The Assessment of Prognostic Factors for Lung Metastasectomy in Colorectal Cancer Patients With Previously Resected Liver Metastases

A total of 138 patients underwent complete lung resection for the first time due to metastases of colorectal cancer between January 2004 and December 2013 at our institution. Among the 138 patients, 33 underwent resection of lung metastases after previous liver metastasectomy from colorectal cancer.

All patients who underwent resection of their pulmonary metastases met the following criteria: (1) no evidence of extrathoracic metastasis except liver metastasis, (2) no evidence of uncontrolled primary site, (3) chest computed tomography demonstrating that complete resection could be warranted regardless of the number of lesions, and (4) good general condition and adequate respiratory function to tolerate lung resection. Lymph node dissection was not routinely performed. The detailed regimens of chemotherapy were different among patients; however, all 33 patients with previously resected liver metastases underwent preoperative or postoperative chemotherapy.

We reviewed each patient's medical record to obtain clinicopathologic information, which included age (dichotomized at the median age of 67 years), sex, smoking history (never or ever smoker), ratio of prethoracotomy forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC; >70% or <70%), prethoracotomy serum carcinoembryonic antigen (CEA) level (cutoff at the normal upper limit of 5 ng/mL), primary site (colon or rectum), Dukes' stage of the primary tumor (A–B or C–D), histologic differentiation of the primary tumor (well differentiated or moderately/poorly differentiated), the disease-free interval between the colorectal resection and the first pulmonary resection (≤24 months or >24 months), tumor laterality (hemilateral or bilateral), time from liver metastasectomy to lung metastasectomy (≤12 months or >12 months), number of pulmonary metastases, and largest diameter of the resected tumor (≤1 cm or >1 cm).

The duration of overall survival rate was calculated in months from the date of pulmonary metastasectomy to the date of death due to any etiology or the date of the last follow-up. In univariate analyses, all cumulative survival curves were estimated using the Kaplan–Meier method, and differences in variables were evaluated using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards regression model. All p values reported were 2-sided, and the significance level was set at less than 0.05. Analyses were performed using the statistical software SPSS 11.0 (Dr. SPSS II for Windows, Standard Version 11.0, SPSS Inc., Chicago, Illinois, USA).

The 5-year survival rate of all 138 patients who underwent complete lung resection was 61.7%. Of the 138 patients, 33 underwent resection of lung metastases after previous liver metastasectomy from colorectal cancer. Characteristics of patients who underwent resection of lung metastases after previous liver metastasectomy are shown in Table 1. The median follow-up period was 22 months (range, 5–69 months). The cohort consisted of 19 women and 14 men. The age ranges from 41 to 79 years with a median of 67 years. Seventeen patients with previously resected primary colorectal cancer first underwent resection of liver metastases and then surgery for lung metastases (Figure 1). The primary tumor, the liver and pulmonary metastasis were simultaneously detected in 3 patients (Figure 1). The simultaneous liver and pulmonary metastasectomies were performed in 6 patients. Three patients underwent pulmonary resection after simultaneous primary colorectal cancer and liver metastases resection (Figure 1). Video-assisted thoracic surgery (VATS) was performed in all the 33 patients. No patients died as a direct result of surgery, and all patients were discharged home after pulmonary metastasectomy.

The 5-year survival rate of the 33 patients was 30.5%, which was significantly lower than that of 105 patients with pulmonary metastasectomy alone (5-year survival rate, 62.4%; P = 0.011; Fig. 1A). Table 1 lists the survival rates at 5 years after the first pulmonary resection according to clinicopathologic features in all 33 patients. Univariate analysis (log-rank test) identified 2 significant prognostic factors: preoperative serum CEA level and maximum tumor size (Table 1). The 5-year survival rates of the patients with a high preoperative CEA level and those with a normal CEA level were 13.2% and 61.5%, respectively (P = 0.035; Fig. 2). The 5-year survival rate of the patients with maximum tumor size greater than 1 cm was 22.3%, which was significantly lower than that of the patients with maximum tumor size of 1 cm or less (44.7%; P = 0.029; Fig. 3). On multivariate analysis using the Cox regression model, preoperative serum CEA level (P = 0.030) and maximum tumor size (P = 0.021) remained statistically significant independent prognostic factors (Table 2).

Subgroup analysis with a combination of these 2 independent prognostic factors (preoperative serum CEA level and maximum tumor size) revealed 2-year survival rates of 100%, 92.3%, and 0% for patients with 0, 1, or 2 risk factors, respectively (Fig. 4). The difference in survival rates was statistically significant between the 0 and 2 risk factor groups (P < 0.001) and between the 1 and 2 risk factor groups (P < 0.001), but not between the 1 and 2 risk factor groups (P = 0.239; Fig. 5). When we divided the patients into 2 groups with 2 factors, or either 0 risk factors or 1 risk factor, the 5-year survival rates were 0% and 95.2%, respectively (P < 0.001).

