Japanese Journal of Clinical Oncology Advance Access originally published online on August 24, 2006
Japanese Journal of Clinical Oncology 2006 36(10):643-648; doi:10.1093/jjco/hyl076
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 Foundation for Promotion of Cancer Research
Surgical Resection of Pulmonary Metastases From Colorectal Cancer: Four Favourable Prognostic Factors
1 Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo and 2 Department of Surgery, Mitsui Memorial Hospital, Tokyo, Japan
For reprints and all correspondence: Rintaro Koga, Department of Gastrointestinal Surgery, Cancer Institute Hospital, Tokyo, 3-10-6 Ariake, Koto-ku, Tokyo, 135-8550, Japan. E-mail: rintaro.koga{at}jfcr.or.jp
Received April 7, 2006; accepted June 17, 2006
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Background: Surgical resection has been the first choice for treatment of pulmonary metastases from colorectal cancer; however, indications for surgery have yet to be adequately clarified. In considering strategies for the treatment of pulmonary metastases from colorectal carcinoma, determination of disease status as either systemic or pre-systemic is of primary importance. The aim of this study is to define the characteristics of those patients who are most likely to benefit from surgical resection.
Methods: Fifty-eight patients who underwent pulmonary resection for colorectal metastases were retrospectively reviewed and examined for clinicopathological factors.
Results: Overall, 5-year survival rates were 29%, with a median survival time (MST) of 27 months. Multivariate analysis identified four factors that indicate independent and favourable prognostic impact: three or less tumours, metachronous metastasis, negative hilar and/or mediastinal lymph node metastasis and normal prethoracotomy serum carcinoembryonic antigen level. The 5-year survival rate for 16 patients who satisfied all of these favourable characteristics was 62% (MST = 86 months), which was significantly better than those patients lacking these characteristics. The 5-year survival rate for 13 patients who underwent repeated metastasectomy was 37% (MST = 32 months).
Conclusions: The four factors selected in our multivariate analysis appear to be favourable factors for the practical identification of those patients who are most likely to benefit from surgical resection. Repeated pulmonary resection for lung-only recurrence may benefit carefully selected patients.
Key Words: colorectal cancer • pulmonary metastasis • prognosis • surgical indication
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
More than half of all patients undergoing resection for colorectal carcinoma have recurrence of this disease, while
10% develop pulmonary metastases (1–3). Since Blalock (4) first described pulmonary resection for metastases from colorectal carcinoma, surgical resection has been the first choice for the treatment of pulmonary metastases, as for liver metastases. Previous studies reported outcomes ranging from 27 to 40.5% and discussed significant prognostic factors (5–11). As the safety of the operation has improved over time, indications have been extended more widely; however, a substantial proportion of pulmonary metastases tend to be part of systemic disease, so criteria for the resection of pulmonary metastases have yet to be established. In the present study, we aim to define those patients who are most likely to benefit from surgical resection by investigating outcome, long-term results and factors associated with prolonged survival. |
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
A total of 58 consecutive patients who had undergone pulmonary resection for metastatic colorectal cancer between January 1978 and December 1997 at the Mitsui Memorial Hospital, Tokyo, Japan, were included in this study. The pulmonary lesions were evaluated with conventional chest computed tomography and measurement of serum carcinoembryonic antigen (CEA) level in all 58 patients. Indications for pulmonary resection of metastatic colorectal cancer were as follows: (i) completely resectable lung lesions diagnosed by preoperative imaging, (ii) ability of the patient to tolerate the required surgical procedure and that the remaining respiratory function would be sufficient for normal life and (iii) surgically controllable extra-pulmonary disease, including the primary lesion.
