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Ann Thorac Surg 2009;87:1684-1688. doi:10.1016/j.athoracsur.2009.03.034
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Prognostic Factors for Recurrence After Pulmonary Resection of Colorectal Cancer Metastases

Mark W. Onaitis, MDa,*, Rebecca P. Petersen, MDa, John C. Haney, MDa, Leonard Saltz, MDb, Bernard Park, MDc, Raja Flores, MDc, Nabil Rizk, MDc, Manjit S. Bains, MDc, Joseph Dycoco, BSc, Thomas A. D'Amico, MDa, David H. Harpole, MDa, Nancy Kemeny, MDb, Valerie W. Rusch, MDc, Robert Downey, MDc

a Department of Surgery, Duke University Medical Center, Durham, North Carolina
b Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
c Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Accepted for publication March 12, 2009.

* Address correspondence to Dr Onaitis, Duke University Medical Center, Box 3305, Durham, NC 27710 (Email: mark.onaitis{at}duke.edu).


   Abstract
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 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: This study was undertaken to review a large series of resections of colorectal pulmonary metastases in the era of modern chemotherapy.

Methods: A retrospective chart review of prospectively maintained thoracic surgery databases identified 378 patients who underwent pulmonary resection for colorectal cancer metastases with curative intent from 1998 to 2007.

Results: The primary site of disease was rectum (52%), left colon (26%), right colon (16%), and unknown (6%). Before thoracic recurrence, 166 patients (44%) had previously undergone resection of extrathoracic metastases. Median disease-free interval (DFI) was 24 months from the time of the primary operation. The number of metastatic deposits resected was one in 60%, two in 20%, three in 10%, and four or more in 10%. Chemotherapy was administered to 87 patients (23%) before resection and to 169 patients (45%) after resection. Three-year recurrence-free survival was 28%, and 3-year overall survival was 78%. Multivariable analysis revealed age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three as independent predictors of recurrence. Of 44 patients with three or more lesions and less than 1 year DFI, none was cured by operation. By contrast, recurrence-free survival was 49% at 3 years for those with one lesion and DFI greater than 1 year.

Conclusions: Age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three predict recurrence. Medical management alone should be considered standard for patients who have both three or more pulmonary metastases and less than 1 year DFI.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Surgical resection of pulmonary metastases from colorectal cancer is potentially curative [1–13]. Reported predictors of death have included number of metastases [3, 4, 6, 7, 13], pre-resection carcinoembryonic antigen level [2, 4, 7–9, 13] and presence of intrathoracic lymph nodes harboring metastatic disease [6, 7, 9], size of the largest nodule [10], high stage of the primary colorectal cancer [3], short disease-free interval (DFI) between primary resection and identification of pulmonary metastases [8], and less-than-anatomic resection [10].

This literature consists of single-institution reports including relatively small numbers of patients, inclusion of patients from multiple eras of treatment, and reliance on overall survival as the primary end point. In this study, we attempt to address these issues by reporting the likelihood of disease-free survival after pulmonary resection for colorectal metastasis based on the experience at two large cancer centers using modern chemotherapy. We note that because cure is the goal of metastasectomy, it is long-term disease-free survival after resection, rather than overall survival with or without disease, that is the appropriate metric for reporting and evaluating the usefulness of surgical resection.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Prospectively maintained thoracic surgery databases were queried for diagnosis of colorectal cancer from 1998 to 2007. Institutional review board approval was obtained at both institutions. Patients who underwent only diagnostic surgical biopsy were excluded. The records of all remaining patients were then reviewed for demographic information, stage and treatment of the primary colorectal tumor, induction and adjuvant therapies received, DFI before development of pulmonary metastases, treatment of extrathoracic recurrences, extent, size, and treatment of thoracic metastases, complications, and disease-free and overall survival. When multiple metastases were present, the size of the largest metastasis was recorded. In the case of previous resection of extrathoracic recurrence, DFI was calculated from the extrathoracic resection until the thoracic recurrence. For all patients, disease-free survival was calculated from the date of pulmonary metastasectomy to the date of first documented recurrence or death, and survival was calculated from the date of pulmonary metastasectomy to death. If bilateral operations were performed, metrics were calculated from the time of the second resection. All statistical calculations were performed using Enterprise Guide Version 4.0 for SAS Version 9.1 (SAS Institute, Cary, NC). Survival was estimated by the Kaplan-Meier method with differences assessed by log-rank test. Cox proportional hazard modeling was used for multivariable survival analysis.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Between 1998 and early 2007, 378 patients underwent resection of colorectal metastases with curative intent at Duke University Medical Center or Memorial Sloan-Kettering Cancer Center. Of these, 273 patients underwent resection at Memorial Sloan-Kettering Cancer Center by 9 surgeons, and 105 patients underwent resection at Duke University Medical Center by 5 surgeons.

