A total of 126 patients underwent pulmonary metastasectomy at the Department of Thoracic Surgery, Gifu University Hospital between March 2000 and December 2019. The study’s retrospective protocol was approved by our institutional review board (approval number ‘2019-253’). Among the 126 patients included, 47 (37.3%) had pulmonary recurrence after initial pulmonary metastasectomy, and 26 (20.6%) who met the surgical criteria underwent a second pulmonary metastasectomy (Figure 1).
All patients who underwent pulmonary metastasectomy met the following criteria based on the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines for the treatment of CRC : (1) The patient was capable of tolerating surgery, (2) The primary colorectal tumor was controlled or could be controlled, (3) The metastatic lung tumor could be completely resected, (4) Any extra-thoracic metastases could be controlled, and (5) The function of the remaining lung would be adequate.
A controllable tumor is a tumor that can be completely resected, or a tumor without the appearance of new lesions and regrowth after treatment such as surgery, chemotherapy, and radiation.
Preoperative assessments included clinical examination, blood tests, electrocardiogram,
standard chest radiograph, spirometry, echocardiogram, contrast enhanced computed tomography scan (CT) of the chest and abdomen, and positron emission tomography (PET) whole body scan. Endobronchial ultrasound-guided transbronchial biopsy was not performed routinely in this study.
Regarding the extent of pulmonary resection, if metastatic tumor was anatomically present in the outer third of the lung and partial resection was possible, we performed partial resection. If it was located inside lung, segmentectomy and lobectomy were performed.
Mediastinal lymph node dissection was performed according to primary lung cancer in the cases in which lymph node metastasis was suspected (swelling with short axis on CT ≧10mm and PET positive). If lymph node metastasis was suspected during surgery, this lymph node was submitted to intraoperative consultation. If positive, mediastinal lymph node dissection was performed. In addition, in the case of lobectomy and segmentectomy, the regional and interlobar lymph nodes were dissected. Otherwise, mediastinal lymph node dissection was not performed.
The surgery was considered curative if all known pulmonary nodules were removed. Patients who had complete resection of all known pulmonary disease were included in this study. We reviewed each patient’s medical records to obtain clinicopathological information of the initial and second pulmonary metastasectomy.
We collected information on patients and primary colorectal tumor characteristics including gender, age at the initial pulmonary metastasectomy, smoking habits (non-smoker or smoker), Brinkman index, primary colorectal tumor location (colon or rectum/ right or left side), histological differentiation of the primary colorectal tumor (well-, moderately-, or poorly differentiated), pathological Union for International Cancer Control-TNM classification (8th edition)  of the primary colorectal tumor, past history of extra-thoracic metastasis (present or absent), adjuvant chemotherapy after the primary colorectal operation (yes or no), and the number of pulmonary metastasectomies.
The clinical characteristics of pulmonary metastases included diagnosis period (synchronous or metachronous), number (solitary or multiple), location (unilateral or bilateral), disease-free interval, maximum tumor size, mediastinal lymph node metastasis (positive or negative in postoperative histological lymph node status), preoperative carcinoembryonic antigen (CEA) (normal or elevated, normal upper limit being 5 ng/ml), preoperative carbohydrate antigen 19-9 (CA19-9) (normal or elevated, normal upper limit being 37 ng/ml), perioperative chemotherapy (yes or no), recurrence after pulmonary metastasectomy (yes or no), and recurrent distant organ. In this study, lung lesions diagnosed within 1 year from resection of the primary colorectal tumor were defined as synchronous metastases, and those diagnosed after 1 year were defined as metachronous metastases. The disease-free interval (DFI) referred to both the period from primary colorectal tumor resection to diagnosis of the initial pulmonary metastasis and the period from the initial pulmonary metastasectomy to diagnosis of the second pulmonary metastasis. In our department, as a general rule, perioperative chemotherapy was indicated in cases excluding solitary pulmonary metastasis with DFI > 1year.
Finally, the surgical characteristics of pulmonary metastasectomy were operation method (partial resection, segmentectomy, lobectomy/video-assisted thoracic surgery (VATS), or open surgery), operation time, intraoperative blood loss, preoperative percent vital capacity (%VC), preoperative forced expiratory volume percent in 1 second (FEV1.0%), preoperative respiratory dysfunction (absent or present), postoperative complications after pulmonary metastasectomy (Clavien-Dindo classification  Grade ≥2: yes or no), postoperative mortality, and hospital stay.
For comparisons of variables between the initial and second pulmonary metastasectomy groups, Fisher’s exact test was used for categorical variables, and the Mann-Whitney U test was used for continuous and ordinal variables.
Overall survival was calculated in months from the date of the initial pulmonary resection to the date of the last follow-up. All cumulative survival curves were estimated using the Kaplan-Meier method, and in the univariate analysis, the log-rank test was used to evaluate differences between groups. A Cox relative risk regression model was used to estimate risk ratios and 95% confidence intervals (CIs) for multivariate analysis. The significance level was set at < 0.05. All statistical analyses were performed using JMP software (SAS Institute Inc., Cary, NC, USA).