International Journal of Surgery 11 (2013) 244e248 Contents lists available at SciVerse ScienceDirect International Journal of Surgery journal homepage: www.theijs.com Original research Pulmonary metastasectomy for colorectal cancer: Long-term survival and prognostic factors R.N. Younes, F. Abrao *, J. Gross Oncology Center of Hospital Sao Jose, Department of Surgery, University of Sao Paulo, LIM-62, Rua Martiniano de Carvalho, 965, Sao Paulo (SP) 01321-001, Brazil article info abstract Article history: Received 16 October 2012 Received in revised form 20 December 2012 Accepted 12 January 2013 Available online 19 January 2013 Keywords: Metastases/metastasectomy Outcomes Colorectal neoplasms Background: Despite the development of novel chemotherapy and biological agents, surgery is still an important option for patients with pulmonary metastases. Predictors of survival usually include disease-free interval, histology of the primary tumor, number of metastases and complete resection. The aim of this study was to report the outcomes of patients with pulmonary metastases from colorectal carcinoma submitted to surgical resection, and to identify prognostic factors that significantly affect overall survival. Methods: We retrospectively analyzed 120 patients with previously treated colorectal carcinoma that had developed pulmonary metastases, admitted between 1990 and 2006. Overall survival was estimated using KaplaneMeier analysis. The log-rank and Breslow tests were used to compare survival differences for each variable. Multivariate analyses to determine the independent prognostic factors for overall survival were performed using the Cox proportional hazard model as identified by the univariate analyses. Results: The median follow-up was 20.3 months (range: 3.27e134.2 months). The patients included in this study underwent a total of 165 thoracotomies (mean of 1.37 thoracotomies/patient). The median overall survival for all patients was 34.73 months, with an estimated 5-year survival rate of 24.39%. Multivariate analyses identified unilateral lesions, neoadjuvant chemotherapy at lung resection and complete resection as independent prognostic factors for overall survival. Conclusions: These results indicate that prognostic factors identified in studies on pulmonary metastasectomy for all primary tumors should be interpreted carefully for patients with possibility of pulmonary metastasectomy from colorectal carcinoma. Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. 1. Introduction More than half of all patients who undergo resection for colorectal carcinoma are expected to have recurrence of their disease, and the most frequent sites of distant recurrences are the liver and the lungs. 1,2 Patients with untreated metastatic disease have a median survival of less than one-year and a five-year survival of less than 5%. 3 Despite the development of novel chemotherapy and biological agents, surgery is still an important option for patients with pulmonary metastases. Although a large number of published series have reported the results of surgical resection of lung metastases from colorectal carcinoma, the effectiveness of such approach remains unclear and reliable predictors of long-term survival are controversial. 4 Predictors of survival usually include disease-free interval, histology of the primary tumor, number of metastases and complete resection. Among these, the most consistent predictor of survival is * Corresponding author. Rua Souza Ramos, 144, App 11, Sao Paulo (SP) 04120 080, Brazil. Tel.: þ55 11 8225 5088; fax: þ55 11 5573 4866. E-mail address: fernandocabrao@uol.com.br (F. Abrao). complete resection. 5,6 The number of metastatic nodules and their impact on survival was initially considered to be an independent predictor of survival. 5 However, if complete resection can be achieved, the number of pulmonary metastatic nodules does not seem to influence survival. 5,6 Since the early 1990s, our institution has employed a prospective protocol-oriented approach for the treatment of patients with resectable lung metastases to define factors related to outcome following lung metastasectomy. The aim of this study was to report the outcomes of patients with pulmonary metastases from colorectal carcinoma submitted to surgical resection, and to identify prognostic factors that significantly affect overall survival (OS). 2. Material and methods We retrospectively analyzed 120 patients with previously treated colorectal carcinoma that had developed pulmonary metastases, admitted between 1990 and 2006. All patients were included and followed according to a prospective protocol. This study was approved by the ethics review board at our institution. Data were collected following a medical record review of each patient. The following characteristics of the primary colorectal tumors were recorded: completeness of surgical resection, neoadjuvant and adjuvant treatment. 1743-9191/$ e see front matter Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijsu.2013.01.003