Median age of the patients at the time of pulmonary resection was 61 years (range, 23 to 81 years), and 225 (60%) of the patients were male. Half of the patients had been smokers with an average of 13 ± 19 pack-years. Among the 67% of patients who underwent preoperative pulmonary function testing, mean forced expiratory volume in 1 second was 94% ± 18% predicted, and mean diffusion capacity was 91% ± 21% predicted.

Primary colorectal tumor information is depicted in Figure 1. At the time of primary resection, 26% of patients were found to have synchronous metastatic disease to the lung at the time of primary tumor resection. Forty-nine percent of patients had positive lymph nodes in the primary resection specimen with 35% pathologically N1. One hundred seventeen patients received induction chemoradiation for rectal cancer, with the vast majority receiving a combination of 5-fluorouracil and radiation. Two hundred forty patients received adjuvant treatment after primary colon or rectum resection; however, 73% received 5-fluorouracil and only 20% also received either oxaliplatin or irinotecan.


Figure 1
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  		Fig 1. Primary colorectal tumor resection information. Type of resection (A), stage (B), and nodal stage (C) of primary colorectal cancer patients included in the study.

 
First recurrence after colon resection was noted in an extrathoracic location in 166 patients (44%). Of these, 144 underwent liver resection and 22 underwent resection of other abdominal or pelvic recurrence. Twenty-one patients presented with synchronous lung and liver metastases. In the remaining 123 patients, median DFI between liver resection and lung metastasis was 21.5 months (range, 0.39 to 1,289.5 months). No survival difference was noted between these two groups (3-year RFS, 43% in both groups). In the patients without previous extrathoracic recurrence, thoracic recurrence occurred at a median of 17 months (range, 0 to 328 months) after the primary tumor was resected. Median carcinoembryonic antigen level at the time of thoracic recurrence was 3.4 ng/mL (range, 0 to 475 ng/mL).

Chemotherapy was administered to 87 patients after diagnosis but before resection of thoracic metastases (Fig 2). Of these patients, 62 received either oxaliplatin or irinotecan, 14 Xeloda, and 8 5-fluorouracil and leucovorin. After lung resection, adjuvant chemotherapy was administered to 169 patients (Fig 2), of whom 107 received either oxaliplatin or irinotecan, 27 Xeloda, and 10 5-fluorouracil and leucovorin.


Figure 2
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  		Fig 2. Chemotherapeutic agents administered to patients before (A) and after (B) pulmonary resection of colorectal metastases. (FU = 5-fluorouracil; Irino = irinotecan; LV = leucovorin; Oxal = oxaliplatin.)

 
The type of thoracic resection was wedge resection or multiple wedge resections in 72% (271 patients; Fig 3). Anatomic lung resection was performed in the remaining 28% (lobectomy in 19% [71 patients], segmentectomy in 7% [25 patients], bilobectomy in 1.8% [7 patients], and pneumonectomy in 0.2% [1 patient]). Pulmonary metastatic nodules were relatively evenly distributed among lobes, and 113 patients had resections of multiple lobes (Fig 4). A solitary pulmonary metastasis was resected in 226 patients (60%). Forty patients (11%) had resection of four or more nodules. Mean size of the largest nodule was 1.5 ± 1.9 cm.


Figure 3
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  		Fig 3. Extent of pulmonary resection of colorectal metastases.

 

Figure 4
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  		Fig 4. Lobes involved (A) and number of nodules resected (B) during pulmonary resection of colorectal metastases.

 
Four patients (1%) died perioperatively. Major complications occurred with the following frequencies: atrial fibrillation, 3%; prolonged air leak, 2%; clinical pneumonia, 2%; urinary tract infection, 0.5%; empyema, 0.5%; stroke, 0.5%; colitis, 0.5%; ileus, 0.5%; and hemorrhage requiring reoperation, 0.5%. One patient experienced nonfatal myocardial infarction, and 1 patient had a nonfatal pulmonary embolus. Although there was no difference in perioperative or long-term mortality between those undergoing thoracoscopic surgery versus those undergoing thoracotomy, chest tube duration (median, 2 days versus 4 days) and length-of-stay (median, 3 days versus 5 days) were statistically significantly shorter in the thoracoscopy group of patients (p < 0.001).

By the method of Kaplan-Meier, recurrence-free survival estimate was 25% at 5 years (Fig 5). On Cox proportional hazard univariate analysis (Table 1), DFI less than 1 year, number of metastases greater than three, and female sex were significant predictors of recurrence. Previous extrathoracic recurrence, primary tumor stage greater than III, and age younger than 65 years trended toward prognostic significance. In a multivariable model including these variables, number of metastases greater than three, DFI less than 1 year, female sex, and young age were significant predictors of recurrence. Of 44 patients with three or more lesions resected and less than 1 year DFI, none was cured by operation. By contrast, recurrence-free survival was 49% at 3 years for those with one lesion and DFI greater than 1 year. Overall survival estimate was 56% at 5 years.


