Int J Clin Oncol DOI 10.1007/s10147-015-0838-z

ORIGINAL ARTICLE

Gefitinib treatment in patients with postoperative recurrent non‑small‑cell lung cancer harboring epidermal growth factor receptor gene mutations Yuhei Yokoyama1 · Makoto Sonobe1 · Tetsu Yamada1 · Masaaki Sato1 · Toshi Menju1 · Akihiro Aoyama1 · Toshihiko Sato1 · Fengshi Chen1 · Mitsugu Omasa1 · Hiroshi Date1 

Received: 3 February 2015 / Accepted: 28 April 2015 © Japan Society of Clinical Oncology 2015

Abstract  Background The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib is an effective treatment for recurrent or advanced lung cancer harboring EGFR gene mutations, and has improved progression-free survival in several clinical trials. However, the effect of gefitinib treatment for recurrent lung cancers with EGFR gene mutations after complete resection and the influence of the timing of such treatment have not been fully elucidated in a practical setting. Methods  We investigated 64 patients (median age: 68 years; men: 22; women: 42; adenocarcinoma: 61; adenosquamous cell carcinoma: 2; combined large cell neuroendocrine carcinoma: 1) with recurrent lung cancer after complete resection who received gefitinib for the recurrent lesions and in whom the tumors had EGFR gene mutations. Progression-free survival, response rate, and safety were analyzed. Results  Complete response and partial response were achieved in 2 patients and in 42 patients, respectively (objective response rate: 69 %). Stable disease was obtained in 16 patients, the disease control rate was 94 %, and median progression-free survival was 16 months. The timing of gefitinib treatment (first line, second line, or later) and the type of EGFR gene mutation present did not influence progression-free survival. However, a smaller number of recurrent sites at the start of gefitinib treatment was linked to better progression-free survival. Hematologic

* Makoto Sonobe [email protected]‑u.ac.jp 1



Department of Thoracic Surgery, Kyoto University Hospital, Shogoin‑Kawahara‑cho 54, Sakyo‑ku, Kyoto 606‑8507, Japan

and nonhematologic toxicities were generally mild, but 1 patient experienced interstitial lung disease. Conclusions  Our results suggest that gefitinib treatment for recurrent lung cancer with gene EGFR mutations is a useful option in a practical setting, irrespective of the timing of such treatment and the type of EGFR gene mutation present. Keywords  Lung cancer · Epidermal growth factor receptor · Postoperative recurrence · Gefitinib

Introduction Lung cancer is one of the major causes of death in many countries, including Japan. The most common type of lung cancer is non-small-cell lung cancer (NSCLC), and surgery is the mainstay of treatment for patients with resectable NSCLC [1]. However, tumor recurrence remains a major cause of postoperative death [2]. Recent advances in chemotherapy, including molecularly targeted therapy, can facilitate the long-term survival of recurrent or advanced lung cancer patients [3]. Tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) have been successful treatment options [4]. Following the identification of specific mutations in the tyrosine kinase domain of the EGFR gene within exons 18, 19, and 21 in most NSCLC patients who responded to EGFR-TKI [5, 6], several phase III clinical trials of EGFR-TKIs for recurrent or advanced NSCLC with EGFR gene mutations were conducted; those trials showed that EGFR-TKI provides better progressionfree survival than conventional platinum-based chemotherapy [7–12]. It is worth noting, however, the patients enrolled on those clinical trials presented good performance status and

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adequate organ function, and patients assigned to the chemotherapy group were able to receive platinum-based chemotherapy [7–12]. In a practical setting, patients who receive EGFR-TKIs are not always in good condition. In addition, some of these patients have unresectable IIIB/IV disease or postoperative recurrent disease. and the effectiveness of EGFR-TKIs in patients with postoperative recurrence may differ from their effectiveness in patients with advanced NSCLC. Thus, the effectiveness of EGFR-TKIs in patients with postoperative recurrence in a clinical setting needs to be analyzed independently from their effectiveness in clinical trials. In the Japanese population, several studies focusing on this issue have been reported, but the number of patients in each was small or the follow-up period was short, so detailed analyses of types of EGFR gene mutations present or the timing of EGFR-TKI treatment were not fully performed [13–16]. From July 2004 on, we started to analyze EGFR gene mutations in patients with postoperative recurrence of NSCLC before administering gefitinib treatment [17]. In this study, we assessed the efficacy and safety of gefitinib treatment in patients with recurrent EGFR gene-mutated NSCLCs after complete resection.

