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Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases
Lung Cancer 75 (2012) 209–212
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases Daigo Kawano ∗ , Sadanori Takeo, Shuichi Tsukamoto, Masakazu Katsura, Eri Masuyama, Yu Nakaji Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 1-8-1 Jigyo, Fukuoka 810-8563, Japan
a r t i c l e
i n f o
Article history: Received 8 April 2011 Received in revised form 8 July 2011 Accepted 13 July 2011 Keywords: Colorectal carcinoma Metastatic hepatic tumor Metastatic pulmonary tumor Metastectomy Number of metastases Metachronous
a b s t r a c t Background: The value of surgical treatment for patients with pulmonary and hepatic metastases from colorectal carcinoma is controversial. The purpose of this study was to analyze our initial experience with this aggressive strategy, and to define the prognosis and the surgical indications. Methods: The records of 35 patients who underwent surgical treatments for both hepatic and pulmonary metastases from colorectal carcinoma, from January 1997 to December 2008, were retrospectively analyzed. Results: There were 18 females and 17 males with a median age was 62.0 years. The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection, respectively. For patients who underwent metachronous hepatic and pulmonary surgical treatment, the 10-year survival rate was 40.9%, which was significantly better than that of those undergoing synchronous hepatic and pulmonary surgical treatment (p = 0.0265). Patients who have pulmonary less than ten of metastasis thus seemed to have a better prognosis than those with more than ten, but the difference was quite significant (p = 0.0719). In a multivariate Cox proportional hazards model, synchronous hepatic and pulmonary metastases was identified as an independent predictor of adverse survival (p = 0.0073). Conclusions: The results of our study suggest that hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma. We believe that aggressive metastasectomy can be an option for selected patients, even if a patient has been previously treated for hepatic and pulmonary metastases from colorectal carcinoma. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Background Colorectal carcinoma is a major cause of cancer-related mortality. Hepatic and pulmonary metastases are the major determinants of survival for patients who have undergone curative resection of colorectal carcinoma. Approximately 40% of patients who have undergone curative resection of colorectal carcinoma will develop hepatic metastases [1]. In addition, 25% of patients with isolated hepatic metastases have tumors that can be resected curatively, and 21–48% will survive over 5 years with low morbidity and mortality [1–3]. The lung is the most common extraabdominal site of metastases from colorectal carcinoma [4], and resectable metastatic disease is limited to the lung in approximately 1–2% of patients after curative resection of colorectal carcinoma [5,6]. After resection of pulmonary metastases, 5-year survival rates range
∗ Corresponding author. Tel.: +81 92 852 0700; fax: +81 92 847 8802. E-mail address: [email protected] (D. Kawano). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.07.010
from 24 to 63%, and most have reported survival around 40% [6–14]. However, although numerous studies have demonstrate long term survival after resection of isolated pulmonary or isolated hepatic metastases, only a few authors have report surgical resection of pulmonary and hepatic metastases after resection of colorectal carcinoma. Resection of metastatic pulmonary lesions from colorectal carcinoma was first performed by Blalock [15]. Thereafter, Thomford noted criteria indicating the resection of metastatic lung tumors: (i) the patients must be a good risk for surgical intervention, (ii) the primary malignancy is controlled, (iii) there is no evidence of metastatic disease elsewhere, and (iv) the roentgenologic evidence of pulmonary metastasis is limited to one lung [16]. Since that time, extended pulmonary metastasectomy has become practical in patients with bilateral pulmonary metastases or with distant metastasis such as hepatic metastasis. However, the value of an aggressive surgical treatment for patients with hepatic and pulmonary metastases is still controversial. The purpose of this study was to analysis our initial experience with this aggressive surgical
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strategy, and to define which patients can obtain a better prognosis as a result of surgery.
