Concurrent erlotinib and radiotherapy has been associated with increased risk of radiation pneumonitis among patients with lung cancer. Radiation pneumonitis (even without concurrent erlotinib) is radiation dose-related, but the molecular-pathway underpinnings of this toxicity remain unclear and the search for molecular biomarkers is nascent. However, recent reports suggest that pretreatment interstitial lung disease is a key risk factor for radiation pneumonitis and that prognostic imaging and blood biomarker tests might well allow for risk stratification of cancer patients who are being considered for thoracic radiotherapy.

Radiation pneumonitis is a common, dose-limiting—and sometimes life-threatening—complication of external-beam radiotherapy of the chest and thorax. Also known as radiation-induced lung disease, it is associated with increased vascular permeability and edema and inflammation of the lungs’ alveoli. Rates of symptomatic radiation pneumonitis are as high as 28% among patients treated for lung cancer with stereotactic body radiotherapy (SBRT); symptoms can include cough, chest pain or discomfort, and dyspnea.1 Grade 3 radiation pneumonitis is rare (3% to 4% of cases), but it can profoundly impact patients’ quality of life and is potentially life-threatening.1-3 Recent reports suggest that concurrent erlotinib and thoracic radiotherapy is associated with increased risk of radiation pneumonitis, and that radiation dosimetric variables (V5, V10, V15, V20, and V30) might be predictive of this side effect.4

The genomic and molecular pathways leading to an increased risk of radiation pneumonitis in this and other radiotherapy patient populations are not yet well understood, although a model that has gained favor in recent years is that radiation triggers local inflammatory pathways. However, even though higher radiation doses do appear to increase risk—even among patients who are not receiving erlotinib—specific, strongly predictive candidate dosimetric variables have not yet been validated.1


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However, interstitial lung disease before radiotherapy begins appears to be an important risk factor for severe symptomatic radiation pneumonitis.5 Recent reports suggest that pretreatment computed tomography (CT) or positron emission tomography (PET) imaging and serum biomarkers of interstitial pneumonitis allow risk stratification for patients with lung cancer who are being considered for SBRT.1,6,7 For example, on CT images, interstitial pneumonitis shadow has been associated with increased risk of severe radiation pneumonitis, particularly when accompanied by high serum levels of surfactant protein D and Krebs von den Lungen-6 (KL-6).1 Researchers at the University of Tokyo Hospital in Japan report that lung cancer patients with these risk factors are not considered candidates for SBRT at their hospital, and that the hospital’s rate of severe radiation pneumonitis has declined sharply since that policy was adopted in 2006.1

Consistent with an inflammatory-pathway hypothesis, postradiotherapy white blood cell counts appear to be a diagnostic and possibly a predictive biomarker of radiation pneumonitis.8 Other candidate biomarkers to predict or detect radiation pneumonitis in patients undergoing radiotherapy include LIN28B gene variants (which are involved in stem cell self-renewal), transforming growth factor-beta-1 (TGF-β1, a cytokine involved in cancer and lung fibrosis), circulating endothelial progenitor cells, and anti-p16 (tumor-suppressor protein) autoantibodies.9-11 Like the white blood cell count finding, an association of TGF-β1, which influences production of proinflammatory cytokines, might support the inflammation model of radiation pneumonitis.However, it is important to note that all of these candidate biomarkers have been only preliminarily identified and await replication and validation.

New prevention and prophylactic measures might also be on the horizon, which might someday allow even patients deemed to be at-risk for radiation pneumonitis to benefit from radiotherapy. For example, a recent study of lab animals suggests that radiation to the skin a few hours after whole-thorax irradiation might reduce morbidity associated with radiation pneumonitis, and that the angiotensin-converting enzyme (ACE) inhibitor captopril helped mitigate resulting radiation dermatitis.12 However, these preclinical study results are preliminary at best, and it is far too early to draw meaningful clinical lessons from such research.

 

REFERENCES

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2. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-1076. doi:10.1001/jama.2010.261.

3. Nishio T, Kunieda E, Shirato H, et al. Dosimetric verification in participating institutions in stereotactic body radiotherapy trial for stage I non-small cell lung cancer: Japan clinical oncology group trial (JCOG0403). Phys Med Biol. 2006;51(2):5409-5417.

4. Zhuang H, Hou H, Yuan Z, et al. Preliminary analysis of the risk factors for radiation pneumonitis in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy. Onco Targets Ther. 2014;7:807-813. doi:10.2147/OTT.S62707.

5. Ueki N, Matsuo Y, Togashi Y, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol. 2015;10(1):116-125.

6. Castillo R, Pham N, Ansari S, et al. Pre-radiotherapy FDG PET predicts radiation pneumonitis in lung cancer. Radiat Oncol. 2014;9:74. www.ro-journal.com/content/9/1/74. Accessed March 3, 2015.

7. Cunliffe AR, Armato SG 3rd, Straus C, et al. Lung texture in serial thoracic CT scans: correlation with radiologist-defined severity of acute changes following radiation therapy. Phys Med Biol. 2014;59(18):5387-5398. doi:10.1088/0031-9155/59/18/5387.

8. Tang C, Gomez DR, Wang H, et al. Association between white blood cell count following radiation therapy with radiation pneumonitis in non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;88(2):319-325. doi:10.1016/j.ijrobp.2013.10.030.

9. Wen J, Liu H, Wang Q, et al. Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Eur J Cancer. 2014;50(10):1706-1716. doi:10.1016/j.ejca.2014.03.008.

10. Liu Y, Xia T, Zhang W, et al. Variations of circulating endothelial progenitor cells and transforming growth factor-beta-1(TGF-β1) during thoracic radiotherapy are predictive for radiation pneumnonitis. Radiat Oncol. 2013;8:189. www.ro-journal.com/content/8/1/189. Accessed March 3, 2015.

11. Wang W, Wei J, Zhong W. Autoantibodies against p16 protein-derived peptides predict radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2014;90(5 suppl):S69-S70.

12. Gao F, Fish BL, Szabo A, et al. Enhanced survival from radiation pneumonitis by combined irradiation to the skin. Int J Radiat Biol. 2014;90(9):753-761. doi:10.3109/09553002.2014.922722.