Patients and methods Patients From January 2001 to December 2011, 1457 patients underwent complete resection for NSCLC in our hospital, excluding low-grade malignant tumors. Of these, 440 patients had developed tumor recurrence by December 2013. Sixty-four of those patients received gefitinib during the treatment of their recurrent tumor after confirming the presence of EGFR gene mutations in their primary NSCLC lesion after 2004, when the extreme response of EGFR-mutated lung carcinomas to EGFR-TKIs was reported. Those 64 patients were analyzed in this retrospective study. NSCLC histology was classified according to the World Health Organization classification [18]. Pathological staging was reclassified on the basis of the current edition of the International System for Staging Lung Cancer [19]. EGFR gene mutations in exons 18, 19, and 21 were analyzed using the single-strand conformation polymorphism method, as previously described [20]. The characteristics of the 64 patients are shown in Table 1. Written informed consent for EGFR gene mutation analyses and gefitinib treatment was obtained from each patient, and the study—including the EGFR gene mutation analyses—was approved by our institutional ethics committee.

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Int J Clin Oncol Table 1  Characteristics of the 64 patients with recurrent NSCLC who received gefitinib Variables

n (range or %)

Age (median) Sex  Men  Women ECOG PS at the start of gefitinib  PS-0  PS-1 Smoking status  Never smoked  Smoker Tumor histology  Adenocarcinoma  Adenosquamous cell carcinoma  Combined large cell neuroendocrine carcinoma Pathological stage at the time of resection  Stage I  Stage II  Stage III EGFR gene mutations  Exon 18 point mutation  Exon 19 in-frame deletion  Exon 21 point mutation Mode of recurrence  Locoregional only  Distant metastasis to 1 region without brain metastasis

68 years (37–85) 22 (34 %) 42 (66 %) 47 (73 %) 17 (27 %) 43 (67 %) 21 (33 %) 61 (95 %) 2 (3 %) 1 (2 %) 28 (44 %) 13 (20 %) 23 (36 %) 1 (2 %) 34 (53 %) 29 (45 %) 6 (11 %) 22 (34 %)

 Distant metastases to 2 or more regions without brain metastasis

21 (31 %)

 Distant metastases to brain and 1 or more regions Timing of gefitinib treatment  First-line

15 (23 %)

 Second-line or later-line

51 (80 %) 13 (20 %)

ECOG PS Eastern Cooperative Oncology Group Performance Status, EGFR epidermal growth factor receptor

Gefitinib treatment The gefitinib treatment depended on the patient’s general condition, the patient’s request, and the location of the recurrent tumor, and was decided upon after discussions by the thoracic oncology board of our hospital. Patients received 250 mg of gefitinib per day administered daily at first. However, the dose was reduced to 5 days per week, alternate days, or 3 days per week on the basis of toxicity. When a grade 1 skin rash, grade 1 diarrhea, or a grade 1 increase in alanine aminotransferase and/or aspartate aminotransferase was observed, we usually reduced the dose of gefitinib to 5 days per week. However, when the patient

