Ann Thorac Surg 2010;89:375-380. doi:10.1016/j.athoracsur.2009.10.005
© 2010 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Pulmonary Resection for Metastases of Colorectal Adenocarcinoma
Marc Riquet, MD, PhDa,*,
Christophe Foucault, MDa,
Aurélie Cazes, MD, PhDb,
Emmanuel Mitry, MD, PhDd,
Antoine Dujon, MDe,
Françoise Le Pimpec Barthes, MD, PhDa,
Jacques Médioni, MD, PhDc,
Philippe Rougier, MD, PhDd
a Department of Thoracic Surgery, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital, Paris, France
b Department of Pathology, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital, Paris, France
c Department of Medical Oncology, Paris Descartes University, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital, Paris, France
d Department of Gastroenterology, University of Versailles, Assistance Publique-Hôpitaux de Paris, Ambroise Paré Hospital, Paris, France
e Department of Thoracic Surgery, Cedar Surgical Centre, BoisGuillaume, Paris, France
Accepted for publication October 6, 2009.
* Address correspondence to Dr Riquet, Thoracic Surgery Department, Georges Pompidou European Hospital, 20 rue Leblanc, Paris, 75015, France (Email: marc.riquet{at}egp.aphp.fr).
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Abstract
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Background: Surgery is a safe and effective treatment for patients with lung metastases from colorectal carcinoma. Combining chemotherapy and surgery seems to prolong survival time after metastasectomy. Our purpose was to review the effectiveness of surgery with time and evolving managements.
Methods: The records of 127 patients were retrospectively analyzed. The characteristics of primary cancer, lung metastases, resections, and associated therapy were studied according to their incidence on survival.
Results: There were 74 male and 53 female patients (mean age, 65 years); 223 operations were performed and 314 metastases were resected. Completeness of surgery (n = 117) was the main factor for prolonged survival (5- and 10-year survival, 41% and 27%, versus 0%). There was no factor of significantly better prognosis, but a tendency to higher survival rates was observed in cases of single metastasis, in patients undergoing several lung operations, and in patients in whom liver metastases were previously removed. Three of 7 patients with mediastinal lymph node involvement survived more than 5 years; 58 patients were operated on before January 2000, and 59 between January 2000 and December 2007. Five-year survival rates were 35.1% versus 63.5%, respectively (p = 0.0096), probably related to better selection with modern workup, more frequent use of chemotherapy, and repeated pulmonary resections.
Conclusions: Different treatment protocols were reported in the literature and in our series with time, resulting in better survival rates and a more aggressive surgical tendency. The beneficial role of such combined therapy justifies further research, including prospective trials.
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Introduction
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Surgery initially proved to be the treatment of choice in patients with technically resectable lung metastases from colorectal carcinoma when no other disease was present [1]. Afterward, criteria for resectability broadened to include recurrent pulmonary metastases as well as synchronous or metachronous liver metastases [1]. Recently, schedules combining chemotherapy and surgery have permitted us to prolong survival after metastasectomy, or to downsize to resectability patients previously unsuitable for surgery [2]. Our purpose was to retrospectively review the effectiveness of evolving managements and surgery as a function of time.
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Patients and Methods
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The records of 127 consecutive patients who underwent pulmonary resection for metastases of colorectal adenocarcinomas between 1985 and 2007 at Georges Pompidou European Hospital, Paris, and Cedar Surgical Centre, Bois-Guillaume, were reviewed. Both institutional review boards waived obtaining patient consent for this retrospective study. Preoperative selection criteria were as follows: completely resectable lesions, no evidence of synchronous extrathoracic metastasis, and controlled primary colorectal tumor without local recurrence, documented by computed tomography and helical computed tomography as well as positron emission tomography staging in the most recent years, sufficient lung function, and no contraindication as a result of concomitant disease. All resected specimens were pathologically confirmed to be pulmonary metastases from colorectal carcinoma by each institution's pathology division.
The investigated variables included sex, age, site of primary tumor (either colon or rectum), time of occurrence of pulmonary metastases, previously resected hepatic metastases, prethoracotomy carcinoembryonic antigen serum level, type of pulmonary resection, completeness of resection, number and maximum diameter of the pulmonary metastases, vascular and lymphatic invasion, visceral pleura invasion, presence of hilar or mediastinal lymph node involvement, postoperative morbidity and mortality, adjuvant therapy, and survival. Involved lymph node stations were classified according to Mountain and Dresler [3]. Survival was calculated from the time of the pulmonary resection until death or the date of the most recent follow-up. Follow-up information was obtained either from the hospital case records or from a questionnaire completed by the local chest physician or general practitioner or from death certificates. The median follow-up interval was 46 months (range, 2 to 256 months); no patient was lost at follow-up. Induction and adjuvant therapy was progressively more frequently introduced during the late 1990s, and we compared the variables of the patients operated on before January 2000 with those of patients operated on after 2000.
