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E-JCRT CORRESPONDENCE
Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 1037

Lung reexpansion of obstructive atelectasis caused by radiotherapy after continuous gefitinib treatment in nonsmall cell lung cancer


Cancer Center, Daping Hospital, Third Military Medical University, Chongqing, China

Date of Web Publication15-Feb-2016

Correspondence Address:
Xueqin Yang
Cancer Center, Daping Hospital, Third Military Medical University, No.10 Changjiang Zhi lu, Daping Yuzhong - 400 042, Chongqinge
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.138109

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 > Abstract 


A 75-year-old male was diagnosed with central squamous cell carcinoma of the left lung, who has been given 3-dimensional conformal radiotherapy of total dose with 60 Gy in 30 fractions. Three years later, the tumor relapsed in situ and he received another stereotactic radiotherapy with a total dose of 40 Gy at a margin of planning target volume (PTV) in 10 (5 fractions/week) at 4 Gy/fraction. Gefitinib (250 mg/day) was initiated immediately after radiotherapy. Obstructive atelectasis in the left lung and increased pleural effusion occurred at the fourth month after radiotherapy. As this patient has been detected with deletion in exon 19 of the EGFR gene, gefitinib was continuous administered without interruption. After another 4 months, the atelectasis in the left lung reexpanded significantly. To the best of our knowledge, this is the first report in the literature that EGFR tyrosine kinase inhibitors (EGFR-TKI) reversed the radiation atelectasis of pulmonary in the nonsmall cell lung cancer (NSCLC) patient.

Keywords: Gefitinib, nonsmall cell lung cancer, radiotherapy


How to cite this article:
Yang X, Xu M, Xiong Y, Peng B. Lung reexpansion of obstructive atelectasis caused by radiotherapy after continuous gefitinib treatment in nonsmall cell lung cancer. J Can Res Ther 2015;11:1037

How to cite this URL:
Yang X, Xu M, Xiong Y, Peng B. Lung reexpansion of obstructive atelectasis caused by radiotherapy after continuous gefitinib treatment in nonsmall cell lung cancer. J Can Res Ther [serial online] 2015 [cited 2020 Aug 3];11:1037. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/1037/138109




 > Introduction Top


Approximately 80% of nonsmall cell lung cancer (NSCLC) cases are already in the advanced stage at the time of diagnosis. With the increase of targeted therapy for lung cancer, the combination of targeted therapy and radiotherapy has become a feasible therapeutic modality for the advanced stage.[1] As the most serious complication is interstitial pneumonia, both for radiotherapy and gefitinib, this combination in the clinic is used with caution.[2] However, in the study, we first observed that EGFR-TKI reversed the radiation atelectasis of pulmonary in a NSCLC patient during the combination of gefitinib and stereotactic body radiation therapy (SBRT) treatment.


 > Case Report Top


A 75-year-old male was diagnosed with central squamous cell carcinoma of the left lung, which was staged T2N0M0. As spirometry showed severe obstructive ventilatory impairment, he was deemed unsuitable for surgery. Thus three-dimensional conformal radiotherapy (3D-RT) of total dose with 60 Gy in 30 fractions was given. Three years later, the tumor relapsed in situ. Computed tomography (CT) scan showed that the tumor size was 3.2 × 5.5 cm, accompanied with bronchial obstruction in the left upper and inferior lobe and left pleural effusion [Figure 1]a. However, no cancer cells were observed on pleural effusion cytology. The performance status (PS) upon admission was 1 point according to the Eastern Cooperative Oncology Group scale. CT scan of abdomen, magnetic resonance scan of brain and bone scan showed no other metastasis. The cancer was still staged T2N0M0.
Figure 1: Thoracic CT scans of the patient. (a) before radiotherapy; (b) 1 month after radiotherapy and gefitinib; (c) 4 months after radiotherapy and gefitinib; (d) 8 months after radiotherapy and gefitinib. (White arrow indicates tumor lesion)

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He received γ-ray SBRT to the lesions in his left lung at doses and fractions as previously described.[3] Briefly, CT-guided simulation was available for delineation of the gross tumor volume (GTV). The planning target volume (PTV) was generated with an additional 0.5 cm in the axial plane and 1.0 cm in the longitudinal plane to the GTV. The γ-SBRT plan met with 50% isodose line covering more than 95% of PTV and 70% isodose line covering more than 90% of GTV. A total dose of 40 Gy was prescribed at a margin of PTV in 10 fractions (5 fractions/week) at 4 Gy/fraction, and the corresponding dose of 56 Gy was prescribed at a margin of GTV (5.6 Gy/fraction) [Figure 2].
Figure 2: Dose distribution of SBRT treatment plan (40 Gy/10 fractions)

