Prognostic impact of postoperative recurrence in patients with epidermal growth factor receptor-positive non-small cell lung cancer.

Prognostic impact of postoperative recurrence in patients with epidermal growth factor receptor-positive non-small cell lung cancer. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic impact of postoperative recurrence in patients with epidermal growth factor receptor-positive non-small cell lung cancer. Meiko Morita, Akira Ono, Motoki Sekikawa, Kosei Doshita, Keita Miura, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3439432/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : There are no reports conducted with a long follow-up period on a large number of EGFR+ non small cell lung carcinoma (NSCLC) patients withpostoperative recurrence (PR). Methods : We conducted a retrospective review of the data of EGFR+ NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. The post-recurrence overall survival (PRS) and postoperative overall survival (POS) were estimated using the Kaplan-Meier method. Multivariate analysis using a Cox proportional hazards model was performed to identify any associations between the clinical variables at recurrence and the PRS. Logistic regression analysis was performed to evaluate the associations between the variables at the baseline and the prognostic factors at recurrence. Results : The median observation time was 4.95 (range, 0.82-13.25) years. The median PRS was 5.17 years (95% CI, 3.90-5.61) and the POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male gender (MST: 3.32 vs. 5.39 years; p<0.05), presence of bone metastasis (MST: 2.43 vs. 5.33 years; p<0.05), and presence of central nervous system (CNS) metastasis (MST: 3.05 vs. 5.39 years; p<0.05), and multivariate analysis identified the presence of bone metastasis (HR, 2.01; 95% CI, 1.23-3.28; p<0.05) and presence of CNS metastasis (HR. 1.84; 95% CI, 1.14-2.98; p<0.05) as poor prognostic factors. The pattern of recurrence was not prognostic factor. Logistic regression analysis revealed male was associated with the presence bone/CNS metastasis at recurrence. Conclusion: New treatment strategies require to be developed for patients with bone/CNS metastasis at first recurrence. EGFR non-small-cell lung cancer postoperative recurrence prognostic factors oligometastasis Figures Figure 1 Figure 2 Introduction The efficacy of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) for EGFR + NSCLC is now well established ( 1 ). Based on the finding in the FLAURA trial of a significantly prolonged progression-free survival (PFS) and overall survival (OS) in the osimertinib arm as compared with the standard treatment arm (median PFS: 18.9 months [95% confidence interval (CI), 15.2–21.4] vs. 10.2 months [95% CI, 9.6–11.1]; Hazard Ratio (HR), 0. 46; p < 0.001; median OS: 38.6 months [95% CI, 34.5–41.8] vs. 31.8 months [95% CI, 26.6–36.0]; HR 0.80; p = 0.046) ( 2 – 3 ), osimertinib is now considered as the standard treatment agent for advanced EGFR-positive NSCLC patients. In the ADAURA trial, postoperative adjuvant osimertinib therapy improved the disease-free survival (DFS) and OS in patients with EGFR-positive NSCLC. The 5-year survival in the osimertinib/placebo arm was 88% (95% CI, 83–91)/78% (95% CI, 73–82) (HR 0.49, p < 0. 0001) in the osimertinib/placebo group for patients with stage IB-IIIA disease, and 85% (95% CI, 79–89)/73% (95% CI, 66–78) (HR 0.49, p = 0.0001.) for patients with stage II-IIIA disease ( 4 – 5 ). Therefore, adjuvant osimertinib is now offered as an option after complete resection for patients with EGFR-positive NSCLC, although in actual clinical practice, patients often refuse the drug due to concerns about toxicity and treatment duration, or do not wish to resume the drug after withdrawal due to toxicity in the adjuvant setting. Ko et al. compared the prognosis following treatment with gefitinib between EGFR-positive NSCLC patients with stage IV disease (119 patients) and EGFR-positive NSCLC patients with PR (49 patients), and reported that the prognosis was better in the patients with PR (MST: 22.2 vs. 51.1 months [HR 0.39, 95% CI 0.22–0.66; p < 0.001] [median observation time, 24.6 months]). In addition to postoperative recurrence, performance status and distant metastasis have also been reported as prognostic factors ( 6 ); this study was limited by the insufficient number of patients and short observation time. Although several reports have suggested male gender and presence of brain metastasis as poor prognostic factors in NSCLC patients with PR ( 7 – 8 ), there are no reports of prognostic factors identified in EGFR + NSCLC patients with PR. It has also been reported that in NSCLC patients with PR with oligo recurrence have a better post-recurrence survival (PRS) than those with non oligo recurrence (5-year PRS: 32.9 vs. 9.9%, p < 0.001) ( 9 ). We hypothesized that the presence or absence of central nervous system (CNS) metastasis and the pattern of recurrence (oligo vs. non oligo recurrence) might be associated with the survival in EGFR + NSCLC patients with PR Therefore, in this study, we investigated the impact of variables on the prognosis in EGFR NSCLC patients with PR by long-term follow-up of the OS of the patients. Materials and methods Patients Of the 631 patients who underwent complete R0 or R1(cy+) resection and developed recurrence at our institution between October 2002 and November 2017, 442 had wild type EGFR, 168 had EGFR mutations, and 21 could not be traced. Of the 168 with EGFR mutations, 162 with common mutations were included in this analysis. The median observation time from surgery was 4.95 (range, 0.82–13.25) years. The histological and cytological diagnoses were performed according to the WHO classification criteria ( 10 ). All patients were staged based on the International Association for the Study of Lung Cancer (IASLC) TNM (tumor-node-metastasis) classification, 7th edition ( 11 ). This study was conducted with the approval of the Institutional Review Board of the Shizuoka Cancer Center (IRB registration number; J2022-133), and the opt-out method was adopted for obtaining informed consent from the patients. Postoperative follow-up and diagnosis of recurrence. Follow-up examinations included physical examination, hematological examination and chest radiography. Chest and abdominal computed tomography (CT) were performed every 6 months during the first 3 years, and CT and chest radiography were performed alternately every 6 months thereafter. When disease recurrence was suspected, brain magnetic resonance imaging (MRI), bone scintigraphy, and fluorodeoxyglucose–positron emission tomography (FDG-PET) were performed in addition. Recurrent NSCLC was diagnosed based on the results of physical examination and of the findings of diagnostic imaging of lesions consistent with recurrent disease. Differentiating between a second primary lung cancer and intrapulmonary metastasis was, in general, performed according to the definitions proposed by Martini and Melamed ( 12 ). Finally, we determined if a patient had recurrence or not by consensus at a multidisciplinary conference. Histological confirmation of the diagnosis was obtained where clinically feasible. The date of recurrence was defined as the date of radiological or histological confirmation, or in cases diagnosed based on clinical evidence, the date of recognition of recurrent disease at the multidisciplinary conference. Oligo recurrence was defined as distant metastasis limited to 1–3 sites ( 13 ). In this study, only the first recurrence after surgery was evaluated. Mediastinal lymph nodes were considered as one site, regardless of the number of lymph nodes affected. In the R classification, R0 was defined as no residual tumor and R1 as microscopic residual tumor. If the pleural fluid was positive, it was designated R1(cy+). In this study, complete resection was defined as R0 resection or R1(cy+) resection. Characterization of the EGFR mutations was outsourced to a commercial clinical laboratory. Statistical analyses PRS was defined as the time from the date of the first confirmed recurrence to death or last confirmed survival. Postoperative overall survival (POS) was defined as the time from the date of surgery to death from any cause or last confirmed survival. In the ADAURA trial, the allowed interval