More than half the patients who undergo resection

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1 Early Intrapulmonary Recurrence After Pulmonary Metastasectomy Related to Colorectal Cancer Mi Ri Hwang, MD, Ji Won Park, MD, Dae Yong Kim, MD, Hee Jin Chang, MD, Sun Young Kim, MD, Hyo Seong Choi, MD, Moon Soo Kim, MD, Jae Ill Zo, MD, and Jae Hwan Oh, MD Center for Colorectal Cancer and Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea Background. Early intrapulmonary recurrence is a major problem after pulmonary metastasectomy related to colorectal cancer. However, the risk factors for early intrapulmonary recurrence are not clear. Methods. Between August 2001 and December 2007, 125 patients underwent pulmonary metastasectomy after colorectal cancer. The prognostic factors for overall survival were evaluated, including early (within 6 months) intrapulmonary recurrence. The factors related to early intrapulmonary recurrence were also analyzed. Results. Thirteen patients (10.4%) had early intrapulmonary recurrence. The median follow-up was 46 months (range, 21 to 99). Early intrapulmonary recurrence (hazard ratio 2.716; 95% confidence interval: to 7.182; p 0.044), extrapulmonary metastasectomy, metastatic hilar or mediastinal lymph nodes, and high prethoracotomy carcinoembryonic antigen levels were independent prognostic factors on multivariate analysis. Extrapulmonary metastasectomy (odds ratio 4.840; 95% confidence interval: to ; p 0.018) and bilateral pulmonary metastasis (odds ratio 6.228; 95% confidence interval: to ; p 0.006) were independent risk factors for early intrapulmonary recurrence. Conclusions. Early intrapulmonary recurrence after pulmonary metastasectomy related to colorectal cancer is a prognostic factor for poor overall survival. Extrapulmonary metastasectomy and bilateral pulmonary metastasis are risk factors for early intrapulmonary recurrence. Pulmonary metastasectomy in patients with these risk factors should be considered carefully. (Ann Thorac Surg 2010;90: ) 2010 by The Society of Thoracic Surgeons More than half the patients who undergo resection for colorectal cancer can be expected to experience recurrence of the disease [1, 2]. The most frequent site of recurrence is the liver, followed by the lung. Approximately 10% of patients with colorectal cancer have lung metastasis [3, 4]. Patients with untreated metastatic disease have a median survival of less than 10 months and a 5-year survival rate of less than 5% [5, 6]. Hepatic and pulmonary resection is currently a potentially curative treatment for colorectal metastasis. Similar to the hepatic resection results, most studies have reported that the overall 5-year survival for all patients undergoing complete (R0) resection for pulmonary metastases was 24% to 56.0% [7, 8]. Several prognostic factors after pulmonary resection related to colorectal cancer have been suggested: disease-free interval, carcinoembryonic antigen (CEA), number of lesions, and thoracic lymph node involvement [9]. The recurrence rate after pulmonary resection is reported to be 68.6% [10]. More than 50% of patients suffer relapse in the chest after pulmonary metastasectomy [10 12]. A small proportion of these patients fulfill the Accepted for publication April 12, Address correspondence to Dr Park, Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, 809 Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do , Republic of Korea; sowisdom@ncc.re.kr. criteria for repeated resection. Repeated resection in patients with early intrapulmonary recurrence may be especially difficult because of the increased rate of major complications and reduced resectability. The risk factors for early intrapulmonary recurrence after pulmonary metastasectomy have yet to be studied in detail. The aims of this study were to determine the correlation between early intrapulmonary recurrence and overall survival and to evaluate the clinicopathologic factors predicting early intrapulmonary recurrence after pulmonary metastasectomy related to colorectal cancer. Patients and Methods Patients Between August 2001 and December 2007, 125 consecutive patients underwent pulmonary metastasectomy related to colorectal cancer at the National Cancer Center, Republic of Korea. The study was approved by the Institutional Review Board. All patients underwent a chest computed tomography (CT) scan before surgery. The criteria for pulmonary metastasectomy were according to the National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology [13]. Pulmonary metastasectomy was performed when the metastatic lesions were confined to the lung, and all lesions were technically resectable using oncologic principles while 2010 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg HWANG