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In addition, deletions were found in exon 19 of theEGFR gene of the patient, indicating EGFR-TKI sensitivity. Gefitinib (250 mg/day) was initiated immediately after radiotherapy. At the one-month review, CT scan revealed mitigated local lesions, remission of atelectasis in the left lung, and resolution of left pleural effusion [Figure 1]b. Objective efficacy evaluation indicated partial remission. However, the patient experienced worsened postexertional shortness of breath after an additional 3 months. The symptom did not improve after intravenous infusion antiinflammatory drugs and oral traditional Chinese medicine for 2 weeks. CT scan showed completed obstructive atelectasis in the left lung and increased pleural effusion [Figure 1]c. The patient refused fiber optic bronchoscopy and positron emission tomography-computer tomography (PET-CT). He was suggested to continue gefitinib (250 mg/day) as his EGFR status ruled out emergence of premature drug resistance, and stop other drugs including antiinflammatory drugs and traditional Chinese medicine. After another 4 months (at the 8-month review after radiotherapy), the symptom of the dyspnea disappeared. CT scan showed that the atelectasis in the left lung reexpanded and the pleural effusion receded significantly [Figure 1]d. The tumor relapsed in situ at 13th month after the second radiotherapy, which was confirmed by PET-CT. Thus second SBRT (or third radiotherapy) was given. No pulmonary atelectasis occurred until 4 months after the third radiotherapy. One additional month after the last CT scan, this patient died of massive hemoptysis. The overall survival time is 63 months.


 > Discussion Top


This case with central lung lesions developed severe obstructive atelectasis after undergoing SBRT, which interrupted our evaluation of gefitinib efficacy. The patient had gene mutations with deletions in exon 19 of the EGFR gene. As we know, EGFR-TKI is more effective for patients with such deletions than the site mutation in exon 21.[4] The median progression-free survival (PFS) is 9.3 m for the patients with this deletion. Thus despite the emergence of obstructive atelectasis, we chose not to blindly terminate gefitinib. Follow-up review confirmed that obstructive atelectasis was actually caused by radiotherapy rather than disease progression.

As this patient has received radiotherapy two times, our analysis indicated that the occurrence of obstructive atelectasis mainly resulted from 3D-RT and SBRT for lesions located in the hilum of the lung, which caused the late complication of radiation bronchial fibrosis that in turn caused bronchial stenosis. To our surprise, the atelectasis in the left lung reexpanded significantly 4 months later. As we know, the most serious complication for gefitinib is interstitial pneumonia. However, Miyake [5] reported that gefitinib treatment increased the infiltration of inflammatory cells, which produced more proinflammatory cytokines interleukin-6, interleukin-1β, in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. Thus gefitinib treatment augmented pneumonitis, but attenuated lung fibrosis in response to radiation injury in rats. Ishii et al.[6] reported that gefitinib can attenuate the pulmonary fibrosis induced by bleomycin. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited by gefitinib. Several other studies also found that EGFR-TKI had antifibrotic effectiveness on proliferative cholangitis [7] and prevent renal vascular and glomerular fibrosis from hypertension.[8] However, all these results came from animal experiments. It was the first time that EGFR-TKI reversing the fibrosis of bronchus was observed in the NSCLC patient. Moreover, no radiation pulmonary fibrosis occurred in the last two radiotherapies. In clinical, there are many diseases related to fibrosis, such as radiation esophageal stricture and local radiation pulmonary fibrosis. No more effective drugs except corticosteroid treat these diseases until now. Thus EGFR-TKI may be another choice for these diseases. A new clinical trial on EGFR-TKI reversing or attenuating fibrosis is anticipated in the future.

 
 > References Top

1.
Chang CC, Chi KH, Kao SJ, Hsu PS, Tsang YW, Chang HJ, et al. Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: A mono-institutional experience. Lung Cancer 2011;73:189-94.  Back to cited text no. 1
    
2.
Okamoto I, Takahashi T, Okamoto H, Nakagawa K, Watanabe K, Nakamatsu K, et al. Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer 2011;72:199-204.  Back to cited text no. 2
    
3.
Wang J, Xia TY, Wang YJ, Li HQ, Li P, Wang JD, et al. Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e59-65.  Back to cited text no. 3
    
4.
Won YW, Han JY, Lee GK, Park SY, Lim KY, Yoon KA, et al. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J Clin Pathol 2011;64:947-52.  Back to cited text no. 4
    
5.
Miyake K, Tani K, Kakiuchi S, Suzuka C, Toyoda Y, Kishi J, et al. Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats. J Med Invest 2012;59:174-85.  Back to cited text no. 5
    
6.
Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med 2006;174:550-6.  Back to cited text no. 6
    
7.
Li F, Zhou Y, Cheng N, Mao H, Jiang L, Li N, et al. Epidermal growth factor receptor as a target for anti-proliferative treatment of proliferative cholangitis in hepatolithiasis. J Surg Res 2011;166:87-94.  Back to cited text no. 7
    
8.
Francois H, Placier S, Flamant M, Tharaux PL, Chansel D, Dussaule JC, et al. Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition. FASEB J 2004;18:926-8.  Back to cited text no. 8
    


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