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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 2  |  Issue : 1  |  Page : 22-24

Preoperative neoadjuvant gefitinib used in the treatment of a nonsmall cell lung cancer patient


1 Major of Oncology, First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, ; Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
2 Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

Date of Submission06-Dec-2016
Date of Acceptance11-Jan-2017
Date of Web Publication21-Mar-2017

Correspondence Address:
Weimin Mao
Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ts.ts_33_16

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  Abstract 


The epidermal growth factor receptor tyrosine kinase inhibitor (TKI) has been mainly applied in the second- and third-line treatment of advanced nonsmall cell lung cancer (NSCLC), but it is rarely used as a neoadjuvant therapy. This article aims to summarize and analyze a relevant case so as to provide some clinical experience for targeted neoadjuvant treatment modalities. A patient with NSCLC received the TKI gefitinib for preoperative neoadjuvant targeted therapy. A 76-year-old female who was given gefitinib for the neoadjuvant treatment was analyzed. The patients' general condition and also gender, age, smoking history, and efficacy of the targeted therapy and associated surgical experience were recorded. After the neoadjuvant treatment, the tumor shrinkage was obvious. At surgery, the surface vascular expansion on the tumor was observed. There was no increase in postoperative complications. The surgical pathology was adenocarcinoma of the lung associated with bronchioloalveolar carcinoma. Neoadjuvant targeted therapy could be a useful clinical treatment in NSCLC.

Keywords: Epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, neoadjuvant therapy, nonsmall cell lung cancer


How to cite this article:
Zheng W, Mao W. Preoperative neoadjuvant gefitinib used in the treatment of a nonsmall cell lung cancer patient. Transl Surg 2017;2:22-4

How to cite this URL:
Zheng W, Mao W. Preoperative neoadjuvant gefitinib used in the treatment of a nonsmall cell lung cancer patient. Transl Surg [serial online] 2017 [cited 2020 Jul 11];2:22-4. Available from: http://www.translsurg.com/text.asp?2017/2/1/22/202646




  Introduction Top


All over the world, lung cancer is the leading cause of death from cancer. Nonsmall cell lung cancer (NSCLC) accounts for 80%–85% of lung cancer.[1] In recent years, with the rapid development of molecular biology technology, innovative molecular-targeting drugs have been developed. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were confirmed to have the most prominent curative effect in treating NSCLC. Gefitinib is one of the representative EGFR-TKI drugs. Gefitinib is safer and more easily tolerated when compared to other chemotherapeutic drugs. Preoperative targeted therapy is a new treatment, and it may be more suitable for older patients. Our case was an elderly female nonsmoker. To the best of our knowledge, there are <10 cases of NSCLC who have received gefitinib therapy before the operation.[2],[3]


  Case Report Top


A 76-year-old nonsmoking female was healthy until she developed a dry cough with blood-streaked sputum. She visited the local hospital and underwent chest computed tomography (CT) scan which demonstrated 3.5 cm × 3.5 cm lung mass in the upper right lobe with enlarged pulmonary hilar lymph nodes [Figure 1]a. A positron emission tomography-CT scan was performed that revealed increased fluorodeoxyglucose uptake in the mass and lymph node. She was highly diagnosed as lung cancer with Stage IIIa (T2, N2, M0) based on imaging. Initially, she declined surgery and preferred to take gefitinib at a dose of 250 mg/day for 3 months. After 1-month gefitinib therapy, repeat CT scan showed 1.5 cm × 1.9 cm upper right lobe lung nodule with decrease in the enlarged pulmonary hilar lymph nodes [Figure 1]b. Obviously, the second CT imaging showed a rapid decrease in the size of the tumor. At the same time, the patient suffered serious skin reaction, including severe face skin rash, conjunctival congestion, and increased skin crumbs.
Figure 1: The chest computed tomography in different times. (a) The first computed tomography before any therapy. (b) The computed tomography for after 1-month Iressa therapy. (c) The computed tomography for after 3-month Iressa therapy and before surgery

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After 3 months of gefitinib therapy, a repeat CT scan showed that the tumor was stable. Then, she visited our hospital requesting for surgery. CT scan was performed in our hospital to confirm the fact that the lung tumor had gradually diminished and the enlarged pulmonary hilar lymph nodes had almost disappeared [Figure 1]c. The clinical stage of the patient based on imaging was now down to Stage Ib (T2, N0, M0).

Because of the serious skin rash and the patient's desire for surgery, the gefitinib was discontinued. A pneumonectomy with mediastinal lymph node dissection was done. During the surgery, the lung was obviously hyperemic. Only a 1.2 cm × 1.3 cm area of induration was palpated. The mediastinal lymph nodes were not enlarged. The operation took about 2.5 h.

Postoperative pathology was reported as adenocarcinoma and bronchioloalveolar lung carcinoma mixed subtypes (mainly bronchioloalveolar carcinoma). There were twenty lymph nodes harvested; none of them was positive. Postoperative pathologic stage was Stage Ib (T2a, N0, M0). Postoperatively, the EGFR gene mutations test on coding exon 19 showed that the 746-754 codon had no mutation and exon 21 of L858R and L861Q had no mutation. Test results showed the EGFR gene was of the wild type [Figure 2].
Figure 2: The epidermal growth factor receptor mutation results

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The patient did not undergo any other anticancer therapy and was discharged 10 days after the surgery. This patient has had 28 months of progression-free survival time after surgery. She continued to take gefitinib for maintenance treatment after a recurrence when the CT scan has shown a tumor in the left lung again, but she still alive.