ET AL 2010;90: EARLY INTRAPULMONARY RECURRENCE preserving the lung function. If the patient had a resectable extrapulmonary metastatic lesion, complete resection of the extrapulmonary metastatic lesion was performed before the pulmonary metastasectomy. All patients had a pathologically proven metastatic pulmonary adenocarcinoma derived from colorectal cancer. The surgical procedures performed for the primary tumor were low anterior resection (n 69), anterior resection (n 17), abdominoperineal resection (n 16), right hemicolectomy (n 9), Hartmann s operation (n 4), total proctocolectomy (n 4), transanal excision (n 3), pelvic exenteration (n 2), and left hemicolectomy (n 1). After resection of the primary tumor, 84 patients (67.2%) received adjuvant chemotherapy and/or radiotherapy according to tumor location and stage. The median interval from primary tumor resection to pulmonary metastasectomy was 25 months (range, 1 to 87 months). Surgical Procedure All patients underwent complete R0 resection of the pulmonary metastasis. Two operation types were performed: nonanatomic resection (wedge resection) and anatomic resection (segmental, lobectomy, or pneumonectomy). If the metastatic lesion was located in the lobar bronchus or there were multiple lesion in one or two lobes, anatomic resection was performed. Wedge resection (precision excision technique) was the preferred option in most patients, and the hilar or mediastinal lymph nodes were dissected in 101 patients. Thoracotomy was performed in 107 patients, and remaining 18 patients underwent video-assisted thoracic surgery (VATS). 399 the liver, 1 in the kidney, and 1 in an isolated mesenteric nodule. Six patients had local recurrence at the anastomosis site, and 2 patients had recurrence in the pelvic lateral lymph node. Clinical Follow-Up After pulmonary metastasectomy, postoperative chemotherapy was commenced within 8 weeks of surgery. The regimen was chosen according to the preference of the medical oncologist, and was maintained for at least 6 months. These patients were closely followed up with diagnostic imaging after metastasectomy. Their CEA levels, abdomen CT, and chest CT were checked every 3 or 6 months. After 5 years, the patients were followed up every 6 months or annually. Overall survival was evaluated. Survival was measured from the date of pulmonary metastasectomy to death or to the date of the last follow-up evaluation. The median follow-up time was 46 months (range, 21 to 99). Statistical Analysis The 2 test and Student s t test were used to compare the data between the subgroups based on the time to recurrence. Analysis of survival was performed using the Kaplan-Meier method, and differences between the curves were tested with the log rank test. Factors related to survival were analyzed with the Cox proportional hazards regression model, using the forward stepwise method. Factors related to early intrapulmonary recurrence were analyzed with logistic binary regression. A p value of less than 0.05 was considered statistically significant. GENERAL THORACIC Data Collection and Definition We retrospectively reviewed the medical records of these patients for the following clinicopathologic data: age at thoracotomy, sex, location of the primary colorectal cancer, prelaparotomy CEA level, stage of the primary tumor, histological type of the primary tumor, use of adjuvant chemotherapy, extrapulmonary metastasectomy, interval between resection of the colorectal primary tumor and pulmonary metastasectomy, time of pulmonary metastasis (metachronous/synchronous), prethoracotomy CEA level, maximal standardized uptake value (maxsuv), number and distribution of pulmonary metastases, maximum diameter of the pulmonary metastases, method of lung resection (anatomic/ nonanatomic), presence of hilar or mediastinal tumorinfiltrated lymph nodes, and the interval between the pulmonary metastasectomy and pulmonary recurrence. Early intrapulmonary recurrence was defined as intrapulmonary recurrence within 6 months of the pulmonary metastasectomy. Extrapulmonary metastasectomy was defined as curatively resected metastasis (except to the lung) performed before lung metastasectomy. In this study, 37 patients underwent extrapulmonary metastasectomy. Thirty-one patients experienced systemic recurrence, and 8 experienced local recurrence. Twenty-nine patients experienced systemic recurrence in Results Patient Characteristics The patients included 50 women and 75 men, with a median age of 60 years (range, 32 to 80 years) at the time of pulmonary metastasectomy. The primary colorectal cancer was located in the colon in 35 patients and in the rectum in 90 patients. There were 28 stage I to II tumors, 56 stage III tumors, and 38 stage IV tumors. Forty-one