ando

Ushijima

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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tial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.

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Section: Discussionmentioning

confidence: 99%

Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice

Washino

Ando

Ushijima

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Among the previous studies of everolimus-induced ILD written in English, we could find only nine articles that described the pathological findings of ILD (1,(11)(12)(13)(14)(15)(16)(17)(18). Table 3 presents descriptions of the pathological findings of everolimus-induced ILD in these nine articles, which included 13 cases.…”

Section: Discussionmentioning

confidence: 99%

Granuloma-forming Interstitial Pneumonia Occurring One Year after the Start of Everolimus Therapy

et al. 2013

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We experienced a case of interstitial lung disease (ILD) that occurred one year after the start of everolimus therapy for renal cell carcinoma. The pathological features included interstitial pneumonia with granuloma formation. Everolimus is known to cause ILD; however, its pathology is unclear. Granuloma-forming interstitial pneumonia associated with everolimus is uncommon, although it may be one of the pathological patterns associated with everolimus-induced ILD. This is a slow-onset case of everolimus-induced ILD in a patient with renal cell carcinoma. Physicians should thus be aware of the potential for the development of ILD at any time during the administration of everolimus therapy.

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“…Everolimus was used for the treatment of advanced RCC, and PNET. The frequencies of ILD related to everolimus ranged from 8 to 14% of treated patients [36][37][38][39][40][41][42]. The mortality rate due to ILD was reported to be 3.8% (4 of 105 patients) in a previous study [4].…”

Section: Mammalian Target Of Rapamycin (Mtor) Inhibitorsmentioning

confidence: 97%

Interstitial Lung Disease Induced by Targeted Therapy for Non-Small Cell Lung Cancer: A Review of Diagnosis, Workup, and Management

Chen

Luo²

2014

J Palliat Care Med

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Targeted therapies are being increasingly used for cancer treatments and had been proven to improve clinical outcomes. Although targeted therapies demonstrate survival benefit in particular patient populations, they may also increase the frequency of treatment-related toxicities and morbidity. The pulmonary toxicities, especially drug induced-interstitial lung disease (ILD), have emerged as critical adverse drug reactions which are potentially fatal. The main managment of targeted therapy-induced ILD includes drug discontinuation and corticosteroid therapy, but no standard guideline for the treatment of targeted therapy-induced ILD was established. Clinical physicians must cautiously weigh the benefits and risks of targeted therapies causing ILD in order to provide optimal treatments and favorable outcomes. Relevant clinical information regarding management of targeted therapy-induced ILD was reviewed in this article.

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Patterns of Interstitial Lung Disease During Everolimus Treatment in Patients with Metastatic Renal Cell Carcinoma

Cited by 25 publications

References 16 publications

Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice

Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice

Granuloma-forming Interstitial Pneumonia Occurring One Year after the Start of Everolimus Therapy

Interstitial Lung Disease Induced by Targeted Therapy for Non-Small Cell Lung Cancer: A Review of Diagnosis, Workup, and Management

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