between surgery and randomization was 10 weeks in patient who did not receive adjuvant chemotherapy, and 26 weeks in those who received adjuvant chemotherapy. The probability of survival was estimated using the Kaplan–Meier method. Prognostic factors among the covariates at recurrence were identified using Cox proportional hazards analysis. The prognostic significances of all the variables were measured by calculating the adjusted hazard ratio (HR) with 95% confidence interval (95% CI). Logistic regression analysis was performed to identify significant background characteristics of the patients associated with bone or CNS metastases at recurrence. P values less than 0.05 were considered as denoting statistical significance. All analyses were carried out using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) ( 14 ). Results Patient characteristics A flow-diagram of patient enrollment for this analysis is shown in Fig. 1 . The baseline characteristics of the patients are summarized in Table 1 . The median age at recurrence was 70 (range, 37–88) years, and the median time from sample collection to EGFR gene testing was 370 (range, 0-2899) days. The majority of patients were female (62.3%) and non-smokers (58%). The predominant histopathological type of NSCLC was adenocarcinoma (95%). Lobectomy was the most commonly used resection procedure (90.1%). Of the 6 patients in whom wedge resection was performed, the reason was technical difficulties caused by severe adhesions in 1 patient, and presence of double cancers in the remaining 5 patients. The pathological stage was stage I in 37.7%, stage II in 25.9%, and stage III in 36.4% patients. None of the patients had received neoadjuvant chemotherapy, and 82 patients (50%) had received postoperative adjuvant chemotherapy. Eight patients had received investigational drugs as adjuvant chemotherapy, excluding the ADAURA cases. The residual lesions followed R0 resection in 132 patients and R1 resection in 30 patients. All R1 patients were evaluated as R1(cy+). Table 1 Patient Characteristics(N = 162) N (%) Median age at recurrence, years (range) 70 (37–88) Median time to EGFR gene testing, days (range) 370 (0-2899) Median observation time, years (range) 4.95 (0.82–13.25) Gender Male 61 (37.7) Female 101 (62.3) Smoking status Never smoker 94 (58.0) Current or former smoker 68 (42.0) Lung cancer resection type Lobectomy 146 (90.1) Segmentectomy 6 (3.7) Pneumonectomy 4 (2.5) Wedge resection 6 (3.7) Histology Adenocarcinoma 154 (95.0) Adenosquamous carcinoma 5 (3.1) Combined LCNEC 1 (0.63) Large cell carcinoma 1 (0.63) Pleomorphic carcinoma 1 (0.63) EGFR genotype Exon 19 deletion / L858R point mutation 79 (48.8) /83 (51.2) Residual lesion R0 /R0(un) /R1(cy+) 99 (61.1) / 33 (20.4) / 30 (18.5) Pathological stage I /II /III 61 (37.7) / 42 (25.9) / 59 (36.4) Neoadjuvant chemotherapy Yes /No 0 (0) /162 (100) Adjuvant chemotherapy Yes /No 82 (50.6) /80 (49.4) UFT 22 CDDP regimen 49 CBDCA regimen 3 Investigational drugs 8 Table 2 First recurrence sites and pattern of recurrence CNS: central nervous system N (%) Diagnostics of recurrence Clinical assessment 0 (0) Histological assessment 27 (16.7) Imaging assessment 135 (83.3) First recurrence sites Bone metastasis 33 (20.4) Vertebra 16 Others 17 Involving other metastatic sites 21 CNS 35 (21.6) Single brain metastasis 15 Multiple brain metastasis 17 Meningitis 3 Involving other metastatic sites 16 Pattern of recurrence Oligo recurrence 67 (41.4) Non oligo recurrence 95 (58.6) CNS: central nervous system Pattern of first recurrence and initial treatment The diagnosis of recurrence was confirmed by histology in 27 patients and by radiologic imaging in 135 patients, with no reliance on the clinical diagnosis alone in any patients. Oligo recurrence occurred in 67 patients (41.4%) and non oligo recurrence in 95 patients (58.6%). Bone metastasis was observed as the first recurrence in 33 patients (spine, 16; other bone sites, 17), associated with metastasis at other sites in 21 of these patients, and CNS metastasis was observed in 39 patients (single site, 15; multiple sites, 21; meningitis, 3), associated with metastasis at other sides in 21 of these patients (Table.2). EGFR-TKIs were used (any treatment line) post recurrence in 155 patients (95.7%), in 61 of 67 patients with oligo recurrence, and in 94 of 95 patients with non oligo recurrence. TKIs were used as first-line therapy in 122 patients (75.3%), as second-line therapy in 23 patients (14.2%), as third-line therapy in 6 patients (3.7%), as fourth-line therapy in 1 patient (0.6%), and as fifth-line therapy in 2 patients (1.2%). The TKI used was gefitinib in 106 patients, erlotinib in 56 patients, osimertinib in 48 patients, and afatinib in 3 patients. Osimertinib was used as first-line therapy in 23 patients, as second-line therapy in 9 patients, and as third- or subsequent-line therapy in 16 patients. Survival/regression analysis Survival analysis was performed on the 162 NSCLC patients with common EGFR mutations. The median PRS was 5.17 years (95% CI, 3.90–5.61) (Fig. 2 A). The median POS was 7.07 years (95% CI, 5.88–8.01) (Fig. 2 B), and the 5-year survival rate post surgery was 67.7% (95% CI, 59.8–74.4). The MST adjusted according to the ADAURA trial for the starting point was 6.70 years (95% CI, 5.43–7.66) and the 5-year survival rate was 61.6% (95% CI, 53.4–68.7). The median observation time was 4.95 years (range 0.82–13.25). The clinical variables identified by univariate analysis as being associated with significantly unfavorable survival were the presence of bone metastasis (MST: 5.33 vs. 2.43 years; p < 0.05), presence of CNS metastasis (MST: 5.39 vs. 3.05 years; p < 0.05), and male gender (MST: 5.39 vs. 3.32 years; p < 0.05). Multivariate analysis identified presence of bone metastasis (HR 2.01, 95% CI 1.23–3.28; p < 0.05) and presence of CNS metastasis (HR 1.84, 95% CI 1.14–2.99; p < 0.05) as being independent unfavorable prognostic factors. No significant association was found with the pattern of recurrence (HR, 1.01; 95% CI, 0.67–1.54; p = 0.95) (Table 3 ). With regard to the factors associated with the presence of bone metastasis and CNS metastasis in this study population, there was a significant association between the presence of bone metastasis and male gender (OR, 0.14; 95% CI, 0.04–0.46; p < 0.05), and a trend toward an association between the presence of CNS metastasis and male gender (OR, 0.35; 95% CI, 0.12–1.05; p = 0.062). Table 3 Variables associated with overall survival among 162 patients Co-variable No. Univariate analysis Multivariate analysis MST (years) P Variate HR 95% CI P Median age at recurrence < 75 117 5.39 75≦ 45 4.53 0.10 Gender Male 61 3.32 Male 0.89 0.51–1.58 0.70 Female 101 5.39 < 0.05 Smoking status Yes 68 3.69 Yes 1.44 0.82–2.52 0.20 No 94 5.39 0.09 EGFR mutation Ex19 deletion 79 5.30 L858R 83 3.90 0.30 L858R 1.07 0.71–1.61 0.76 Pattern of recurrence Oligo 67 5.24 Oligo 1.01 0.67–1.54 0.95 Non oligo 95 5.17 0.91 Bone metastasis Yes 33 2.43 Yes 2.01 1.23–3.28 < 0.05 No 129 5.33 < 0.05 CNS metastasis Yes 35 3.05 Yes 1.84 1.14–2.98 < 0.05 No 127 5.39 < 0.05 Discussion An important finding of this study was that the presence of bone and/or CNS metastases at recurrence was predictive of a poor prognosis in EGFR + NSCLC patient with PR Furthermore, the pattern of recurrence was not identified as exerting any significant influence on the prognosis. In NSCLC patients with PR the presence or absence of EGFR mutation, number and sites of recurrence (intra/extra thoracic), and presence/absence of CNS metastasis have been well-established as prognostic factors ( 15 – 16 ), although there are conflicting opinions regarding the influence of bone metastases at recurrence on the prognosis ( 7 – 8 ). While the presence of bone metastasis at recurrence is reported as a poor prognostic factor in terms of both the PFS and OS in patients with advanced EGFR-positive NSCLC ( 17 ), there are no reports until date on the prognostic impact of bone metastasis in EGFR + NSCLC patients with PR. According to a previous report, the reason for the poor prognosis associated with bone metastasis in patients with advanced EGFR-positive NSCLC is the presence, at a high frequency (72.7, of multiple (3 or more) distant metastases in these patients ( 17 ). In the present study, among the 