The medical charts of 58 patients were reviewed and examined for age; sex; site of primary tumour; grade of primary tumour (Dukes' classification); time of appearance of pulmonary metastases; disease-free interval (DFI); prethoracotomy serum CEA level; mode of operation; presence of pathological hilar and/or mediastinal lymph node metastasis; hepatectomy for liver metastases before thoracotomy; duration of survival; location, number and size of pulmonary metastases; postoperative chemotherapy; and date of pulmonary resection. Survival was calculated from the time of thoracotomy until death or the date of the most recent follow-up. Statistical calculations were performed with a statistical analysis package (SPSS 9.0, SPSS, Inc, Chicago, III). The actuarial overall survivals were calculated using the Kaplan–Meier method, and differences in the resulting distributions were compared using the log–rank test. The Cox proportional hazards model was employed for multivariate analysis.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
All 58 patients underwent complete resection for pulmonary metastases from colorectal cancer. There was no operative or in-hospital mortality.
The patients comprised 30 men and 28 women, with a median age of 63 years (range: 33–87 years). The primary carcinoma was located in the colon in 38 patients (caecum: 5, ascending: 13, transverse: 2, descending: 2, sigmoid: 16) and in the rectum in 20. Twenty-two patients graded in Dukes' B, 34 in Dukes' C and 2 patients were unknown who were operated for the primary tumour in the other hospital. We had no patient graded in Dukes' A. The median interval between primary colorectal surgery and metastatic pulmonary resection was 25 months (range: 0–76 months). Twenty-seven patients had a DFI of <2 years, of whom eight had synchronous lung metastases. Twenty-three patients had solitary metastases, 16 had 2 metastases, 10 had 3 metastases, and 9 had 4 or more (maximum 12) metastases. The CEA level was elevated in 32 patients (cut-off value 
5.0 ng/ml). Seventeen patients had liver metastases and had undergone a complete hepatic metastasectomy before thoracotomy. Because the lung metastases were near the pulmonary hilus or the size of the nodule was large, hilar and/or mediastinal lymph nodes were dissected or sampled with segmentectomy or lobectomy in 28 patients. Twenty-four patients received postoperative systemic chemotherapy by oral administration or drip infusion.
Median follow-up interval after initial thoracotomy was 24 months (range: 5–233 months). Overall survival rates at 5 and 10 years were 29 and 20%, respectively. Median survival time (MST) was 27 months (Fig. 1). At the time of the present study, all six 10-year survivors were alive with no evidence of recurrence. One of the 10-year survivors had limited lung metastasis and underwent repeated pulmonary resection.
|
Eleven of the 58 patients (19%) have no evidence of recurrence, 7 of whom are currently alive. Median follow-up interval of them was 129 months (range: 5–233 months). The remaining 47 patients (81%) developed recurrence. Thirty-five of 47 patients (74%) had recurrence in the lungs, of whom 17 had lung-only metastases; 13 of these 17 patients underwent repeated pulmonary resection for recurrence. Ten patients underwent thoracotomy twice while three patients had three or more resections. During the second thoracotomy, wedge resection was performed in eight patients, lobectomy in four patients and pneumonectomy in one patient. There were no operative deaths and all patients returned to a normal quality of life. The median follow-up interval after the second thoracotomy was 32 months (range: 10–102 months). The median interval between the first and second pulmonary resections was 16 months (range: 6–44 months). Five-year survival for all 13 patients from the date of the second thoracotomy was 37% (MST = 32 months). One patient underwent thoracotomy five times and lived for 81 months from the time of the first thoracotomy. The mode of recurrence of 35 patients who did not undergo repeated thoracotomy was unresectable multiple nodules in the lung, liver, brain, bones, abdominal lymph nodes and other organs, independently or combined.
Univariate analysis revealed that the following factors significantly affect survival: number of pulmonary metastases and hilar and/or mediastinal lymph node metastasis (Table 1). The 5-year survival rate for patients with <3 metastases was 35%. No patients with four or more nodules survived >3 years (44% at 2-year survival, P = 0.002). Similarly, no patients with positive mediastinal lymph node metastases survived longer than 3 years. Time to appearance of metastasis and prethoracotomy serum CEA level showed marginal significance for post-resection prognosis (P = 0.09, 0.057, respectively). None of the other factors listed in Table 1 was chosen as a prognostic factor.
|
Table 2 shows the results of multivariate analysis. Thirteen potential prognostic factors from the factors listed in Table 1 were entered into the Cox proportional hazards regression model. Factors that retained independent and favourable prognostic impact were three or less tumours, metachronous metastasis, negative hilar and/or mediastinal lymph node metastasis and normal prethoracotomy serum CEA level (Table 2). Sixteen of 58 patients satisfied all of these favourable characteristics, 10 of whom (63%) are currently alive without recurrence; 2 patients died of other causes. The 5- and 10-year survival rates for these 16 patients were 62 and 43%, respectively (MST = 86 months; Fig. 2). Meanwhile, the remaining 42 patients who did not have all of the favourable characteristics had 5- and 10-year survival rates of 17 and 10%, respectively (MST = 25 months). There was a statistically significant difference in the survival rates between these two groups (P < 0.001).
|
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Since Thomford et al. (12) first reported the indications for pulmonary metastasectomy in 1965, resection of pulmonary metastases has been recognized as the only curative therapy, as no curative chemotherapy is available for metastatic colorectal adenocarcinoma. Many authors have investigated the factors that significantly influence post-thoracotomy prognosis, including (i) number of pulmonary metastases (6,9,10), (ii) hilar and/or mediastinal lymph node metastasis (7–9,13), (iii) prethoracotomy CEA level (13–16), (iv) time of appearance of metastasis, (v) liver metastasis before thoracotomy (7), (vi) mode of operation and (vii) location of pulmonary metastases (8).
In the present study, four factors were identified as independent prognostic factors for survival after metastasectomy: (i) number of pulmonary metastases, (ii) time of appearance of metastasis, (iii) hilar and/or mediastinal lymph node metastasis and (iv) prethoracotomy serum CEA level. The significantly favourable outcome of the patients satisfying all four factors indicates that such patients are the most promising candidates for pulmonary resection. The outcome of the favourable group is similar to that of stage III primary rectal carcinoma, that is, without distant metastasis (17).
Metastasectomy of the lung for patients with multiple metastases once had poor survival rates (18); however, recent studies have shown that the survival of patients with oligometastasis (two or three lesions) is better than previously reported. Pfannschmidt et al. (9) reported solitary metastases as a significant prognostic factor. In addition, patients with up to four metastases demonstrated a better survival than patients with more than four metastases.
In our study, the 5-year survival rate of those patients with three or fewer lesions was 35%. The post-resection outcome of those patients with four or more lesions was very poor. Seven of 26 patients who had oligometastases have lived >5 years; on the other hand none of them has lived >3 years. And there was no significance in the analysis between solitary and multiple, or between two and three metastases. Similar results were reported after resection of multiple colorectal liver metastases (19). A recent study has indicated that tumour number is not a limiting factor for surgical resection for colorectal liver metastasis (20). This study was relatively small and there was unbalanced distribution of the number of metastasis. Thus, further data on resecting multiple lung metastases from colorectal cancer is necessary to draw a conclusion regarding the relationship between multiple lesions and favourable surgical outcome. Patients with oligometastases might benefit from surgical pulmonary resection.
Hilar and/or mediastinal lymph node metastasis has been reported as a significant prognostic factor of survival (7–9,13). Survival of patients with lymph node metastasis is very poor. In our study, hilar and/or mediastinal lymph nodes were examined in 28 patients. There were no patients with a lymph node metastasis who lived >3 years. Both univariate and multivariate analysis showed a statistically significant difference in survival between patients with lymph node metastases and those without. We have no evidence that hilar and/or mediastinal lymph node dissection can control disease.
For colorectal liver metastasis, as well as lung metastasis, the presence of regional lymph node metastases in the hepatoduodenal ligament carries a certainty of poor post-resection outcome (20,21). As involving regional lymph nodes of the metastatic organ such as liver and lung may indicate a strong likelihood of systemic disease, dissection of those lymph nodes rarely contributes to prolonged survival for patients with positive nodes. However, sampling of hilar and/or mediastinal lymph nodes is important for predicting the clinical course after metastasectomy and therefore should be attempted (8,9,13). The presence of positive nodes in preoperative images may be a strong factor for negative selection for surgical resection, although the accuracy of assessing the lymph nodes for the possible presence of metastatic tumour is disputable (9). So, the histological evaluation of enlarged hilar and/or mediastinal lymph nodes during the operation should be performed, because the finding of metastatic nodal involvement would determine inoperability or indicate a systemic chemotherapy.
Prethoracotomy CEA level is also an independent prognostic factor for post-resection outcome, as reported in previous studies. CEA level is a potential indicator of both total tumour mass and the ability of tumour cells to express CEA (22). Several previous studies found that CEA levels showed no correlation with tumour burden (23,24), while Mayer et al. reported that CEA enhanced liver metastases by functioning as an attachment factor (25). CEA is known to participate in intracellular recognition and promote adhesion of tumour cells to host cells (26). CEA level might therefore reflect the highly malignant nature of cancer cells that induce systemic dissemination. In the present study, an abnormal CEA level was identified as an independent prognostic factor.
As regards the the size of the metastasis, Goya et al. (2) reported a significant difference between patients in whom the maximal size was 3 cm or more and patients in whom the size was <3 cm, although other reports (7,8,18) have denied these results. In this study, patients divided to subgroup by 3 cm, but we could not find out the significant difference.
The 5-year survival rate of repeated pulmonary resection for recurrence of colorectal carcinoma in the remnant lungs has been reported as 24.5–52.1% (6,8,27). In the present study, the 5-year survival rates for repeated resection for colorectal pulmonary metastases was 37% (MST = 32 months), similar to the 5-year survival rates for the first pulmonary resection. Of 17 patients surviving >5 years, 6 underwent repeated pulmonary resection. While the rate of repeated pulmonary resection was not high (49%), this procedure might provide a cure for carefully selected patients, as in repeated liver resection for recurrent colorectal liver metastases (28).
This study emphasizes the fact that surgical approach for colorectal pulmonary metastases is beneficial to selected patients. For the determination of disease status as systemic or pre-systemic, the four factors, (i) number of pulmonary metastases, (ii) time of appearance of metastasis, (iii) hilar and/or mediastinal lymph node metastasis, and (iv) prethoracotomy serum CEA level, appear to be robust and practical indicators. Repeated pulmonary resection for lung-only recurrence may be beneficial for a highly selective subgroup of patients, and should be employed when possible.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 McCormack PM, Burt ME, Bains MS, Martini N, Rusch VW, Ginsberg RJ. Lung resection for colorectal metastases. 10-year results. Arch Surg 1992;127:1403–6.[Abstract]
2 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;64:1418–21.[CrossRef][ISI][Medline]
3 August DA, Ottow RT, Sugerbaker PH. Clinical prospective of human colorectal cancer metastasis. Cancer Metastasis Rev 1984;3:303–24.[CrossRef][ISI][Medline]
4 Blalock A. Recent advances in surgery. N Engl J Med 1944;231:261–7.
5 Kondo D, Goya T, Kondo H, Tsuchiya R, Naruke T, Suemasu K. [Surgical treatment in pulmonary metastases of colorectal cancer]. Nippon Geka Gakkai Zasshi 1989;90:75–81.[Medline]
6 McAfee MK, Allen MS, Trastek VF, Ilstrup DM, Deschamps C, Pairolero PC. Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 1992;53:780–5; discussion 785–6.
7 Okumura S, Kondo H, Tsuboi M, Nakayama H, Asamura H, Tsuchiya R, et al. Pulmonary resection for metastatic colorectal cancer: experiences with 159 patients. J Thorac Cardiovasc Surg 1996;112:867–74.
8 Saito Y, Omiya H, Kohno K, Kobayashi T, Itoi K, Teramachi M, et al. Pulmonary metastasectomy for 165 patients with colorectal carcinoma: a prognostic assessment. J Thorac Cardiovasc Surg 2002;124:1007–13.
9 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;126:732–9.
