Abstract
Background/Aim: Surgery may be curative in some patients with metastatic colorectal cancer (mCRC). We analyzed the role of lung metastatectomy in this population. Patients and Methods: In this retrospective cohort study, cases were defined as mCRC patients with lung metastases (LM's) who underwent metastatectomy. Controls had LM's but did not undergo resection. Results: There were 28 cases and 46 controls. The median overall survival (OS) was 53 months among the cases and 26.3 months for the controls. The cases were more likely to have 1 or 2 lung metastases, unilateral versus bilateral LM's, metachronous versus synchronous presentation of LM's and more likely to have a carcinoembryonic antigen (CEA) level less than 10 ng/ml at diagnosis. The interval from diagnosis to the development of lung metastases was significantly longer in cases versus controls (22.9 versus 8.5 months). Conclusion: Patients selected using these criteria may have prolonged survival with therapy that includes lung metastatectomy.
Colorectal cancer (CRC) is one of the most common malignancies and the second leading cause of cancer-related deaths in the United States (1). There were an estimated 142,820 new cases diagnosed in the United States in 2014 and 50,830 deaths due to this disease (2). More than half of the patients who undergo resection for localized CRC eventually have a recurrence, with the most frequent sites of metastases being the liver and the lungs (3, 4). Isolated lung metastases occur in approximately 5% of patients following curative resection of colon cancer and 11-15% of rectal cancer (5).
Systemic chemotherapy and targeted-therapy are the mainstay of treatment for patients with metastatic colorectal cancer (mCRC). Improvements in systemic therapy have led to prolongation of survival for patients with stage IV disease; the median overall survival (OS) seen with historical trials of fluorouracil and leucovorin was 14 months (6), compared to more contemporary trials with median OS times exceeding 2 years (7). As systemic therapies have gotten better, patients with oligo-metastatic disease are increasingly being referred for surgery. The role of surgery is well-established in patients with liver metastases with 5-year survival rates of 20 to 80% by the use of combination chemotherapy and liver resection (8-13).
The typical pattern of lung metastasis from CRC is single or multiple nodules rather than miliary tumors or lymphangitic spread. Therefore, metastatectomy is commonly performed, especially in patients where the primary colonic tumor is controlled, there are no other metastatic sites, the surgery is technically feasible and there is adequate cardiopulmonary reserve (14, 15). Using these criteria, patients undergoing lung metastatectomy can achieve 5-year survival rates of 40%-61% (8, 16-20). The data supporting the role of lung metastatectomy are all retrospective. Therefore, we designed a retrospective cohort study comparing patients who underwent resection versus a non-surgical group of controls. Our specific objectives were to determine the survival of CRC patients with lung metastases who underwent lung resection compared to a matched group of CRC patients with lung metastases that did not undergo lung resection and to determine predictors of better survival after lung resection for CRC metastases.
Baseline characteristics.
Patients and Methods
We conducted an Institutional Review Board-approved retrospective cohort study with two groups - cases (resection group) were patients with mCRC who underwent lung resection and controls (non-resection group) were patients with mCRC who had lung metastases but did not undergo lung resection. The cases were first identified by searching the surgical database at our institutions for all patients with lung metastases who underwent thoracotomy or thoracoscopy for resection. The search range was limited to January 2000 to December 2012. Only patients with a colon or rectal primary were included. Next, controls were selected by searching the Florida Cancer Data System (FCDS). This registry was queried for patients treated between January 2000 to December 2012 with colon or rectal cancer and lung metastases. A random selection of these patients was used to make up the control group.
A chart review was performed to extract demographic and clinical baseline characteristics of each patient, as well as treatment administered. Specific variables included age at diagnosis, gender, stage at diagnosis, histological grade, number of lung metastasis, performance status, synchronous vs. metachronous disease, carcinoembryonic antigen (CEA) level at the time of primary tumor and lung metastasis diagnosis, type of chemotherapy received, number of lines of chemotherapy, liver resection, type of thoracotomy, subsequent thoracotomies, size and number of lung metastases. Survival was calculated using the date of death or last follow-up and the vital status was obtained for all patients from the FCDS.