Figure 5
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  		Fig 5. Overall survival (A) and recurrence-free survival (B) among patients undergoing pulmonary resection for colorectal metastases.

 

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  		Table 1 Predictors of Colorectal Cancer Recurrence After Pulmonary Resection
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
When a patient presents with pulmonary metastases from colorectal cancer, the clinician must decide whether pulmonary resection may offer the chance for cure. Studies of determinants of curability by resection of pulmonary metastases have been limited by small sample sizes, single-center experiences, and inclusion of patients from many treatment intervals. Because treatment of metastases from colorectal cancer has improved greatly as a result of the introduction of new chemotherapeutic agents (irinotecan [14], oxaliplatin [15], cetuximab [16], and bevacizumab [17]), we sought to examine patients treated recently at two large cancer centers.

The present study reveals pulmonary resection in these circumstances to be safe. Complication rates are low, and length of stay is short. The gradual acceptance of thoracoscopic procedures has improved both chest tube duration and length of stay in the present series, and no perioperative deaths occurred in this cohort of 193 patients. Also, despite previous concerns over oncologic efficacy [5], no recurrence-free survival difference was noted between the two approaches after controlling for all other factors. Multiple explanations are possible for this lack of difference in recurrence-free survival. First, we may be underpowered to show a significant difference. Alternatively, thoracoscopic palpation may allow palpation of the lung parenchyma that is equivalent to that performed through thoracotomy. All patients had received computed tomographic imaging before metastasectomy. Perhaps the increasing resolution of these scans allows identification of the vast majority of even small lesions. This may allow targeted thoracoscopic palpation or resection of suspicious lesions. Finally, even if palpation thoracoscopically is inferior to that performed through thoracotomy, resection of very small nodules may not significantly contribute to recurrence-free survival.

In this retrospective study, the patients received a variety of imaging procedures preoperatively. All patients were followed by medical oncologists with surveillance mainly consisting of computed tomography. More recently, many of the patients underwent positron emission tomography when suspicious lesions were found. Elucidation of the role and accuracy of positron emission tomography in this setting is beyond the scope of this paper and awaits further study.

Although operations on older patients are predicted to be riskier than those on younger patients, patients in this series older than age 65 enjoyed a survival advantage. This may reflect selection bias in that, for a given disease burden, younger patients are more often offered aggressive treatment.

Most of the primary tumors in this series originated in the rectum (52%). This percentage is similar to the rate reported in most other series in the literature (25% to 60%) [2, 3, 6–13]. Given the direct hematogenous route for pulmonary metastasis from rectal veins, these percentages may seem low. However, the increasing acceptance of hepatic resection for metastatic colorectal cancer [18–21] may be responsible. In the present series, 144 patients (38%) had undergone a liver resection before pulmonary resection.

The efficacy of chemotherapy in increasing the cure rate cannot be accurately ascertained from this small series. Patients received widely varied regimens of chemotherapy both before and after colorectal resection. Small numbers of patients with similar regimens prohibit meaningful statistical analysis.

The strongest predictors of recurrence after lung resection probably reflect the underlying biology of the disease. The most potent predictor of recurrence was number of metastases. Patients who had three or more pulmonary metastases were twice as likely to experience a recurrence. Multiple other groups have reported similar data when modeling overall survival [3, 4, 6, 7, 13]. The second strongest predictor of recurrence was a DFI of less than 1 year. Patients with DFI less than 1 year have a 1.6-fold chance of recurrence. Others have also reported DFI as predictive of overall survival [8, 12, 13]. Most important, none of the patients with three or more nodules and a DFI of less than 1 year were cured by surgery. As such, patients fulfilling these criteria cannot be reasonably offered a curative operation and so should be managed nonsurgically.

Based on the present data, we recommend systemic chemotherapy treatment only, without surgery, for patients with three or more nodules and a DFI less than 1 year. All other patients with oligometastatic colorectal cancer confined to the lung should be considered for resection. We favor the use of adjuvant or neoadjuvant chemotherapy when possible, especially in patients with either short DFI or multiple nodules, although at this time this preference is based on extrapolation from resection of liver metastases of colorectal cancer [22], as adequately powered randomized trials of such approaches have not been conducted in colorectal patients with pulmonary metastases.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. The International Registry of Lung Metastases Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases J Thorac Cardiovasc Surg 1997;113:37-49.[Abstract/Free Full Text]
  2. Girard P, Ducreux M, Baldeyrou P, et al. Surgery for lung metastases from colorectal cancer: analysis of prognostic factors J Clin Oncol 1996;14:2047-2053.[Abstract/Free Full Text]
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  4. McAfee MK, Allen MS, Trastek VF, Ilstrup DM, Deschamps C, Pairolero PC. Colorectal lung metastases: results of surgical excision Ann Thorac Surg 1992;53:780-786.[Abstract/Free Full Text]
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Robert Downey
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