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who developed such toxicity was aged or small in stature, the dose of gefitinib was reduced to alternate days or 3 days per week at the attending doctor’s discretion. Patients received blood examination and chest X-ray at least once every 2 weeks up to 8 weeks after the start of gefitinib treatment, and received whole-body computed tomography (CT) 2 months after the start of treatment. The patients then received medical checkups and chest X-rays every 2 months and whole-body CT every 4 months until cessation of gefitinib. If needed, the patients received brain CT or magnetic resonance imaging (MRI). When progressive disease (PD) was observed, gefitinib was stopped and other treatment modalities were introduced if possible. However, 2 patients continued to receive gefitinib in a manner of so-called “beyond PD” because of their condition. Evaluation Tumor response to gefitinib was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria for each CT evaluation during gefitinib treatment. In cases of lung metastases in the form of multiple small nodules and bone metastases to which the RECIST criteria could not be applied, tentative evaluation criteria were employed: complete response (CR) meant that no lesions were detected in the imaging study; stable disease (SD) meant that the target lesions were detected and were similar or smaller in size or number than they were before the gefitinib treatment; and PD meant that the target lesions were larger in size or that new lesion(s) had developed. The maximum response obtained for each patient by the cessation of gefitinib was designated the response of the patient. Response rate was the sum of CR and partial response (PR), and disease control rate was the sum of CR, PR, and SD. Progression-free survival (PFS) of gefitinib treatment was defined as the time between the day of gefitinib treatment initiation and the day when PD (according to RECIST) was observed. Evaluations of tumor response to gefitinib and the survival data of patients were fixed in January 2015. Toxicity was evaluated in accordance with the National Cancer Institute Common Terminology Criteria, version 4.0 (CTC-AE). Statistical analysis The collected data included age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), tumor histology, type of EGFR gene mutation, timing of gefitinib introduction (first line, second line, or later), and follow-up information until death or December 2014. The impacts of EGFR gene mutation type and timing of gefitinib introduction on PFS were evaluated. Categorical data were examined using the chi square test or Fisher’s exact test. PFS curves were calculated using the

Kaplan–Meier method and compared using the log-rank test. JMP software, version 9.03 (SAS Institute, Cary, NC, USA), was used to carry out all statistical calculations. All statistical tests were two-sided, and differences were considered to be statistically significant if the P value was less than 0.05.

Results Patients Most of the patients enrolled in the study had adenocarcinoma. Two patients with adenosquamous cell carcinoma had never been smokers. One patient with combined large cell neuroendocrine carcinoma, which consisted of large cell neuroendocrine carcinoma and adenocarcinoma at the resection, underwent a biopsy of the recurrent tumor lesion, and that recurrent lesion was proven to be an adenocarcinoma. Regarding EGFR gene mutations, an exon 18 point mutation within codon 720 (Ser720Phe) was detected in 1 patient, exon 19 in-frame deletion mutations around codons 747–749 were detected in 34 patients, and exon 21 point mutations within codon 858 (Leu858Arg) were detected in 29 patients. Of the 47 patients with ECOG PS-0, 36 patients received gefitinib as the first-line treatment and 11 patients received it as the second-line treatment. Of the 17 patients with ECOG PS-1, 15 patients received gefitinib as the first-line, 1 as the second-line, and 1 as the third-line treatment. ECOG PS did not influence the timing of gefitinib treatment (P = 0.485, Fisher’s exact test). Response to gefitinib The antitumor effects of gefitinib treatment are shown in Table 2. The responses of three patients could not be evaluated because they discontinued gefitinib treatment before the first evaluation at 2 months after the start of gefitinib treatment. Two CRs, 42 PRs, and 16 SDs were observed in the 64 patients. The objective response rate was 69 % and the disease control rate was 94 %. Table 2  Patient response to gefitinib treatment Variables

n (%)

Complete response Partial response Stable disease Progressive disease Unmeasurable Objective response rate

2 (2 %) 42 (66 %) 16 (25 %) 1 (2 %) 3 (5 %) 44 (69 %)

Disease control rate

60 (94 %)