Postoperative mortality was defined as any death during hospitalization or within 30 days from surgery. Late mortality was defined as any subsequent death. Actuarial survival curves were estimated by the Kaplan-Meier method. Statistical comparisons between survival distributions were made using the log-rank test. For both univariate and multivariate analyses, differences were considered significant if the calculated probability value was less than 0.05. A probability values less than or equal to 0.20 was set as the cutoff point for the selection of variables for multivariate analysis. The Cox model was used for multivariate survival analysis. The statistical software used for the analysis was SEM (Anticancer Centre Jean Perrin, Clermont-Ferrand, France) [4].
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Results
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There were 74 men and 53 women. The median age was 65 years (range, 36 to 85 years). The primary tumor was located in the rectum in 61 patients (47.3%) and in the colon in 52 patients (40.3%), and the precise location was not available in 14 ("colorectal" carcinomas, 12.4%). The mean interval between colon and lung surgery was 37.8 months (±21.5 months), and the median was 36 months (range, 1 to 134 months). Lung metastases were diagnosed during colorectal cancer workup (synchronous metastases) in 4 patients. Prethoracotomy carcinoembryonic antigen serum level was available in 37 patients, and was found to be elevated in 16. Thirty-one patients (24.4%) had undergone complete metastasectomy for hepatic (n = 27), hepatic and adrenal gland (n = 1), hepatic and peritoneum (n = 1), and adrenal gland metastases (n = 2).
A total of 223 operations were performed. Eighty-eight patients underwent only a single operation (complete in 78 patients and incomplete in 10 because of contralateral metastases that were not operated on). Thirty-nine patients underwent several operations (n = 134): on the same lung in 7 patients, on the same lung or on the other lung in 10 patients, and on both lungs because of synchronous bilateral metastases in 22 patients.
All operations involved a posterolateral thoracotomy or video-assisted thoracic surgery and were sequential. There was no sternotomy. The type of resections included 125 wedge resections or segmentectomies, 81 lobectomies, and 17 pneumonectomies. All metastases were completely resected on the basis of the preoperative computed tomography scan of the chest and operative thorough examination except in 10 patients with bilateral lung metastases whose second side was never operated on. The total number of resected metastases was 314: 75 patients had a single metastasis and 42 had two or more. Median size of the resected pulmonary metastases was 30.2 ± 19 mm, range was 2 to 90 mm. Systematic mediastinal lymph node dissection was performed in 82 of 117 patients. Hilar and mediastinal lymph nodes were involved in 13 patients.
There was no postoperative death. Complications occurred in 17 patients, and consisted of atrial fibrillation in 2, persistent air leaks in 6, atelectasis in 1, empyema in 2, hemorrhage in 2, pneumonia in 1, recurrent nerve palsy in 1, and miscellaneous in 2. Overall 5- and 10-year survival rates were 41% and 27%, respectively; the median survival was 45 months. The survival rates expressed according to the different variables studied are shown in Tables 1, 2, and 3.
There was a tendency for a better prognosis in patients with a single metastasis, and in those without lymph node involvement. Only the absence of vascular microinvasion demonstrated a significantly better prognosis in univariate and multivariate analysis (Table 3). Three of 7 patients with mediastinal lymph node involvement survived more than 5 years.
Among the 117 patients who underwent a complete resection, 58 were operated on during the 1980s and 1990s (before January 2000), and 59 between January 2000 and December 2007 (Table 4). Five-year survival rates and median survival were better during the second period (35.1%, 39 months versus 63.5%, no median, respectively; p = 0.0096; Fig 1). During the second period there were more patients also treated for liver metastases, and a more frequent use of chemotherapy (12 of 58 versus 35 of 59, respectively; p = 0.000020) and a tendency to more repeated pulmonary resections (17 of 58 versus 21 of 59; p = 0.094) were observed.
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Fig 1. Survival of patients operated on with curative intent before December 1999 (curve 1) and after January 2000 (curve 2).
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Comment
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The first case series of resection for pulmonary metastases was published in 1947 [5]. Thirty years later, at the end of the 1970s, more generous indication for lung metastases was advocated [6, 7]. In 1997, the International Registry of Lung Metastases was established and reported on 5,206 patients who underwent metastasectomy [8]. Bowel metastases represented the most important cohort, accounting for 12.4% of the patients (n = 645). When considering colorectal cancer, approximately 10% of all patients with clinically isolated lung metastases are candidates for surgery [9]. Colorectal cancer is becoming the third most common cancer in the United States, and above all, the second cause of cancer-related mortality [10], and a large number of published series reported experience with metastasectomy in that cancer. All the same, the effectiveness of such surgery remains unclear. Pfannschmidt and colleagues [2] reviewed 20 relevant series reporting the outcome of surgical resection with curative intent of colorectal pulmonary metastases published between 1995 and December 2006. Global results indicated that postoperative mortality after lung metastasis surgery was commonly low (0% to 2.5%), with many authors reporting no mortality at all, as in our series. Five-year survival rates ranged from 41.1% to 56%; we observed that those encouraging results were also persisting with time (5-, and 10-year survival being 41% and 27%, respectively). Such results do not merit further discussion when considering that patients with untreated metastatic disease have a 5-year survival rate of less than 5% [11, 12].