  Discussion Top


How to select proper patients for neoadjuvant EGFR-TKI therapy is an important issue. Since 2004, papers in Science and N Engl J Med have shown that the EGFR mutation is a strong indicator for the response of patients to gefitinib.[4],[5] The common experience has been, “The strongest predictor of response was EGFR mutation.” Hence, first-line use EGFR-TKI should be utilized in patients with EGFR mutation. They can also be utilized in both mutation and nonmutation patients as salvage treatment in patients with recurrent NSCLC after first-line chemotherapy. However, this still does not answer the question of whether or not we should select mutation patients before neoadjuvant EGFR-TKI therapy. Some studies in early-stage NSCLC did not select patients with EGFR mutation before using EGFR-TKI induction therapy.[2],[3],[6] In this study, in the patient, the EGFR mutation was not detected before surgery.

As we know, EGFR mutations in-frame deletions in exon 19 and point mutation in exon 21 are the most common mutation patterns and are associated with the therapeutic response to gefitinib. Interestingly, in our case, the tumor showed dramatic regression after gefitinib treatment, but in the operative specimen, the EGFR gene mutations' test showed that no mutation in exon 19 and exon 21. This indicates that even patients without EGFR mutations can also benefit from EGFR-TKI therapy. In Lara-Guerra's [2] report, patients with tumor reduction, including one patient who achieved partial response, had wild-type EGFR. Wang et al.[7] reported a 46-year-old nonsmoking Chinese woman whose sequencing analysis of the removed tumor samples showed no mutation in exons 18–21 of the EGFR gene. The patient had an unresectable NSCLC tumor with Stage IIIa (N2). However, the tumor stage was downgraded to I after EGFR-TKI preoperative adjuvant therapy and achieved complete resection.[7] The mechanism of benefit from TKI in patients with wild-type EGFR is unknown. Furthermore, it is also unknown if patients with EGFR mutations when first diagnosed developed wild-type EGFR by the time the specimens were removed at the time of surgery. Several studies had reported that gene expression profiles were different between primary tumors and metastases,[8],[9] reminding us that the EGFR status may be different before and after TKI neoadjuvant therapy. Because of this, before definitive surgery, the EGFR status test by biopsy is necessary.

However, a negative result from a core needle biopsy may be due to lack of sufficient tissue. The exclusion of patients with wild-type EGFR from receiving targeted therapy might eliminate the patients' opportunity for TKI treatment as the neoadjuvant therapy and miss a chance for surgery. Improvement of the accuracy of the EGFR mutation test and discovering new methods such as from peripheral blood, plasma DNA, or exhaled breath condensate to test the EGFR mutation are future research fields.[10],[11],[12]

In conclusion, neoadjuvant therapy with TKIs is a new clinical treatment possibility. There are still many questions to be answered. The present neoadjuvant targeted therapy is mostly only at the case report level. Large-scale prospective clinical trials are needed, especially in advanced NSCLC. While the effects of TKIs treatment are significant in some patients, these patients are not necessary those with EGFR mutations. The mechanism of TKIs in those sensitive patients with EGFR wild-type is worthy of further research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Didkowska J, Wojciechowska U, Mańczuk M, Łobaszewski J. Lung cancer epidemiology: Contemporary and future challenges worldwide. Ann Transl Med 2016;4 (8):150.  Back to cited text no. 1
    
2.
Lara-Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, Paul N, Boerner S, Sakurada A, Ludkovski O, Ma C, Squire J, Liu G, Shepherd FA, Tsao MS, Leighl NB. Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol 2009;27 (36):6229-36.  Back to cited text no. 2
    
3.
Haura EB, Sommers E, Song L, Chiappori A, Becker A. A pilot study of preoperative gefitinib for early-stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance. J Thorac Oncol 2010;5 (11):1806-14.  Back to cited text no. 3
    
4.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350 (21):2129-39.  Back to cited text no. 4
    
5.
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304 (5676):1497-500.  Back to cited text no. 5
    
6.
Shen H, Zhong X, Ge XQ, Huang JJ, Yuan Y. Surgical resection of lung adenocarcinoma without EGFR mutation after neoadjuvant gefitinib treatment. Clin Respir J 2010;4 (3):192-3.  Back to cited text no. 6
    
7.
Wang Q, Wang H, Li P, Zhu H, He C, Ma Z, Wei B, Ma J, Ma Z. Erlotinib-based perioperative adjuvant therapy for a case of unresectable stage IIIA (N2) nonsmall cell lung cancer. Am J Med Sci 2010;340 (4):321-5.  Back to cited text no. 7
    
8.
Nicoś M, Krawczyk P, Jarosz B, Sawicki M, Szumiłło J, Trojanowski T, Milanowski J. Analysis of KRAS and BRAF genes mutation in the central nervous system metastases of non-small cell lung cancer. Clin Exp Med 2016;16 (2):169-76.  Back to cited text no. 8
    
9.
Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res 2009;15 (14):4554-60.  Back to cited text no. 9
    
10.
Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, Ward TH, Backen A, Clack G, Hughes A, Ranson M, Blackhall FH, Dive C. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J Thorac Oncol 2012;7 (2):306-15.  Back to cited text no. 10
    
11.
Hofman V, Ilie MI, Long E, Selva E, Bonnetaud C, Molina T, Vénissac N, Mouroux J, Vielh P, Hofman P. Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: Comparison of the efficacy of the CellSearch Assay™ and the isolation by size of epithelial tumor cell method. Int J Cancer 2011;129 (7):1651-60.  Back to cited text no. 11
    
12.
Hanssen A, Loges S, Pantel K, Wikman H. Detection of circulating tumor cells in non-small cell lung cancer. Front Oncol 2015;5:207.  Back to cited text no. 12
    


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