R.N. Younes et al. / International Journal of Surgery 11 (2013) 244e248 245 All patients were evaluated for the presence of lung nodules before treatment of the primary colorectal carcinoma, followed by evaluations at routine follow-up appointments. The disease free interval was defined as the time period between treatment of the primary tumor and the diagnosis of pulmonary metastases. Patients with the following characteristics were considered eligible for pulmonary resection: (1) controlled primary tumor, (2) nodules confined to the lung parenchyma without other sites of metastases, (3) nodules that were amenable to surgical resection by computed tomography (CT), (4) pulmonary function and clinical condition compatible with the scheduled operation, and (5) the unavailability of more effective treatment options for the patient at that time. All patients underwent a chest CT prior to surgery for assessment of resectability of the nodules. Radiological characteristics were analyzed in each patient as follows: the number of pulmonary nodules, the size of the largest nodule and the laterality of the nodules. The number of nodules reported in this study was the final number confirmed by the surgeon after complete resection. A staged lateral thoracotomy was employed when bilateral nodules were discovered at admission. This procedure was typically initiated on the side where complete resection was deemed more difficult and included the number and size of the nodules identified by the chest CT scan, the anatomical position of one or more nodules relative to the pulmonary hilum, and the potential need for a more complex and extensive lung resection. Patients underwent open surgery with general anesthesia and single lung ventilation. A complete resection was attempted in all cases after palpation, while preserving the lung parenchyma with a 10-mm margin. At our institution, mediastinal lymph node dissection is not routinely performed in patients with lung metastases. Wedge resection was used in peripheral nodules and lobectomy as well as pneumonectomy in hilar nodules. In cases of a single pulmonary nodule at surgery, frozen sections were collected. If the histological evidence suggested the possibility of primary lung cancer with different histology of the nodule as compared to the primary colorectal tumor, the patient was submitted to lobectomy with radical mediastinal lymph node dissection whenever possible. The date of surgery, type of resection (complete or incomplete), number of malignant or benign nodules resected, size of the largest nodule resected, laterality of the pulmonary nodules and type of lung resection (wedge, non-anatomic segmentectomy, lobectomy or pneumonectomy) were documented. Some patients received chemotherapy based on discretion of a medical oncologist, preceding surgical resection of the lung metastases. The type of radiological response (partial, stable, complete, or progression) as defined by RECIST12. These both criteria were documented. After surgery, the patients were discharged from the hospital following chest tube removal and in good clinical condition. After hospital discharge, the patients were followed-up with clinical and radiological examinations (chest X-ray and CT scan) every three months during the first two years and everysix months subsequently until the fifth year. An annual radiological (chest X-ray) follow-up was performed after five years. The observed postoperative complications were fever >38 C, bleeding, air leakage for more than seven days, intensive care unit stay for more than two days, cardiac complications (arrhythmia, ischemia, and infarction), pulmonary atelectasis, embolism or respiratory failure, stroke and infection. Recurrence was recorded when new lesions were identified in the lung or elsewhere. Whenever necessary, a histological confirmation of the new tumor was performed. If the recurrence was confined to the lungs and if the nodules were considered resectable by the thoracic surgeon, the patient was offered another attempt at complete disease resection. 3. Statistical analyses The main outcome evaluated was death associated with the tumor. Survival was calculated from the time of first metastasectomy to death or until the last follow-up. Overall survival was estimated using KaplaneMeier analysis. The log-rank and Breslow tests were used to compare survival differences for each variable. Multivariate analyses to determine the independent prognostic factors for overall survival were performed using the Cox proportional hazard model as identified by the univariate analyses. Survival time was determined whenever more than one pulmonary metastasectomy was performed, with time zero denoting the first thoracotomy. Statistical analyses were performed using SPSS 11.5 for Windows. Significant differences were defined as p <0.05. (24%) patients. The size of the nodules ranged between 1 and 6 cm, where size of 368 nodules was up to 3 cm. We found 370 peripheral nodules and 18 hilar nodules. All hilar nodules were treated through lobectomy. All the other nodules were treated