patients had only surgery, and 84 also received adjuvant chemotherapy. Eighty-seven (69.6%) had metachronous pulmonary metastasis, and 38 (30.4%) had synchronous pulmonary metastasis. The median prethoracotomy CEA level was 3.2 ng/ml (range, 0.5 to 51 ng/ml). Anatomic resection was performed in 8 patients (6.4%) and nonanatomic resection was performed in 117 (93.6%). The hilar or mediastinal lymph nodes were dissected in only 101 patients, and only 17 (13.6%) of these patients had cancer-positive thoracic lymph nodes. One hundred thirteen patients underwent preoperative positron emission tomography/ct, and the median maxsuv level for pulmonary metastasis was 4.0 (range, 0 to 32). After pulmonary metastasectomy, the median diameter of the pulmonary metastatic lesion was 1.8 cm (range, 0.5 to 7.0 cm). Seventy-seven patients (61.6%) had a single pulmonary

3 400 HWANG ET AL Ann Thorac Surg EARLY INTRAPULMONARY RECURRENCE 2010;90: metastatic lesion, and 94 (75.2%) had a unilateral pulmonary metastatic lesion. There was no postoperative mortality. Post-thoracotomy chemotherapy was not given to 13 patients (10.4%) for economic reasons or patient refusal. Recurrence occurred in 69 patients (55.2%): pulmonary recurrence occurred in 46 (66.7%) and occurred within 6 months in 13 (18.8%). The median time to recurrence was months (range, 1 to 49 months). Univariate Analysis of Overall Survival Fifty patients had died at the time of the last follow-up in September 2009, so the median survival was 37 months. Early intrapulmonary recurrence, extrapulmonary metastasectomy, prethoracotomy CEA, the number of pulmonary tumors above 3, and the presence of hilar or mediastinal tumor-infiltrated lymph nodes were significant prognostic factors for overall survival. The overall survival rate of patients with early intrapulmonary recurrence was lower than that of patients with late intrapulmonary recurrence or no pulmonary recurrence (p 0.001; Fig 1). The correlations between the clinicopathological factors and overall survival are given in Table 1. Multivariate Analysis of Overall Survival Multivariate analysis was applied to the five significant predictors of outcome on univariate analysis. On multivariate analysis, early pulmonary recurrence (hazard ratio [HR] 2.716; 95% confidence interval [CI]: to 7.182; p 0.044), extrapulmonary metastasectomy (HR 4.134; 95% CI: to 8.444; p ), metastatic hilar or mediastinal lymph nodes (HR 3.696; 95% CI: to 7.627; p ), and prethoracotomy CEA (HR 2.125; 95% CI: to 4.299; p 0.036) remained significant. The indicators that did not meet the forward stepwise Fig 1. Overall survival after pulmonary metastasectomy related to colorectal cancer according to the interval of intrapulmonary recurrence: pulmonary recurrence within 6 months (early intrapulmonary recurrence [dotted line]) versus recurrence after 6 months or no recurrence (p [solid line]). Fig 2. Overall survival after pulmonary metastasectomy related to colorectal cancer according to the presence of risk factors affecting early intrapulmonary recurrence. Group 1 (solid line): neither extrapulmonary metastasectomy nor bilateral pulmonary metastasis; group 2 (dashed line): either extrapulmonary metastasectomy or bilateral pulmonary metastasis; group 3 (dot-dashed line): both extrapulmonary metastasectomy and bilateral pulmonary metastasis. entry criteria using the likelihood ratio statistic included the number of tumors. Risk Factors for Early Intrapulmonary Recurrence After Pulmonary Metastasectomy The patients were divided into two groups based on the time of pulmonary recurrence: group A experienced early recurrence (within 6 months), and group B experienced recurrence after 6 months or had no pulmonary recurrence. Table 2 shows the features of the two groups in detail. Extrapulmonary metastasectomy was more frequent in group A than in group B, and the numbers and distributions of the pulmonary metastases differed between the two groups. On logistic binary regression analysis, extrapulmonary metastasectomy (odds ratio 4.840; 95% CI: to ; p 0.018) and bilateral pulmonary metastasis (odds ratio 6.228; 95% CI: to ; p 0.006) correlated with early pulmonary recurrence (Table 3). Based on these results, the patients were divided into groups according to the risk factors: group 1 (n 63) had neither extrapulmonary metastasectomy nor bilateral pulmonary metastasis, group 2 (n 56) had either extrapulmonary metastasectomy or bilateral pulmonary metastasis, and group 3 (n 6) had both extrapulmonary metastasectomy and bilateral pulmonary metastasis. The early intrapulmonary recurrence rate was 3.2% in group 1, 14.3% in group 2, and 50% in group 3 (p 0.001). Figure 2 shows the estimated overall survival rates according to group (p 0.001).