Table 1 Patient characteristics. Variables
2. Patients and methods A total 81 patients with primary colorectal carcinoma underwent resection of pulmonary metastases, from January 1997 to December 2008 in the Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center (Fukuoka, Japan). The study was approved by our Institutional Review Board. Informed consent was not required for this retrospective study. Among these patients, 35 (43.2%) had undergone surgical treatments for hepatic metastases, including resection or microwave coagulo-necrotic therapy (MCN). Preoperative evaluations were performed using chest roentgenograms and computed tomography (CT) images for pulmonary nodules, and ultrasound (US) and magnetic resonance imaging (MRI) for hepatic nodules. Only those patients whose metastatic sites were confined to the lung or with hepatic metastases that could be completely treated after surgery were included in this study. Patients who had a pulmonary biopsy only were excluded. The record of each patient was reviewed for age, gender, location and stage of the primary colorectal carcinoma, according to the International Union Against Cancer TNM staging system [17,18], the existence of metastases on the unilateral or bilateral lungs, number of pulmonary metastases, the number of pulmonary resections, prethoracotomy carcinoembryonic antigen (CEA) level, the timing of hepatic and pulmonary metastases (synchronous or metachronous), disease free interval, and duration of survival. Survival was calculated from the time of surgery for primary colorectal carcinoma to the last follow-up. Statistical calculations were carried out with Stat View software program (SAS Institute, Inc, Cary, NC). Overall survival was calculated using the Kaplan–Meier method. The differences between survival curves were analyzed using the log-rank test for univariate analyses. The multivariate analysis was performed according to the Cox proportional hazards model to estimate the relative risk with 95% confidence interval (CI). The results of the analysis were regarded as statistically significant at a p < 0.05.
Gender Female Male Age Median (range) age (year) Site of primary cancer Rectum Colon TMN stage Stage I Stage II Stage III Stage IV Unknown Location Unilateral Bilateral Tumor number Median (range) 1 2–9 ≥10 CEA serum concentration Normal (<6 ng/ml) Abnormal (>6 ng/ml) Presentation Synchronous Metachronous Disease free interval >1 year 1–2 years <2 years
No. of patients 18 (51.4%) 17 (48.6%) 62.0 (34–92) 12 (34.3%) 23 (65.7%) 0 (0%) 7 (20.0%) 13 (37.2%) 11 (31.4%) 4 (11.4%) 18 (51.4%) 17 (48.6%) 4.2 (1–20) 12 (34.3%) 19 (54.3%) 4 (11.4%) 11 (31.4%) 24 (68.6%) 8 (22.9%) 27 (77.1%) 16 (45.7%) 11 (31.4%) 8 (22.9%)
3. Results There were 18 females and 17 males with a median age was 62.0 years (range 34–92 years). The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). These patients’ characteristics are shown in Table 1. The pathological TMN staging of primary colorectal carcinoma was stage I in 0 patients (0%), stage II in 7 patients (20.0%), stage III in 13 patients (37.2%), and stage IV in 11 patients (31.4%), the staging of 4 patients (11.4%) was unknown. Eighteen patients (51.4%) had unilateral tumors, and 17 patients (48.6%) had lesions located in bilateral lungs. The median number of pulmonary metastases was 4.2 (range 1–20). Eleven patients (31.4%) showed a normal serum CEA level before pulmonary resection, and 24 patients (68.6%) showed an abnormal serum CEA level. Eight patients (22.9%) had synchronous hepatic and pulmonary surgical treatments, and 27 patients (77.1%) underwent metachronous surgical treatments (3 patients underwent hepatic treatment after pulmonary resection). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of the primary colorectal resection (median, 66.9 months) (Fig. 1). The overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of the first pulmonary resection (median, 39.5 months) (Fig. 2). For patients who underwent metachronous hepatic and pulmonary surgical treatment, 10-year survival rate was 40.9%, which was significantly better than those who underwent syn-
Fig. 1. The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection (median, 66.9 months).
Fig. 2. The overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of the first pulmonary resection (median, 39.5 months).
