Ethical approval
This study was approved by the Ethics Committee of Kitasato University Hospital (approval no. B22-005) and was conducted in accordance with the principles embodied in the Declaration of Helsinki. This study was performed retrospectively, and individual patients could not be identified from their data; therefore, the requirement for written informed consent from each patient was waived.
Study design and patients
Between January 2004 and December 2014, 811 consecutive patients with NSCLC underwent lobectomy or more invasive resection with systematic lymph node dissection and achieved complete resection at Kitasato University Hospital in Kanagawa, Japan. Of these 811 patients, 244 developed recurrence. After the patients without detailed information were excluded, 118 patients exhibited oligo-recurrence, of whom 35 had EGFR mutations; one of these 35 patients did not receive active treatment. The remaining 34 patients were divided according to whether they received radical local therapy or not, and their prognosis was examined. A flowchart of patient selection is shown in Figure 1.
Complete resection was defined as cancer-free surgical margins on macroscopic and histologic assessments, and oligo-recurrence was defined as one to two metachronous recurrences.
Follow-up after resection and recurrence
Eligible patients were followed-up every three months for the first year after surgical resection and once a year thereafter. Patients underwent physical examination, blood examination including tumor markers, and chest radiography. In addition, chest computed tomography (CT) scans were performed annually. Further examinations, such as abdominal CT scans, brain magnetic resonance imaging, bone scintigraphy, and/or positron emission tomography-CT, were performed if symptoms or signs of recurrence were observed. Patients who developed recurrence and received post-recurrence treatment were followed-up at intervals of three to six months in the same manner as that after resection.
Evaluation of patients with recurrence after resection
In this study, the differentiation between a recurrence and second primary lung cancer was based on the criteria of Martini and Melamed (Martini and Melamed 1975) and was determined by a lung cancer conference including thoracic surgeons, medical oncologists, radiologists, and pathologists. The pathological stage was determined according to the 7th edition of the Union for International Cancer Control staging system (Postmus et al. 2007).
Recurrence was divided into two categories: locoregional and systemic. Locoregional recurrence was defined as a tumor within the ipsilateral pleural cavity (lung pleura), mediastinum, and/or bronchi, while systemic recurrence was defined as other recurrences (tumor in the contralateral intrathorax or outside the hemithorax). The total number of recurrent lesions was calculated as the sum of the number of locoregional and systemic recurrent lesions.
Choice of treatment for recurrences
The treatment method was chosen by comprehensively judging the patients’ general condition, performance status, respiratory function, social background, and hopes. For patients with difficulty in selecting a treatment method, the decision was made at a lung cancer conference. Radical local therapy included complete surgical resection, stereotactic body radiotherapy, stereotactic radiosurgery, gamma knife, other curative irradiation, and proton beam therapy for curative purposes.
Statistical analysis
Different categorical data were compared using the Fisher’s exact test, and normally distributed continuous variables were compared using the Student’s t-test. Post-recurrence survival (PRS) was estimated using the Kaplan‒Meier method, and comparisons between groups were evaluated using a log-rank test. Cox regression analyses were used for univariate and multivariate analyses of PRS. PRS was defined as the period from the date of diagnosis of the first recurrence to death or final follow-up. If the patient experienced no adverse events, the final follow-up date was set. All statistical analyses were performed using JMP Pro software version 15.0.