Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Feb 6.
Published in final edited form as: Target Oncol. 2013 Jul 13;9(3):195–204. doi: 10.1007/s11523-013-0289-2

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: a systematic review and meta-analysis

Benjamin A Gartrell 1,✉, Jian Ying 2, Shanthi Sivendran 3, Kenneth M Boucher 4, Toni K Choueiri 5, Guru Sonpavde 6, William K Oh 7, Neeraj Agarwal 8, Matthew D Galsky 9
PMCID: PMC4744485  NIHMSID: NIHMS734814  PMID: 23852656

Abstract

Mammalian target of rapamycin (mTOR) inhibitors have gained regulatory approval for use in several cancer types. Pulmonary adverse events associated with mTOR inhibitors are well recognized but their frequency has varied considerably among trials. PubMed and ASCO abstracts were searched to identify clinical trials of mTOR inhibitors in solid tumors. Twenty-two eligible trials on which 4,242 patients were treated met the criteria for inclusion in this systematic review and meta-analysis. Adverse event data were extracted and used to determine the incidence rate and incidence rate ratio for pneumonitis, dyspnea, and cough. The incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors was 0.11 (95 % confidence interval (CI), 0.06–0.17) per patient, while the incidence of grade 3–4 pneumonitis was 0.03 (95 % CI, 0.01–0.04) per patient. The incidence rate ratio (IRR) of any grade pneumonitis with mTOR inhibitors relative to controls was 19.0 (95 % CI, 6.5–55.4), and for grade 3–4 pneumonitis was 8.0 (95 % CI, 2.6–24.1). The incidence rate for any grade and grade 3–4 cough was 0.23 (95 % CI, 0.20–0.27) per patient and 0.01 (95 % CI, 0.00–0.01) per patient, respectively. The incidence rate for any grade and grade 3–4 dyspnea was 0.15 (95 % CI, 0.10–0.21) per patient and 0.03 (95 % CI, 0.02–0.04) per patient, respectively. Compared to control, treatment with mTOR inhibitors were associated with a significant increase in any grade cough [IRR=1.9 (95 % CI, 1.6–2.4)] and grade 3–4 dyspnea [IRR=2.0 (95 % CI, 1.2–3.3)]. This study provides an estimation of the risk of pulmonary adverse events in solid tumor patients treated with mTOR inhibitors. While pulmonary adverse events are relatively common with mTOR inhibitors, most are low grade and asymptomatic.

Keywords: Systematic review, Meta-analysis, mTOR inhibitor, Adverse event, Solid tumor, Pneumonitis

Introduction

Drugs targeting signaling pathways involved in cancer pathogenesis play an increasing role in cancer therapy. These agents differ from traditional cytotoxic chemotherapy not only in mechanism of action but also with regard to toxicity profile. Importantly, each new class of “targeted” therapeutic is often associated with a unique side effect profile related to both on-target and off-target effects.

One such novel class of “targeted” anticancer agents is the inhibitors of the mammalian target of rapamycin (mTOR). The mTOR pathway is critical to several oncogenic processes such as cell survival, cell growth, and tumor angiogenesis [1]. Inhibiting this pathway with mTOR inhibitors or rapalogs has demonstrated anticancer effects across a wide variety of tumor types. Currently, two mTOR inhibitors have received regulatory approval from the United States Food and Drug Administration for the treatment of cancer, temsirolimus for use in advanced renal cell carcinoma (RCC) and everolimus for the treatment of advanced RCC, advanced breast cancer, unresectable/advanced pancreatic neuroendocrine tumors (PNET), and for subependymal giant cell astrocytoma associated with tuberous sclerosis. Ridaforolimus, which has not yet gained regulatory approval, has been evaluated in several large clinical trials.

Common toxicities of mTOR inhibitors include metabolic abnormalities, increased susceptibility to infection, mucositis, fatigue, and pulmonary complications. Pulmonary complications, particularly pneumonitis, have been reported in the majority of large clinical trials of these agents. However, the incidence and risk of pneumonitis with mTOR inhibitors has varied among trials and has not been comprehensively evaluated. Furthermore, the incidence of risk of pulmonary symptoms with these agents has not been assessed. Therefore, we conducted a systematic review and meta-analysis of clinical trials to better determine the incidence and incidence rate ratio of pneumonitis, cough, and dyspnea associated with the use of mTOR inhibitors in cancer patients.