D. Kawano et al. / Lung Cancer 75 (2012) 209–212
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Table 2 Multivariate predictors of survival. Variables Age Gender Primary tumor site Pathological stage Location Tumor number CEA level Timing of metastases Disease free interval
<60 Female Colon IV Unilateral 1 10 or <10 Abnormal Synchronous <1 year
chronous hepatic and pulmonary surgical treatment (p = 0.0265) (Fig. 3A). Patients who had fewer than ten pulmonary metastatic lesions (n = 4) seemed to have a better outcome than those with more than ten metastatic lesions, but the difference was not significant (p = 0.0719) (Fig. 3B). No other factors were found to be correlated with survival. Additionally, no factors were found to be correlated with survival from the date of the first pulmonary resection. On multivariate Cox proportional hazards model (Table 2), the presence of synchronous hepatic and pulmonary metastases was identified as an independent predictor of decreased survival, associated with a hazard ratio of 3.731 (1.427–9.803; p = 0.0073). 4. Discussion The management of patients with both hepatic and pulmonary metastases from colorectal carcinoma is controversial. Although Thomford excluded patients with extrapulmonary metastases as
Fig. 3. The Kaplan–Meier survival analysis: the x-axis indicates the years after the time of surgery for primary colorectal carcinoma to the last follow-up. (A) Synchronous versus metachronous survival curves. (B) The survival curve based on the number of pulmonary metastases (<10 versus ≥10).
RR
95% CI
p-Value
1.070 1.124 0.773 1.174 1.102 0.750 2.691 1.156 3.731 0.720
0.383–2.986 0.448–2.821 0.292–2.047 0.433–3.182 0.441–2.752 0.276–2.034 0.873–8.296 0.413–3.235 1.427–9.803 0.207–2.504
0.8973 0.8028 0.6038 0.7526 0.8351 0.5717 0.0847 0.7828 0.0073 0.6055
candidates for thoracotomy [16], there have been several reports about successful pulmonary resection for patients with extrapulmonary metastases. McAfee et al. [19] reported that the presence of resectable extrapulmonary metastases before or at the time of thoracotomy was not associated with a decreased survival. Several other studies have demonstrated that previous resection of hepatic metastases was not found to be a statistically significant prognostic factor [8,13,20,21]. The 5-year survival ranged from 25% to 47.9% in these reports. In our study, the overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of first pulmonary resection (median, 39.5 months). This result compares favorably with the previous studies [6–14], since our patients had both hepatic and pulmonary metastases, and given that the median survival with chemotherapy is only 18–20 months [22,23]. In the current literature, there are only a few reports with relatively low patient numbers about the outcome after resection of both hepatic and pulmonary metastases from colorectal carcinoma. Our study adds to the evidence that resection of combined liver and lung metastases can extend patient survival. In our study, survival was calculated from the time of surgery for primary colorectal carcinoma to the last date of follow-up. Because of this, many patients underwent pulmonary resection after hepatic treatment, and the duration from primary surgery for primary colorectal carcinoma to pulmonary resection was very long (average 31 months). Therefore, we thought that the 10-year survival would be a more accurate measure for the effects of treatment for patients with both hepatic and pulmonary metastases from colorectal carcinoma. Patients who underwent metachronous hepatic and pulmonary surgical treatment had significantly better survival than those who underwent synchronous surgical treatment (40.9% versus 0%, p = 0.0265). Meanwhile, the 5-year survival from the time of pulmonary resection for the metachronous group seemed to be better than that of the synchronous group, but the difference did not quite reach significance (43.6% versus 15.6%, p = 0.085). This is identical to the 5-year survival of 0–13% reported for hepatic resection for metastatic colorectal carcinoma in patients with other extrahepatic disease [24–26]. In the metachronous group, there were no differences between the cases who had previously developed pulmonary metastases and the cases who had previously developed hepatic metastases. However, there were only 3 cases who had experienced previous pulmonary metastases, so these results need to be confirmed in a larger study. Nevertheless, these data suggest that synchronous pulmonary metastases with hepatic metastases is a poor prognostic factor for surgical treatment. Carcinoembryonic antigen (CEA) expression is associated with the progression of colorectal carcinomas and is maintained in more than 95% of colorectal carcinomas and their metastases, making this glycoprotein the most widely used human tumor marker [27]. In several studies, data demonstrated that the prethoracotomy serum CEA was one of the most significant prognostic factors for survival after resection of pulmonary metastases [9–12,28,29]. In addition,