4 Ann Thorac Surg HWANG ET AL 2010;90: EARLY INTRAPULMONARY RECURRENCE Table 1. Correlation Between Clinicopathological Factors and Overall Survival After Pulmonary Resection for Colorectal Pulmonary Metastasis Variable Value No. of Patients 5-Year Overall Survival (%) 401 p Value GENERAL THORACIC Host factor Age, years Sex Primary tumor factor Primary tumor location Prelaparotomy CEA a Male Female Colon Rectum Primary tumor stage b Primary tumor histological type WD/MD PD/SRC/MUC Adjuvant chemotherapy Extrapulmonary metastasectomy Pulmonary metastasectomy factor Pulmonary metastasis time Prethoracotomy CEA MaxSUV c Number of tumors Maximum diameter of tumor (cm) Distribution of metastasis Lung resection method Hilar or mediastinal tumor-infiltrated lymph nodes d Intrapulmonary recurrence Metachronous Synchronous Unilateral Bilateral Anatomic Nonanatomic 6 months 6 months or no % 58.1% 56.1% 35.9% 36.7% 52.8% 55.4% 47.6% 55.7% 48.8% 36.4% 47.8% 38.9% 36.7% 53.3% 58.0% 13.7% 52.3% 36.4% 51.2% 38.3% 40.1% 55.5% 51.6% 24.3% 44.8% 55.0% 51.1% 38.0% 60.0% 46.5% 53.3% 19.6% 0% 52.6% a Prelaparotomy CEA: 89 cases available (36 cases: other hospital operation, no record). b Primary tumor stage: 122 case available (3 cases: other hospital operation, no record). c MaxSUV: 113 cases available. d Hilar or mediastinal lymph nodes: 101 cases available (mediastinal lymph node dissection and pathology confirmed). CEA carcinoembryonic antigen; MaxSUV maximal standardized uptake value; MD moderately differentiated; MUC mucinous; PD poorly differentiated; SRC signet-ring cell; WD well differentiated. Comment Since Thomford and colleagues [14] proposed the criteria for the resection of pulmonary metastases, pulmonary metastasectomy has been widely accepted. Several studies have reported the overall survival and disease-free survival after the resection of solitary pulmonary metastases arising from colorectal cancer [2, 3, 10, 15 18]. The results of surgical resection were favorably compared with those of chemotherapy for pulmonary metastatic colorectal cancer, and support the view that, for selected patients, surgery is the most effective therapy because it offers greater potential long-term survival. Several prognostic factors after pulmonary metastasectomy have been suggested: age at thoracotomy, stage and histology of the primary tumor, preoperative CEA level, disease-free interval, number of pulmonary metastases, maximum diameter of the pulmonary metastases, lung resection method (anatomic/nonanatomic), hilar or mediastinal tumor-infiltrated lymph nodes, liver resection, and repeated pulmonary resection. However, various studies have produced contrasting results because of differences in study design and limited numbers of patients [19 24]. Our study found that extrapulmonary metastasectomy, hilar or mediastinal tumor-infiltrated