33 patients with PR, including those with bone metastasis, 12 (36.4%) had bone metastases only and 21 (63.6%) had other distant metastases in addition, showing a tendency for the presence of other distant metastases at a high frequency in patients with bone metastasis; this was consistent with the aforementioned report ( 17 ), although the number of coexistent metastases differed between the two studies. The number of patients who survived for more than 10 years after the diagnosis of recurrence was 20 (12.3%), including 8 patients with pathological stage I disease, 4 with pathological stage II disease, and 8 with pathological stage III disease. Only one of these patients had bone metastasis, two had CNS metastasis (in one site of the CNS in 1 patient, and in 2 sites in the other patient), and about a half of these patients (11 patients) had oligo recurrence. Numerous studies have reported the relatively high risk of bone and CNS metastases in NSCLC patients with PR ( 18 – 19 ). According to one previous report, women are less likely to develop bone metastasis ( 18 ). Also, associations of the preoperative carcinoembryonic antigen levels (> 5 ng/mL) and positive pathologic lymph nodes with the development of bone metastasis, and of poorly differentiated tumor and positive pathologic lymph nodes with the development of CNS metastasis have been reported ( 20 ). Bone metastasis and male gender are thought to be associated regardless of the presence/absence of EGFR gene mutations, but further investigation of the tumor markers and pathological findings and the risk of bone and CNS metastases in postoperative EGFR-positive NSCLC patients is needed. In the ADAURA trial, a subgroup analysis showed a trend toward worse OS in male patients as compared with female patients (HR 0.62 [95% CI, 0.33–1.13] for male patients and HR 0.41 [95% CI, 0.25–0.66] for female patients) ( 5 ). In this study also, male gender was associated with the presence of bone and CNS metastases, and new treatment strategies are needed for patients with bone and CNS metastases at first recurrence. Among the NSCLC patients with PR the PRS was higher in the oligo recurrence group than in the non oligo recurrence group, and local therapy in the oligo group improved the PRS further ( 9 ). However, local therapy has been reported as exerting no influence on the PRS in EGFR + NSCLC patients with PR as TKIs are very effective in this patient group ( 21 ). In the present study, 52 patients (78%) of the oligo recurrence group received local therapy, such as chemoradiotherapy, radiotherapy or resection, but neither the treatment strategy used nor the pattern of recurrence had any influence on the prognosis, as previously reported ( 21 ). Because the number of patients taking osimertinib developing recurrence could be expected to increase, further studies are needed to develop effective treatments for postoperative NSCLC patients with bone/CNS metastasis at first recurrence. A randomized controlled phase III trial comparing systemic versus local therapy for postoperative oligo recurrence in NSCLC patients is currently being planned (JCOG2108). The reported PRS in EGFR + NSCLC patients with PR treated with TKIs is 4.08 years ( 8 ), and shorter than that determined in this study. This could be attributable to the larger number of patients treated with osimertinib in this study. In both the osimertinib and placebo arms, the 5-year survival rates were higher in the ADAURA trial than in this study. This result could be explained by the fact that 79 (38.5%) of the 205 patients in the placebo group who showed disease relapse in the ADAURA trial received osimertinib as the primary treatment after recurrence ( 5 ), as compared to the 23 (14.2%) patients in the present study, and that we only enrolled patients with PR in this study. In the 23 patients in this study who received osimertinib as first-line therapy after recurrence, the PRS was still NA at the time of writing (95% CI NA-NA) and the 5-year PRS was 100% (95% CI NA-NA). This result lends support to the rationale of using osimertinib as the first-line therapy after postoperative recurrence. Although it was demonstrated in the ADAURA trial that osimertinib treatment was associated with a reduced incidence of bone and CNS metastases ( 22 ), some patients still hesitate to take adjuvant osimertinib treatment owing to the reported adverse effects. In the ADAURA trial, 36 patients in the osimertinib group developed adverse events, and in 30 of these, the treatment was discontinued at the patient's request ( 4 ). We consider that the findings of our present study are useful for patients considering resuming osimertinib. This study had several limitations. Firstly, it was a retrospective study conducted at a single institution, and the possibility of selection bias cannot be ruled out. Secondly, histological confirmation was not obtained at recurrence in all patients. Thirdly, we did not compare the prognostic factors with those in NSCLC patients with wild-type EGFR. Fourthly, osimertinib was not used in all patients. The FLAURA trial showed that osimertinib prevented progression of CNS metastases significantly more effectively than first- or second-generation TKIs in advanced EGFR-positive NSCLC patients ( 23 ); therefore, the use of osimertinib may significantly improve the prognosis in patients with CNS metastasis. Also, in the ADAURA trial, osimertinib treatment yielded better CNS DFS in patients with stage II-IIIA disease (HR 0.24 [95% CI 0.14–0.42]) and a reduced incidence of bone metastasis (13 vs. 32 patients) ( 22 ). Because patients treated with osimertinib as adjuvant therapy is expected to increase, the poor prognosis population in this study could be expected to decrease. But we expect that the results of our present study will be helpful for countries in which osimertinib is still not approved as adjuvant therapy for NSCLC, and for patients who refuse to take osimertinib. Conclusions Bone metastasis and CNS metastasis were identified as predictors of a poor prognosis in EGFR + NSCLC patients with PR. Thus, it would be necessary to develop more effective treatment strategies for EGFR + NSCLC patients presenting with bone/CNS metastasis at first recurrence. Declarations Ethics approval All procedures performed in the human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards . Consent to participate We have applied an opt-out method to obtain informed consent for this study by posting a document about this study. The document has been approved by the institutional ethics review board of Shizuoka Cancer Center (IRB number: J2022-133-2022-1-3). Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflicts of interest The authors have no conflict of interest. Funding We did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors for conducting this research. Acknowledgements We gratefully thank the staff members of the Division of Thoracic Oncology and Surgery, Shizuoka Cancer Center, Shizuoka, for their suggestions and assistance. Author contribution MM and AO conceived the study, performed statistical analysis and drafted the manuscript. All authors reviewed, approved the final version of the manuscript. References Hirsch FR, Suda K, Wiens J, et al. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388:1012–24. Sonia JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113–25. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020;382:41–50. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383:1711–23. Tsuboi M, Roys S, Herbst, Thomas J, et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023;389(2):137–47. Ko R, Kenmotsu H, Hisamatsu Y, et al. The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Int J Clin Oncol. 2015;20:668–73. Endo C, Sakurada A, Notsuda H, et al. Results of Long Term Follow-Up of Patients With Completely Resected Non-Small Cell Lung Cancer. Ann Thorac Surg. 2012;93:1061–9. Takenaka T, Takenoyama M, Yamaguchi M, et al. Impact of the epidermal growth factor receptor mutation status on the post -recurrence survival of patients with surgically resected non -small-cell lung cancer. Eur J Cardiothorac Surg. 2015;47:550–5. Hishida T, Yoshida J, Aokage K, et al. Postoperative oligo-recurrence of non-small-cell lung cancer:clinical features and survival. Eur J Cardiothorac Surg. 2016;49:847–53. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–14. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606–12. Miyawaki T, Wakuda K, Kenmotsu H, et al. Proposing synchronous oligometastatic non-small-cell lung cancer based progression after first-line systemic therapy. Cancer Sci. 2021;112:359–68. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452–8. Sugimura H, Francis C, Nichols P, Yang, et al. Survival After Recurrent Non-small-Cell Lung Cancer. After Complete Pulmonary Resection. Ann Thorac Surg. 2007;83:409–18. Saisho S, Yasuda K, Maeda A, et al. Post- recurrence survival of patients with non-small cell lung cancer after curative resection or without induction/adjuvant chemotherapy. Interact Cardiovasc Thorac Surg. 2013;16:166–72. Chen Y-Y, Wang P-P, Yang, -Fu, et al. Inferior outcome of bone metastasis in non-small-cell-lung-cancer patients treated with epidermal growth factor receptor inhibitors. J Bone Oncol. 2021;29:100369. Hung JJ, Jeng WJ, Wu YC, et al. Factors predicting organ specific distant metastasis in patients with completely resected lung adenocarcinoma. Oncotarget. 2016;7(36):58261–73. Chang WY, Wu YL, Su PL, et al. The impact of EGFR mutations on the incidence and survival of stages I to III NSCLC patients with subsequent brain metastasis. PLoS ONE. 2018;13(2):e0192161. Mizuno T, Konnno H, Nagata T, et al. Osteogenic and brain metastasis after non-small-cell lung cancer resection. Int J Clin Oncol. 2021;26:1840–6. Sonoda D, Kondo Y, Maruyama R, et al. Examination of the effectiveness of local therapy for oligo-recurrence of EGFR-mutated NSCLC. Thorac cancer. 2023;14:766–72. Herbst RS, Wu YL, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023;41:1830–40. Reungwetwattana T, Nakagawa K, Cho CC, et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36:3290–7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3439432","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":243988220,"identity":"4e5aefa5-196a-436d-b740-59a40dc2b743","order_by":0,"name":"Meiko Morita","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Meiko","middleName":"","lastName":"Morita","suffix":""},{"id":243988222,"identity":"ec2aa268-d3bb-4155-9564-d72bb042646a","order_by":1,"name":"Akira Ono","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAoElEQVRIiWNgGAWjYNCCCiCWgGIiwRmStTC2kaKcv4H52IOP8+rk+Wf3PmCw3EGEFokDbOmGM7cdNpxx57gBg+QZYqw5wGMmzbvtQIKBRBoDg2QbETrkwVrm1JGgxQCspYGZBC2Gh9nSJGccA/rlRhrDAaL8Ine8+ZjEhxpgiM1IY3wsSUyIMTAjsQ9LNhCjBRkwfiRZyygYBaNgFIwEAAAMMC3I7PI5/wAAAABJRU5ErkJggg==","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Ono","suffix":""},{"id":243988224,"identity":"36a5a312-0f6d-43ec-b8db-a4fb6c1f553b","order_by":2,"name":"Motoki Sekikawa","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Motoki","middleName":"","lastName":"Sekikawa","suffix":""},{"id":243988226,"identity":"92138623-24a6-44f7-be03-e4517d495174","order_by":3,"name":"Kosei Doshita","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kosei","middleName":"","lastName":"Doshita","suffix":""},{"id":243988227,"identity":"b4a6e5ce-e0cd-44e1-8691-e414bda327c6","order_by":4,"name":"Keita Miura","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Miura","suffix":""},{"id":243988228,"identity":"489d989d-8bff-4e3f-889a-3dcfff2e3409","order_by":5,"name":"Hiroaki Kodama","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Kodama","suffix":""},{"id":243988231,"identity":"7313ba6c-56a7-49ce-bf6c-0c7bd320fa52","order_by":6,"name":"Michitoshi Yabe","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michitoshi","middleName":"","lastName":"Yabe","suffix":""},{"id":243988233,"identity":"c417c108-92ea-4d09-b0d7-a7f03eefbd3b","order_by":7,"name":"Noboru Morikawa","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noboru","middleName":"","lastName":"Morikawa","suffix":""},{"id":243988235,"identity":"d3d8a00e-bc04-41b4-8cf5-8d45ef8624b4","order_by":8,"name":"Yuko Iida","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Iida","suffix":""},{"id":243988238,"identity":"f46b24bb-9d86-4600-8a9c-e0551e8c9bec","order_by":9,"name":"Nobuaki Mamesaya","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nobuaki","middleName":"","lastName":"Mamesaya","suffix":""},{"id":243988239,"identity":"88b2bae2-0816-4808-929a-59e787b76fa2","order_by":10,"name":"Haruki Kobayashi","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haruki","middleName":"","lastName":"Kobayashi","suffix":""},{"id":243988240,"identity":"89aa1eeb-3b26-4605-9c73-27e5ea4bf7ed","order_by":11,"name":"Ryo Ko","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Ko","suffix":""},{"id":243988241,"identity":"cb1a4b84-0366-4cc1-a7b1-a78f11a757af","order_by":12,"name":"Kazushige Wakuda","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazushige","middleName":"","lastName":"Wakuda","suffix":""},{"id":243988242,"identity":"f13617cf-ed5e-45fa-9b51-20221db9231a","order_by":13,"name":"Hirotsugu Kenmotsu","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Kenmotsu","suffix":""},{"id":243988243,"identity":"02dff36b-4cf8-4ecb-b9d6-ce1867c404e9","order_by":14,"name":"Tateaki Naito","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tateaki","middleName":"","lastName":"Naito","suffix":""},{"id":243988244,"identity":"28e2431b-349a-4a58-9a89-731bd1dd429e","order_by":15,"name":"Haruyasu Murakami","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haruyasu","middleName":"","lastName":"Murakami","suffix":""},{"id":243988245,"identity":"54f646d7-6692-4143-a80a-54f6642b4882","order_by":16,"name":"Mitsuhiro Isaka","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mitsuhiro","middleName":"","lastName":"Isaka","suffix":""},{"id":243988246,"identity":"e07fb7f6-9364-47e9-83c5-c4495dc180bc","order_by":17,"name":"Yasuhisa Ohde","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasuhisa","middleName":"","lastName":"Ohde","suffix":""},{"id":243988247,"identity":"5b3ee407-1bed-4c83-9ebc-da7f730c9ace","order_by":18,"name":"Toshiaki Takahashi","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toshiaki","middleName":"","lastName":"Takahashi","suffix":""}],"badges":[],"createdAt":"2023-10-13 01:29:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3439432/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3439432/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":45673091,"identity":"055b4a99-91e1-4870-abe0-94a65c85488d","added_by":"auto","created_at":"2023-11-01 18:12:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30059,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of patient screening and enrollment\u003c/p\u003e","description":"","filename":"Binder11.png","url":"https://assets-eu.researchsquare.com/files/rs-3439432/v1/d45bce330146a8f96725269b.png"},{"id":45673092,"identity":"3472d043-4e27-4938-a0e1-2ade890a8e3b","added_by":"auto","created_at":"2023-11-01 18:12:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":161360,"visible":true,"origin":"","legend":"\u003cp\u003eA. Kaplan–Meier analysis of PRS\u003c/p\u003e\n\u003cp\u003eB. Kaplan–Meier analysis of POS\u003c/p\u003e","description":"","filename":"Binder12.png","url":"https://assets-eu.researchsquare.com/files/rs-3439432/v1/6bc21889a708404c8dec2345.png"},{"id":48719971,"identity":"9dd148e3-ab63-4b9f-b171-3799bec75679","added_by":"auto","created_at":"2023-12-23 13:07:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":480154,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3439432/v1/a2b1e35f-a0e2-4b6b-903b-561616c85196.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic impact of postoperative recurrence in patients with epidermal growth factor receptor-positive non-small cell lung cancer.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe efficacy of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) for EGFR\u0026thinsp;+\u0026thinsp;NSCLC is now well established (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Based on the finding in the FLAURA trial of a significantly prolonged progression-free survival (PFS) and overall survival (OS) in the osimertinib arm as compared with the standard treatment arm (median PFS: 18.9 months [95% confidence interval (CI), 15.2\u0026ndash;21.4] vs. 10.2 months [95% CI, 9.6\u0026ndash;11.1]; Hazard Ratio (HR), 0. 46; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; median OS: 38.6 months [95% CI, 34.5\u0026ndash;41.8] vs. 31.8 months [95% CI, 26.6\u0026ndash;36.0]; HR 0.80; p\u0026thinsp;=\u0026thinsp;0.046) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), osimertinib is now considered as the standard treatment agent for advanced EGFR-positive NSCLC patients.\u003c/p\u003e \u003cp\u003eIn the ADAURA trial, postoperative adjuvant osimertinib therapy improved the disease-free survival (DFS) and OS in patients with EGFR-positive NSCLC. The 5-year survival in the osimertinib/placebo arm was 88% (95% CI, 83\u0026ndash;91)/78% (95% CI, 73\u0026ndash;82) (HR 0.49, p\u0026thinsp;\u0026lt;\u0026thinsp;0. 0001) in the osimertinib/placebo group for patients with stage IB-IIIA disease, and 85% (95% CI, 79\u0026ndash;89)/73% (95% CI, 66\u0026ndash;78) (HR 0.49, p\u0026thinsp;=\u0026thinsp;0.0001.) for patients with stage II-IIIA disease (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Therefore, adjuvant osimertinib is now offered as an option after complete resection for patients with EGFR-positive NSCLC, although in actual clinical practice, patients often refuse the drug due to concerns about toxicity and treatment duration, or do not wish to resume the drug after withdrawal due to toxicity in the adjuvant setting.\u003c/p\u003e \u003cp\u003eKo et al. compared the prognosis following treatment with gefitinib between EGFR-positive NSCLC patients with stage IV disease (119 patients) and EGFR-positive NSCLC patients with PR (49 patients), and reported that the prognosis was better in the patients with PR (MST: 22.2 vs. 51.1 months [HR 0.39, 95% CI 0.22\u0026ndash;0.66; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001] [median observation time, 24.6 months]). In addition to postoperative recurrence, performance status and distant metastasis have also been reported as prognostic factors (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e); this study was limited by the insufficient number of patients and short observation time.\u003c/p\u003e \u003cp\u003eAlthough several reports have suggested male gender and presence of brain metastasis as poor prognostic factors in NSCLC patients with PR (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), there are no reports of prognostic factors identified in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR. It has also been reported that in NSCLC patients with PR with oligo recurrence have a better post-recurrence survival (PRS) than those with non oligo recurrence (5-year PRS: 32.9 vs. 9.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). We hypothesized that the presence or absence of central nervous system (CNS) metastasis and the pattern of recurrence (oligo vs. non oligo recurrence) might be associated with the survival in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR Therefore, in this study, we investigated the impact of variables on the prognosis in EGFR NSCLC patients with PR by long-term follow-up of the OS of the patients.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eOf the 631 patients who underwent complete R0 or R1(cy+) resection and developed recurrence at our institution between October 2002 and November 2017, 442 had wild type EGFR, 168 had EGFR mutations, and 21 could not be traced. Of the 168 with EGFR mutations, 162 with common mutations were included in this analysis. The median observation time from surgery was 4.95 (range, 0.82\u0026ndash;13.25) years. The histological and cytological diagnoses were performed according to the WHO classification criteria (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). All patients were staged based on the International Association for the Study of Lung Cancer (IASLC) TNM (tumor-node-metastasis) classification, 7th edition (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). This study was conducted with the approval of the Institutional Review Board of the Shizuoka Cancer Center (IRB registration number; J2022-133), and the opt-out method was adopted for obtaining informed consent from the patients.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePostoperative follow-up and diagnosis of recurrence.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eFollow-up examinations included physical examination, hematological examination and chest radiography. Chest and abdominal computed tomography (CT) were performed every 6 months during the first 3 years, and CT and chest radiography were performed alternately every 6 months thereafter. When disease recurrence was suspected, brain magnetic resonance imaging (MRI), bone scintigraphy, and fluorodeoxyglucose\u0026ndash;positron emission tomography (FDG-PET) were performed in addition. Recurrent NSCLC was diagnosed based on the results of physical examination and of the findings of diagnostic imaging of lesions consistent with recurrent disease. Differentiating between a second primary lung cancer and intrapulmonary metastasis was, in general, performed according to the definitions proposed by Martini and Melamed (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Finally, we determined if a patient had recurrence or not by consensus at a multidisciplinary conference. Histological confirmation of the diagnosis was obtained where clinically feasible. The date of recurrence was defined as the date of radiological or histological confirmation, or in cases diagnosed based on clinical evidence, the date of recognition of recurrent disease at the multidisciplinary conference. Oligo recurrence was defined as distant metastasis limited to 1\u0026ndash;3 sites (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In this study, only the first recurrence after surgery was evaluated. Mediastinal lymph nodes were considered as one site, regardless of the number of lymph nodes affected. In the R classification, R0 was defined as no residual tumor and R1 as microscopic residual tumor. If the pleural fluid was positive, it was designated R1(cy+). In this study, complete resection was defined as R0 resection or R1(cy+) resection. Characterization of the EGFR mutations was outsourced to a commercial clinical laboratory.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003ePRS was defined as the time from the date of the first confirmed recurrence to death or last confirmed survival. Postoperative overall survival (POS) was defined as the time from the date of surgery to death from any cause or last confirmed survival. In the ADAURA trial, the allowed interval between surgery and randomization was 10 weeks in patient who did not receive adjuvant chemotherapy, and 26 weeks in those who received adjuvant chemotherapy. The probability of survival was estimated using the Kaplan\u0026ndash;Meier method. Prognostic factors among the covariates at recurrence were identified using Cox proportional hazards analysis. The prognostic significances of all the variables were measured by calculating the adjusted hazard ratio (HR) with 95% confidence interval (95% CI). Logistic regression analysis was performed to identify significant background characteristics of the patients associated with bone or CNS metastases at recurrence. P values less than 0.05 were considered as denoting statistical significance. All analyses were carried out using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eA flow-diagram of patient enrollment for this analysis is shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The baseline characteristics of the patients are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at recurrence was 70 (range, 37\u0026ndash;88) years, and the median time from sample collection to EGFR gene testing was 370 (range, 0-2899) days. The majority of patients were female (62.3%) and non-smokers (58%). The predominant histopathological type of NSCLC was adenocarcinoma (95%). Lobectomy was the most commonly used resection procedure (90.1%). Of the 6 patients in whom wedge resection was performed, the reason was technical difficulties caused by severe adhesions in 1 patient, and presence of double cancers in the remaining 5 patients. The pathological stage was stage I in 37.7%, stage II in 25.9%, and stage III in 36.4% patients. None of the patients had received neoadjuvant chemotherapy, and 82 patients (50%) had received postoperative adjuvant chemotherapy. Eight patients had received investigational drugs as adjuvant chemotherapy, excluding the ADAURA cases. The residual lesions followed R0 resection in 132 patients and R1 resection in 30 patients. All R1 patients were evaluated as R1(cy+).