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elevated prethoracotomy serum CEA was associated with a significant decrease in the survival of patients who had both hepatic and pulmonary metastases from colorectal carcinoma [19]. In our study, we did not observed this correlation with survival. However, this may have been because most of the patients had elevated serum CEA levels. Kobayashi and associates reported that only the number of pulmonary metastases affected the survival after the last metastectomy in patients with both pulmonary and hepatic metastases [30]. Okumura et al. reported that the 5-year survival after thoracotomy in 22 patients with hepatic metastases and a solitary pulmonary metastasis was 43.7% [31]. In our study, patients who had fewer than ten pulmonary metastatic lesions seemed to have a better outcome than those with more lesions, but the difference was not quite significant (p = 0.0719). In addition, when we compared the data for patients with solitary or multiple lesions, we did not find any correlation with survival (p = 0.570). When we considered the cause of death, 5 patients died of liver failure, 7 of liver metastasis, 4 from primary colorectal carcinoma, 3 from brain metastasis, and none of the patients died from pulmonary failure or metastasis. Therefore, surgical treatment should be aggressively performed, even if patients have multiple pulmonary metastases, because aggressive surgery provides a survival benefit and is not associated with an increase in mortality. 5. Conclusion Hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma, because surgery remains the only potentially curative treatment. We believe that aggressive metastasectomy can be an option for selected patients, even if patients have been previously treated for hepatic and pulmonary metastases from colorectal carcinoma. Conflict of interest statement No conflict of interest of any of the authors. References [1] Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993;71:4252–66. [2] Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995;19:59–71. [3] Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Bachellier P. Surgical resection of colorectal carcinoma metastases to the liver. Cancer 1996;77:1254–62. [4] Galandiuk S, Wieand HS, Moertel CG, Cha SS, Fitzgibbons RJ, Pemberton JH. Patterns of recurrence after curative resection of carcinoma of colon and rectum. Surg Gynecol Obstet 1992;174:27–32. [5] McCormack PM, Attiyeh FF. Resected pulmonary metastases from colorectal cancer. Dis Colon Rectum 1979;22:553–6. [6] Goya T, Miyazawa N, Kondo H, Tsuchiya R, Naruke T, Suemasu K. Surgical resection of pulmonary metastases from colorectal cancer. 10-year follow-up. Cancer 1989;64:553–6.
[7] Ishikawa K, Hayashiguchi Y, Mochizuki H, Ozeki U, Ueno H. Extranodal cancer deposit at the primary tumor site and the number of pulmonary lesions are useful prognosis factors after surgery for colorectal lung metastases. Dis colon rectum 2003;46:629–36. [8] Saito Y, Omiya H, Kohno K. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: a prognostic assessment. J Thorac Cardiovasc Surg 2002;124:1007–13. [9] Rena O, Casadio C, Viano F. Pulmonary resection for metastases from colorectal cancer: factors influencing prognosis. Twenty-year experience. Eur J Cardiothorac Surg 2002;21:906–12. [10] Sakamoto T, Tsubota N, Ishikawa K, Yuki T, Matsuoka H, Yoshimura M. Pulmonary resection for metastases from colorectal cancer. Chest 2001;119:1069–72. [11] Girard P, Ducreux M, Baldeyrou P. Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 1996;14:2047–53. [12] Inoue M, Kotake Y, Nakagawa K, Fujiwara K, Fukuhara K, Yasumitsu T. Surgery for pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2000;70:380–3. [13] Yano T, Hara N, Ichinose Y, Yokoyama H, Miura T, Ohta M. Results of pulmonary resection of metastatic colorectal cancer and its application. J Thorac Cardiovasc Surg 1993;106:875–9. [14] Riquet M, Foucault C, Cazes A. Pulmonary resection for metastases of colorectal adenocarcinoma. Ann Thorac Surg 2010;89:375–80. [15] Blalock A. Recent advances in surgery. N Engl J Med 1944;231:261–7. [16] Thomford NR, Woolner LB, Clagett OT. The surgical treatment of metastatic tumors in the lung. J Thorac Cardiovasc Surg 1965;49:357–63. [17] Sobin LH, Wittekind C. TNM classification of malignant tumors. 