Methods

Data source

An independent PubMed search was performed to identify studies published between January 1, 1997 and April 30, 2012. Prospective studies of temsirolimus, everolimus, and ridaforolimus were identified. The search was limited to clinical trials published in english. Abstracts and presentations from the American Society of Clinical Oncology (ASCO) annual meeting from 1997 to 2011 were also searched to identify additional clinical trials. Each publication, abstract, and presentation was reviewed.

Study selection

The objectives of our study were to determine the incidence rate and incidence rate ratio of pulmonary adverse events with the use of mTOR inhibitors in the treatment of solid tumors. Criteria used for determining trial eligibility were the following: (1) prospective phase II and III trials exploring an mTOR inhibitor for the treatment of solid tumors, (2) reported data on treatment-emergent pulmonary adverse events, and (3) used an mTOR inhibitor alone or in combination with another non-cytotoxic agent. Phase I trials and trials involving mTOR inhibitors administered in combination with cytotoxic chemotherapy were excluded. Only clinical trials which had been published or from which final results had been presented were included in this analysis. If the same clinical trial was described in multiple publications, only the most recent and/or most complete report of the trial was included. The quality of randomized trials was determined using the Jadad 7-item scale [2].

Data extraction

Data extraction was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [3]. The data extracted from each publication included key study characteristics such as first author name, year of publication, phase of trial, cancer type, treatments administered, number of patients evaluable for adverse event data, and adverse event data including grade for pneumonitis, cough, and dyspnea.

Adverse events were assessed as per versions 2.0 or 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) criteria. These versions are similar in defining pulmonary adverse events (Table 1). Data extraction was performed independently by two authors (B.G., S.S.). Discrepancies were resolved by consensus among the study team.

Table 1.

Grade determination for relevant pulmonary adverse events as per CTCAE v2.0 and v3.0

Grade 1 2 3 4
CTCAE v2.0
Pneumonitis Radiographic changes but asymptomatic or symptoms not requiring steroids Radiographic changes and requiring steroids or diuretics Radiographic changes and requiring oxygen Radiographic changes and requiring assisted ventilation
Cough Mild, relieved by nonprescription medication Requiring narcotic antitussive Severe cough or coughing spasms, poorly controlled or unresponsive to treatment No grade 4
Dyspnea No grade 1 DOE Dyspnea at normal level of activity Dyspnea at rest or requiring ventilator support
CTCAE v3.0
Pneumonitis Asymptomatic, radiographic findings only Symptomatic, not interfering with ADL Symptomatic, interfering with ADL; O2 indicated Life-threatening; ventilatory support indicated
Cough Symptomatic, non-narcotic medication only indicated Symptomatic and narcotic medication indicated Symptomatic and significantly interfering with sleep or ADL No grade 4
Dyspnea DOE, but can walk one flight of stairs without stopping DOE, but unable to walk one flight of stairs or one city block without stopping Dyspnea with ADL Dyspnea at rest; intubation/ventilator indicated
Open in a new tab

DOE dyspnea on exertion, ADL activities of daily living

Statistical analysis

Meta-analysis using a random effects model was employed to determine the incidence rate of pulmonary toxicities in the mTOR inhibitor treatment group and the incidence rate ratio between the mTOR inhibitor treatment group and the control group [4]. The event number (X) was assumed to follow a Poisson distribution. Where N is the number of patients, the variance of the incidence rate X/N is X/N [2]. Publication bias was assessed by Egger’s regression test [5].