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Survival The median PFS time for all patients was 16.1 months (Fig. 1a). The median PFS was 16.7 months in patients with EGFR gene mutations within exon 19 and 12.9 months in those with mutations within EGFR exon 21 (Fig. 1b). There was therefore no difference in median PFS according to the type of EGFR gene mutation present (P = 0.667, log-rank test). The median PFS was 14.7 months in patients who received gefitinib as the first-line treatment and 22.6 months in those who received it as second-line or later-line treatment (Fig. 1c). There was therefore no difference in median PFS according to the timing of gefitinib introduction (P  = 0.358, log-rank test). The median PFS was 30.2 months in patients whose recurrence developed in a single region (locoregional only or distant metastasis to one region without brain metastasis) and 11.5 months in those whose recurrence developed in multiple regions (distant metastases to two or more regions without brain metastasis or distant metastases to brain and one or more region) (Fig.  1d), which corresponded to a significant difference between these sets of patients (P  = 0.006, log-rank test). The median PFS was 16.1 months in patients whose pathological stage of NSCLC at the time of resection had been stage 1, 15.2 months in those whose pathological stage of NSCLC at the time of resection had been stage 2, and 21.9 months in those whose pathological stage of NSCLC at the time of resection had been stage 3. There was no difference in median PFS among the pathological stages of NSCLC at the time of resection (P  = 0.991, log-rank test). The median overall survival time (OS) of all patients after the introduction of gefitinib was 37.1 months, and the 5-year OS was 24 % (Fig. 1e). Treatment after PD Until January 2015, PD (according to RECIST) was observed in 52 patients, consisting of 42 receiving gefitinib as first-line treatment and 10 receiving it as secondline or later-line treatment. Among the 42 patients who received gefitinib as first-line treatment and developed PD, 15 patients (36 %) received best supportive care, 2 (5 %) continued gefitinib (“beyond PD”), 7 (17 %) began erlotinib treatment, 15 (36 %) received cytotoxic chemotherapy, including a platinum doublet regimen (6) and a singleagent regimen (9), and 3 (7 %) received radiation therapy. Among the 7 patients who received erlotinib and the 15 patients who received cytotoxic chemotherapy as secondline treatment, 10 of those patients received third-line or later-line chemotherapy with cytotoxic drug(s). Among the 10 patients who received gefitinib as second-line or later-line treatment and developed PD, 5 patients (50 %) received best supportive care, 1 (10 %) began erlotinib

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treatment, and 4 (40 %) received cytotoxic chemotherapy, including a platinum doublet regimen (1) and a singleagent regimen (3). Toxicity The most common adverse effects of gefitinib treatment are listed in Table 3. Observed grade 3 or higher nonhematologic adverse effects (according to the CTC-AE) were interstitial lung disease (n  = 1, grade 3), gastrointestinal bleeding (n  = 1, grade 3), and severe acneiform rash (n  = 1, grade 3). The patient who experienced interstitial lung disease partially recovered but died from respiratory failure 4 months after discontinuing gefitinib. The other two patients recovered from adverse effects after discontinuing gefitinib. Liver function abnormalities were demonstrated by elevations of aspartate aminotransferase or alanine aminotransferase levels, but these events were clinically asymptomatic.

Discussion In this retrospective study of gefitinib treatment in patients with recurrent NSCLC harboring EGFR gene mutations after complete resection, the response rate of gefitinib was 69 %, the disease control rate was 94 %, the median PFS was 16.1 months, and the toxicities experienced were acceptable. These results suggest that gefitinib treatment is a useful option for the treatment of postoperative recurrent NSCLC with EGFR gene mutations in a practical setting. In clinical trials of gefitinib treatment for recurrent or advanced NSCLC with EGFR gene mutations, the response rates and disease-control rates were 71.2 and 91.7 % in the IPASS study [7, 10], 73.7 and 89.5 % in the NEJ002 study [8], and 62.1 and 93.1 % in the WJTOG3405 study [9]. Although the gefitinib dose was often reduced because of the practical setting in our study, the response rate and disease-control rate were similar to those seen in the clinical trials. Satoh et al. [21] reported that the efficacy of lowdose gefitinib was not inferior to that of standard-dose gefitinib, suggesting that an antitumor effect can be obtained with tolerable doses of gefitinib. The median PFS of 16.1 months observed in this study was longer than those reported for the IPASS (9.5 months) [7, 10], NEJ 002 (10.8 months) [8], and WJTOG3405 (9.2 months) [9] studies. Our study only included patients with recurrent NSCLC after resection. Therefore, the tumor burden of a patient at the start of gefitinib treatment was probably smaller than that of patients with recurrent or stage III/IV NSCLCs in the clinical trials. A small tumor burden could decrease the chance of tumor cells developing gefitinib tolerance, and it may be responsible for the