Many different factors were tested for prognostic relevance in the literature [2]. Patient sex was not a significant prognostic factor, nor was age, which was reported only once to affect prognosis. Only one of nine studies analyzing the stage of the primary tumor as a measurement for long-term survival confirmed statistical significance. The intestinal localization was in general not a significant prognosticator for survival, as was also the case in our series. Different immunohistochemical measurements have been tested for prognostic significance, but the information yet available does not add much to our knowledge. Different histopathologic measurements such as vascular invasion at metastatic site appeared of prognostic significance for survival in one report, which was confirmed in our study. Prethoracotomy carcinoembryonic antigen serum level has been consistently reported to be a potential prognostic factor (nine studies demonstrating elevated carcinoembryonic antigen level to be associated with poor prognosis; also the study of Lee and colleagues [13]), but in seven studies, as we also observed, carcinoembryonic antigen level was not a significant prognosticator.
The disease-free interval between the resection of the primary tumor and the pulmonary metastasectomy was extensively studied by nearly all studies of the review by Pfannschmidt and colleagues (13 of 20) [2], but only two studies and the one of Yedibela and colleagues [14] reported disease-free interval as an independent factor for long-term survival. In our series as in the study of Lee and colleagues [13], this was not confirmed (Table 1). This is in contradiction with the results provided by the International Registry of Lung Metastases established in 1997 [8] reporting long disease-free interval to be a favorable measurement for long-term survival after metastasectomy in general: perhaps it is a more particular feature of colorectal lung metastases management.
The impact of the number of pulmonary metastases on long-term survival could not be confirmed by the majority of studies, but patients with single metastasis were supposed to have a better outcome: we observed a tendency to better survival in this case in our series (5-year survival 50.9% versus 32.5%; Table 3), but this was not significant. Unilateral or bilateral distribution of pulmonary metastases was reported in 12 studies, and could not be proven to be a prognosticator for survival. In our series, 5-year survival rates observed in case of complete bilateral metastasectomies curiously tended to be better than those observed in case of complete unilateral metastasectomies (68% versus 35.5%; p = 0.09; Table 2). In the same way, 5-year survival rates were good in case of multiply operated unilateral lung metastases (Table 1), which is corroborated by the review of Pfannschmidt and colleagues (no study finding repeated pulmonary resection for recurrence to be an ominous prognostic factor) [2], and Kim and colleagues [15]. Patients with bilateral or recurring metastases received more frequent chemotherapy and were likely more rigorously selected for surgery with, probably more importantly, chances to undergo a curative resection. Indeed, the completeness of lung metastases resection remains the main prognosticator, as demonstrated since 1991 [8], even if some long-term survivals may have been observed in the other eventuality [2].
Good results are also observed in case of associated extrathoracic metastasis, and particularly with liver metastases. Three studies specially focused on the surgical treatment of hepatic and pulmonary metastases from colorectal cancer [2]. No significant difference in outcome was observed between patients with and without previous history of resected hepatic metastases, with 5-year survival rates ranging from 30% to 42%. On the contrary, mediastinal lymph node metastases are considered to indicate poor prognosis with no 5-year survivors [16], which is in contradiction to the long-term survival that we observed. Our results thus support the importance of performing lymphadenectomy at the time of metastasectomy to enhance the chance of being curative.
Associated chemotherapy did not appear to be of prognostic significance for long-term survival [2]. However, improvement in the systemic therapy of colorectal cancer has markedly changed the prognosis of patients with metastatic disease, as it was demonstrated by the more favorable results obtained by chemotherapy combined with surgery of hepatic metastases [17]. We were not able to determine the contribution to overall survival of systemic chemotherapy in association with pulmonary metastasectomy. Different treatment protocols have been applied in our series as a function of time, but there was, nevertheless, a great difference in prognosis between patients operated on before 2000 and the others (Fig 1). Chemotherapy was significantly more frequently associated in the second period (59.3% versus 20.8%), and emerging new protocols including molecular targeted therapies may have played an important role in the observed better survival rates [18]. Chemotherapy might contribute to the completeness of resection by canceling micrometastases. Review of our data and literature lead us to suggest the algorithm provided in Figure 2. However, there are still too many optional guidelines, and the question of the clinical value of therapeutic metastasectomy should be discussed in the light of new prospective clinical trials combining chemotherapy with surgery [19].
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Fig 2. Suggested algorithm for management of patients with pulmonary metastases from colorectal cancer.
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References
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- Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series Ann Thorac Surg 2007;84:324-338.[Abstract/Free Full Text]
- Mountain C, Dresler CM. Regional lymph node classification for lung cancer staging Chest 1997;111:1718-1723.[Abstract/Free Full Text]
- Kwiatkowski F. SEM (Statistiques, Epidémiologie, Médecine): un outil de gestion informatique et statistique adapté à la recherche en cancérologie Bull Cancer 2000;87:715-721.[Medline]
- Alexander J, Haight C. Pulmonary resection for solitary metastatic sarcomas and carcinomas Surg Gynecol Obstet 1947;85:129-146.[Medline]
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Abstract
Introduction