Results

Search results

The literature search identified 243 potentially relevant clinical trials evaluating the mTOR inhibitors temsirolimus, everolimus, and ridaforolimus. Studies excluded from the analysis and the reasons for their exclusion are shown in Fig.1. Twenty-two trials were identified that met our inclusion criteria. Twenty trials reported pneumonitis events, eight trials reported cough, and twelve trials reported dyspnea. Sixteen trials (seven temsirolimus, eight everolimus, and one ridaforolimus) were single arm studies or randomized patients to different doses/schedules of an mTOR inhibitor (Table 2) [6–21]. Six trials (one temsirolimus, four everolimus, and one ridaforolimus) randomized patients to an mTOR inhibitor arm or a non-mTOR inhibitor control arm (Table 3) [22–27]. The most common malignancies involved in these studies included renal cell carcinoma (four trials), breast cancer (three trials), neuroendocrine carcinomas (three trials), and sarcoma (three trials).

Fig. 1.

Fig. 1

Open in a new tab

Selection process for trials included in the meta-analysis

Table 2.

Studies identified in the systematic review that reported pulmonary adverse events (pneumonitis, cough, or dyspnea) but no non-mTOR inhibitor control arm

Source Phase Malignancy mTOR
inhibitor		 Dose No. of
patients
Okuno et al. [6] 2 Advanced sarcoma Temsirolimus 25 mg weekly 40
Atkins et al. [7] 2Ra Advanced RCC Temsirolimus 25, 50, or 75 mg weekly 110
Pandya et al. [8] 2Rb Extensive-stage SCLC Temsirolimus 25 or 250 mg weekly 86
Duran et al. [9] 2 Advanced NEC Temsirolimus 25 mg weekly 36
Galanis et al. [10] 2 Recurrent GBM Temsirolimus 250 mg weekly 65
Behbakht et al. [11] 2 Ovarian and primary peritoneal carcinoma Temsirolimus 25 mg weekly 54
Oza et al. [12] 2c Recurrent or metastatic endometrial carcinoma Temsirolimus 25 mg weekly 60
Soria et al. [13] 2 NSCLC Everolimus 10 mg daily 85
Tarhini et al. [14] 2 Recurrent SCLC Everolimus 10 mg daily 40
Slomovitz et al. [15] 2 Recurrent endometrial cancer Everolimus 10 mg daily 35
Yao et al. [16] 2Rd Metastatic PNET Everolimus 10 mg daily 115
Ellard et al. [17] 2Re Metastatic breast cancer Everolimus 10 mg daily or 70 mg weekly 49
Amato et al. [18] 2 Metastatic RCC Everolimus 10 mg daily 39
Seront et al. [19] 2 Advanced UC Everolimus 10 mg daily 37
Yoon et al. [20] 2 Gastric adenocarcinoma Everolimus 10 mg daily 54
Chawla et al. [21] 2 Advanced sarcoma Ridaforolimus 12.5 mg IV weekly for 5 days every 2 weeks 212
Open in a new tab

RCC renal cell carcinoma, SCLC small cell lung cancer, NEC neuroendocrine carcinoma, GBM glioblastoma multiforme, NSCLC non-small cell lung cancer, PNET pancreatic neuroendocrine tumor, UC urothelial carcinoma

a

Randomized to temsirolimus 25 mg (n=36), 50 mg (n=38), or 75 mg (n=36) IV weekly. Patients were combined for our study

b

Randomized to temsirolimus 25 mg (n=45) or 250 mg (n=41) IV weekly. Patients combined for this study

c

Combined sequential phase 2 studies

d

Randomized to everolimus (n=115) or everolimus + octreotide (n=45). Only everolimus alone group included in this analysis

e

Randomized to everolimus 10 mg PO daily (n=33) or 70 mg PO weekly (n=16). These patients are combined for our analysis

Table 3.

Studies identified in the systematic review that reported pulmonary adverse events (pneumonitis, cough, or dyspnea) and included a non-mTOR inhibitor control arm

Source Phase Malignancy mTOR
inhibitor		 Dose Patients Control arm Jadad
score
Hudes et al. [22] 3 Advanced RCC Temsirolimus (1) 25 mg/week
(2) 15 mg/week + IFN		 416 (n=208 arms 1 & 2) (3) IFN (n=200) 3
Baselga et al. [23] 2R Breast cancer (neoadjuvant) Everolimus 10 mg daily + letrozole 137 placebo + letrozole (n=132) 4
Motzer et al. [24] 3 Metastatic RCC Everolimus 10 mg daily 274 Placebo (n=137) 4
Yao et al. [25] 3 Advanced PNET Everolimus 10 mg daily 204 Placebo (n=203) 5
Baselga et al. [26] 3 Advanced breast cancer Everolimus 10 mg daily + exemestane 482 Placebo + exemestane (n=238) 5
Chawla et al. [27] 3 Metastatic sarcoma Ridaforolimus 40 mg PO 5 days weekly 343 Placebo (n=359) Unable to assess
Open in a new tab

RCC renal cell carcinoma, PNET pancreatic neuroendocrine tumor

We did include one phase III trial, the results of which had been presented but not yet published. This study was presented at ASCO 2011 and data regarding adverse events were extracted from the presentation [27]. In one instance, a phase III trial [22] reported no data on pneumonitis, but a later publication [28] gave data on treatment-related pneumonitis in that trial. For this one instance, treatment-related as opposed to treatment-emergent adverse event data were used. In multiple instances, trials randomized patients to different doses or schedules of an mTOR inhibitor. For the purposes of our analysis, these arms were combined and used for incidence rate determination but not for evaluation of incidence rate ratio.

Study quality

Study quality was assessed for randomized studies using the Jadad 7-item scale. Of the five published randomized studies, the Jadad score ranged from 3–5 (Table 3). Only the Global ARCC Trial received a Jadad score of less than 4. This trial was open-label given the typical and anticipated adverse event profile of interferon.

Publication bias

No significant publication bias was detected for the 22 trials included in the meta-analysis for the incidence of pulmonary adverse events (p=0.76) or for the six trials included in the calculation of pulmonary adverse event incidence rate ratio (p=0.27).

Patients

A total of 4,242 patients (2,973 treated with mTOR inhibitors and 1,269 treated with controls) from 22 trials were included in this analysis. The 2,973 patients treated with mTOR inhibitors were included in the systematic review for determination of the incidence rate of pulmonary complications with mTOR inhibitor treatment. Six of these trials randomized patients to an mTOR inhibitor (1,856 patients) or a non-mTOR containing control treatment (1,269 patients) and were used in the determination of incidence rate ratios for pulmonary adverse events: 2,261 (710 controls) patients were treated on everolimus studies, 1,067 (200 controls) were treated on temsirolimus studies, and 914 (359 controls) were treated on ridaforolimus studies.

Only trials in which the adverse events of interest were reported were included in the determination of incidence rate or incidence rate ratios. Thus, if a trial reported pneumonitis but not cough or dyspnea, the patients treated in such a trial would be used only for calculation of pneumonitis incidence rate and incidence rate ratio. Trials reporting dyspnea included 2,526 patients (707 controls), trials reporting cough included 2,970 patients (1,066 controls), and trials reporting pneumonitis included 4,117 patients (1,269 controls). Patients included in these studies were typical of patient populations included in advanced solid tumor clinical trials. Patients generally had an Eastern Oncology Cooperative Group performance status of 0–1, preserved end organ function, and had not been treated with an mTOR inhibitor previously.

Incidence of pulmonary events

The pulmonary adverse event data for each of the trials included is shown in Table 4. The average incidence rate of any grade pneumonitis in the 20 trials reporting this adverse event was 0.11 (95 % confidence interval (CI), 0.06–0.17) per patient, while the incidence rate for grade 3–4 pneumonitis was found to be 0.03 (95 % CI, 0.01–0.04) per patient (Figure 2). The average incidence rate for any grade dyspnea in the 12 trials reporting it was 0.15 (95 % CI, 0.10–0.21) per patient, while the incidence rate for grade 3–4 dyspnea was found to be 0.03 (95 % CI, 0.02–0.04) per patient. The average incidence rate for cough in the eight trials reporting it was 0.23 (95 % CI, 0.20–0.27) per patient, while the incidence rate for grade 3–4 cough was found to be 0.01 (95 % CI, 0.00–0.01) per patient.

Table 4.

Pulmonary adverse events reported in the identified trials

Source Phase Malignancy mTOR inhibitor Patients Pneumonitis Cough Dyspnea Lung
mets
(%)
Total 1–
2		 3–
4		 Total 1–
2		 3–
4		 Total 1–
2		 3–
4
Okuno et al. [6] 2 Sarcoma Temsirolimus 40 NR NR NR 11 11 0 7 5 2 56
Atkins et al. [7] 2R RCC Temsirolimus 110 6 NR NR NR NR NR NR NR NR 75
Pandya et al. [8] 2R SCLC Temsirolimus 86 NR NR 4 NR NR NR NR NR 6 NR
Duran et al. [9] 2 NEC Temsirolimus 36 7 7 0 NR NR NR NR NR NR NR
Galanis et al. [10] 2 GBM Temsirolimus 65 NR NR 3 NR NR NR NR NR NR NR
Behbakht et al. [11] 2 Ovarian Temsirolimus 54 3 0 3 NR NR NR NR NR NR NR
Oza et al. [12] 2R Endometrial Temsirolimus 60 25 20 5 13 13 0 11 9 2 50
Soria et al. [13] 2 NSCLC Everolimus 85 NR NR NR 21 20 1 34 26 8 NR
Tarhini et al. [14] 2 SCLC Everolimus 40 3 1 2 NR NR NR 3 1 2 NR
Slomovitz et al. [15] 2 Endometrial Everolimus 35 2 0 2 NR NR NR 1 1 0 NR
Yao et al. [16] 2R PNET Everolimus 115 7 7 0 NR NR NR 8 6 2 17
Ellard et al. [17] 2R Breast Everolimus 49 17 14 3 NR NR NR 12 9 3 37
Amato et al. [18] 2 RCC Everolimus 39 19 12 7 NR NR NR NR NR NR 80
Seront et al. [19] 2 UC Everolimus 37 2 1 1 NR NR NR NR NR NR 51
Yoon et al. [20] 2 Gastric Everolimus 54 8 5 3 NR NR NR NR NR NR 4
Chawla et al. [21] 2 Sarcoma Ridaforolimus 212 5 NR NR NR NR NR NR NR NR 77
Hudes et al. [22] 3 RCC Temsirolimus 208 4 3 1 54 52 2 58 39 19 NR
Temsirolimus + IFN 208 0 0 0 48 44 4 54 33 21 NR
IFN 200 1 1 0 28 28 0 48 36 12 NR
Baselga et al. [23] 2R Breast (neoadjuvant) Everolimus + letrozole 137 4 1 3 NR NR NR 10 9 1 NR
Placebo + letrozole 132 0 0 0 NR NR NR 2 2 0 NR
Motzer et al. [24] 3 RCC Everolimus 274 37 27 10 82 79 3 66 47 19 73
Placebo 137 0 0 0 22 22 0 20 16 4 81
Yao et al. [25] 3 PNET Everolimus 204 35 30 5 22 22 0 NR NR NR 14
Placebo 203 0 0 0 4 4 0 NR NR NR 15
Baselga et al. [26] 3 Breast Everolimus + exemestane 482 58 44 14 106 101 5 88 69 19 29
Placebo + exemestane 238 0 0 0 26 26 0 21 18 3 33
Chawla et al. [27] 3 Sarcoma Ridaforolimus 343 34 24 10a 106 105 1 NR NR NR 67
Placebo 359 1 0 1 57 56 1 NR NR NR 64
Open in a new tab
a

This includes one grade 5 pneumonitis

Fig. 2.

Fig. 2

Open in a new tab

Incidence rate of any grade (a) and grade 3–4 (b) pneumonitis

Risk of pulmonary events

Analysis of 3,125 patients in six randomized trials revealed an incidence rate ratio (IRR) of any grade pneumonitis with mTOR inhibitors relative to controls of 19.0 (95 % CI, 6.5–55.4) and for grade 3–4 pneumonitis was 8.0 (95 % CI, 2.6–24.1) (Figure 3). The IRR for the development of any grade dyspnea with mTOR inhibitors relative to controls is 1.7 (95 % CI, 0.99–2.9) and for grade 3–4 dyspnea is 2.0 (95 % CI, 1.2–3.3). The IRR for the development of any grade cough with mTOR inhibitors relative to controls is 1.9 (95 % CI, 1.6–2.4) and for grade 3–4 cough is 2.7 (95 % CI, 0.7–10.4).

Fig. 3.

Fig. 3

Open in a new tab

Incidence rate ratio of any grade (a) and grade 3–4 (b) pneumonitis

Discussion

We determined the incidence of pulmonary complications associated with mTOR inhibition in the treatment of solid malignancies by performing a systematic review of the literature and meta-analysis. We found that pulmonary complications, most notably pneumonitis, are fairly common with the use of mTOR inhibitors, occurring in approximately one of nine solid tumor patients treated with these drugs. Rates of pneumonitis were found to be 19-fold higher with mTOR inhibitors compared to controls.

While ours is the first meta-analysis to evaluate pulmonary complications in cancer patients treated with mTOR inhibitors, a number of groups have performed retrospective evaluations of imaging from large clinical trials of mTOR inhibitors to better assess the incidence of pneumonitis. Though treatment-emergent pneumonitis was not commented upon in the final report of the Global ARCC trial [22], a later publication described four cases of treatment-associated pneumonitis among the 208 patients treated with temsirolimus alone [28]. A review of imaging found that 52 of 178 (29.2 %) treated with temsirolimus had radiological evidence of pneumonitis compared to 8 of 138 (5.8 %) patients treated with interferon. Of patients with radiological evidence of pneumonitis, 52 % had any pulmonary symptom compared to 48 % in those patients without radiological evidence of pneumonitis. A retrospective review of imaging from the RECORD-1 trial was also conducted [29]. As per the final report of the trial, 37 of 274 (13.5 %) patients receiving everolimus developed pneumonitis [24]. Post-treatment CT scans were available for review in 377 of the 411 patients. Compared to 15.2 % in the placebo group, 53.9 % of patients in the everolimus group showed radiographic development or worsening of baseline pneumonitis (which was present in 20 % of patients). Of patients treated with everolimus not clinically identified as having pneumonitis during the trial, 38.9%had radiological evidence of pneumonitis upon review of imaging. Of 37 patients with clinical pneumonitis, 51.4 % had cough, 43.2 % had dyspnea, and 32.4 % had both cough and dyspnea. Of patients without clinical pneumonitis, rates of cough (20.6 vs. 16.2 %) and dyspnea (29.0 vs. 25.0 %) were similar in patients with and without radiological evidence of pneumonitis.

While the pathophysiology of mTOR inhibitor-associated pneumonitis is not certain, several mechanisms have been proposed. Helper T cells have been identified in both bronchoalveolar lavage and transbronchial biopsy specimens from solid organ transplant patients suffering from sirolimus-associated pneumonitis [30, 31]. It has been suggested that mTOR inhibitors may lead to exposure of cryptic pulmonary antigens triggering an autoimmune response and subsequent pneumonitis [31]. Others have speculated that mTOR inhibitors may act as haptens upon exposure to plasma proteins thereby triggering a delayed-type hypersensitivity reaction [32]. Regardless of the exact pathophysiology, the response to corticosteroids strongly suggests an immune mediated mechanism.

A strength of our study includes the analysis of not only pneumonitis, given the limitations noted above, but also pulmonary symptoms. Importantly, our findings demonstrate that while the risk of pneumonitis is increased 19-fold in patients receiving mTOR inhibitors, the magnitude of increase in pulmonary symptoms is much smaller.

This study also has several potential limitations. First, studies of different tumor types and different mTOR inhibitors were included. This is of potential significance as the incidence of pulmonary toxicity could vary between tumor types and with different mTOR inhibitors. Three of the phase II studies involved patients with lung cancer; while the risk of pulmonary symptoms such as cough or dyspnea are likely higher in these patients, these studies only comprised 5 % of the total study population. Among 4/6 randomized studies reporting the incidence of lung metastases, the proportion of patients with lung metastases were similar in the mTOR inhibitor and control arms; thus, the IRR for pulmonary adverse events with mTOR inhibitors is unlikely to be significantly affected. The incidence of pulmonary complications appeared lower in earlier reports, and this is likely a result of heightened awareness/detection of this side effect in later studies. As noted, retrospective analyses have revealed a higher incidence of pneumonitis compared to the reported incidence in the initial clinical trial publications. In total, the variability in awareness, diagnosis, and reporting may have resulted in an underestimation of the incidence and risk of pulmonary complications. Finally, we did not have individual patient data and therefore utilized aggregate published clinical trial data for our analysis; however, prior analyses have suggested that these approaches generally yield similar results [33] and meta-analyses using individual patient data are also subject to potential unique biases [34].

It is apparent from our analysis, and others mentioned herein, that many cases of mTOR inhibitor-associated pneumonitis are either asymptomatic or minimally symptomatic. When symptoms do occur, they are most commonly cough, dyspnea, and hypoxia [35]. Suggested approaches for the management of mTOR inhibitor-associated pneumonitis have been proposed [29, 35]. Patients who are asymptomatic and have only radiographic evidence of pneumonitis can likely be maintained on an mTOR inhibitor without dose interruption or dose modification, but should be monitored closely for pulmonary symptoms and educated about the need to immediately report any such symptoms. For patients with symptomatic pneumonitis, the grade of the adverse event should be used to guide decisions with regard to management, which in addition to dose interruption or modification, often involves the use of corticosteroids. The potential significance of mTOR inhibitor-associated pulmonary adverse events should not be minimized as grade 5 pneumonitis, while very rare, has been reported [10, 27].

In conclusion, mTOR inhibitor-associated pulmonary adverse events are relatively common and physicians involved in the care of patients treated with these agents should be well aware of the risk for mTOR inhibitor-associated pulmonary adverse events, should closely monitor for pulmonary symptoms and be familiar with the management of mTOR inhibitor-associated pneumonitis.

Footnotes

Conflict of interest The authors report no conflicts of interest relevant to the submitted manuscript.

Contributor Information

Benjamin A. Gartrell, Email: bgartrel@montefiore.org, Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Jian Ying, Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Shanthi Sivendran, Hematology/Oncology Medical Specialists, Lancaster General Health, Lancaster, PA, USA.

Kenneth M. Boucher, Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

Toni K. Choueiri, Dana-Farber Cancer Institute, Boston, MA, USA

Guru Sonpavde, University of Alabama Birmingham Comprehensive Cancer Center, Birmingham, AL, USA.

William K. Oh, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA

Neeraj Agarwal, Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Matthew D. Galsky, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA

References

  • 1.Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005;11:353–361. doi: 10.1016/j.molmed.2005.06.007. [DOI] [PubMed] [Google Scholar]
  • 2.Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. doi: 10.1016/0197-2456(95)00134-4. [DOI] [PubMed] [Google Scholar]
  • 3.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi: 10.1136/bmj.b2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Viechtbauer W. Conducting meta-analyses in R with the meta for package. J Stat Softw. 2010;36:1–48. [Google Scholar]
  • 5.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Okuno S, Bailey H, Mahoney MR, et al. A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C) Cancer. 2011;117:3468–3475. doi: 10.1002/cncr.25928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2004;22:909–918. doi: 10.1200/JCO.2004.08.185. [DOI] [PubMed] [Google Scholar]
  • 8.Pandya KJ, Dahlberg S, Hidalgo M, et al. A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500) J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2007;2:1036–1041. doi: 10.1097/JTO.0b013e318155a439. [DOI] [PubMed] [Google Scholar]
  • 9.Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95:1148–1154. doi: 10.1038/sj.bjc.6603419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central cancer treatment group study. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23:5294–5304. doi: 10.1200/JCO.2005.23.622. [DOI] [PubMed] [Google Scholar]
  • 11.Behbakht K, Sill MW, Darcy KM, et al. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a gynecologic oncology group study. Gynecol Oncol. 2011;123:19–26. doi: 10.1016/j.ygyno.2011.06.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC clinical trials group. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:3278–3285. doi: 10.1200/JCO.2010.34.1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Soria JC, Shepherd FA, Douillard JY, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol: Off J Eur Soc Med Oncol/ESMO. 2009;20:1674–1681. doi: 10.1093/annonc/mdp060. [DOI] [PubMed] [Google Scholar]
  • 14.Tarhini A, Kotsakis A, Gooding W, et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2010;16:5900–5907. doi: 10.1158/1078-0432.CCR-10-0802. [DOI] [PubMed] [Google Scholar]
  • 15.Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer. 2010;116:5415–5419. doi: 10.1002/cncr.25515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol : Off J Am Soc Clin Oncol. 2010;28:69–76. doi: 10.1200/JCO.2009.24.2669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Ellard SL, Clemons M, Gelmon KA, et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC clinical trials group IND.163. J Clin Oncol: Off J Am Soc Clin Oncol. 2009;27:4536–4541. doi: 10.1200/JCO.2008.21.3033. [DOI] [PubMed] [Google Scholar]
  • 18.Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer. 2009;115:2438–2446. doi: 10.1002/cncr.24280. [DOI] [PubMed] [Google Scholar]
  • 19.Seront E, Rottey S, Sautois B, et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2012 doi: 10.1093/annonc/mds057. [DOI] [PubMed] [Google Scholar]
  • 20.Yoon DH, Ryu MH, Park YS, et al. Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer. 2012;106:1039–1044. doi: 10.1038/bjc.2012.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol : Off J Am Soc Clin Oncol. 2012;30:78–84. doi: 10.1200/JCO.2011.35.6329. [DOI] [PubMed] [Google Scholar]
  • 22.Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281. doi: 10.1056/NEJMoa066838. [DOI] [PubMed] [Google Scholar]
  • 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 : Off J Am Soc Clin Oncol. 2009;27:2630–2637. doi: 10.1200/JCO.2008.18.8391. [DOI] [PubMed] [Google Scholar]
  • 24.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. 2010;116:4256–4265. doi: 10.1002/cncr.25219. [DOI] [PubMed] [Google Scholar]
  • 25.Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523. doi: 10.1056/NEJMoa1009290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–529. doi: 10.1056/NEJMoa1109653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Chawla SP, Blay J, Ray-Coquard IL, et al. Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT) J Clin Oncol. 2011;29(suppl) abstr 10005. [Google Scholar]
  • 28.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: Off J Eur Soc Med Oncol/ESMO. 2008;19:1387–1392. doi: 10.1093/annonc/mdn066. [DOI] [PubMed] [Google Scholar]
  • 29.White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010;182:396–403. doi: 10.1164/rccm.200911-1720OC. [DOI] [PubMed] [Google Scholar]
  • 30.Howard L, Gopalan D, Griffiths M, Mahadeva R. Sirolimus-induced pulmonary hypersensitivity associated with a CD4 T-cell infiltrate. Chest. 2006;129:1718–1721. doi: 10.1378/chest.129.6.1718. [DOI] [PubMed] [Google Scholar]
  • 31.Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation. 2001;72:787–790. doi: 10.1097/00007890-200109150-00008. [DOI] [PubMed] [Google Scholar]
  • 32.Pham PT, Pham PC, Danovitch GM, et al. Sirolimusassociated pulmonary toxicity. Transplantation. 2004;77:1215–1220. doi: 10.1097/01.tp.0000118413.92211.b6. [DOI] [PubMed] [Google Scholar]
  • 33.Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA : J Am Med Assoc. 2008;299:914–924. doi: 10.1001/jama.299.8.914. [DOI] [PubMed] [Google Scholar]
  • 34.Sud S, Douketis J. ACP Journal Club. The devil is in the details…or not? A primer on individual patient data meta-analysis. Annals of internal medicine. 2009;151:JC1-2–JC1-3. doi: 10.7326/0003-4819-151-2-200907210-02002. [DOI] [PubMed] [Google Scholar]
  • 35.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: Off J Eur Soc Med Oncol/ESMO. 2012;23:1943–1953. doi: 10.1093/annonc/mds115. [DOI] [PubMed] [Google Scholar]

RESOURCES