6th ed. NY: Wiley & Sons; 2002. [18] Greene FL, Page DL, Fleming ID. AJCC cancer staging manual. 6th ed. NY: Springer-Verlag; 2002. [19] McAfee MK, Allen MS, Trastek VF. Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 1992;53:780–6. [20] Regnard JF, Grunenwald D, Spaggiari L. Surgical treatment to hepatic and pulmonary metastases from colorectal cancers. Ann Thorac Surg 1992;53: 780–6. [21] Headrick J, Miller DL, Nagorney DM. Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001;71: 975–80. [22] Porschen R, Arkenau H, Kubicka S. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO colorectal study group. J Clin Oncol 2007;25:4217–23. [23] Diaz-Rubio E, Taberno J, Gomez-Espana A. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish cooperative group for the treatment of digestive tumors trial. J Clin Oncol 2007;25:4224–30. [24] Stangl R, Hofmann AA, Charnley RM. Factors influencing the natural history of colorectal liver metastases. Lancet 1994;343:1405–10. [25] Gayowski TJ, Iwatsuki S, Madariago JR. Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathological risk factors. Surgery 1994;116:703–11. [26] Jenkins LT, Millikan KW, Bines SD. Hepatic resection for metastatic colorectal cancer. Am Surg 1997;63:605–10. [27] Hammarstrom S. The carcinoembryonic antigen (CEA) family: structure, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 1999;9:67–81. [28] Pfannschmidt J, Muley T, Hoffmann H. Prognostic factors and survival after complete resection of pulmonary metastases from colorectal carcinoma: experiences in 167 patients. J Thorac Cardiovasc Surg 2003;126: 732–9. [29] Izawa T, Suzuki M, Yoshida S. Prediction of prognosis and surgical indications for pulmonary metastectomy from colorectal cancer. Ann Thorac Surg 2006;82:254–60. [30] Izawa T, Suzuki M, Yoshida S. Prediction of prognosis and surgical indications for pulmonary metastectomy from colorectal cancer. J Thorac Cardiovasc Surg 1999;118:1090–6. [31] Okumura S, Kondo H, Tsuboi M. Pulmonary resection for metastatic colorectal cancer: experience with 159 patients. J Thorac Cardiovasc Surg 1996;112:867–74.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases Daigo Kawano ∗ , Sadanori Takeo, Shuichi Tsukamoto, Masakazu Katsura, Eri Masuyama, Yu Nakaji Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 1-8-1 Jigyo, Fukuoka 810-8563, Japan
a r t i c l e
i n f o
Article history: Received 8 April 2011 Received in revised form 8 July 2011 Accepted 13 July 2011 Keywords: Colorectal carcinoma Metastatic hepatic tumor Metastatic pulmonary tumor Metastectomy Number of metastases Metachronous
a b s t r a c t Background: The value of surgical treatment for patients with pulmonary and hepatic metastases from colorectal carcinoma is controversial. The purpose of this study was to analyze our initial experience with this aggressive strategy, and to define the prognosis and the surgical indications. Methods: The records of 35 patients who underwent surgical treatments for both hepatic and pulmonary metastases from colorectal carcinoma, from January 1997 to December 2008, were retrospectively analyzed. Results: There were 18 females and 17 males with a median age was 62.0 years. The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection, respectively. For patients who underwent metachronous hepatic and pulmonary surgical treatment, the 10-year survival rate was 40.9%, which was significantly better than that of those undergoing synchronous hepatic and pulmonary surgical treatment (p = 0.0265). Patients who have pulmonary less than ten of metastasis thus seemed to have a better prognosis than those with more than ten, but the difference was quite significant (p = 0.0719). In a multivariate Cox proportional hazards model, synchronous hepatic and pulmonary metastases was identified as an independent predictor of adverse survival (p = 0.0073). Conclusions: The results of our study suggest that hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma. We believe that aggressive metastasectomy can be an option for selected patients, even if a patient has been previously treated for hepatic and pulmonary metastases from colorectal carcinoma. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Background Colorectal carcinoma is a major cause of cancer-related mortality. Hepatic and pulmonary metastases are the major determinants of survival for patients who have undergone curative resection of colorectal carcinoma. Approximately 40% of patients who have undergone curative resection of colorectal carcinoma will develop hepatic metastases [1]. In addition, 25% of patients with isolated hepatic metastases have tumors that can be resected curatively, and 21–48% will survive over 5 years with low morbidity and mortality [1–3]. The lung is the most common extraabdominal site of metastases from colorectal carcinoma [4], and resectable metastatic disease is limited to the lung in approximately 1–2% of patients after curative resection of colorectal carcinoma [5,6]. After resection of pulmonary metastases, 5-year survival rates range
∗ Corresponding author. Tel.: +81 92 852 0700; fax: +81 92 847 8802. E-mail address: [email protected] (D. Kawano). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.07.010
from 24 to 63%, and most have reported survival around 40% [6–14]. However, although numerous studies have demonstrate long term survival after resection of isolated pulmonary or isolated hepatic metastases, only a few authors have report surgical resection of pulmonary and hepatic metastases after resection of colorectal carcinoma. Resection of metastatic pulmonary lesions from colorectal carcinoma was first performed by Blalock [15]. Thereafter, Thomford noted criteria indicating the resection of metastatic lung tumors: (i) the patients must be a good risk for surgical intervention, (ii) the primary malignancy is controlled, (iii) there is no evidence of metastatic disease elsewhere, and (iv) the roentgenologic evidence of pulmonary metastasis is limited to one lung [16]. Since that time, extended pulmonary metastasectomy has become practical in patients with bilateral pulmonary metastases or with distant metastasis such as hepatic metastasis. However, the value of an aggressive surgical treatment for patients with hepatic and pulmonary metastases is still controversial. The purpose of this study was to analysis our initial experience with this aggressive surgical
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strategy, and to define which patients can obtain a better prognosis as a result of surgery.
Table 1 Patient characteristics. Variables
2. Patients and methods A total 81 patients with primary colorectal carcinoma underwent resection of pulmonary metastases, from January 1997 to December 2008 in the Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center (Fukuoka, Japan). The study was approved by our Institutional Review Board. Informed consent was not required for this retrospective study. Among these patients, 35 (43.2%) had undergone surgical treatments for hepatic metastases, including resection or microwave coagulo-necrotic therapy (MCN). Preoperative evaluations were performed using chest roentgenograms and computed tomography (CT) images for pulmonary nodules, and ultrasound (US) and magnetic resonance imaging (MRI) for hepatic nodules. Only those patients whose metastatic sites were confined to the lung or with hepatic metastases that could be completely treated after surgery were included in this study. Patients who had a pulmonary biopsy only were excluded. The record of each patient was reviewed for age, gender, location and stage of the primary colorectal carcinoma, according to the International Union Against Cancer TNM staging system [17,18], the existence of metastases on the unilateral or bilateral lungs, number of pulmonary metastases, the number of pulmonary resections, prethoracotomy carcinoembryonic antigen (CEA) level, the timing of hepatic and pulmonary metastases (synchronous or metachronous), disease free interval, and duration of survival. Survival was calculated from the time of surgery for primary colorectal carcinoma to the last follow-up. Statistical calculations were carried out with Stat View software program (SAS Institute, Inc, Cary, NC). Overall survival was calculated using the Kaplan–Meier method. The differences between survival curves were analyzed using the log-rank test for univariate analyses. The multivariate analysis was performed according to the Cox proportional hazards model to estimate the relative risk with 95% confidence interval (CI). The results of the analysis were regarded as statistically significant at a p < 0.05.
