Abstract
Objective:
mTOR inhibitor-associated pneumonitis is common and often asymptomatic. We describe a waxing and waning pattern of pneumonitis observed on computed tomography (CT) scans of patients with renal cell carcinoma who were being treated with mTOR inhibitor molecular targeted therapy.
Materials and Methods:
In this HIPAA-compliant, IRB-approved retrospective single-institution study, 25 renal cell carcinoma patients were identified who received single-therapy temsirolimus or everolimus between January 2011 and June 2015 and who had chest CT scans available for review both before and after initiation of mTOR inhibitor treatment. A detailed review of the electronic medical record and serial chest CT examinations was performed.
Results:
Radiologic findings compatible with pneumonitis were identified in 13/25 (52%) patients on mTOR inhibitors in our study. Of the patients with CT findings of pneumonitis, 8/13 (62%) demonstrated a waxing and waning pattern; of whom 7 had clinical symptoms of pneumonitis. Of the 17 patients who received temsirolimus, 9/17 (53%) developed radiologic findings compatible with pneumonitis and 4/9 (44%) developed a waxing and waning pattern. Of the 8 patients who received everolimus, 4/8 (50%) had radiologic findings compatible with pneumonitis and 4/4 (100%) developed a waxing and waning pattern.
Conclusion:
Waxing and waning is an unrecognized pattern of mTOR inhibitor-associated pneumonitis. Recognition of this pattern will promote clinical-radiologic concordance and may facilitate patient management.
Keywords: mTOR, toxicity, temsirolimus, everolimus, pulmonary chemotoxicity, pneumonitis, renal cell carcinoma
1. INTRODUCTION
Knowledge of the toxicity profiles of molecular targeted therapies is important for identifying drug-related complications. Molecular targeted therapies halt production of specific enzymes or cellular proteins which sustain cell function. Toxicities occur when the targeted enzymes in normal cells cease to function and cell processes – e.g., cell repair, cell maintenance, or apoptosis – are interrupted. Some toxicities are asymptomatic and are detected only at the time of their radiologic presentation. In comparison, classic cytotoxic chemotherapy agents typically have toxicities that are symptomatic, cumulative, and often require cessation of therapy.
One class of molecular targeted agents consists of mTOR (mammalian target of rapamycin) inhibitors, including temsirolimus and everolimus. mTOR is part of the P13K/AKT/mTOR intracellular signaling pathway, which regulates normal cell processes including protein synthesis, glucose metabolism, cellular migration, and cell survival [1]. Currently, mTOR inhibitors are FDA-approved for patients with advanced renal cell carcinoma; in addition, they have proven efficacy in other solid tumors including some breast cancers, nonfunctional neuroendocrine tumors, and subependymal giant-cell astrocytomas in tuberous sclerosis, and their applications are growing [2–5].
A well-known complication of mTOR inhibitors is pulmonary toxicity [6–11]. Symptoms of this non-infectious drug-related pneumonitis can range from asymptomatic to life-threatening. Because mTOR- pneumonitis can be asymptomatic or well-tolerated with mild to moderate symptoms, therapy is often continued if there is clinical benefit. In this setting, radiologists may first encounter this adverse event. Computed tomography (CT) findings may precede the development of clinical symptoms, with emergence of new CT findings identified on routine examinations performed to monitor response to therapy [12]. Reported findings of mTOR inhibitor pulmonary toxicity include groundglass opacities, airspace consolidation, interlobular septal thickening and/or interstitial changes, traction bronchiectasis, and pleural effusion. [8–11].
Here, we report an observational study with a waxing and waning pattern defined as new or progressive pulmonary findings and spontaneous resolution of other pulmonary findings in the same scan interval, despite continuation of treatment on single-line mTOR inhibitor therapy. We describe and attempt to estimate the incidence of this waxing and waning pattern, which has not been previously characterized, for single-therapy temsirolimus or everolimus. We report our observation of the natural course of pneumonitis without intervention or drug discontinuation/dose reduction.
2. METHODS
Our institutional review board approved this HIPAA-compliant study and waived the need for informed consent.