5 402 HWANG ET AL Ann Thorac Surg EARLY INTRAPULMONARY RECURRENCE 2010;90: Table 2. Clinicopathological Characteristics of 125 Patients With Colorectal Pulmonary Metastasis According to Interval of Intrapulmonary Recurrence Variable Value Intrapulmonary Recurrence Within 6 Months (n 13) Intrapulmonary Recurrence After 6 Months and No Recurrence (n 112) p Value Host factor Age, years Sex Primary tumor factor Primary tumor location Prelaparotomy CEA a Male Female Colon Rectum Primary tumor stage b Primary tumor histologic type WD/MD PD/SRC/MUC Adjuvant chemotherapy Extrapulmonary metastasectomy Interval between primary and pulmonary resection (months) Pulmonary metastasectomy factor Pulmonary metastasis time Prethoracotomy CEA MaxSUV c Number of tumors Maximum tumor diameter, cm Distribution of metastasis Lung resection method Hilar or mediastinal tumor-infiltrated lymph nodes d Metachronous Synchronous Unilateral Bilateral Anatomic Nonanatomic 8 (12.5%) 5 (8.2%) 9 (12.0%) 4 (8.0%) 1 (2.9%) 12 (13.3%) 6 (15.4%) 3 (6.0%) 2 (7.1%) 7 (12.5%) 4 (10.5%) 13 (11.2%) 0 (0%) 4 (9.8%) 9 (10.7%) 6 (6.8%) 7 (18.9%) 56 (87.5%) 56 (91.8%) 66 (88.0%) 46 (92.0%) 34 (97.1%) 78 (86.7%) 33 (84.6%) 47 (94.0%) 26 (92.9%) 49 (87.5%) 34 (89.5%) 103 (88.8%) 9 (100%) 37 (90.2%) 75 (89.3%) 82 (93.2%) 30 (81.1%) (10.3%) 4 (10.5%) 8 (9.2%) 5 (13.2%) 8 (14.3%) 4 (7.0%) 9 (8.3%) 4 (25.0%) 10 (11.8%) 3 (7.5%) 6 (6.4%) 7 (22.6%) 1 (12.5%) 12 (10.3%) 7 (8.3%) 2 (11.8%) 78 (89.7%) 34 (89.5%) 79 (90.8%) 33 (86.8%) 48 (85.7%) 53 (93.0%) 100 (91.7%) 12 (75.0%) 75 (88.2%) 37 (92.5%) 88 (93.6%) 24 (77.4%) 7 (87.5%) 105 (89.7%) 77 (91.7%) 15 (88.2%) a Prelaparotomy CEA: 89 cases available. b Primary tumor stage: 122 cases available. c MaxSUV: 113 cases available. d Hilar or mediastinal Lymph nodes: 101 cases available. CEA carcinoembryonic antigen; MaxSUV maximal standardized uptake value; MD moderately differentiated; MUC mucinous; PD poorly differentiated; SRC signet-ring cell; WD well differentiated. lymph nodes, early intrapulmonary recurrence, and prethoracotomy CEA levels were prognostic factors for survival after pulmonary metastasectomy. Contrary to our results, most studies have reported that a history of hepatic metastasis at the time of pulmonary resection is not a significant factor affecting survival, and the outcomes after combined hepatic and pulmonary resection were similar to those after hepatectomy alone or pulmonary resection alone [25 27]. Some studies have reported that hilar or mediastinal lymph node metastasis is a significant prognostic factor for survival. However, routine thoracic lymph node dissection in pulmonary metastasectomy after colorectal cancer is controversial. Hilar and mediastinal lymph node dissection may be required in selected patients with node enlargement on chest CT. Several studies showed that 5-year survival was 0% to 15.6% with thoracic lymph node involvement and 38.7% to 45.1% with no thoracic lymph node involvement [26, 27]. Our study included only 101 patients who had undergone thoracic lymph node dissection, and their 5-year survival rates were 19.6% with thoracic lymph node involvement and 53.3% without. In many studies, an elevated prethoracotomy CEA level was an important prognostic indicator associated with a poor prognosis [21, 24, 27]. The present results are consistent with these earlier studies.