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Fig.  1  a Kaplan–Meier curve showing the progression-free survival (PFS) after the start of gefitinib treatment in all 64 patients. Median PFS time was 16.1 months. Pts. at risk indicates the number of patients at risk. b Kaplan–Meier curve showing the PFS after the start of gefitinib treatment according to the type of epidermal growth factor receptor (EGFR) gene mutation. There was no difference in PFS between patients with EGFR exon 19-mutated tumors and patients with EGFR exon 21-mutated tumors (P  = 0.667, log-rank test). Asterisk indicates the number of patients at risk in each group. c Kaplan–Meier curve showing the PFS after the start of gefitinib treatment according to the timing of gefitinib treatment. There was no difference in PFS between the patients who received first-line gefitinib

treatment and the patients who received second-line or later-line gefitinib treatment (P = 0.358, log-rank test). Asterisk indicates the number of patients at risk in each group. d Kaplan–Meier curve showing the PFS after the start of gefitinib treatment according to the mode of recurrence. There was a significant difference between the PFS of patients with a single recurrent region and that of patients with multiple recurrent regions (P = 0.006, log-rank test). Asterisk indicates the number of patients at risk in each group. e Kaplan–Meier curve showing the overall survival after the start of gefitinib for all 64 patients. Median survival time was 37.1 months. Pts. at risk indicates the number of patients at risk

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Table 3  Toxicities associated with gefitinib treatment Toxicity

Grade 1 Grade 2 Grade 3 Grade 4 Grade 3/4 (%)

Skin rash Dry skin Pruritus Paronychia Diarrhea Constipation Nausea Stomatitis Impaired hearing

36 21 2 2 22 2 4 9 2

3 1 0 1 0 0 0 0 0

1 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

1 (2 %) 0 0 0 0 0 0 0 0

Interstitial lung disease

0

0

1

0

1 (2 %)

Gastrointestinal bleeding

0

0

1

0

1 (2 %)

AST elevation ALT elevation Total bilirubin elevation

27 25 1

5 12 0

1 1 0

0 0 0

1 (2 %) 1 (2 %) 0

6

1

0

0

0

Anemia

AST aspartate aminotransferase, ALT alanine aminotransferase

long-term antitumor effect of gefitinib. Indeed, in our study, a longer PFS was found for the group where the mode of recurrence was locoregional or restricted to a single region, in which the tumor burden was thought to be small. In addition, in the WJTOG3405 study, the median PFS in patients with postoperative recurrence was 13.7 months, longer than that in patients with stage IIIB/IV disease (8.4 months) [9], thus supporting our speculation. Another explanation for the tendency for a longer PSF in patients with postoperative recurrence is that recurrent NSCLC is evaluated as being surgically resectable and potentially possessing less malignant potential than unresectable IIIB/ IV NSCLC, so gefitinib could be more effective over the long term. The analysis of EGFR gene mutations was performed using the surgically resected specimen, and patients whose tumors did not harbor EGFR gene mutations and who hardly responded to gefitinib were reliably excluded from our study, partially explaining the good PFS seen in our analysis. In our study, patients with only locoregional recurrence or with distant metastasis to a single region (so-called oligo-recurrence [22, 23]) presented better PFS with gefitinib than patients with multiple metastases did. The concept of oligo-recurrence mainly arose from the observation that surgical resection or radiation therapy with curative intent for recurrent regions that are limited in both number and involved organs, and where there is no local recurrence at the primary site, can facilitate long-term survival [22,