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient Characteristics(N\u0026thinsp;=\u0026thinsp;162)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian age at recurrence, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (37\u0026ndash;88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian time to EGFR gene testing, days (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e370 (0-2899)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian observation time, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.95 (0.82\u0026ndash;13.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e101 (62.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNever smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94 (58.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCurrent or former smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (42.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLung cancer resection type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLobectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146 (90.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSegmentectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePneumonectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWedge resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e154 (95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenosquamous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombined LCNEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLarge cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePleomorphic carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR genotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExon 19 deletion / L858R point mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 (48.8) /83 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eResidual lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR0 /R0(un) /R1(cy+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99 (61.1) / 33 (20.4) / 30 (18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePathological stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI /II /III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (37.7) / 42 (25.9) / 59 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeoadjuvant chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes /No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0) /162 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes /No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (50.6) /80 (49.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUFT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDDP regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBDCA regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvestigational drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eFirst recurrence sites and pattern of recurrence CNS: central nervous system\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiagnostics of recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistological assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImaging assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst recurrence sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVertebra\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvolving other metastatic sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (21.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSingle brain metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple brain metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMeningitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvolving other metastatic sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePattern of recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOligo recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon oligo recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eCNS: central nervous system\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePattern of first recurrence and initial treatment\u003c/h2\u003e\n \u003cp\u003eThe diagnosis of recurrence was confirmed by histology in 27 patients and by radiologic imaging in 135 patients, with no reliance on the clinical diagnosis alone in any patients. Oligo recurrence occurred in 67 patients (41.4%) and non oligo recurrence in 95 patients (58.6%). Bone metastasis was observed as the first recurrence in 33 patients (spine, 16; other bone sites, 17), associated with metastasis at other sites in 21 of these patients, and CNS metastasis was observed in 39 patients (single site, 15; multiple sites, 21; meningitis, 3), associated with metastasis at other sides in 21 of these patients (Table.2).\u003c/p\u003e\n \u003cp\u003eEGFR-TKIs were used (any treatment line) post recurrence in 155 patients (95.7%), in 61 of 67 patients with oligo recurrence, and in 94 of 95 patients with non oligo recurrence. TKIs were used as first-line therapy in 122 patients (75.3%), as second-line therapy in 23 patients (14.2%), as third-line therapy in 6 patients (3.7%), as fourth-line therapy in 1 patient (0.6%), and as fifth-line therapy in 2 patients (1.2%). The TKI used was gefitinib in 106 patients, erlotinib in 56 patients, osimertinib in 48 patients, and afatinib in 3 patients. Osimertinib was used as first-line therapy in 23 patients, as second-line therapy in 9 patients, and as third- or subsequent-line therapy in 16 patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eSurvival/regression analysis\u003c/h2\u003e\n \u003cp\u003eSurvival analysis was performed on the 162 NSCLC patients with common EGFR mutations. The median PRS was 5.17 years (95% CI, 3.90\u0026ndash;5.61) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The median POS was 7.07 years (95% CI, 5.88\u0026ndash;8.01) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB), and the 5-year survival rate post surgery was 67.7% (95% CI, 59.8\u0026ndash;74.4). The MST adjusted according to the ADAURA trial for the starting point was 6.70 years (95% CI, 5.43\u0026ndash;7.66) and the 5-year survival rate was 61.6% (95% CI, 53.4\u0026ndash;68.7). The median observation time was 4.95 years (range 0.82\u0026ndash;13.25). The clinical variables identified by univariate analysis as being associated with significantly unfavorable survival were the presence of bone metastasis (MST: 5.33 vs. 2.43 years; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), presence of CNS metastasis (MST: 5.39 vs. 3.05 years; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and male gender (MST: 5.39 vs. 3.32 years; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Multivariate analysis identified presence of bone metastasis (HR 2.01, 95% CI 1.23\u0026ndash;3.28; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and presence of CNS metastasis (HR 1.84, 95% CI 1.14\u0026ndash;2.99; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as being independent unfavorable prognostic factors. No significant association was found with the pattern of recurrence (HR, 1.01; 95% CI, 0.67\u0026ndash;1.54; p\u0026thinsp;=\u0026thinsp;0.95) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). With regard to the factors associated with the presence of bone metastasis and CNS metastasis in this study population, there was a significant association between the presence of bone metastasis and male gender (OR, 0.14; 95% CI, 0.04\u0026ndash;0.46; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and a trend toward an association between the presence of CNS metastasis and male gender (OR, 0.35; 95% CI, 0.12\u0026ndash;1.05; p\u0026thinsp;=\u0026thinsp;0.062).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eVariables associated with overall survival among 162 patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCo-variable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMST (years)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian age at recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75≦\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.51\u0026ndash;1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.82\u0026ndash;2.