6 Ann Thorac Surg HWANG ET AL 2010;90: EARLY INTRAPULMONARY RECURRENCE Table 3. Logistic Binary Regression Analysis of Factors Affecting Early Intrapulmonary Recurrence a Variable Odds Ratio 95% CI p Value Extrapulmonary metastasectomy Distribution of metastasis Unilateral Bilateral 1 (reference) (reference) a Indicator that did not meet forward stepwise entry criteria using the likelihood ratio statistic include number of tumors. CI confidence interval. Previous reports of hepatic resection have shown that patients with disease recurrence within 6 months have a poorer prognosis [28, 29]. Like hepatic resection, early intrapulmonary recurrence after pulmonary resection also had a poorer prognosis in this study, reflecting the fact that few patients could undergo a further resection for recurrent disease. In this study, pulmonary resection was repeated in 2 (15.4%) of the patients with early intrapulmonary recurrence and in 12 (36.4%) of the patients with late intrapulmonary recurrence. At the time of diagnosis of intrapulmonary recurrence, most patients with early intrapulmonary recurrence had extensive disease, but it was confined to the lung (no extrapulmonary recurrence). Conversely, 18.2% of patients with late intrapulmonary recurrence had extrapulmonary metastasis. Of the patients with extrapulmonary metastasis, 16.7% underwent curative resection. Lin and coworkers [30] reported that patients with lung metastasis within 1 year of primary tumor resection should be followed up carefully because of their poor prognosis. However, our study indicated that the time of pulmonary metastasis (metachronous/synchronous) was not a significant prognostic factor for overall survival. The 87 patients with metachronous lung metastasis were divided into two groups: 20 patients had lung metastasis within 1 year of surgery and 67 patients had lung metastasis after 1 year. When the survival of the two groups was compared, there was a borderline significant difference in their 5-year survival (53.4% versus 84.0%, respectively; p 0.062). To clarify the prognostic effect of the disease-free interval, further studies that include large numbers of patients are required. Patients with early intrapulmonary recurrence may be encountered during follow-up after pulmonary metastasectomy. In these cases, repeated pulmonary resection may not be feasible because of the patient s intolerance or remnant lung capacity, or for technical reasons. Patients with extrapulmonary metastasectomy or bilateral pulmonary metastasis are at risk of early intrapulmonary recurrence. In patients with these factors, chemotherapy followed by resection may be a treatment option after the status of the disease has been established. By selecting patients who would benefit from surgery, unnecessary resection can be avoided. Even after pulmonary metastasectomy, close monitoring for recurrence is required in patients with extrapulmonary metastasectomy or bilateral pulmonary metastasis. Therefore, careful selection of the treatment for pulmonary metastasectomy is necessary. Oxaliplatin-based or irinotecan-plus-fluorouracil based chemotherapy has improved the survival of patients with metastatic colorectal cancer, with acceptable tolerability [31, 32]. In patients with hepatic colorectal metastases, a combination of chemotherapy and surgery may prolong the time to hepatic metastasis after resection or increase the resectability of the tumors in patients previously judged inoperable. This strategy may be applied to patients with pulmonary metastases. Repeated pulmonary resection has been reported in only a few studies, and the 5-year survival rate was 24.5% to 54.6% [21, 27]. Even now, repeated pulmonary resection is not a clear prognostic factor. In this study, pulmonary resection was repeated in 14 patients, and the 3- and 5-year overall survival rates were 100% and 53.4%, respectively. These results show that repeated pulmonary resection is not itself an ominous sign, and some patients may benefit from repeated resection. However, the number of reported cases is small, and further studies are required. In conclusion, early intrapulmonary recurrence after pulmonary metastasectomy is a prognostic factor for poor overall survival. Extrapulmonary metastasectomy and bilateral pulmonary metastasis are risk factors for early intrapulmonary recurrence after pulmonary metastasectomy associated with colorectal cancer. Hence, pulmonary metastasectomy in patients with these risk factors should be considered carefully. 