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23]. Our data indicate that highly effective systemic chemotherapeutic agents such as gefitinib (and other EGFR-TKIs) for NSCLC with EGFR gene mutations may be counted among the armamentarium for oligo-recurrence. However, further investigations are needed to evaluate the effect of EGFR-TKIs in cases of oligo-recurrence. There was no difference in PFS between patients with tumors harboring in-frame deletions within exon 19 and those harboring point mutations within exon 21 in our study. In the NEJ 002 study [8] and in the WJTOG3405 study, there was no significant difference in PFS with respect to patients with tumors harboring exon 19 and 21 mutations who underwent gefitinib treatment. LocatelliSanchez et al. reported similar results in a practical setting for patients who received gefitinib or erlotinib treatment [24]. However, Yamada et al. showed that the PFS of patients with tumors harboring exon 21 mutations (11 months) appeared to be longer than that of patients harboring exon 19 mutations (8 months) upon receiving erlotinib treatment [25]. In a recent clinical trial of afatinib for lung adenocarcinoma with EGFR gene mutations (LUX Lung 3), afatinib seemed to facilitate a longer PFS in patients with tumors showing exon 19 mutations than in patients with exon 21 mutations [26]. Therefore, the selection of EGFR-TKIs based on the type of EGFR gene mutation present may be necessary in the future. The timing of gefitinib treatment (first-line, second-line, or later) did not influence the median PFS in our study. Locatelli-Sanchez et al. reported that there was no difference in PFS between patients who underwent first-line or second-line gefitinib treatment in a practical setting [24]. Rosell et al. suggested that erlotinib might be similarly effective in cases of EGFR-mutated NSCLC, regardless of the timing [27]. In the follow-up report of the NEJ 002 study [26], the OS of the gefitinib group was similar to that of the chemotherapy (carboplatin and paclitaxel) group, although the PFS of the gefitinib group was longer than that of the chemotherapy group. A similar result was observed in the WJTOG3405 study [9]. These results could imply that the second-line use of gefitinib in the chemotherapy group was as effective as first-line use, thus compensating for the shorter PFS afforded by chemotherapy. Regardless of the timing, gefitinib (or other EGFR-TKIs) should be incorporated into the treatment strategy for EGFR-mutated NSCLC. In our study, 1 of 64 patients (1.6 %) developed grade 3 interstitial lung disease. This incidence was lower than that observed when gefitinib treatment was used without selection on the basis of EGFR gene mutations (3.2–4.0 %) at that time in Japan [29–31]. Because patients with tumors harboring EGFR gene mutations tend to be women and exsmokers or those who have never smoked [17], and they have a small risk of developing interstitial lung disease

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with gefitinib [29, 30], we believe that selecting patients for gefitinib treatment in accordance with EGFR gene mutation status could mitigate the risk of developing interstitial lung disease. However, the reported incidences of interstitial lung disease in the NEJ002 study (5.3 %) and in the WJTOG3405 study (2.3 %) are still high [8, 9]. Therefore, close observation during gefitinib treatment is needed, as emphasized in the Japanese literature [8, 9, 29–31]. The incidence of grade 3 or higher elevations of aspartate aminotransferase and/or alanine aminotransferase was smaller in our study (2 %) than in the NEJ002 study (26 %) and in the WJTOG 3405 study (28 %) [8, 9]. Practitioners tended to reduce the dose of gefitinib in grade 1 or 2 elevation of liver enzymes. Our study has several limitations. Because it was a retrospective study, a follow-up imaging study was not necessarily performed and the PFS may have been overestimated, and adverse effects may have been incompletely recorded so they may have been underestimated. However, our data should aid further discussion on gefitinib treatment in a practical setting. In our study, gefitinib treatment was effective and safe for patients with postoperative recurrence and with tumors harboring EGFR gene mutations. Because the effectiveness of first-line gefitinib treatment was similar to that of second-line use, gefitinib treatment should be included among the treatment modalities for NSCLC with EGFR gene mutations. Acknowledgments  This study was not supported by any fund, trader, or manufacturer. Conflict of interest  The authors declare that they have no conflict of interest.

