Clinical significance of gefitinib antitumor activity in patients with lung adenocarcinoma

Wang,Zhun; Han,Qian‑Bo; Gu,Jia‑Lei; Yu,Xin‑Min; Sun,Xiao‑Jiang; Lin,Qing‑Ren; Fang,Jun; Wang,Yue‑Zhen; Xu,Ya‑Ping; Mao,Wei‑Min

doi:10.3892/ol.2014.2664

Clinical significance of gefitinib antitumor activity in patients with lung adenocarcinoma

Authors:
- Zhun Wang
- Qian‑Bo Han
- Jia‑Lei Gu
- Xin‑Min Yu
- Xiao‑Jiang Sun
- Qing‑Ren Lin
- Jun Fang
- Yue‑Zhen Wang
- Ya‑Ping Xu
- Wei‑Min Mao
View Affiliations

Affiliations: Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
Published online on: November 4, 2014 https://doi.org/10.3892/ol.2014.2664
Pages: 257-261

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non‑small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib‑induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one‑year progression‑free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007‑0.083; P=0.035). One‑year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2‑16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long‑term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood‑brain barrier in order to prolong PFS in patients with lung adenocarcinoma.

View Figures

View References

1	Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 21:2237–2246. 2003. View Article : Google Scholar : PubMed/NCBI
3	Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 290:2149–2158. 2003. View Article : Google Scholar : PubMed/NCBI
4	Jänne PA, Gurubhagavatula S, Yeap BY, et al: Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, ‘Iressa’) on an expanded access study. Lung Cancer. 44:221–230. 2004. View Article : Google Scholar
5	Santoro A, Cavina R, Latteri F, et al: Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer. Ann Oncol. 15:33–37. 2004. View Article : Google Scholar
6	Park J, Park BB, Kim JY, et al: Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res. 10:4383–4388. 2004. View Article : Google Scholar : PubMed/NCBI
7	Konishi J, Yamazaki K, Kinoshita I, et al: Analysis of the response and toxicity to gefitinib of non-small cell lung cancer. Anticancer Res. 25:435–441. 2005.PubMed/NCBI
8	Simon GR, Ruckdeschel JC, Williams C, et al: Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control. 10:388–395. 2003.PubMed/NCBI
9	Lee DH, Han JY, Lee HG, et al: Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res. 11:3032–3037. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
11	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
12	Okamoto I, Takahashi T, Okamoto H, 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. 72:199–204. 2011. View Article : Google Scholar
13	Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 97:643–655. 2005. View Article : Google Scholar : PubMed/NCBI
14	Hirsch FR, Herbst RS, Olsen C, et al: Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol. 26:3351–3357. 2008. View Article : Google Scholar : PubMed/NCBI
15	Cappuzzo F, Magrini E, Ceresoli GL, et al: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 96:1133–1141. 2004. View Article : Google Scholar : PubMed/NCBI
16	Engelman JA, Jänne PA, Mermel C, et al: ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA. 102:3788–3793. 2005. View Article : Google Scholar : PubMed/NCBI
17	Mitsudomi T, Kosaka T, Endoh H, et al: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 23:2513–2520. 2005. View Article : Google Scholar : PubMed/NCBI
18	Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 23:2493–2501. 2005. View Article : Google Scholar : PubMed/NCBI
19	Hirsch FR, Varella-Garcia M, McCoy J, et al: Southwest Oncology Group: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 23:6838–6845. 2005. View Article : Google Scholar : PubMed/NCBI
20	Tokumo M, Toyooka S, Kiura K, et al: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 11:1167–1173. 2005.PubMed/NCBI
21	Kim KS, Jeong JY, Kim YC, et al: Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res. 11:2244–2251. 2005. View Article : Google Scholar : PubMed/NCBI
22	Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 23:6829–6837. 2005. View Article : Google Scholar : PubMed/NCBI
23	Riely GJ, Pao W, Pham D, et al: Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 12:839–844. 2006. View Article : Google Scholar : PubMed/NCBI
24	Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar
25	Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys. 47:13–47. 2000. View Article : Google Scholar : PubMed/NCBI
26	Cella D, Herbst RS, Lynch TJ, et al: Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial. J Clin Oncol. 23:2946–2954. 2005. View Article : Google Scholar : PubMed/NCBI
27	Yokouchi H, Yamazaki K, Kinoshita I, et al: Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer. BMC Cancer. 7:512007. View Article : Google Scholar : PubMed/NCBI
28	Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
29	Park K and Goto K: A review of the benefit-risk profile of gefitinib in Asian patients with advanced non-small-cell lung cancer. Curr Med Res Opin. 22:561–573. 2006. View Article : Google Scholar : PubMed/NCBI
30	Inoue A, Suzuki T, Fukuhara T, et al: Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 24:3340–3346. 2006. View Article : Google Scholar : PubMed/NCBI
31	Hotta K, Matsuo K, Ueoka H, et al: Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience. Ann Oncol. 16:1817–1823. 2005. View Article : Google Scholar : PubMed/NCBI
32	Yang JJ, Chen HJ, Yan HH, et al: Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer. 79:33–39. 2013. View Article : Google Scholar
33	Omuro AM, Kris MG, Miller VA, et al: High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 103:2344–2348. 2005. View Article : Google Scholar : PubMed/NCBI
34	Fukuhara T, Saijo Y, Sakakibara T, et al: Successful treatment of carcinomatous meningitis with gefitinib in a patient with lung adenocarcinoma harboring a mutated EGF receptor gene. Tohoku J Exp Med. 214:359–363. 2008. View Article : Google Scholar : PubMed/NCBI
35	Jackman DM, Holmes AJ, Lindeman N, et al: Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol. 24:4517–4520. 2006. View Article : Google Scholar : PubMed/NCBI
36	Ma S, Xu Y, Deng Q and Yu X: Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer. 65:198–203. 2009. View Article : Google Scholar
37	Ma S, Xu Y, et al: Prophylactic Cranial Irradiation (PCI) in Erlotinib/Gefitinib-Responders With Non-small Cell Lung Cancer (NSCLC) (RT1001). ClinicalTrialsgov Identifier: NCT01158170. 2010.