with wedge resection and non-anatomic segmentectomy. The median follow-up was 20.3 months (range: 3.27e134.2 months). Fifty-two (43.3%) patients were alive at the time of the final analyses, and 21 (17.5%) showed no evidence of disease. Thirty-seven patients (30.8%) died due to metastatic colorectal carcinoma, and two (1.6%) patients were considered lost to followup after missing two medical evaluations. The postoperative complication rate was 4.16% (n ¼ 5). Fever and prolonged air leakage (>7 days) occurred in 3 patients, infection and prolonged hospital stay (>30 days) occurred in 2 patients. There was no 30-day mortality associated with the surgery used in this series. The median overall survival for all patients was 34.73 months, with an estimated 5-year survival rate of 24.39% (Fig. 1). No significant difference in survival was detected between the groups with respect to the number of thoracotomies (p ¼ 0.18). Some factors evaluated in the univariate analyses, including type of procedure and size of the largest nodule were not statistically significant (p > 0.05). The patients characteristics and complete univariate analyses are shown in Tables 1and 2. Multivariate analyses identified laterality of the nodule including bilateral involvement, chemotherapy prior to lung resection and complete resection as independent prognostic factors for overall survival (Figs. 2 and 3). 5. Discussion Improved survival following the resection of lung metastases has increased the surgical indications for such lesions, thus confirming that surgery itself affects the outcomes of patients who are candidates for a complete resection of nodules confined to the lungs. To date, several parameters, such disease-free interval, number of lesions and completeness of resection and have been reported as prognostic factors. 5,7 In this study better OS was observed for patients with unilateral metastatic disease that received chemotherapy prior to lung resection and were submitted to complete resection. Many groups have investigated the difference between unilateral and bilateral lesions in terms of survival. 8 However, two articles reported unilateral pulmonary metastases as a positive prognostic factor for OS. 9,10 According to our study, it is expected that patients with bilateral metastases will gain less surgical benefit even if all 4. Results The patients included in this retrospective study (n ¼ 120) underwent a total of 165 thoracotomies (mean of 1.37 thoracotomies/ patient); 388 nodules were resected, with a mean of 2.35 nodules per thoracotomy and more than four nodules were resected in 20 Fig. 1. Overall survival after pulmonary metastasectomy for colorectal cancer.
246 R.N. Younes et al. / International Journal of Surgery 11 (2013) 244e248 Table 1 Univariate analysis and demographic data of the 120 patients submitted to pulmonary metastasectomy. Variables N Median survival p (Log Rank/ Breslow) (months) Age (years) 0.08/0.32 Less than 40 4 21.73 Between 40 and 65 58 29.16 >65 58 50.86 Gender 0.65/0.92 Female 43 39.53 Male 77 34.73 Chemotherapy preceding 0.42/0.11 resection of colorectal tumor (neoadjuvant) Yes 31 37.70 No 89 29.16 Chemotherapy following 0.003/0.0012 resection of colorectal tumor (adjuvant) Yes 78 22.23 No 42 39.86 Disease-free interval greater than 24 months 47 50.86 0.01/0.24 Disease-free interval less than 24 months 71 29.26 Number of nodules identified on CT scan 0.24/0.55 1 55 34.90 2 23 29.53 3 42 29.20 Laterality of the nodules 0.005/0.018 Unilateral 71 37.70 Bilateral 49 29.30 Chemotherapy preceding 0.0001/0.0007 lung resection Yes 110 34.90 No 10 19.10 Objective tumor response to 0.0001/0.0007 neoadjuvant chemotherapy prior to thoracotomy Yes 110 34.90 No 10 19.10 metastatic nodules are extirped. This is partly because the existence of bilateral lesions might imply more tumor progression or development than that of unilateral ones. 9 Chemotherapy prior to lung resection was a positive prognostic factor in our study. However, to the best of our knowledge, no study reported this variable as a positive factor for OS. 8,11e13 The use of chemotherapy prior to lung resection has a number of potential advantages in patients with pulmonary metastases. First, it helps the selection of systemic agents and consequently provides information on tumor sensitivity. Another advantage is the possibility of selecting candidates for resection by having a short treatment interval. Moreover, determining the role of chemotherapy prior to lung resection for patients with pulmonary metastases of colorectal origin can only be achieved through future prospective studies. Objective tumor response to neoadjuvant chemotherapy was not tested before as prognostic factor and it was not a prognostic factor in the present study. On the other hand, the literature reports that evaluation of objective metastatic disease response could influence the therapeutic decision and consequently, treatment results. 14 Therefore, future studies could demonstrate that objective tumor response to chemotherapy preceding pulmonary resection influence the results of metastasectomy in colorectal cancer. Nodules identified on CT scan were not a prognostic factor on long-term survival. Some studies showed that the number of nodules identified by CT is frequently used as a prognostic factor. 15,16 However, the possibility of additional benign lesions found during surgery is real. Chung et al. reported benign lesions in 20% of Table 2 Univariate analysis and patients outcomes of the 120 patients submitted to pulmonary metastasectomy. Variables N Median survival (months) p (Log Rank/ Breslow) Complete resection 0.002/0.01 Yes 116 34.90 No 4 12.16 Type of procedure 0.44/0.27 Wedge/non-anatomic segmentectomy 98 32.66 Lobectomy 18 30.17 Exploratory thoracotomy 4 11.95 Number of nodules resected 0.73/0.76 1 24 29.16 2 50 34.90 3 46 39.50 Number of nodules 0.09/0.15 resected actually malignant 1 58 46.93 2 38 34.73 3 24 39.50 Size of the largest nodule (cm) Less than 1 24 39.53 0.50/0.29 Between 1 and 3 74 29.53 >3 20 23.83 Number of thoracotomies 1 79 34.73 0.18/0.38 2 33 29.53 3 4 59.20 4 2 39.53 Last thoracotomy 0.002/0.10 resulted in complete resection Yes 114 34.73 No 6 12.16 surgeries for resection of lung metastases. 15 Possibly benign lesions are responsible for different results about TC. Microscopic complete surgical resection has been considered to play an important role in the treatment of pulmonary metastases. 17 Nonetheless, there have been reports in the literature about patients who underwent incomplete resection and the impact on survival was not detected. 18,19 It is possible that some patients may benefit from incomplete resection, because they have a lesser tumor burden left behind. However, each one of these studies included small number of patients with incomplete resection (less than 15% of the patients). Our study reported a significant improvement in long-term survival after complete surgical resection. Melloni et al. in 2006 confirmed the importance of complete resection as a prognostic factor. 7 Few studies in the last ten years analyzed patients with repeated resection separately for five-year survival and none of them found Fig. 2. Overall survival after pulmonary metastasectomy for colorectal cancer according to the chemotherapy prior to lung resection.
R.N. Younes et al. / International Journal of Surgery 11 (2013) 244e248 247 Funding The authors disclose that they have no sources of funding in the study. Author contribution Riad Naim Younes e study design, data analysis. Fernando Abrao e data analysis, writing. Jefferson Gross e data collections, study design. Conflict of interest The authors disclose that they have no conflicts of interest in the study. Fig. 3. Overall survival after pulmonary metastasectomy for colorectal cancer according to complete resection. repeat pulmonary resection as an ominous prognostic factor. The 5- year survival reported by Saito et al. was 24.5% and the median interval between the first and second resection was 14 months. 11 We did no find repeat pulmonary resection as prognostic factor. Despite the difference on the long-term survival, the statistical significant was not seen. Of all surgical procedures, the most common thoracic procedure reported in the literature was segmentectomy. Vogelsang et al. found that patients (n ¼ 52) undergoing segmentectomy seemed to have a better outcome than patients (n ¼ 23) with anatomic lung resections. 20 Literature did not show other studies confirming the report of Vogelsang et al., including our report. Maximum tumor size was analyzed in many studies and was not a significant prognostic factor in most studies. 8 Younes et al. reported tumor size as a prognostic factor and established a limit of three centimeters for impact on long-term survival. However, this report included other malignances. 21 Two studies involving only patients with colorectal pulmonary metastases found tumor size as a prognostic factor. 20,22 We did not find tumor size to be a prognostic factor. This article has some limitations. Unfortunately, PET-CT was not available at our institution for most of the patients in this study. The positron emission tomography using 18-Fluorodeoxyglucose (FDG PET-CT) has proven to be of clinical value for the proper staging of cancer patients to select better the candidates for resection. According to Pastorino et al., this method can eliminate 21% of patients who are otherwise considered to be surgery candidates. 23 Another problem is that our study describes patients treated over a long period of 17 years. The limitations presented above could perhaps explain our low 5-years overall survival. Furthermore, the following study did not examine some known prognostic factors such as lymphadenectomy because our team does not utilize this approach due to its controversial prognosis, 10,24 as there are no sufficient data about the positive influence of lymph node dissection. 25 The current practice of pulmonary metastasectomy for colorectal carcinoma is well justified. 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