2.1. Study Population
A retrospective search of the clinical database at our institution, a specialized cancer center, was performed to identify all patients with pathology proven renal cell carcinoma who had one of the following terms in the electronic medical record between January 2011 and July 2015: temsirolimus, CCI-779 (initial drug name for temsirolimus), everolimus, or RAD001 (initial drug name for everolimus). Following this initial search, medical records were reviewed to identify eligible patients for this study. The inclusion criteria were: treatment with mTOR-inhibitor monotherapy for at least 6 weeks, available baseline chest CT, and at least 3 available chest CT scans after mTOR-inhibitor initiation. Patients were excluded if there were other factors that could explain resolution of pulmonary findings, such as dose reduction or interruption, or use of antibiotics or steroids (for any reason) during treatment. Lastly, patients with pre-existing interstitial disease or bronchial obstructing lesions were excluded as these could produce similar pulmonary CT findings as pneumonitis.
The search criteria identified 52 unique patients eligible for the study, of whom we excluded 27 patients for the following reasons: mTOR inhibitor dose reduction or interruption (n=13); use of antibiotics or steroids during treatment (n=9); and pre-existing interstitial disease or endobronchial lesion (n=5). Thus, our study population consisted of 25 patients.
2.2. Data Collection
Six radiologists subspecialized in oncologic body imaging were involved in chart review and data collection for this study. Electronic medical records were reviewed, including clinic notes, pulmonary consults, Common Terminology Criteria for Adverse Events charts, and toxicity recordings to search for exclusion criteria. New clinical symptoms of unexplained dyspnea or dry cough were recorded when they occurred in the time between, or 1 month following, the available CT scans.
Chest CT scans of each patient were independently reviewed by two radiologists. Discrepancies were adjudicated by a thoracic oncologic radiologist (AP). The baseline CT scan (CTb), prior to initiation of mTOR inhibitor therapy, was reviewed to evaluate for pre-existing interstitial disease or bronchial obstructing lesions. Up to 10 consecutive chest CT scans following the initiation of mTOR inhibitor therapy (CT1–10) were reviewed to evaluate for the following pulmonary findings: groundglass opacities, airspace consolidation, interlobular septal thickening and/or interstitial changes, traction bronchiectasis, and pleural effusion. A waxing and waning pattern was defined by the presence of new pulmonary findings on at least two of the CT1–10 scans, with improved or resolved findings during the same scan interval.
Electronic medical records were then reviewed again to confirm clinical suspicion of pneumonitis, within 1 month of a CT scan demonstrating findings of pneumonitis. Findings were deemed consistent with pneumonitis if both the CT findings and the clinical notes were compatible with pneumonitis during this time frame.
3. RESULTS
Our study population of 25 patients consisted of 7 women and 18 men. The average age at the time of renal cell carcinoma diagnosis was 61 years and average age at mTOR inhibitor treatment initiation was 63. All patients received monotherapy with either temsirolimus (n=17) or everolimus (n=8).
Patients received chest CT scans at variable intervals, with 1–16 weeks between chest CT scans. The majority had routine chest CT scans every 4–8 weeks for 16 weeks and then every 8–16 weeks thereafter. Additional CT scans were sometimes performed if a patient was symptomatic.
Thirteen patients had radiologic findings compatible with pneumonitis including: groundglass opacities (12/13), airspace consolidation (6/13), or interlobular septal thickening or interstitial changes (4/13). In addition to these parenchymal findings, 8 patients also had a pleural effusion. Most patients showed more than one pulmonary finding on chest CT. No CT showed traction bronchiectasis. Table 1 shows the timeframe of CT scans for the 13 patients with pneumonitis.
Table 1.
Table of the 13/25 patients with CT scans showing mTOR inhibitor-associated pneumonitis.
| # CT scans, including CTb | Scan Intervals (weeks)* | First CT with pneumonitis | First CT with waxing & waning | |
|---|---|---|---|---|
| 1 | 10 | 8 | CT 1 | CT 2 |
| 2 | 8 | 4–6, 10–12 | CT 1 | CT 3 |
| 3 | 4 | 8, 12 | CT 1 | CT 3 |
| 4 | 5 | 4, 8 | CT 2 | CT 3 |
| 5 | 7 | 8 | CT 4 | CT 5 |
| 6 | 5 | 8 | CT 1 | |
| 7 | 6 | 8 | CT 1 | CT 2 |
| 8 | 5 | 8, 12 | CT 3 | |
| 9 | 5 | 8, | CT 1 | CT 3 |
| 10 | 11 | 8, 12 | CT 1 | CT 2 |
| 11 | 4 | 4, 8 | CT 1 | |
| 12 | 6 | 4, 8 | CT 3 | |
| 13 | 4 | 12, 8 | CT 1 and CT 3 |
CTb = baseline CT scan, prior to initiation of mTOR inhibitor therapy
A comma indicates a change in scan interval between the first 16 weeks and after 16 weeks
Eight patients had radiologic findings demonstrating a waxing and waning pattern. Seven of these patients developed clinical symptoms including dyspnea (in 6 patients) and dry cough (in 7 patients). In the 8 patients with a waxing and waning pattern, CT findings of pneumonitis was identified on average 9.9 weeks after mTOR initiation (range 4.3–31.0 weeks, median 7.2).
Of the patients who received temsirolimus, 9/17 (53%) developed radiologic findings compatible with pneumonitis and 4/9 (44%) developed a waxing and waning pattern. Of the 8 patients who received everolimus, 4/8 (50%) had radiologic findings compatible with pneumonitis and 4/4 (100%) developed a waxing and waning pattern.
Pulmonary consultation was performed for 4 patients with pulmonary symptoms during the time frame of this study. Three were diagnosed with progressive pulmonary metastatic disease. In one patient, pulmonary consultation confirmed the relationship of drug-associated pneumonitis with CT findings of pneumonitis. No patient had a bronchoscopy.
Three of 25 patients ultimately discontinued the mTOR inhibitor for toxicity (1 pulmonary and 2 other). All 3 patients who discontinued the drug due to toxicity had clinical and radiologic findings compatible with pneumonitis, however a waxing and waning pattern was only seen in one patient with non-pulmonary toxicity. One patient discontinued the drug for an external reason (trauma). The remaining 21 patients discontinued the drug for progression of disease.
4. DISCUSSION
Pneumonitis is a known adverse event in patients receiving mTOR inhibitors and up to 50% of cases are symptomatic. Although clinical manifestations are typically mild to moderate, e.g., experiencing dyspnea on exertion and dry cough, rare cases of death have been reported [7, 8, 13]. Toxicity can occur early (within days to weeks) or late (months to years) after treatment initiation. Radiologic findings of pneumonitis associated with mTOR therapy have been reported in up to 54% of patients [6–8, 12]. The radiologic patterns have been described in prior reports, with the most prevalent manifestations being groundglass opacities and patchy areas of consolidation. However, a variable appearance with “the patterns frequently changing over time” has been previously reported only once [8]. This single comment in a paper initially reporting pneumonitis with everolimus in 2010 was unnoticed until the writing of this paper. It therefore warrants repeating and clarification for purposeful application.
In our study, we found evidence of pneumonitis in 52% (13/25) of patients who received mTOR inhibitors, of whom 62% (8/13) had a waxing and waning pattern on serial chest CT exams, with new or progressive findings appearing in the same scan interval while others spontaneously resolved, despite the continuation of treatment; this is 32% (8/25) of our study population. This is a previously unrecognized and unique pattern of drug-induced pneumonitis.
This study has several limitations. After applying our strict exclusion criteria to eliminate other possible explanations of a waxing and waning pattern, we identified only 25 patients who never received antibiotics, steroids, or dose reduction/interruption, and yet had enough CT imaging to follow over time. There were several patients who developed pulmonary findings but did not have sufficient follow-up imaging as per our inclusion criteria to prove a waxing and waning pattern, since it takes several scans to demonstrate this occurrence.
This paper describes a unique chest CT pattern in renal cell carcinoma patients treated with mTOR inhibitors and describes the natural course of pneumonitis without intervention. mTOR inhibitor-associated pneumonitis can show a waxing and waning pattern over several CT scans, all of which occur while the patient remains on therapy without dose reduction or treatment with antibiotics or steroids. In our small -- and highly-controlled -- study population at a tertiary care cancer center, this characteristic pattern was seen in 32% of patients and persisted over the course of therapy. mTOR inhibitor-associated pneumonitis is seen in other patient populations as well, including patients with breast and neuroendocrine cancers [14-17].
It is likely that this CT pattern can be more broadly generalized beyond advanced renal cell carcinoma patients. We predict that studies of other populations, such as breast or neuroendocrine cancer patients, will confirm the waxing and waning pattern of mTor inhibitor-associated pneumonitis which we have described, and that as the application of this drug expands, the waxing and waning effect will be seen and reported by radiologists on an increasing basis across radiological disciplines.
Knowledge of this ongoing waxing and waning process of mTOR inhibitor-associated pneumonitis can help radiologists interpret and contextualize abnormal CT findings. Possible pulmonary toxicity related to mTOR-inhibitor therapy can be suggested, potentially avoiding further diagnostic workup and hopefully facilitating patient management.
In conclusion, waxing and waning is an unrecognized characteristic pattern of mTOR-associated pneumonitis in patients with renal cell carcinoma, which can continue while patient remains on therapy. Recognition of this pattern promotes clinical-radiologic concordance.
Figure 1.
Case 1: Patient developed new left anterior groundglass opacities (a); three months later, the same patient showed clearing of the anterior opacities and a new left posterior groundglass opacity (b). Another three months later, there were new consolidations in the right lower lung, with clearing of left lung (c). Three months later, improved right lower lobe consolidation, and increased consolidative and groundglass opacity in the right middle lobe (d). After two months, the patient showed overall improvement of the right lung with reappearance of left anterior mixed opacity on follow up (e) while still on therapy. Clear baseline CT not shown.
Figure 2.
Case 2: Patient developed a new left lower lobe mixed consolidative and groundglass opacity (a) which improved on the next CT examination performed three months later (b). After another three months, the posterior left lower lobe airspace opacity continued to improve, with a new consolidation in the anterior left lower lobe (c). Yet another three months later, clearing of all airspace opacities (d) was shown while the patient was still on therapy. Clear baseline CT not shown.
HIGHLIGHTS:
One-half of our patients on mTOR inhibitors developed pneumonitis (52%).
Of those with pneumonitis, two-thirds had a waxing and waning pattern.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Declarations of Interest: This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
REFERENCES
- [1].Voss MH, Molina AM, Motzer RJ. mTOR inhibitors in advanced renal cell carcinoma. Hematology/oncology clinics of North America 2011;25(4):835–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Faes S, Santoro T, Demartines N, Dormond O. Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy. Cancers 2017;9(11). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Xie J, Wang X, Proud CG. mTOR inhibitors in cancer therapy. F1000Research 2016;5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Gomez-Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematology/oncology clinics of North America 2012;26(3):483–505, vii. [DOI] [PubMed] [Google Scholar]
- [5].Peddi PF, Shatsky RA, Hurvitz SA. Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer. Cancer treatment reviews 2014;40(2):320–6. [DOI] [PubMed] [Google Scholar]
- [6].Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. European journal of cancer (Oxford, England : 1990) 2006;42(12):1875–80. [DOI] [PubMed] [Google Scholar]
- [7].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). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2009;4(11):1357–63. [DOI] [PubMed] [Google Scholar]
- [8].White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. American journal of respiratory and critical care medicine 2010;182(3):396–403. [DOI] [PubMed] [Google Scholar]
- [9].Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, et al. Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011;29(13):1750–6. [DOI] [PubMed] [Google Scholar]
- [10].Atkinson BJ, Cauley DH, Ng C, Millikan RE, Xiao L, Corn P, et al. Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes. BJU international 2014;113(3):376–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Nozawa M, Ohzeki T, Tamada S, Hongo F, Anai S, Fujimoto K, et al. Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma. International journal of clinical oncology 2015;20(4):790–5. [DOI] [PubMed] [Google Scholar]
- [12].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. International journal of cancer 2016;138(10):2312–21. [DOI] [PubMed] [Google Scholar]
- [13].Almeida F, Amorim S, Sarmento A, Santos L. Life-Threatening Everolimus-Associated Pneumonitis: A Case Report and a Review of the Literature. Transplantation proceedings 2018;50(3):933–8. [DOI] [PubMed] [Google Scholar]
- [14].Alvarez RH, Bechara RI, Naughton MJ, Adachi JA, Reuben JM. Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer. Oncologist 2018;23(6):660–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366(6):520–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].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 2016;53:163–70. [DOI] [PMC free article] [PubMed] [Google Scholar]