Gender Female Male Age Median (range) age (year) Site of primary cancer Rectum Colon TMN stage Stage I Stage II Stage III Stage IV Unknown Location Unilateral Bilateral Tumor number Median (range) 1 2–9 ≥10 CEA serum concentration Normal (<6 ng/ml) Abnormal (>6 ng/ml) Presentation Synchronous Metachronous Disease free interval >1 year 1–2 years <2 years
No. of patients 18 (51.4%) 17 (48.6%) 62.0 (34–92) 12 (34.3%) 23 (65.7%) 0 (0%) 7 (20.0%) 13 (37.2%) 11 (31.4%) 4 (11.4%) 18 (51.4%) 17 (48.6%) 4.2 (1–20) 12 (34.3%) 19 (54.3%) 4 (11.4%) 11 (31.4%) 24 (68.6%) 8 (22.9%) 27 (77.1%) 16 (45.7%) 11 (31.4%) 8 (22.9%)
3. Results There were 18 females and 17 males with a median age was 62.0 years (range 34–92 years). The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). These patients’ characteristics are shown in Table 1. The pathological TMN staging of primary colorectal carcinoma was stage I in 0 patients (0%), stage II in 7 patients (20.0%), stage III in 13 patients (37.2%), and stage IV in 11 patients (31.4%), the staging of 4 patients (11.4%) was unknown. Eighteen patients (51.4%) had unilateral tumors, and 17 patients (48.6%) had lesions located in bilateral lungs. The median number of pulmonary metastases was 4.2 (range 1–20). Eleven patients (31.4%) showed a normal serum CEA level before pulmonary resection, and 24 patients (68.6%) showed an abnormal serum CEA level. Eight patients (22.9%) had synchronous hepatic and pulmonary surgical treatments, and 27 patients (77.1%) underwent metachronous surgical treatments (3 patients underwent hepatic treatment after pulmonary resection). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of the primary colorectal resection (median, 66.9 months) (Fig. 1). The overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of the first pulmonary resection (median, 39.5 months) (Fig. 2). For patients who underwent metachronous hepatic and pulmonary surgical treatment, 10-year survival rate was 40.9%, which was significantly better than those who underwent syn-
Fig. 1. The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection (median, 66.9 months).
Fig. 2. The overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of the first pulmonary resection (median, 39.5 months).
D. Kawano et al. / Lung Cancer 75 (2012) 209–212
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Table 2 Multivariate predictors of survival. Variables Age Gender Primary tumor site Pathological stage Location Tumor number CEA level Timing of metastases Disease free interval
<60 Female Colon IV Unilateral 1 10 or <10 Abnormal Synchronous <1 year
chronous hepatic and pulmonary surgical treatment (p = 0.0265) (Fig. 3A). Patients who had fewer than ten pulmonary metastatic lesions (n = 4) seemed to have a better outcome than those with more than ten metastatic lesions, but the difference was not significant (p = 0.0719) (Fig. 3B). No other factors were found to be correlated with survival. Additionally, no factors were found to be correlated with survival from the date of the first pulmonary resection. On multivariate Cox proportional hazards model (Table 2), the presence of synchronous hepatic and pulmonary metastases was identified as an independent predictor of decreased survival, associated with a hazard ratio of 3.731 (1.427–9.803; p = 0.0073). 4. Discussion The management of patients with both hepatic and pulmonary metastases from colorectal carcinoma is controversial. Although Thomford excluded patients with extrapulmonary metastases as
Fig. 3. The Kaplan–Meier survival analysis: the x-axis indicates the years after the time of surgery for primary colorectal carcinoma to the last follow-up. (A) Synchronous versus metachronous survival curves. (B) The survival curve based on the number of pulmonary metastases (<10 versus ≥10).
RR
95% CI
p-Value
1.070 1.124 0.773 1.174 1.102 0.750 2.691 1.156 3.731 0.720
0.383–2.986 0.448–2.821 0.292–2.047 0.433–3.182 0.441–2.752 0.276–2.034 0.873–8.296 0.413–3.235 1.427–9.803 0.207–2.504
0.8973 0.8028 0.6038 0.7526 0.8351 0.5717 0.0847 0.7828 0.0073 0.6055
candidates for thoracotomy [16], there have been several reports about successful pulmonary resection for patients with extrapulmonary metastases. McAfee et al. [19] reported that the presence of resectable extrapulmonary metastases before or at the time of thoracotomy was not associated with a decreased survival. Several other studies have demonstrated that previous resection of hepatic metastases was not found to be a statistically significant prognostic factor [8,13,20,21]. The 5-year survival ranged from 25% to 47.9% in these reports. In our study, the overall 5-year and 10-year survival rates were 36.7% and 18.3% from the date of first pulmonary resection (median, 39.5 months). This result compares favorably with the previous studies [6–14], since our patients had both hepatic and pulmonary metastases, and given that the median survival with chemotherapy is only 18–20 months [22,23]. In the current literature, there are only a few reports with relatively low patient numbers about the outcome after resection of both hepatic and pulmonary metastases from colorectal carcinoma. Our study adds to the evidence that resection of combined liver and lung metastases can extend patient survival. In our study, survival was calculated from the time of surgery for primary colorectal carcinoma to the last date of follow-up. Because of this, many patients underwent pulmonary resection after hepatic treatment, and the duration from primary surgery for primary colorectal carcinoma to pulmonary resection was very long (average 31 months). Therefore, we thought that the 10-year survival would be a more accurate measure for the effects of treatment for patients with both hepatic and pulmonary metastases from colorectal carcinoma. Patients who underwent metachronous hepatic and pulmonary surgical treatment had significantly better survival than those who underwent synchronous surgical treatment (40.9% versus 0%, p = 0.0265). Meanwhile, the 5-year survival from the time of pulmonary resection for the metachronous group seemed to be better than that of the synchronous group, but the difference did not quite reach significance (43.6% versus 15.6%, p = 0.085). This is identical to the 5-year survival of 0–13% reported for hepatic resection for metastatic colorectal carcinoma in patients with other extrahepatic disease [24–26]. In the metachronous group, there were no differences between the cases who had previously developed pulmonary metastases and the cases who had previously developed hepatic metastases. However, there were only 3 cases who had experienced previous pulmonary metastases, so these results need to be confirmed in a larger study. Nevertheless, these data suggest that synchronous pulmonary metastases with hepatic metastases is a poor prognostic factor for surgical treatment. Carcinoembryonic antigen (CEA) expression is associated with the progression of colorectal carcinomas and is maintained in more than 95% of colorectal carcinomas and their metastases, making this glycoprotein the most widely used human tumor marker [27]. In several studies, data demonstrated that the prethoracotomy serum CEA was one of the most significant prognostic factors for survival after resection of pulmonary metastases [9–12,28,29]. In addition,
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elevated prethoracotomy serum CEA was associated with a significant decrease in the survival of patients who had both hepatic and pulmonary metastases from colorectal carcinoma [19]. In our study, we did not observed this correlation with survival. However, this may have been because most of the patients had elevated serum CEA levels. Kobayashi and associates reported that only the number of pulmonary metastases affected the survival after the last metastectomy in patients with both pulmonary and hepatic metastases [30]. Okumura et al. reported that the 5-year survival after thoracotomy in 22 patients with hepatic metastases and a solitary pulmonary metastasis was 43.7% [31]. In our study, patients who had fewer than ten pulmonary metastatic lesions seemed to have a better outcome than those with more lesions, but the difference was not quite significant (p = 0.0719). In addition, when we compared the data for patients with solitary or multiple lesions, we did not find any correlation with survival (p = 0.570). When we considered the cause of death, 5 patients died of liver failure, 7 of liver metastasis, 4 from primary colorectal carcinoma, 3 from brain metastasis, and none of the patients died from pulmonary failure or metastasis. Therefore, surgical treatment should be aggressively performed, even if patients have multiple pulmonary metastases, because aggressive surgery provides a survival benefit and is not associated with an increase in mortality. 5. Conclusion Hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma, because surgery remains the only potentially curative treatment. We believe that aggressive metastasectomy can be an option for selected patients, even if patients have been previously treated for hepatic and pulmonary metastases from colorectal carcinoma. Conflict of interest statement No conflict of interest of any of the authors. References [1] Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993;71:4252–66. [2] Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995;19:59–71. [3] Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Bachellier P. Surgical resection of colorectal carcinoma metastases to the liver. Cancer 1996;77:1254–62. [4] Galandiuk S, Wieand HS, Moertel CG, Cha SS, Fitzgibbons RJ, Pemberton JH. Patterns of recurrence after curative resection of carcinoma of colon and rectum. Surg Gynecol Obstet 1992;174:27–32. [5] McCormack PM, Attiyeh FF. Resected pulmonary metastases from colorectal cancer. Dis Colon Rectum 1979;22:553–6. [6] Goya T, Miyazawa N, Kondo H, Tsuchiya R, Naruke T, Suemasu K. Surgical resection of pulmonary metastases from colorectal cancer. 10-year follow-up. Cancer 1989;64:553–6.
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