10 Watanabe I, Arai T, Ono M, Sugito M, Kawashima K, Ito M, et al. Prognostic factors in resection of pulmonary metastasis from colorectal cancer. Br J Surg 2003;90:1436–40.[CrossRef][ISI][Medline]
11 Vogelsang H, Haas S, Hierholzer C, Berger U, Siewert JR, Prauer H. Factors influencing survival after resection of pulmonary metastases from colorectal cancer. Br J Surg 2004;91:1066–71.[CrossRef][ISI][Medline]
12 Thomford NR, Woolner LB, Clagett OT. The surgical treatment of metastatic tumors in the lungs. J Thorac Cardiovasc Surg 1965;49:357–63.[ISI][Medline]
13 Inoue M, Kotake Y, Nakagawa K, Fujiwara K, Fukuhara K, Yasumitsu T. Surgery for pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2000;70:380–83.
14 Rena O, Casadio C, Viano F, Cristofori R, Ruffini E, Filosso PL, et al. Pulmonary resection for metastases from colorectal cancer: factors influencing prognosis. Twenty-year experience. Eur J Cardiothorac Surg 2002;21:906–12.
15 Higashiyama M, Kodama K, Higaki N, Takami K, Murata K, Kameyama M, et al. Surgery for pulmonary metastases from colorectal cancer: the importance of prethoracotomy serum carcinoembryonic antigen as an indicator of prognosis. Jpn J Thorac Cardiovasc Surg 2003;51:289–96.[Medline]
16 Sakamoto T, Tsubota N, Iwanaga K, Yuki T, Matsuoka H, Yoshimura M. Pulmonary resection for metastases from colorectal cancer. Chest 2001;119:1069–72.
17 Muto T, Kotake K, Koyama Y. Colorectal cancer statistics in Japan: data from JSCCR registration, 1974–1993. Int J Clin Oncol 2001;6:171–6.[CrossRef][Medline]
18 Mansel JK, Zinsmeister AR, Pairolero PC, Jett JR. Pulmonary resection of metastatic colorectal adenocarcinoma. A ten year experience. Chest 1986;89:109–12.
19 Iwatsuki S, Esquivel CO, Gordon RD, Starzl TE. Liver resection for metastatic colorectal cancer. Surgery 1986;100:804–10.[ISI][Medline]
20 Minagawa M, Makuuchi M, Torzilli G, Takayama T, Kawasaki S, Kosuge T, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000;231:487–99.[CrossRef][ISI][Medline]
21 Kokudo N, Miki Y, Sugai S, Yanagisawa A, Kato Y, Sakamoto Y, et al. Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma: minimum surgical margins for successful resection. Arch Surg 2002;137:833–40.
22 Regnard JF, Grunenwald D, Spaggiari L, Girard P, Elias D, Ducreux M, et al. Surgical treatment of hepatic and pulmonary metastases from colorectal cancers. Ann Thorac Surg 1998;66:214–18; discussion 218–19.
23 Mayer RJ, Garnick MB, Steele GD Jr, Zamcheck N. Carcinoembryonic antigen (CEA) as a monitor of chemotherapy in disseminated colorectal cancer. Cancer 1978;42(3 Suppl):1428–33.[CrossRef][ISI][Medline]
24 Steele G Jr, Zamcheck N. The use of carcinoembryonic antigen in the clinical management of patients with colorectal cancer. Cancer Detect Prev 1985;8:421–7.[ISI][Medline]
25 Hostetter RB, Augustus LB, Mankarious R, Chi KF, Fan D, Toth C, et al. Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastasis. J Natl Cancer Inst 1990;82:380–5.
26 Gutman M, Fidler IJ. Biology of human colon cancer metastasis. World J Surg 1995;19:226–34.[CrossRef][ISI][Medline]
27 Ogata Y, Matono K, Hayashi A, Takamor S, Miwa K, Sasatomi T, et al. Repeat pulmonary resection for isolated recurrent lung metastases yields results comparable to those after first pulmonary resection in colorectal cancer. World J Surg 2005;29:363–8.[CrossRef][ISI][Medline]
28 Yamamoto J, Kosuge T, Shimada K, Yamasaki S, Moriya Y, Sugihara K. Repeat liver resection for recurrent colorectal liver metastases. Am J Surg 1999;178:275–81.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||