References 1. Masuda M, Kuwano H, Okumura M et al; Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery (2014) Thoracic and cardiovascular surgery in Japan during 2012: annual report by The Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg 62:734–764 2. Sonobe M, Yamada T, Sato M et al (2014) Identification of subsets of patients with favorable prognosis after recurrence in completely resected non-small cell lung cancer. Ann Surg Oncol 21:2546–2554 3. Non-Small Cell Lung Cancer Collaborative Group (2010) Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 5:CD007309. doi:10.1002/14651858.CD007309.pub2 4. Lee CK, Brown C, Gralla RJ et al (2013) Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 105:595–605 5. Lynch TJ, Bell DW, Sordella R et al (2004) 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

6. Paez JG, Jänne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500 7. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957 8. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388 9. Mitsudomi T, Morita S, Yatabe Y et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128 10. Fukuoka M, Wu YL, Thongprasert S et al (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29:2866–2874 11. Zhou C, Wu YL, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742 12. Rosell R, Carcereny E, Gervais R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246 13. Furukawa K, Ishida J, Inagaki M et al (2012) A population-based study of gefitinib in patients with postoperative recurrent nonsmall cell lung cancer. Exp Ther Med 3:53–59 14. Mitsudomi T, Kosaka T, Endoh H et al (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patient with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513–2520 15. Okami J, Taniguchi K, Higashiyama M et al (2007) Prognostic factors for gefitinib-treated postoperative recurrence in nonsmall cell lung cancer. Oncology 72:234–242 16. Katayama T, Matsuo K, Kosaka T et al (2010) Effect of gefitinib on the survival of patients with recurrence of lung adenocarcinoma after surgery: a retrospective case-matching cohort study. Surg Oncol 19:e144–e149 17. Sonobe M, Kobayashi M, Ishikawa M et al (2012) Impact of KRAS and EGFR gene mutations on recurrence and survival in patients with surgically resected lung adenocarcinomas. Ann Surg Oncol 19(Suppl 3):S347–S354 18. Travis WD, Brambilla E, Muller-Hermelink HK et al (2004) World Health Organization classification of tumours: pathology and genetics of tumours of the lung, pleura, thymus and heart. IARC, Lyon 19. Vallières E, Shepherd FA, Crowley J et al (2009) International Association for the Study of Lung Cancer International Staging Committee and participating institutions. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 4:1049–1059 20. Sonobe M, Manabe T, Wada H et al (2005) Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 93:355–363 21. Satoh H, Inoue A, Kobayashi K et al (2011) Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations. J Thorac Oncol 6:1413–1417

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22. Hellman S, Weichselbaum RR (1995) Oligometastases. J Clin Oncol 13:8–10 23. Niibe Y, Hayakawa K (2010) Oligometastases and oligo recurrence: the new era of cancer therapy. Jpn J Clin Oncol 40:107–111 24. Locatelli-Sanchez M, Couraud S, Arpin D et al (2013) Routine EGFR molecular analysis in non-small-cell lung cancer patients is feasible: exons 18–21 sequencing results of 753 patients and subsequent clinical outcomes. Lung 191:491–499 25. Yamada K, Takayama K, Kawakami S et al (2013) Phase II trial of erlotinib for Japanese patients with previously treated non-small-cell lung cancer harboring EGFR mutations: results of Lung Oncology Group in Kyushu (LOGiK0803). Jpn J Clin Oncol 43:629–635 26. Sequist LV, Yang JC, Yamamoto N et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334 27. Rosell R, Moran T, Queralt C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967

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Int J Clin Oncol 28. Inoue A, Kobayashi K, Maemondo M et al (2013) Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 24:54–59 29. Ando M, Okamoto I, Yamamoto N et al (2006) Predicitive factors for interstitial lung disease, anti-tumor response and survival in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol 24:2549–2556 30. Kudoh S, Kato H, Nishiwaki Y et al (2008) Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008(177):1348–1357 31. Nakagawa M, Nishimura T, Teramukai S et al (2009) Interstitial lung disease in gefitinib-treated Japanese patients with non-small cell lung cancer—a retrospective analysis: JMTO LC03-02. BMC Res Notes 2:157. doi:10.1186/1756-0500-2-157

Gefitinib treatment in patients with postoperative recurrent non-small-cell lung cancer harboring epidermal growth factor receptor gene mutations.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib is an effective treatment for recurrent or advanced lung cancer harbor...
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