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEx19 deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.71\u0026ndash;1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePattern of recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOligo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOligo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.67\u0026ndash;1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon oligo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.23\u0026ndash;3.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.14\u0026ndash;2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAn important finding of this study was that the presence of bone and/or CNS metastases at recurrence was predictive of a poor prognosis in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patient with PR Furthermore, the pattern of recurrence was not identified as exerting any significant influence on the prognosis.\u003c/p\u003e \u003cp\u003eIn NSCLC patients with PR the presence or absence of EGFR mutation, number and sites of recurrence (intra/extra thoracic), and presence/absence of CNS metastasis have been well-established as prognostic factors (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), although there are conflicting opinions regarding the influence of bone metastases at recurrence on the prognosis (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). While the presence of bone metastasis at recurrence is reported as a poor prognostic factor in terms of both the PFS and OS in patients with advanced EGFR-positive NSCLC (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), there are no reports until date on the prognostic impact of bone metastasis in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR. According to a previous report, the reason for the poor prognosis associated with bone metastasis in patients with advanced EGFR-positive NSCLC is the presence, at a high frequency (72.7, of multiple (3 or more) distant metastases in these patients (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In the present study, among the 33 patients with PR, including those with bone metastasis, 12 (36.4%) had bone metastases only and 21 (63.6%) had other distant metastases in addition, showing a tendency for the presence of other distant metastases at a high frequency in patients with bone metastasis; this was consistent with the aforementioned report (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), although the number of coexistent metastases differed between the two studies. The number of patients who survived for more than 10 years after the diagnosis of recurrence was 20 (12.3%), including 8 patients with pathological stage I disease, 4 with pathological stage II disease, and 8 with pathological stage III disease. Only one of these patients had bone metastasis, two had CNS metastasis (in one site of the CNS in 1 patient, and in 2 sites in the other patient), and about a half of these patients (11 patients) had oligo recurrence.\u003c/p\u003e \u003cp\u003eNumerous studies have reported the relatively high risk of bone and CNS metastases in NSCLC patients with PR (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). According to one previous report, women are less likely to develop bone metastasis (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Also, associations of the preoperative carcinoembryonic antigen levels (\u0026gt;\u0026thinsp;5 ng/mL) and positive pathologic lymph nodes with the development of bone metastasis, and of poorly differentiated tumor and positive pathologic lymph nodes with the development of CNS metastasis have been reported (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Bone metastasis and male gender are thought to be associated regardless of the presence/absence of EGFR gene mutations, but further investigation of the tumor markers and pathological findings and the risk of bone and CNS metastases in postoperative EGFR-positive NSCLC patients is needed. In the ADAURA trial, a subgroup analysis showed a trend toward worse OS in male patients as compared with female patients (HR 0.62 [95% CI, 0.33\u0026ndash;1.13] for male patients and HR 0.41 [95% CI, 0.25\u0026ndash;0.66] for female patients) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this study also, male gender was associated with the presence of bone and CNS metastases, and new treatment strategies are needed for patients with bone and CNS metastases at first recurrence.\u003c/p\u003e \u003cp\u003eAmong the NSCLC patients with PR the PRS was higher in the oligo recurrence group than in the non oligo recurrence group, and local therapy in the oligo group improved the PRS further (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, local therapy has been reported as exerting no influence on the PRS in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR as TKIs are very effective in this patient group (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the present study, 52 patients (78%) of the oligo recurrence group received local therapy, such as chemoradiotherapy, radiotherapy or resection, but neither the treatment strategy used nor the pattern of recurrence had any influence on the prognosis, as previously reported (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Because the number of patients taking osimertinib developing recurrence could be expected to increase, further studies are needed to develop effective treatments for postoperative NSCLC patients with bone/CNS metastasis at first recurrence. A randomized controlled phase III trial comparing systemic versus local therapy for postoperative oligo recurrence in NSCLC patients is currently being planned (JCOG2108).\u003c/p\u003e \u003cp\u003eThe reported PRS in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR treated with TKIs is 4.08 years (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), and shorter than that determined in this study. This could be attributable to the larger number of patients treated with osimertinib in this study. In both the osimertinib and placebo arms, the 5-year survival rates were higher in the ADAURA trial than in this study. This result could be explained by the fact that 79 (38.5%) of the 205 patients in the placebo group who showed disease relapse in the ADAURA trial received osimertinib as the primary treatment after recurrence (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), as compared to the 23 (14.2%) patients in the present study, and that we only enrolled patients with PR in this study. In the 23 patients in this study who received osimertinib as first-line therapy after recurrence, the PRS was still NA at the time of writing (95% CI NA-NA) and the 5-year PRS was 100% (95% CI NA-NA). This result lends support to the rationale of using osimertinib as the first-line therapy after postoperative recurrence. Although it was demonstrated in the ADAURA trial that osimertinib treatment was associated with a reduced incidence of bone and CNS metastases (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), some patients still hesitate to take adjuvant osimertinib treatment owing to the reported adverse effects. In the ADAURA trial, 36 patients in the osimertinib group developed adverse events, and in 30 of these, the treatment was discontinued at the patient's request (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). We consider that the findings of our present study are useful for patients considering resuming osimertinib.\u003c/p\u003e \u003cp\u003eThis study had several limitations. Firstly, it was a retrospective study conducted at a single institution, and the possibility of selection bias cannot be ruled out. Secondly, histological confirmation was not obtained at recurrence in all patients. Thirdly, we did not compare the prognostic factors with those in NSCLC patients with wild-type EGFR. Fourthly, osimertinib was not used in all patients. The FLAURA trial showed that osimertinib prevented progression of CNS metastases significantly more effectively than first- or second-generation TKIs in advanced EGFR-positive NSCLC patients (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e); therefore, the use of osimertinib may significantly improve the prognosis in patients with CNS metastasis. Also, in the ADAURA trial, osimertinib treatment yielded better CNS DFS in patients with stage II-IIIA disease (HR 0.24 [95% CI 0.14\u0026ndash;0.42]) and a reduced incidence of bone metastasis (13 vs. 32 patients) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Because patients treated with osimertinib as adjuvant therapy is expected to increase, the poor prognosis population in this study could be expected to decrease. But we expect that the results of our present study will be helpful for countries in which osimertinib is still not approved as adjuvant therapy for NSCLC, and for patients who refuse to take osimertinib.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBone metastasis and CNS metastasis were identified as predictors of a poor prognosis in EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients with PR. Thus, it would be necessary to develop more effective treatment strategies for EGFR\u0026thinsp;+\u0026thinsp;NSCLC patients presenting with bone/CNS metastasis at first recurrence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in the human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe have applied an opt-out method to obtain informed consent for this study by posting a document about this study. The document has been approved by the institutional ethics review board of Shizuoka Cancer Center (IRB number: J2022-133-2022-1-3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors for conducting this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully thank the staff members of the Division of Thoracic Oncology and Surgery, Shizuoka Cancer Center, Shizuoka, for their suggestions and assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003econtribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM and AO conceived the study, performed statistical analysis and drafted the manuscript. All authors reviewed, approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eHirsch FR, Suda K, Wiens J, et al. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388:1012\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSonia JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRamalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020;382:41\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383:1711\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTsuboi M, Roys S, Herbst, Thomas J, et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023;389(2):137\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKo R, Kenmotsu H, Hisamatsu Y, et al. The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Int J Clin Oncol. 2015;20:668\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEndo C, Sakurada A, Notsuda H, et al. Results of Long Term Follow-Up of Patients With Completely Resected Non-Small Cell Lung Cancer. Ann Thorac Surg. 2012;93:1061\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTakenaka T, Takenoyama M, Yamaguchi M, et al. Impact of the epidermal growth factor receptor mutation status on the post -recurrence survival of patients with surgically resected non -small-cell lung cancer. Eur J Cardiothorac Surg. 2015;47:550\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHishida T, Yoshida J, Aokage K, et al. Postoperative oligo-recurrence of non-small-cell lung cancer:clinical features and survival. Eur J Cardiothorac Surg. 2016;49:847\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTravis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGoldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMartini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMiyawaki T, Wakuda K, Kenmotsu H, et al. Proposing synchronous oligometastatic non-small-cell lung cancer based progression after first-line systemic therapy. Cancer Sci. 2021;112:359\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026apos;EZR\u0026apos; for medical statistics. Bone Marrow Transplant. 2013;48:452\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSugimura H, Francis C, Nichols P, Yang, et al. Survival After Recurrent Non-small-Cell Lung Cancer. After Complete Pulmonary Resection. Ann Thorac Surg. 2007;83:409\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSaisho S, Yasuda K, Maeda A, et al. Post- recurrence survival of patients with non-small cell lung cancer after curative resection or without induction/adjuvant chemotherapy. Interact Cardiovasc Thorac Surg. 2013;16:166\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChen Y-Y, Wang P-P, Yang, -Fu, et al. Inferior outcome of bone metastasis in non-small-cell-lung-cancer patients treated with epidermal growth factor receptor inhibitors. J Bone Oncol. 2021;29:100369.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHung JJ, Jeng WJ, Wu YC, et al. Factors predicting organ specific distant metastasis in patients with completely resected lung adenocarcinoma. Oncotarget. 2016;7(36):58261\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChang WY, Wu YL, Su PL, et al. The impact of EGFR mutations on the incidence and survival of stages I to III NSCLC patients with subsequent brain metastasis. PLoS ONE. 2018;13(2):e0192161.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMizuno T, Konnno H, Nagata T, et al. Osteogenic and brain metastasis after non-small-cell lung cancer resection. Int J Clin Oncol. 2021;26:1840\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSonoda D, Kondo Y, Maruyama R, et al. Examination of the effectiveness of local therapy for oligo-recurrence of EGFR-mutated NSCLC. Thorac cancer. 2023;14:766\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHerbst RS, Wu YL, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023;41:1830\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eReungwetwattana T, Nakagawa K, Cho CC, et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36:3290\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"EGFR, non-small-cell lung cancer, postoperative recurrence, prognostic factors, oligometastasis","lastPublishedDoi":"10.21203/rs.3.rs-3439432/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3439432/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: There are no reports conducted with a long follow-up period on a large number of EGFR+ non small cell lung carcinoma (NSCLC) patients withpostoperative recurrence (PR).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We conducted a retrospective review of the data of EGFR+ NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. The post-recurrence overall \u0026nbsp;survival (PRS) and postoperative overall survival (POS) were estimated using the Kaplan-Meier method. Multivariate analysis using a Cox proportional hazards model was performed to identify any associations between the clinical variables at recurrence and the PRS. Logistic regression analysis was performed to evaluate the associations between the variables at the baseline and the prognostic factors at recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The median observation time was 4.95 (range, 0.82-13.25) years. The median PRS was 5.17 years (95% CI, 3.90-5.61) and the POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male gender (MST: 3.32 vs. 5.39 years; p\u0026lt;0.05), presence of bone metastasis (MST: 2.43 vs. 5.33 years; p\u0026lt;0.05), and presence of central nervous system (CNS) metastasis (MST: 3.05 vs. 5.39 years; p\u0026lt;0.05), and multivariate analysis identified the presence of bone metastasis (HR, 2.01; 95% CI, 1.23-3.28; p\u0026lt;0.05) and presence of CNS metastasis (HR. 1.84; 95% CI, 1.14-2.98; p\u0026lt;0.05) as poor prognostic factors. The pattern of recurrence was not prognostic factor. Logistic regression analysis revealed male was associated with the presence bone/CNS metastasis at recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eNew treatment strategies require to be developed for patients with bone/CNS metastasis at first recurrence.\u003c/p\u003e","manuscriptTitle":"Prognostic impact of postoperative recurrence in patients with epidermal growth factor receptor-positive non-small cell lung cancer.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-01 18:11:56","doi":"10.21203/rs.3.rs-3439432/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"06e8e7bb-e268-418d-87ff-7174b039daf8","owner":[],"postedDate":"November 1st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-23T12:59:43+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-01 18:11:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3439432","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3439432","identity":"rs-3439432","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}