The number of new CRC cases has been increasing annually worldwide. In 2002, the number of new diagnoses was estimated to be about 1.02 million globally , but in 2018, the number had increased to about 1.8 million . Accordingly, the number of patients with pulmonary metastases from CRC is inevitably increasing. However, the development of multidrug chemotherapy regimens such as FOLFOX and FOLFIRI and the emergence of molecular targeting drugs such as anti-VEGF antibody and anti-EGFR antibodies have dramatically improved CRC outcomes. Treatment strategies for pulmonary metastasis of CRC have received attention for the purpose of further improving prognosis [1–8].
In the past, pulmonary metastasis was considered to be a condition in which cancer spread throughout the body, and aggressive treatment was commonly avoided. However, since Thomfold et al.  proposed the principles of surgical treatment for pulmonary metastases, pulmonary metastasectomy has been performed on patients who meet the operative indication, and the prognosis after treatment is relatively good. The 5-year survival rate after pulmonary resection is reported to be 30–68% [1–8]; a similar result was observed in this study (60.8%). In the multicenter aggregate in the JSCCR project study , the 5-year survival rate of lung resection cases was 46.7% and the cumulative 5-year relapse-free survival rate was 33.7%, whereas the 5-year survival rate of non-resected cases was 3.9%. However, the efficacy of lung resection has not been shown in cohort studies or randomized controlled trials, and assessment of surgical outcomes and prognostic factors after pulmonary resection in a large sample size (at least 100 cases or more) is unexpectedly rare. According to some reports [1–8, 15–21], the number of metastases, bilateral lung metastasis, hilar or mediastinal lymph node metastasis, CEA before pulmonary metastasectomy, primary colorectal tumor factors (T factor and N factor), and disease-free interval after resection of the primary colorectal tumor were found to be prognostic factors. In this study, past history of extrathoracic metastasis, maximum tumor size, hilar or mediastinal lymph node metastasis, and elevated tumor marker level before pulmonary metastasectomy were also identified as important prognostic factors. Multivariate analysis identified hilar or mediastinal lymph node metastasis as an independent predictor of poor prognosis. Therefore, excluding cases of hilar or mediastinal lymph node metastasis, our results suggest that pulmonary metastasectomy could lead to improved prognosis in patients who met the operative indication, regardless of the characteristics of not only the patients and the primary colorectal tumor but also the pulmonary metastases.
Hilar or mediastinal lymph node metastasis in patients with pulmonary metastases is considered to reflect the spread of the cancer to the entire body and is therefore likely to be a poor prognostic factor. In our study, although the number of hilar or mediastinal lymph node-positive cases was small number, all had past histories of extrathoracic metastasis. Furthermore, distant metastases to other extrathoracic organs such as the brain, liver, and bone occurred within 1 year after surgery in these patients. Several studies suggested an association of hilar or mediastinal lymph node metastasis with an increased risk of death [15, 17, 18, 21], and a meta-analysis  showed poor 5-year survival among patients with lymph node metastasis (range, 0–33.5%) compared to those without lymph node metastasis (range, 38.7–71%). Our results suggest that lymph node dissection for patients with hilar or mediastinal lymph node metastasis has low therapeutic efficacy for those with other poor prognostic factors, and preventive systematic thoracic lymph node dissection is likely not necessary. Welter et al.  suggested it is more important to offer adjuvant chemotherapy after metastasectomy in cases of nodal metastasis than to perform radical or systematic lymph node dissection in patients with stage IV disease, understanding the risk of recurrence in extrapulmonary organs. In our study, there was no significant difference in survival based on receiving perioperative chemotherapy. Prospective studies on the efficacy and appropriate indications of perioperative chemotherapy are necessary in the future.
The present study also showed that repeat pulmonary metastasectomy for pulmonary re-recurrence is likely to be effective. Repeat pulmonary metastasectomy is a well-established procedure with satisfactory survival [1, 2, 4, 5, 15, 16, 19]. We had 26 patients (20.6% in all 126 cases and 55.3% in 47 pulmonary re-recurrent cases) who underwent repeat pulmonary metastasectomy. They had 1- and 3-year survivals of 90.7% and 84.6% after the second pulmonary metastasectomy, which are similar to the outcomes after the initial metastasectomy (97.4% and 84.9%, respectively). Furthermore, there was no significant difference between two groups in not only clinical characteristics of the primary colorectal tumor and the pulmonary metastases but also the surgical outcomes including postoperative complications, mortality, and length of hospital stay. Only the amount of intraoperative blood loss was significantly higher in the second pulmonary metastasectomy group, probably because of the higher rate of segmentectomy. Therefore, at least one repeat pulmonary metastasectomy can be performed relatively safely and expected to improve the prognosis by strictly complying with operative indications.
Some limitations of this study have to be addressed. First, the major limitation of our study is the single-institution, retrospective design. Second, there was a potential for selection bias, which was compounded by the retrospective design. Inclusion of patients was highly selective, with patients having presumed good performance status and few comorbidities, which might have contributed to the observed long-term survival. These limitations should be considered when evaluating the results of the present study. It is necessary to carry out a prospective study at multiple institutions that have a unified definition of operative indication and treatment strategy.