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7 404 HWANG ET AL Ann Thorac Surg EARLY INTRAPULMONARY RECURRENCE 2010;90: Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. Ann Thorac Surg 2007;84: Mori M, Tomoda H, Ishida T, et al. Surgical resection of pulmonary metastases from colorectal adenocarcinoma. Special reference to repeated pulmonary resections. Arch Surg 1991;126: Demmy TL, Dunn KB. Surgical and nonsurgical therapy for lung metastasis: indications and outcomes. Surg Oncol Clin North Am 2007;16: Inoue M, Ohta M, Iuchi K et al. Benefits of surgery for patients with pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2004;78: Version 2009 NCCNI: clinical practice guidelines in oncology. Available at: physician_gls/pdf/colon.pdf. Accessed September 25, Thomford NR, Woolner LB, Clagett OT. The surgical treatment of metastatic tumors in the lungs. 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Simultaneous detection of colorectal carcinoma liver and lung metastases does not warrant resection. J Am Coll Surg 2001;193: Iizasa T, Suzuki M, Yoshida S, et al. Prediction of prognosis and surgical indications for pulmonary metastasectomy from colorectal cancer. Ann Thorac Surg 2006;82: Pfannschmidt J, Muley T, Hoffmann H, Dienemann H. Prognostic factors and survival after complete resection of pulmonary metastases from colorectal carcinoma: experiences in 167 patients. J Thorac Cardiovasc Surg 2003;126: Malik HZ, Gomez D, Wong V, et al. Predictors of early disease recurrence following hepatic resection for colorectal cancer metastasis. Eur J Surg Oncol 2007;33: Takahashi S, Konishi M, Nakagohri T, Gotohda N, Saito N, Kinoshita T. Short time to recurrence after hepatic resection correlates with poor prognosis in colorectal hepatic metastasis. Jpn J Clin Oncol 2006;36: Lin BR, Chang TC, Lee YC, Lee PH, Chang KJ, Liang JT. Pulmonary resection for colorectal cancer metastases: duration between cancer onset and lung metastasis as an important prognostic factor. Ann Surg Oncol 2009;16: Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343: de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18: INVITED COMMENTARY It is well known that pulmonary metastasectomy of colorectal cancer can offer a significant prolongation of patient survival when a complete resection of the disease can be performed [1]. Unfortunately, because of the heterogeneity of the disease, only a select group of patients with metastatic disease are eligible for surgical resection. Because of such diversity in tumor biology, patient selection is crucial to avoid unnecessary metastasectomy in patients likely to have persistent systemic unresectable disease. Despite well-established prognostic factors predicting survival after metastasectomy, such as disease-free interval, number of lesions, and lymph node involvement, the factors predicting subsequent intrapulmonary relapse have not been well described in the literature. It is disappointing to patients and also to surgeons to face an early recurrence of intrapulmonary disease after a complete eradication of pulmonary metastases. This group of patients poses the additional challenge of more aggressive tumor biology, higher probability of additional systemic disease, and more difficult surgery with repeat resections. In this study by Hwang and colleagues [2], the authors characterize the factors predictive of survival and early intrapulmonary recurrence after pulmonary metastasectomy of colorectal cancer in a review of 125 consecutive patients treated at a single institution. All patients had an R0 resection followed by 6 months of adjuvant chemotherapy. Early intrapulmonary recurrence was defined as lung recurrence within 6 months of surgery and occurred in 13 patients (10.4%). Two factors were significant predictors of early pulmonary recurrence: extrapulmonary metastasectomy and bilateral pulmonary metastases. The significant factors associated with decreased survival were as follows: early intrapulmonary recurrence, positive lymph node metastases, preoperative carcinoembryonic antigen (CEA) level, and extrapulmonary metastasectomy. Because the patients were commonly on chemotherapy at the time of early recurrence, perhaps 2010 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur