MATERIALS AND METHODS

At the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, 1458 consecutive cases underwent lobectomy or more extensive resection complete with systematic lymph node dissection and achieved complete resection for primary NSCLC during January 1990–December 2006. Complete resection was defined as cancer-negative surgical margins both macroscopically and histologically. We investigated the postoperative recurrence of these cases as of January 2018.

After resection, patients were generally examined for 5 years at 6-month intervals; thereafter, they were followed up once a year until 10 years. The survival or death of patients who were lost to follow-up was confirmed via telephone or documentation with the patients or public office.


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The follow-up evaluation included physical examination, chest radiography, and blood examination, including tumor marker evaluation. Moreover, chest computed tomography (CT) scans were performed yearly. Whenever any symptom or sign of recurrence was detected during these examinations, further evaluations were performed, including chest and abdomen CT scans, brain magnetic resonance imaging, bone scintigraphy, and positron emission tomography CT.

Recurrence was diagnosed on the basis of physical examination and diagnostic imaging findings, and was histologically and/or cytologically confirmed, when possible; the histological and/or cytological confirmation of recurrence was consistent with histopathological and immunohistochemical findings. Moreover, when possible, the mutational status of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangement was confirmed in tumors (Figure 1).

The date of recurrence was defined as the date on which the recurrence was confirmed on the basis of imaging findings. The recurrence-free survival period was calculated from the day of resection to the date of the first recurrence or last living confirmation. The recurrence of NSCLC developing over 10 years after complete resection was defined as ultra-late recurrence.

Recurrence was distinguished from a second primary tumor following the criteria of Martini and Melamed.15 When the diagnosis was difficult, thoracic surgeons, respiratory physicians, radiologists, and pathologists conferred to decide whether the tumor was a recurrence or a second primary tumor.

Recurrence was classified into two categories: local recurrence and distant recurrence. Local recurrence was defined as the evidence of a tumor within the ipsilateral lung, ipsilateral pleural cavity, mediastinum, or bronchi. Distant recurrence was defined as the evidence of a tumor in the contralateral lung or outside the hemithorax.

The medical records of each patient were reviewed for clinicopathological information including age; sex; smoking habits and smoking index; pathological stage; lymph node metastasis; maximum tumor dimension in the resected specimen; histology; histological differentiation; and intratumoral lymphatic, vascular, or pleural invasion.

The tumor staging was determined according to the 7th edition of the Union for International Cancer Control (UICC) for Cancer staging system;16 for cases of ultra-late recurrence of NSCLC over 10 years after resection, the invasive size and staging was investigated according to the 8th edition as well.17Histological diagnoses were made on the basis of World Health Organization classification.18

Ultra-late recurrence cases were compared with non-recurrence cases that could be followed up over 10 years after resection, and the factors related to ultra-late recurrence were analyzed.

Clinical characteristics and pathological factors were assessed using log-rank test. Multivariable analyses were performed using Cox’s proportional hazards regression model. P<0.05 was considered as significant. Survival rate was calculated using Kaplan–Meier method. Analyses were performed using JMP pro version 14.0 (SAS Institute Inc., Cary, NC, USA) as windows statistical software.

This study was conducted in accordance with the amended Declaration of Helsinki. Written informed consent was obtained from each patient. The institutional review board of the Japanese Foundation for Cancer Research approved the study protocol (Approval No.2012–1042).

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