Statistical analysis was performed using the SPSS software, version 21 (IBM, New York, NY, USA). The cases versus control groups were compared for differences in baseline characteristics using the student's t-test for continuous data and the chi-squared test (or Fisher's exact test) for categorical data. The Kaplan-Meier method was used for survival analysis and the Cox proportional hazards model was used to identify variables associated with differences in survival.
Results
We identified 28 cases with mCRC who underwent lung metastatectomy and 46 controls with mCRC to the lung who did not have resection of their lung metastases. Table I shows the baseline characteristics of the cases and the controls. The treatments administered are shown in Table II.
Chemotherapy administration.
After a median follow-up of 39 months (range=11-105), the median overall survival (OS) from the time of diagnosis with lung metastases for the cases undergoing resection was 53 months (95% confidence interval (CI)=43.8-62.2) versus 26.3 months (95% CI=11.8-40.8) for the controls (log-rank p=0.009), as shown in Figure 1. The median disease-free interval, defined as the time from initial colorectal cancer diagnosis until lung metastasis, was 22.9 months (95% CI=18.6-27.2) in the cases undergoing resection versus 8.5 months (95% CI=2 -15) for the controls (log-rank p=0.02).
Among the patients who underwent resection, various characteristics were tested for prognostic importance as depicted in Table III. In univariate testing, none of these characteristics were associated with better survival – grade of differentiation, timing of lung metastases (synchronous versus metachronous), number and distribution of metastases, any history of liver metastatectomy, subsequent lung metastastatectomy, type/extent of resection, CEA level at initial diagnosis and CEA level at the time of diagnosis with lung metastases.
Discussion
Resection of lung metastases from colon cancer is a commonly performed surgery and the literature supports prolonged survival in some of these patients. Some consistent factors that have been reported to be associated with better survival in surgical case series are a longer interval from diagnosis to the development of lung metastases, fewer metastases and a lower CEA level at diagnosis with lung metastases (21). The main factor associated with worse survival is involvement of the hilar or mediastinal lymph nodes (21). Patients selected, according to these criteria, can achieve 5-year survival rates of 27-68% (22).
In this retrospective study, patients with mCRC to the lung who were referred for lung resection were more likely to have features of favorable disease biology: longer disease-free interval, solitary and unilateral tumors, metachronous disease and CEA levels at the time of lung metastasis less than 10. We found that patients selected using these criteria, who had surgical resection of their lung metastasis, had a median survival time of 53 months. This figure is in the range of what has been reported in the literature (8-13).
Analysis of prognostic factors among patients undergoing resection.
To date, all the published evidence in support of lung metastatectomy consists of case series of patients undergoing surgery with analyses of prognostic factors among these patients. However, prospective randomized trials have not been performed to delineate which patients are more likely to benefit from this procedure. In the absence of a randomized trial, it is difficult to know if the prolonged survival seen is due to selection of patients with favorable biology who were destined to live longer even if they did not undergo surgery. With the improvement in systemic therapies, it is possible that the combination of effective chemotherapy with good disease biology may be responsible for prolonged survival times. However, given the experience with curative resections for patients with “oligo-metastatic” liver-only disease, it is likely that surgery may be adding some survival advantage for a subset of these patients with lung metastases as well, possibly by removing resistant tumor clones or cancer stem cells, which may have led to faster disease progression if not removed.
Overall survival from the time of diagnosis with lung metastases.
The ongoing PulmiCC trial (23) will add some valuable information to our knowledge in this area. This trial was initiated in 2010 in Europe and is being offered to patients with resectable lung metastases from colorectal cancer who have their primary tumors controlled, have no other sites of metastatic disease that cannot be removed surgically or by some other local/ablative modality and do not have any contraindications to surgery. Until these results are reported, it seems reasonable to continue the current practice of offering lung metastatectomies to patients with low volume disease with otherwise favorable characteristics as described above and who are relatively low-risk for surgical intervention.
Acknowledgements
The Authors would like to thank the Florida Cancer Data System (FCDS) for their support.
Footnotes
Conflicts of Interest
None.
- Received February 23, 2015.
- Revision received March 11, 2015.
- Accepted March 13, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