Iida et al¹³ proposed that metastasis to the lungs and the upstream organs, or to the liver, can be regarded as a “semilocal” disease and can explain favorable outcomes after lung and liver metastasectomy in colorectal cancer patients. They also suggested that once the filtering system in the lungs is collapsed by tumor growth, distant metastases will develop in the organs downstream from the lung, such as the brain and bones, which are generally unresectable and are associated with a poor prognosis. Therefore, even if there are multiple pulmonary metastases, surgical resection still has the potential for better survival as long as the lung's defense system is functioning and preventing tumor cells from spreading to downstream organs. Although surgical resection for lung metastases from colorectal cancer has been widely accepted and performed, the efficacy and indications for resecting both liver and lung metastases are unknown. Several studies have reported the usefulness of resecting both liver and lung metastases from colorectal cancer, reporting 5-year survival rates of 27% to 74%.^14–19  However, Riquet et al¹¹ reported a series of 127 patients who underwent lung metastasectomy; 29 of them (23%) had undergone previous liver surgery for liver metastases. Their data indicate that prior surgery for liver metastases is associated with a higher risk for tumor recurrence and death after lung metastasectomy. Hattori et al¹² recently also reported that the survival rate after both liver and lung metastasectomies was worse than the survival rate after lung metastasectomy alone. In this study, the 5-year survival rate of patients who underwent lung metastasectomy after liver resection for metastatic liver tumor from colorectal cancer was significantly lower than that of patients who underwent lung metastasectomy alone in this study. The main purpose of this study was to investigate the prognostic factors of metastasectomy in patients with previously resected liver metastases, which may be clinically helpful for defining a subset of patients who are most likely to benefit from pulmonary metastasectomy.

Various factors associated with prolonged survival after surgery for lung metastases from colorectal have been identified, including: (1) a long disease-free interval^20–22; (2) prethoracotomy CEA level^7,8,23–25; (3) a single isolated metastasis less than 3 cm in size^26–28 ; and (4) the absence of thoracic lymph node invasion.^8,29  Among the patients who underwent lung metastasectomy after liver resection, univariate analysis identified 2 significant prognostic factors: preoperative serum CEA level and maximum tumor size in this study. In addition, high CEA level before metastasectomy and maximum size of lung metastases remained statistically significant independent poor prognostic factors also on multivariate analysis using the Cox regression model.

Preoperative CEA levels may serve as a biochemical marker for postresection outcome. CEA participates in intracellular recognition and metastasis by functioning as an attachment factor.³⁰  CEA levels may therefore reflect the highly malignant nature of cancer cells that undergo systemic dissemination. In the current study, preoperative CEA was also an independent poor prognostic factor in patients with previous liver metastasectomy. Therefore, the preoperative CEA level should be taken into account when selecting patients for a lung resection.

In this study, the 5-year survival rate of the patients with maximum metastatic tumor size greater than 1 cm was significantly lower than that of patients with maximum metastatic tumor size 1 cm or less. Patients who have undergone liver metastasectomy undergo intensive surveillance in the postoperative follow-up program after liver metastasectomy. Therefore, the larger size of the tumor may indicate more aggressive biology for a rapid growth, ultimately determining poorer overall survival.

When we divided patients into groups of 0, 1, or 2 risk factors using these risk factors (serum CEA level and maximum size of lung metastases) described above, we found 2-year survival rates of 100%, 92.3%, and 0%, respectively. This may help select patients who benefit most from pulmonary metastasectomy.

This was a retrospective study, and the analyses conducted had several limitations. In particular, this study had a retrospective design and consisted of a small patient population. The other drawback is that the recent development of systemic chemotherapy in combination with molecular targeting agents has resulted in prolonged survival for patients with metastases from colorectal cancer. Although adjuvant and/or neoadjuvant systemic chemotherapy is thus thought to play an important role in patients with both liver and pulmonary metastases from colorectal cancer, we did not analyze the patients in this respect.

In conclusion, we identified 2 independent poor prognostic factors for lung metastasectomy in patients with previously resected liver metastases from colorectal cancer: high serum CEA level before lung metastasectomy and larger maximum tumor size. When these 2 factors are combined, higher- and lower-risk subgroups can be identified, which may help select patients with previously resected liver metastases who benefit most from lung metastasectomy.

All work included in the manuscript was performed at the Fujita Health University School of Medicine, Toyoake, Aichi, Japan. The research was approved by the Internal Review Board of the institution. No patient consent was required because the research was a retrospective chart review and no personally identifiable information was included in the manuscript. This study was not supported by any grants. The authors have no conflicts of interest to disclose.